Virus-like particle conjugates comprising photoactivatable dye compounds and methods of making and using the same

Abstract

Disclosed herein are compounds and VLP-compound conjugates comprising a photoactivatable silicon-phthalocyanine dye core and having unique linker groups that facilitate binding the photoactivatable silicon-phthalocyanine dye core VLP-binding moieties. In some aspects, the linker groups can be attached to beta-positions of the compounds and also can be varied in length, which can facilitate improving therapeutic activity of the compounds or VLP-compound conjugates and / or can increase yields associated with methods for making the compounds. Also disclosed are methods of making and using the compounds and VLP-compound conjugates described herein.

Description

4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01VIRUS-LIKE PARTICLE CONJUGATES COMPRISING PHOTOACTIVATABLE DYE COMPOUNDS AND METHODS OF MAKING AND USING THE SAME CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of and priority to the earlier filing date of U.S. Provisional Patent Application No.63 / 690,592, filed on September 4, 2024, the entirety of which is incorporated herein by reference. ACKNOWLEDGMENT OF GOVERNMENT SUPPORT

[0002] This invention was made with government support under project number ZIA BC 011513 awarded by the National Institutes of Health, National Cancer Institute. The government has certain rights in the invention. FIELD

[0003] The present disclosure is directed to conjugates comprising virus-like particles and photoactivatable silicon-phthalocyanine dyes comprising unique linkers and substitution patterns and that are useful in various biological applications. BACKGROUND

[0004] Cancer is diagnosed in more than 1 million people every year in the United States alone. In spite of numerous advances in medical research, cancer remains the second leading cause of death in the United States, accounting for roughly 1 in every four deaths. Although numerous treatments are available for various cancers, many forms of cancer remain uncurable, untreatable, and / or become resistant to standard therapies. For example, tumors may be inoperable because of their location or they may metastasize, making it difficult or impossible to treat the disease. Current therapies have considerable shortcomings. For instance, radiation therapy can cause damage to epithelial surfaces, swelling, infertility, fatigue, fibrosis, hair loss, dryness, and cancer. Chemotherapy can induce nausea, vomiting, diarrhea, constipation, anemia, malnutrition, hair loss, memory loss, depression of the immune system and hence infections and sepsis, hemorrhage, secondary neoplasms, cardiotoxicity, hepatotoxicity, nephrotoxicity, and ototoxicity. Clearly the need for robust techniques to diagnose and treat cancer is manifest

[0005] Viruses have been shown to have tremendous utility in a variety of biomedical applications. Many of these techniques take advantage of the unique ability of viruses to enter cells at high efficiency. Some of these applications exploit viral gene expression and - 1 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01replication to induce expression of an inserted heterologous gene. It is well known that a variety of viruses deliver and express genes in cells (either viral or other genes), which may be useful, for example, in gene therapy, the development of vaccines, or cancer biology.

[0006] There is extensive literature on the use of viral vectors, particularly those based on adenovirus, adeno-associated virus (AAV), herpes virus and retrovirus, to increase the potency of anti-tumor therapy, however, these methodologies are in their infancy. There exists a need in the art for new compounds that can be used in combination with VLPs for detecting the presence of cancer cells and for treating the same. SUMMARY

[0007] Disclosed herein is a conjugate comprising: a virus-like particle compound; and a compound having a structure according to Formula I or Formula II according to the present disclosure, wherein: X is a VLP-binding moiety or a precursor thereto; the Linker has a structure according to a formula {Core}-(CR2)n-Y-(Z)m-(CR2)p[O(CR2)t]q-{X}, wherein {Core} represents attachment to the phthalocyanine core and {X} represents attachment to X; each R, independently for each occurrence, is selected from hydrogen, halogen, aliphatic, heteroaliphatic, or aromatic; Y is selected from (i) a functional group produced from a reaction between two clickable functional groups; (ii) -CH=CH-[Q1]s-, wherein s is 1 or 0 and Q1is selected from aromatic or -C(=O)Y’- or -S(=O)2Y’ wherein Y’ is NR” or O, wherein R” isH, -CN, CF3, or a sulfonyl group; or (iii) -C C-Q2, wherein Q2 is –(CH2)uC(=O)Y’-, wherein uis an integer selected from 1 to 10, Y’ is NR” or O, wherein R” is H, -CN, CF3, or a sulfonyl group; Z is a heteroatom; m is 1 or 0; each of n, p, and t independently is selected from an integer ranging from 0 to 50; and q is an integer selected from 0 to 50; G, if present, is selected from halogen or Linker-X, wherein the linker group and the X group are as defined above; each of R1a, R2a, R3a, R1b, R2b, and R3bindependently is selected from hydrogen, aliphatic, halogen, heteroaliphatic, aromatic, thiol, hydroxyl, or amine; or (i) R1aand R1bjoin together, with the carbon atoms to which they are attached, to form a 6-membered aromatic ring, (ii) R2aand R2bjoin together, with the carbon atoms to which they are attached, to form a six-membered aromatic ring, (iii) R3aand R3bjoin together, with the carbon atoms to which they are attached, to form a six-membered aromatic ring, or (iv) any combination of two or more of (i)-(iii); and L is selected from -(CH2)r-, -Si(R5)2(CH2)r-, -C(=O)(CH2)r-, or -Ph(CH2)r-, wherein each R5independently is aliphatic or aryl, r is an integer selected from 1 to 5 and wherein any CH2 group of the L group is attached to the quaternary amine of Formula I or Formula II. - 2 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0008] Also disclosed is a method for treating a subject or sample using NIR-PIT, comprising: administering a conjugate according to any or all of the above aspects, or a pharmaceutically acceptable composition thereof, to the subject or the sample; and irradiating the conjugate by application of light to a targeted portion of the subject or the sample.

[0009] The foregoing and other objects, features, and advantages of the present disclosure will become more apparent from the following detailed description, which proceeds with reference to the accompanying figures. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG.1 shows combined UV-Vis spectra for compound precursors comprising silicon-based phthalocyanine cores, including dimerized compounds (precursors without linker groups labeled as Xdye1, Xdye-2, and Xdye-3) and compound precursors including styrene-based linker group fragments (labeled as Xdye-4 and Xdye-5).

[0011] FIG.2 shows images of cells that have been treated with IR700 (bottom left image) as a comparative example and a biomolecule-compound conjugate according to the present disclosure, namely ^-Tz IR700C10SE bound to cetuximab.

[0012] FIG.3 shows images of cells that have been treated with IR700 (top row) as a comparative example and biomolecule-compound conjugates according to the present disclosure, including compounds ^-Tz IR700C3SE, ^-Tz IR700C6SE, and ^-Tz IR700C10SE (each bound to cetuximab).

[0013] FIG.4 is a graph summarizing results obtained after exposing compounds according to the present disclosure, namely Pyr-IR700 C6-COOH, Styrl-IR700 C6-COOH, IR700-alkene-COOH, IR700-PEG-COOH, IR700-SA-COOH, IR700-Amd-PEG-COOH, to photolysis conditions, along with a comparison of results obtained using IR700. DETAILED DESCRIPTION

[0014] Overview of Terms

[0015] The following explanations of terms and / or symbols are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. The singular forms “a,” “an,” and “the” refer to one or more than one, unless the context clearly dictates otherwise. The term “or” refers to a single element of stated alternative elements or a combination of two or more elements, unless the context - 3 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01clearly indicates otherwise. As used herein, “comprises” means “includes.” Thus, “comprising A or B,” means “including A, B, or A and B,” without excluding additional elements. All references, including patents and patent applications cited herein, are incorporated by reference.

[0016] Unless otherwise indicated, all numbers expressing quantities of components, molecular weights, percentages, temperatures, times, and so forth, as used in the specification or claims are to be understood as being modified by the term “about.” Accordingly, unless otherwise indicated, implicitly or explicitly, the numerical parameters set forth are approximations that may depend on the desired properties sought and / or limits of detection under standard test conditions / methods. When directly and explicitly distinguishing aspects from discussed prior art, the embodiment numbers are not approximates unless the word “about” is expressly recited.

[0017] Unless explained otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0018] “Substituted,” when used to modify a specified group or moiety, means that at least one, and perhaps two or more, hydrogen atoms of the specified group or moiety is independently replaced with the same or different substituent groups. In a particular embodiment, a group, moiety, or substituent may be substituted or unsubstituted, unless expressly defined as either “unsubstituted” or “substituted.” Accordingly, any of the functional groups specified herein may be unsubstituted or substituted unless the context indicates otherwise or a particular structural formula precludes substitution. In particular aspects, a substituent may or may not be expressly defined as substituted but is still contemplated to be optionally substituted. For example, an “aliphatic” or a “cyclic” moiety may be unsubstituted or substituted, but an “unsubstituted aliphatic” or an “unsubstituted cyclic” is not substituted. In one embodiment, a group that is substituted has at least one substituent up to the number of substituents possible for a particular moiety, such as 1 substituent, 2 substituents, 3 substituents, or 4 substituents. As used herein, the term “substituted” refers to all subsequent modifiers in a term, for example in the term “substituted aliphatic-aromatic,” substitution may occur on the “aliphatic” portion, the “aromatic” portion or both portions of the aliphatic-aromatic group. Any functional group disclosed herein can be substituted or unsubstituted, unless otherwise indicated herein. - 4 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0019] A person of ordinary skill in the art will appreciate that compounds may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism, and / or optical isomerism. For example, certain disclosed compounds can include one or more chiral centers and / or double bonds and as a consequence can exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof, such as racemic mixtures. As another example, certain disclosed compounds can exist in several tautomeric forms, including the enol form, the keto form, and mixtures thereof. As the various compound names, formulae and compound drawings within the specification and claims can represent only one of the possible tautomeric, conformational isomeric, optical isomeric, or geometric isomeric forms, a person of ordinary skill in the art will appreciate that the disclosed compounds encompass any tautomeric, conformational isomeric, optical isomeric, and / or geometric isomeric forms of the compounds described herein, as well as mixtures of these various different isomeric forms. Mixtures of different isomeric forms, including mixtures of enantiomers and / or stereoisomers, can be separated to provide each separate enantiomers and / or stereoisomer using techniques known to those of ordinary skill in the art, particularly with the benefit of the present disclosure. In cases of limited rotation, e.g. around an amide bond or between two directly attached rings such as pyridinyl rings, biphenyl groups, and the like, atropisomers are also possible and are also specifically included in the compounds disclosed herein.

[0020] In any aspects, any or all hydrogens present in the compound, or in a particular group or moiety within the compound, may be replaced by a deuterium or a tritium. Thus, a recitation of alkyl includes deuterated alkyl, where from one to the maximum number of hydrogens present may be replaced by deuterium. For example, methyl refers to both CH3 or CH3 wherein from 1 to 3 hydrogens are replaced by deuterium, such as in CDxH3-x.

[0021] Certain functional group terms used herein include a symbol “-”, which is used to show how the defined functional group attaches to, or within, the compound to which it isbound. Also, a dashed bond (i.e., “ ”) as used in certain formulas described hereinindicates an “optional” bond to a substituent or atom of the formula other than hydrogen in the sense that the bond (and in some aspects, the substituent) may or may not be present. In any formulas comprising a dashed bond, if the optional bond and / or any corresponding substituent is not present, then the valency requirements of any atom(s) bound thereto is completed by a bond to a hydrogen atom.

[0022] The symbol “ ” is used to indicate a bond disconnection in abbreviatedstructures / formulas provided herein. A person of ordinary skill in the art recognizes that the definitions provided below and the compounds and formulas included herein are not - 5 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01intended to include impermissible substitution patterns (e.g., methyl substituted with 5 different groups, and the like). Such impermissible substitution patterns are easily recognized by a person of ordinary skill in the art. In formulas and compounds disclosed herein, a hydrogen atom is present and completes any formal valency requirements (but may not necessarily be illustrated) wherever a functional group or other atom is not illustrated. For example, a phenyl ring that is drawn as comprises a hydrogen atom attached to each carbon atom of the phenyl ring o the “a” carbon, even though such hydrogen atoms are not illustrated. Any functionalgroup disclosed herein and / or defined above can be substituted or unsubstituted, unless otherwise indicated herein.

[0023] To facilitate review of the various aspects of the disclosure, the following explanations of specific terms are provided.

[0024] Activated Ester: A functional group that is susceptible to nucleophilic attack. In some aspects of the disclosure, activation can be imparted by modifying an acyl or alkoxy portion of a normal ester, such as by adding electronegative substituents. In exemplary aspects of the disclosure, an activated ester can comprise a carboxyl group attached to a succinimide via the oxygen bound by a single bond to the carbonyl carbon of the carboxyl group.

[0025] Administration: To provide or give a subject an agent, such as a compound or VLP-compound conjugate disclosed herein, by any effective route. Exemplary routes of administration include, but are not limited to, topical, injection (such as subcutaneous, intramuscular, intradermal, intraperitoneal, intratumoral, peritumor, and intravenous), oral, ocular, sublingual, rectal, transdermal, intranasal, vaginal and inhalation routes.

[0026] Aldehyde: -C(O)H.

[0027] Aliphatic: A hydrocarbon group having at least one carbon atom to 50 carbon atoms (C1-50), such as one to 25 carbon atoms (C1-25), or one to ten carbon atoms (C1-10), and which includes alkanes (or alkyl), alkenes (or alkenyl), alkynes (or alkynyl), including cyclic versions thereof, and further including straight- and branched-chain arrangements, and all stereo and position isomers as well. Aliphatic groups may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0028] Aliphatic-aromatic: An aromatic group that is or can be coupled to a compound disclosed herein, wherein the aromatic group is or becomes coupled through an aliphatic - 6 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01group. Aliphatic-aromatic groups may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0029] Aliphatic-aryl: An aryl group that is or can be coupled to a compound disclosed herein, wherein the aryl group is or becomes coupled through an aliphatic group. Aliphatic- aryl groups may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0030] Aliphatic-heteroaryl: A heteroaryl group that is or can be coupled to a compound disclosed herein, wherein the heteroaryl group is or becomes coupled through an aliphatic group. Aliphatic-heteroaryl groups may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0031] Alkenyl: An unsaturated monovalent hydrocarbon having at least two carbon atom to 50 carbon atoms (C2-50), such as two to 25 carbon atoms (C2-25), or two to ten carbon atoms (C2-10), and at least one carbon-carbon double bond, wherein the unsaturated monovalent hydrocarbon can be derived from removing one hydrogen atom from one carbon atom of a parent alkene. An alkenyl group can be branched, straight-chain, cyclic (e.g., cycloalkenyl), cis, or trans (e.g., E or Z). Alkenyl groups may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0032] Alkoxy: -O-aliphatic, such as -O-alkyl, -O-alkenyl, -O-alkynyl; with exemplary aspects including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy (wherein any of the aliphatic components of such groups can comprise no double or triple bonds, or can comprise one or more double and / or triple bonds). Alkoxy groups may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0033] Alkyl: A saturated monovalent hydrocarbon having at least one carbon atom to 50 carbon atoms (C1-50), such as one to 25 carbon atoms (C1-25), or one to ten carbon atoms (C1-10), wherein the saturated monovalent hydrocarbon can be derived from removing one hydrogen atom from one carbon atom of a parent compound (e.g., alkane). An alkyl group can be branched, straight-chain, or cyclic (e.g., cycloalkyl). Alkyl groups may be substituted - 7 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0034] Alkynyl: An unsaturated monovalent hydrocarbon having at least two carbon atom to 50 carbon atoms (C2-50), such as two to 25 carbon atoms (C2-25), or two to ten carbon atoms (C2-10), and at least one carbon-carbon triple bond, wherein the unsaturated monovalent hydrocarbon can be derived from removing one hydrogen atom from one carbon atom of a parent alkyne. An alkynyl group can be branched, straight-chain, or cyclic (e.g., cycloalkynyl). Alkenyl groups may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0035] Amide: -C(O)NRbRcor –NRbC(O)Rcwherein each of Rband Rcindependently is selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group and can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0036] Amino: -NRbRc, wherein each of Rband Rcindependently is selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group, and can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0037] Aromatic: A cyclic, conjugated group or moiety of, unless specified otherwise, from 5 to 15 ring atoms having a single ring (e.g., phenyl) or multiple condensed rings in which at least one ring is aromatic (e.g., naphthyl, indolyl, or pyrazolopyridinyl); that is, at least one ring, and optionally multiple condensed rings, have a continuous, delocalized ^-electron system. Typically, the number of out of plane ^-electrons corresponds to the Hückel rule (4n + 2). The point of attachment to the parent structure typically is through an aromatic portion of the condensed ring system. For exampl . However, in certain examples, context or express disclosure may indicoint of attachment is through a non-aromatic portion of the condensed ring system. For examp . An aromatic group or moiety may comprise only carbon atoms in theg, an aryl - 8 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01group or moiety, or it may comprise one or more ring carbon atoms and one or more ring heteroatoms comprising a lone pair of electrons (e.g. S, O, N, P, or Si), such as in a heteroaryl group or moiety. Aromatic groups may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0038] Aryl: An aromatic carbocyclic group comprising at least five carbon atoms, and in some aspects having at least five carbon atoms to 15 carbon atoms (C5-C15), such as five to ten carbon atoms (C5-C10), having a single ring or multiple condensed rings, which condensed rings can or may not be aromatic provided that the point of attachment to a remaining position of the compounds disclosed herein is through an atom of the aromatic carbocyclic group. Aryl groups may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0039] Aroxy: -O-aromatic. Aroxy groups may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0040] Azo: -N=NRawherein Rais hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. Azo groups may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0041] Cancer: A malignant tumor characterized by abnormal or uncontrolled cell growth. Other features often associated with cancer include metastasis, interference with the normal functioning of neighboring cells, release of cytokines or other secretory products at abnormal levels and suppression or aggravation of inflammatory or immunological response, invasion of surrounding or distant tissues or organs, such as lymph nodes, etc. “Metastatic disease” refers to cancer cells that have left the original tumor site and migrate to other parts of the body for example via the bloodstream or lymph system. In one example, the cell killed by the disclosed methods is a cancer cell.

[0042] Capsid Protein: A protein monomer, several of which form a capsomer oligomer. A “capsomer,” as used herein, refers to the basic oligomeric structural unit of a viral capsid, which is an outer covering of protein that protects the genetic material of a virus such as, for example, human papillomavirus (HPV). The capsid proteins of the present disclosure can include papillomavirus L1 major capsid proteins and papillomavirus L2 minor capsid - 9 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01proteins. In some aspects, the VLPs of the present disclosure contain only L1 capsid proteins, while in other aspects, the VLPs contain a mixture (or combination) of L1 and L2 capsid proteins. In some aspects, the percentage of L1 capsid proteins in a virus-like particle is greater than the percentage of L2 capsid proteins in the virus-like particle. For example, in some aspects, the percentage of L1 capsid proteins in a virus-like particle is 80% to 100% (of the total number of capsid proteins in the virus-like particle). In some aspects, the percentage of L1 capsid proteins in a virus-like particle is 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%. In some aspects, the percentage of L2 capsid proteins in a virus-like particle is 1% to 25% (of the total number of capsid proteins in the virus-like particle). For example, some aspects, the percentage of L2 capsid proteins in a virus-like particle is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%. In some aspects, a virus-like particle contains 12 to 72 L2 proteins. In some aspects, a virus-like particle contains 360 L1 proteins and 12 to 72 L2 proteins. In some aspects, capsid proteins assemble into viral-like nanoparticles having a diameter of 20 to 60 nm. For example, capsid proteins may assemble into viral-like nanoparticles having a diameter of 20, 25, 30, 35, 40, 45, 50, 55 or 60 nm.

[0043] External Capsid Protein: A capsid protein that is exposed at the surface of a VLP (e.g., L1 proteins).

[0044] Capsomeric Structure (or Capsid or Capsid Particle): This term includes VLPs and pseudoviruses.

[0045] Carbamate: -OC(O)NRbRc, wherein each of Rband Rcindependently is selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. Carbamate groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0046] Carbonate: -OC(O)ORa, wherein Rais selected from aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. Carbonate groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. In independent aspects, Racan be hydrogen.

[0047] Carboxyl: -C(O)OH.

[0048] Carboxylate: -C(O)O- or salts thereof, wherein the negative charge of the carboxylate group may be balanced with an M+counterion, wherein M+may be an alkali ion, - 10 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01such as K+, Na+, Li+; an ammonium ion, such as+N(Rb)4where Rbis H, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, or aromatic; or an alkaline earth ion, such as [Ca2+]0.5, [Mg2+]0.5, or [Ba2+]0.5.

[0049] Click Chemistry: Chemical synthetic methods for forming covalent bonds using compounds that can be joined together using efficient reagent conditions and that can be performed in benign solvents or solvents that can be removed or extracted using facile methods, such as evaporation, extraction, or distillation.

[0050] Clickable Functional Group: A functional group that can be used in click chemistry to form covalent bonds between (i) two moieties that, when reacted, provide a linker group as described in Formulas of the present disclosure; or (ii) a compound of the present disclosure and a clickable functional group-labeled protein.

[0051] Contacting: Placement in direct physical association, including both a solid and liquid form. Contacting can occur in vitro, for example, with isolated cells (e.g., tumor cells); or, in vivo by administering to a subject (such as a subject with a tumor).

[0052] Covalent Bond: A chemical bond that involves sharing electrons to form electron pairs between atoms and can include sigma or pi bonds.

[0053] Cyano: -CN.

[0054] Decrease: To reduce the quality, amount, or strength of something. In one example, a therapeutic composition that includes a compound or VLP-compound conjugate according to the present disclosure decreases the viability of cells to which an VLP- compound conjugate specifically binds, following irradiation of the cells with light (for example, near-infrared light at a wavelength ranging from 650 nm to 1100 nm) at a dose of at least 1 J cm-2, for example, as compared to the response in the absence of the compound or VLP-compound conjugate. In some examples such a decrease is evidenced by the killing of the cells. In some examples, the decrease in the viability is at least 20%, at least 50%, at least 75%, or even at least 90%, relative to the viability observed with a composition that does not include a compound or VLP-compound conjugate according to the present disclosure. In other examples, decreases are expressed as a fold change, such as a decrease in the viability by at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 8-fold, at least 10-fold, or even at least 15 or 20-fold, relative to the viability observed with a composition that does not include a compound or VLP-compound conjugate according to the present disclosure. Such decreases can be measured using the methods disclosed herein. - 11 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0055] Disulfide: -SSRa, wherein Rais selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. Disulfide groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0056] Dithiocarboxylic: -C(S)SRawherein Rais selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. Dithiocarboxylic groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0057] Ether: -aliphatic-O-aliphatic, -aliphatic-O-aromatic, -aromatic-O-aliphatic, or - aromatic-O-aromatic, including any polymers thereof having repeats of any such groups (e.g., polyalkene oxide compounds). Ether groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0058] Halo (or halide or halogen): Fluoro, chloro, bromo, or iodo. In some aspects, halo can also include astatine.

[0059] Haloaliphatic: An aliphatic group wherein one or more hydrogen atoms, such as one to 10 hydrogen atoms, independently is replaced with a halogen atom, such as fluoro, bromo, chloro, or iodo. Haloaliphatic groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0060] Haloaliphatic-aryl: An aryl group that is or can be coupled to a compound disclosed herein, wherein the aryl group is or becomes coupled through a haloaliphatic group. Haloaliphatic-aryl groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0061] Haloaliphatic-heteroaryl: A heteroaryl group that is or can be coupled to a compound disclosed herein, wherein the heteroaryl group is or becomes coupled through a haloaliphatic group. Haloaliphatic-heteroaryl groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. - 12 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0062] Haloalkyl: An alkyl group wherein one or more hydrogen atoms, such as one to 10 hydrogen atoms, independently is replaced with a halogen atom, such as fluoro, bromo, chloro, or iodo. Haloalkyl groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. In an independent embodiment, haloalkyl can be a CX’3group, wherein each X’ independently can be selected from fluoro, bromo, chloro, or iodo.

[0063] Haloheteroaliphatic: A heteroaliphatic group wherein one or more hydrogen atoms, such as one to 10 hydrogen atoms, independently is replaced with a halogen atom, such as fluoro, bromo, chloro, or iodo. Haloheteroaliphatic groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0064] Heteroaliphatic: An aliphatic group comprising at least one heteroatom to 20 heteroatoms, such as one to 15 heteroatoms, or one to 5 heteroatoms, which can be selected from, but not limited to oxygen, nitrogen, sulfur, silicon, boron, selenium, phosphorous, and oxidized forms thereof within the group. Alkoxy, ether, amino, disulfide, peroxy, and thioether groups are exemplary (but non-limiting) examples of heteroaliphatic. Heteroaliphatic groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0065] Heteroaliphatic-aryl: An aryl group that is or can be coupled to a compound disclosed herein, wherein the aryl group is or becomes coupled through a heteroaliphatic group. Heteroaliphatic-aryl groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0066] Heteroaryl: An aryl group comprising at least one heteroatom to six heteroatoms, such as one to four heteroatoms, which can be selected from, but not limited to oxygen, nitrogen, sulfur, silicon, boron, selenium, phosphorous, and oxidized forms thereof within the ring. Such heteroaryl groups can have a single ring or multiple condensed rings, wherein the condensed rings may or may not be aromatic and / or contain a heteroatom, provided that the point of attachment is through an atom of the aromatic heteroaryl group. Heteroaryl groups may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. - 13 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0067] Heteroatom: An atom other than carbon or hydrogen, such as (but not limited to) oxygen, nitrogen, sulfur, silicon, boron, selenium, or phosphorous. In particular disclosed aspects, such as when valency constraints do not permit, a heteroatom does not include a halogen atom.

[0068] Isothiocyanate: -N=C=S.

[0069] IR700 (IRDye® 700DX): A silicon phthalocyanine dye having the following formula:IR700 is currently commercially available from LI-COR (Lincoln, NE). Amino-reactive IR700 is a relatively hydrophilic dye and can be covalently conjugated with an antibody using the NHS ester of IR700.

[0070] Ketone: -C(O)Ra, wherein Rais selected from aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. Ketone groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0071] Maleimide: A chemical group having a core structure, wherein the core structure can comprise substituents bound to the ring carbo

[0072] Organic Functional Group: A functional group that may be provided by any combination of aliphatic, heteroaliphatic, cycloaliphatic, cycloheteroaliphatic, cyclohaloaliphatic, aromatic, and / or haloaliphatic groups, or that may be selected from, but not limited to, aldehyde (i.e., -C(O)H); aroxy (i.e., -O-aromatic); acyl halide (i.e., -C(O)X, wherein X’ is a halogen, such as Br, F, I, or Cl); halogen; nitro (i.e., -NO2); cyano (i.e., -CN); azide (i.e., -N3); carboxyl (i.e., -C(O)OH); carboxylate (i.e., -C(O)O- or salts thereof, wherein the negative charge of the carboxylate group may be balanced with an M+counterion, wherein M+may be an alkali ion, such as K+, Na+, Li+; an ammonium ion, such as+N(Rb)4 where Rbis hydrogen, aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group; or an alkaline earth ion, such as [Ca2+]0.5, [Mg2+]0.5, or [Ba2+]0.5); amide (i.e., - 14 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01-C(O)NRaRbor –NRaC(O)Rbwherein each of Raand Rbindependently is selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group); ketone (i.e., -C(O)Ra, wherein Rais selected from aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group); carbonate (i.e., -OC(O)ORa, wherein Rais selected from aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group); imine (i.e., -C(=NRa)Rbor -N=CRaRb, wherein Raand Rbindependently is selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group); azo (i.e., - N=NRawherein Rais hydrogen, aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group); carbamate (i.e., -OC(O)NRaRb, wherein each of Raand Rbindependently is selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group); hydroxyl (i.e., -OH); thiol (i.e., -SH); sulfonyl (i.e., -SO2Ra, wherein Rais selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group); sulfonate (i.e., -SO3-, wherein the negative charge of the sulfonate group may be balanced with an M+counter ion, wherein M+may be an alkali ion, such as K+, Na+, Li+; an ammonium ion, such as+N(Rb)4 where Rbis hydrogen, aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group; or an alkaline earth ion, such as [Ca2+]0.5, [Mg2+]0.5, or [Ba2+]0.5); oxime (i.e., -CRa=NOH, wherein Rais hydrogen, aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group); sulfonamide (i.e., -SO2NRaRbor -N(Ra)SO2Rb, wherein each of Raand Rbindependently is selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group); ester (i.e., -C(O)ORaor -OC(O)Ra, wherein Rais selected from aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group); thiocyanate (i.e., -S- CN or -N=C=S); thioketone (i.e., -C(S)Rawherein Rais selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group); thiocarboxylic acid (i.e., -C(O)SH, or –C(S)OH); thioester (i.e., -C(O)SRaor –C(S)ORawherein Rais selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group); dithiocarboxylic acid or ester (i.e., -C(S)SRawherein Rais selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group); phosphonate (i.e., -P(O)(ORa)2, wherein each Raindependently is hydrogen, aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group; or wherein one or more Ragroups are not present and the phosphate group therefore has at least one negative charge, which can be balanced by a counterion, M+, wherein each M+independently can be an alkali ion, such as K+, Na+, Li+; an ammonium ion, such as+N(Rb)4 where Rbis hydrogen, aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group; or an alkaline earth ion, such as [Ca2+]0.5, [Mg2+]0.5, or [Ba2+]0.5); phosphate (i.e., -O-P(O)(ORa)2, wherein each Raindependently is hydrogen, aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group; or wherein one or more Ragroups - 15 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01are not present and the phosphate group therefore has at least one negative charge, which can be balanced by a counterion, M+, wherein each M+independently can be an alkali ion, such as K+, Na+, Li+; an ammonium ion, such as+N(Rb)4 where Rbis hydrogen, aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group; or an alkaline earth ion, such as [Ca2+]0.5, [Mg2+]0.5, or [Ba2+]0.5); silyl ether (i.e., -OSiRaRbRc, wherein each of Ra, Rb, and Rcindependently is selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group); sulfinyl (i.e., -S(O)Ra, wherein Rais selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, aromatic, or an organic functional group); thial (i.e., -C(S)H); or combinations thereof.

[0073] Oxime: -CRa=NOH, wherein Rais hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. Oxime groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0074] Peroxy: -O-ORawherein Rais hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. Peroxy groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0075] Pharmaceutical Composition: A chemical compound or composition capable of inducing a desired therapeutic or prophylactic effect when properly administered to a subject. A pharmaceutical composition can include a therapeutic agent, such as one or more compounds or VLP-compound conjugates according to the present disclosure. A therapeutic or pharmaceutical agent is one that alone or together with an additional compound induces the desired response (such as inducing a therapeutic or prophylactic effect when administered to a subject). In a particular example, a pharmaceutical composition includes a therapeutically effective amount of at least one compound or VLP- compound conjugate disclosed herein.

[0076] Pharmaceutically Acceptable Vehicles: The pharmaceutically acceptable carriers (vehicles) useful in this disclosure typically are conventional. Remington’s Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, PA, 19th Edition (1995), describes compositions and formulations suitable for pharmaceutical delivery of one or more therapeutic compounds, such as one or more VLP-compound conjugates according to the present disclosure. - 16 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0077] In general, the nature of the carrier will depend on the particular mode of administration being employed. For instance, parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. For solid compositions (for example, powder, pill, tablet, or capsule forms), conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically-neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.

[0078] Phosphate: -O-P(O)(ORa)2, wherein each Raindependently is hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group; or wherein one or more Ragroups are not present and the phosphate group therefore has at least one negative charge, which can be balanced by a counterion, M+, wherein each M+independently can be an alkali ion, such as K+, Na+, Li+; an ammonium ion, such as+N(Rb)4where Rbis H, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, or aromatic; or an alkaline earth ion, such as [Ca2+]0.5, [Mg2+]0.5, or [Ba2+]0.5. The Ragroups of the phosphate can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0079] Phosphonate: -P(O)(ORa)2, wherein each Raindependently is hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group; or wherein one or more Ragroups are not present and the phosphonate group therefore has at least one negative charge, which can be balanced by a counterion, M+, wherein each M+independently can be an alkali ion, such as K+, Na+, Li+; an ammonium ion, such as+N(Rb)4 where Rbis H, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, or aromatic; or an alkaline earth ion, such as [Ca2+]0.5, [Mg2+]0.5, or [Ba2+]0.5. The Ragroups of the phosphonate group can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0080] Silyl Ether: -OSiRaRbRc, wherein each of Ra, Rb, and Rcindependently is selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. Silyl ether groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. - 17 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0081] Subject or patient: A term that includes human and non-human mammals. In one example, the subject is a human or veterinary subject, such as a mouse. In some examples, the subject is a mammal (such as a human) who has cancer, or is being treated for cancer.

[0082] Succinimide (NHS): A chemical group having a core structure of , wherein the core structure can include substituents attached to the ring carbon auccinimide groups can be coupled to a carboxylic acid to provide an activated ester.

[0083] Sulfinyl: -S(O)Ra, wherein Rais selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. Sulfinyl groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0084] Sulfonyl: -SO2Ra, wherein Rais selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. Sulfonyl groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0085] Sulfonamide: -SO2NRbRcor -N(Rb)SO2Rc, wherein each of Rband Rcindependently is selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. Sulfonamide groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0086] Sulfonate: -SO3-, wherein the negative charge of the sulfonate group may be balanced with an M+counter ion, wherein M+may be an alkali ion, such as K+, Na+, Li+; an ammonium ioh as+N(Rb)4where Rbis H, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, or aromatic; or an alkaline earth ion, such as [Ca2+]0.5, [Mg2+]0.5, or [Ba2+]0.5.

[0087] Therapeutically Effective Amount: An amount of a compound, VLP-compound conjugate, or composition that alone, or together with an additional therapeutic agent(s), is sufficient to achieve a desired effect in a subject, or in a cell, being treated with the agent. The effective amount of the agent (such as a compound or VLP-compound conjugate according to the present disclosure) can be dependent on several factors, including, but not limited to the subject or cells being treated, the particular therapeutic agent, and / or the manner of administration of the therapeutic composition. In one example, a therapeutically effective amount or concentration is one that is sufficient to prevent advancement (such as - 18 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01metastasis), delay progression, or to cause regression of a disease, or which is capable of reducing symptoms caused by the disease, such as cancer. In one example, a therapeutically effective amount or concentration is one that is sufficient to increase the survival time of a patient with a tumor.

[0088] In one example, a desired response is to reduce or inhibit one or more symptoms associated with cancer. The one or more symptoms do not have to be completely eliminated for the composition to be effective. For example, administration of a composition containing a VLP-compound conjugate of the present disclosure, followed by irradiation, can decrease the size of a tumor (such as the volume or weight of a tumor, or metastasis of a tumor), for example by at least 20%, at least 50%, at least 80%, at least 90%, at least 95%, at least 98%, or even at least 100%, as compared to the tumor size in the absence of the VLP-compound conjugate. In one particular example, a desired response is to kill a population of cells by a desired amount, for example by killing at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or even at least 100% of the cells, as compared to the cell killing in the absence of the VLP-compound conjugate and irradiation. In one particular example, a desired response is to increase the survival time of a patient with a tumor (or who has had a tumor recently removed) by a desired amount, for example increase survival by at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or even at least 100%, as compared to the survival time in the absence of the VLP-compound conjugate and irradiation.

[0089] The effective amount of an agent that includes one of the disclosed compounds or VLP-compound conjugates, that is administered to a human or veterinary subject, will vary depending upon a number of factors associated with that subject, for example the overall health of the subject. An effective amount of an agent can be determined by varying the dosage of the product and measuring the resulting therapeutic response, such as the regression of a tumor. Effective amounts also can be determined through various in vitro, in vivo or in situ immunoassays. The disclosed agents can be administered in a single dose, or in several doses, as needed to obtain the desired response. However, the effective amount of an agent can be dependent on the source applied, the subject being treated, the severity and type of the condition being treated, and the manner of administration.

[0090] In particular examples, a therapeutically effective dose of a compound or VLP- compound conjugate according to aspects of the present disclosure is at least 0.5 milligram per 60 kilogram (mg / kg), at least 5 mg / 60 kg, at least 10 mg / 60 kg, at least 20 mg / 60 kg, at least 30 mg / 60 kg, at least 50 mg / 60 kg, for example 0.5 to 50 mg / 60 kg, such as a dose of 1 - 19 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01mg / 60 kg, 2 mg / 60 kg, 5 mg / 60 kg, 20 mg / 60 kg, or 50 mg / 60 kg, for example when administered intravenously. In another example, a therapeutically effective dose of a compound or VLP-compound conjugate is at least 10 µg / kg, such as at least 100 µg / kg, at least 200 µg / kg, or at least 500 µg / kg, for example 10 µg / kg to 1000 µg / kg, such as a dose of 100 µg / kg, 250 µg / kg, about 500 µg / kg, 750 µg / kg, or 1000 µg / kg, for example when administered intratumorally, peritumorally, or intraperitoneally. In one example, a therapeutically effective dose is at least 1 µg / ml, such as at least 500 µg / ml, such as between 20 µg / ml to 100 µg / ml, such as 10 µg / ml, 20 µg / ml, 30 µg / ml, 40 µg / ml, 50 µg / ml, 60 µg / ml, 70 µg / ml, 80 µg / ml, 90 µg / ml or 100 µg / ml administered in topical solution. However, one skilled in the art will recognize that higher or lower dosages also could be used, for example depending on the particular compound or VLP-compound conjugate used. In particular examples, such daily dosages are administered in one or more divided doses (such as 2, 3, or 4 doses) or in a single formulation. The disclosed compounds and / or VLP- compound conjugates of the present disclosure can be administered alone, in the presence of a pharmaceutically acceptable carrier, and / or in the presence of other therapeutic agents (such as other anti-neoplastic agents).

[0091] Generally a suitable dose of irradiation following administration of a compound or VLP-compound conjugate is at least 1 J cm-2at a wavelength of 650 nm to 1100 nm, for example, at least 10 J cm-2at a wavelength of 650 nm to 1100 nm, at least 50 J cm-2at a wavelength of 650 nm to 1100 nm, or at least 100 J cm-2at a wavelength of 650 nm to 1100 nm, for example 1 to 500 J cm-2at a wavelength of 650 nm to 1100 nm. In some examples the wavelength is 650 nm to 1100 nm, such as 650 nm to 1000 nm, or 650 nm to 950 nm, or 650 nm to 900 nm, or 650 nm to 850 nm, or 650 nm to 800 nm, or 650 nm to 750 nm, or 650 nm to 700 nm. In specific examples, a suitable dose of irradiation following administration of the compound or VLP-compound conjugate is at least 1.0 J cm-2at a wavelength of 690 nm for example, at least 10 J cm-2at a wavelength of 690 nm, at least 50 J cm-2at a wavelength of 690 nm, or at least 100 J cm-2at a wavelength of 690 nm, for example 1 to 5001.0 J cm-2at a wavelength of 690 nm. In particular examples, multiple irradiations are performed (such as at least 2, at least 3, or at least 4 irradiations, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 separate administrations), following administration of the compound or VLP-compound conjugate.

[0092] Thial: -C(S)H.

[0093] Thiocarboxylic acid: -C(O)SH, or –C(S)OH.

[0094] Thiocyanate: -S-CN. - 20 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0095] Thioester: -C(O)SRaor –C(S)ORawherein Rais selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. Thioester groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0096] Thioether: -S-aliphatic or –S-aromatic, such as -S-alkyl, -S-alkenyl, -S-alkynyl, -S- aryl, or -S-heteroaryl; or -aliphatic-S-aliphatic, -aliphatic-S-aromatic, -aromatic-S-aliphatic, or -aromatic-S-aromatic. Thioether groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0097] Thioketone: -C(S)Rawherein Rais selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. Thioketone groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group.

[0098] Treating / Treatment: Treatment of a disease or condition of interest in a subject, particularly a human, canine, or feline, having the disease or condition of interest, and includes by way of example, and without limitation: (i) prophylactic administration to prevent the disease or condition from occurring in a subject, or to ameliorate symptoms associated with the condition if required in particular, when such subject is predisposed to the condition but has not yet been diagnosed as having it; (ii) inhibiting the disease or condition, for example, arresting or slowing its development; (iii) relieving the disease or condition, for example, causing regression of the disease or condition or a symptom thereof; or (iv) stabilizing the disease or condition. As used herein, the terms “disease” and “condition” can be used interchangeably or can be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been determined) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, where a more or less specific set of symptoms have been identified by clinicians.

[0099] Tumor, neoplasia, malignancy or cancer: A neoplasm is an abnormal growth of tissue or cells which results from excessive cell division. Neoplastic growth can produce a - 21 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01tumor. The amount of a tumor in an individual is the “tumor burden” which can be measured as the number, volume, or weight of the tumor. A tumor that does not metastasize is referred to as “benign.” A tumor that invades the surrounding tissue and / or can metastasize is referred to as “malignant.” A “non-cancerous tissue” is a tissue from the same organ wherein the malignant neoplasm formed, but does not have the characteristic pathology of the neoplasm. Generally, noncancerous tissue appears histologically normal. A “normal tissue” is tissue from an organ, wherein the organ is not affected by cancer or another disease or disorder of that organ. A “cancer-free” subject has not been diagnosed with a cancer of that organ and does not have detectable cancer.

[0100] Exemplary tumors, such as cancers, that can be treated with VLP-compound conjugates (including compositions thereof) disclosed herein include solid tumors, such as breast carcinomas (e.g. lobular and duct carcinomas), sarcomas, carcinomas of the lung (e.g., non-small cell carcinoma, large cell carcinoma, squamous carcinoma, and adenocarcinoma), mesothelioma of the lung, colorectal adenocarcinoma, stomach carcinoma, prostatic adenocarcinoma, ovarian carcinoma (such as serous cystadenocarcinoma and mucinous cystadenocarcinoma), ovarian germ cell tumors, testicular carcinomas and germ cell tumors, pancreatic adenocarcinoma, biliary adenocarcinoma, hepatocellular carcinoma, bladder carcinoma (including, for instance, transitional cell carcinoma, adenocarcinoma, and squamous carcinoma), renal cell adenocarcinoma, endometrial carcinomas (including, e.g., adenocarcinomas and mixed Mullerian tumors (carcinosarcomas)), carcinomas of the endocervix, ectocervix, and vagina (such as adenocarcinoma and squamous carcinoma of each of same), tumors of the skin (e.g., squamous cell carcinoma, basal cell carcinoma, malignant melanoma, skin appendage tumors, Kaposi sarcoma, cutaneous lymphoma, skin adnexal tumors and various types of sarcomas and Merkel cell carcinoma), esophageal carcinoma, carcinomas of the nasopharynx and oropharynx (including squamous carcinoma and adenocarcinomas of same), salivary gland carcinomas, brain and central nervous system tumors (including, for example, tumors of glial, neuronal, and meningeal origin), tumors of peripheral nerve, soft tissue sarcomas and sarcomas of bone and cartilage, and lymphatic tumors (including B-cell and T- cell malignant lymphoma). In one example, the tumor is an adenocarcinoma.

[0101] The VLP-compound conjugates according to the present disclosure can also be used to treat liquid tumors, such as a lymphatic, white blood cell, or other type of leukemia. In a specific example, the tumor treated is a tumor of the blood, such as a leukemia (for example acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), hairy cell leukemia - 22 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01(HCL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia , and adult T-cell leukemia), lymphomas (such as Hodgkin’s lymphoma and non-Hodgkin’s lymphoma), and myelomas.

[0102] Under conditions sufficient for: A phrase that is used to describe any environment that permits the desired activity. In one example, “under conditions sufficient for” includes administering a compound or VLP-compound conjugate according to the present disclosure to a subject or sample sufficient to allow the compound or VLP-compound conjugate to bind to a cell. In particular examples, the desired activity is killing the cells to which the compound or VLP-compound conjugate is bound, following therapeutic irradiation.

[0103] Untreated cell: A cell that has not been contacted with a desired agent, such as a VLP-compound conjugate according to the present disclosure. In an example, an untreated cell is a cell that receives the vehicle in which the desired agent was delivered.

[0104] Virus-Like Particle (or “VLP”): An organized structure comprising self-assembling ordered arrays of one or more viral capsid proteins that do not include a viral genome. For example, VLPs having papillomavirus L1 capsid protein alone, or having both L1 and L2 capsid proteins together can be prepared. The methods used to prepare recombinant capsid particles for many papillomaviruses are known and can be determined by those in the art, particularly with the benefit of the present disclosure.

[0105] VLP-Compound Conjugate: A conjugate structure that comprises a virus-like particle (or a plurality thereof) conjugated to a photosensitive silicon phthalocyanine dye compound according to the present disclosure via a linker group as described herein.

[0106] Recombinant protein: A protein that is produced using molecular biology techniques, for example, recombinant DNA technology. As an example, “recombinant protein” can refer to a protein from a genetically engineered nucleic acid, such as a “recombinant nucleic acid construct.” Any protein, peptide, or polypeptide can be encoded by an engineered nucleic acid construct or recombinant nucleic acid construct. The term “protein expression” refers to the processes of transcription and translation of nucleic acids to produce polypeptides.

[0107] Pseudoviruses (or Papilloma Pseudoviruses or Papillomavirus Gene Transfer Vectors): One or more papillomavirus capsid proteins that assemble and package heterologous nucleic acids (e.g., DNA) with or without viral nucleic acids (e.g., DNA) into infectious particles. The methods used to produce papilloma pseudoviruses are known in the art and are described, for example, in U.S. Pat. Nos.6,599,739, 7,205,126, and 6,416,945; - 23 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01and in Buck and Thompson, Production of Papillomavirus-Based Gene Transfer Vectors. Current Protocols in Cell Biology 26.1.1-26.1.19, December 2007, the relevant portion of which is incorporated herein by reference.

[0108] Introduction

[0109] The present disclosure concerns conjugates comprising virus-like particles (VLPs) (e.g., papilloma VLPs) (also referred to herein as “virus-like nanoparticles”) that are chemically modified to one or more photosensitive compounds having structures according to formulas described herein without losing their tumor-targeting capability or structural stability. For example, in some aspects, VLPs can be chemically modified to carry more than 50 compounds, more than 100 compounds, or more than 1000 compounds. Virus-like particles assembled from L1, or L1 and L2 capsid proteins, can selectively bind to and infect cancer cells without affecting non-cancerous cells, thereby minimizing the cytotoxicity of treatments. Further, in some aspects, delivering high amounts of photosensitive molecules per particle facilitates selectively killing tumor cells upon light radiation with extremely small amounts of VLP-compound conjugates (e.g., picomolar concentrations).

[0110] A key cell binding characteristic of a VLP is the presence of a high number of heparan sulfate binding sites on the capsid proteins (e.g., L1). Conjugation of compounds according to the present disclosure to surface amino acids (e.g., conjugation via an amide bond to surface amino acids, such as surface lysine residues, arginine residues and histidine residues), does not compromise binding of the VLP to heparan sulfate proteoglycans (HSPGs) on the surface of tumor cells. Although, the present disclosure describes conjugation of photosensitive compounds to surface-exposed peptides of capsid proteins, it should be understood that photosensitive compounds may be conjugated to any peptides of capsid proteins. That is, photosensitive compounds may be conjugated to L1 proteins only or to a combination of L1 and L2 proteins. The protein and amino acid residue to which a photosensitive compounds is conjugated can depend on the composition of the virus-like particle.

[0111] The conjugates according to the present disclosure provide access to novel targeted cancer treatments. For example, the VLP conjugates of the present disclosure provide an advantage relative to other targeting molecules, such as antibodies, which have a very limited delivery capacity. In addition, the VLP conjugates of the present disclosure are useful for targeting a wide range of tumors that otherwise cannot be targeted by antibodies or other targeting molecules because suitable tumor-surface specific determinants have not been identified. Further, the VLP conjugates are useful for treating distant metastases, such as by - 24 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01inducing T cell responses to tumor or neoepitopes that can facilitate treating distant metastases. In addition, the VLP conjugates are useful for diagnosing and treating early malignant or pre-cancerous lesions

[0112] The phthalocyanine-containing compounds of the VLP conjugates disclosed herein comprise unique linker groups and / or substitution patterns that facilitate efficient synthesis methods with improved yields, as well as the ability to modify / tune the particular wavelength used to photoactivate the compounds for therapy. According to aspects of the disclosure, the compounds can be conjugated to VLPs for therapeutic and / or diagnostic applications. Also disclosed herein are dimerized compounds comprising two silicon-based phthalocyanine cores wherein the cores are joined together by a fused ring system functionalized with a linker group according to aspects of the present disclosure, wherein the linker group facilitates conjugation with a VLP.

[0113] Compounds and Conjugates

[0114] Disclosed herein are compounds having a structure according to Formula I. Also disclosed are compounds having a dimer structure as shown in Formula II. Compounds according to aspects of the present disclosure comprise a unique linker group. In some aspects of the present disclosure, compounds according to Formula I comprise the linker group positioned at the “beta” position on a phenyl ring of the phthalocyanine group (carbon labeled “β” in Formula I). In some other aspects, the linker group may be positioned at the “alpha” position on a phenyl ring of the phthalocyanine group (carbon labeled “α” in Formula I). The unique linker group can be formed by coupling clickable functional groups together (wherein one clickable functional group is coupled to the phthalocyanine core and the other is part of a separate moiety) or by coupling wavelength-tunable groups (e.g., styrene-type groups) to the phthalocyanine core. The ability to provide such linker groups provides flexibility in, for example: (i) the installed linker length, which can be tuned to improve efficacy of cellular cytotoxicity, and (ii) linker identity such that the energy of therapeutic light exposure used during any NIR-PIT can be reduced, thereby improving clinical therapeutic efficacy and safety. Compounds according to Formulas I and II further comprise an X group that facilitates the ability to bind to a VLP. - 25 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0115] With reference to Formulas I and II, the following substituent recitations can apply: X is a VLP-binding moiety; the Linker has a structure according to a formula {Core}-(CR2)n-Y-(Z)m- (CR2)p[O(CR2)t]q-{X}, wherein {Core} solely represents attachment to the phthalocyanine core and {X} solely represents attachment to X; each R, independently for each occurrence, is selected from hydrogen, halogen, aliphatic, heteroaliphatic, or aromatic; Y is selected from (i) a functional group produced from a reaction between two clickable functional groups; (ii) -CH=CH-[Q1]s-, wherein s is 1 or 0 and Q1is selected from aromatic, or -C(=O)Y’- or -S(=O)2Y’, wherein Y’ is NR” or O (wherein R” is H, -CN, CF3, or a sulfonyl group, such as SO2Me, SO2CF3, SO2NH2, or SO2NMe2); or (iii) -C C-Q2, wherein Q2 is –(CH2)uC(=O)Y’-, wherein- 26 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01u is an integer selected from 1 to 10, such as 1 to 8, or 1 to 6 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), Y’ is NR” or O (wherein R” is H, -CN, CF3, or a sulfonyl group, such as SO2Me, SO2CF3, SO2NH2, or SO2NMe2); Z is a heteroatom; m is 1 or 0; each of n, p, and t independently is selected from an integer ranging from 0 to 50; and q is an integer selected from 0 to 50; G, if present, is selected from halogen (such as chloro, bromo, fluoro, or iodo) or a Linker-X group (wherein the linker group and the X group as selected from definitions provided above); each of R1a, R2a, R3a, R1b, R2b, and R3bindependently is selected from hydrogen, aliphatic, halogen, heteroaliphatic, aromatic, thiol, hydroxyl, or amine; or (i) R1aand R1bjoin together, with the carbon atoms to which they are attached, to form a 6-membered aromatic ring, (ii) R2aand R2bjoin together, with the carbon atoms to which they are attached, to form a six-membered aromatic ring, (iii) R3aand R3bjoin together, with the carbon atoms to which they are attached, to form a six-membered aromatic ring, or (iv) any combination of two or more of (i)-(iii); and L is selected from -(CH2)r-, -Si(R5)2(CH2)r-, -C(=O)(CH2)r-, or -Ph(CH2)r-, wherein each R5independently is aliphatic (such as alkyl, including C1-10alkyl) or aryl (such as phenyl), r is an integer selected from 1 to 5, such as 1, 2, 3, 4, or 5, wherein any CH2group of the L group is attached to the quaternary amine of Formula I or Formula II.

[0116] In some aspects, X is a VLP-binding moiety or a precursor thereto. The VLP- binding moiety can be a moiety capable of binding a VLP. In some aspects of the disclosure, the VLP-binding moiety is a moiety that can form a chemical bond with one or more amino acids of a VLP. In some aspects, the VLP-binding moiety comprises an ester group (e.g., an activated ester group or a precursor thereto), a thiol group, a thiol-reactive group (e.g., maleimide), an amine, or a clickable functional group. In particular aspects of the disclosure, the VLP-binding moiety comprises an activated ester group that facilitates coupling with an amino acid of a VLP. In yet other aspects, the VLP-binding moiety comprises a clickable functional group that can react with another clickable functional group that is present on a VLP. Such clickable functional groups can be selected from those described herein for the linker group. - 27 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0117] The linker group of Formulas I and II has a structure according to a formula {Core}- (CR2)n-Y-(Z)m-(CR2)p[O(CR2)t]q-{X}, wherein the variables of this formula are defined as above and wherein “{Core}” and “{X}” are provided solely to illustrate how the linker is bound to the phthalocyanine core and variable X of Formula I. In some aspects, the linker group has a structure according to a formula {Core}-(CR2)n-Y-(CR2)p-{X}, {Core}-(CR2)n-Y- (CR2)p[O(CR2)t]q-{X}, {Core}-(CR2)n-Y-(Z)m-(CR2)p-{X}, or {Core}-(CR2)n-Y- (Z)m(CR2)p[O(CR2)t]q-{X}. In some aspects of the disclosure, at least one of n and p is selected from an integer greater than zero such that R groups are present. In such aspects, each R group independently, for each occurrence, is selected from hydrogen, Cl, F, Br, I, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloheteroalkyl, cycloheteroalkenyl, cycloheteroalkynyl, aryl, or heteroaryl. In some particular aspects, each R group independently, for each occurrence, is hydrogen or lower alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl). In particular aspects, each of n, p, and / or t independently is an integer selected from 0 to 50, such as 0 to 25, or 0 to 24, or 0 to 23, or 0 to 22, or 0 to 21, or 0 to 20, or 0 to 15, or 0 to 10, or 0 to 9. In some aspects, each of n, p, and / or t independently is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In particular aspects, n is an integer selected from 0, 1, 2, 3, or 4, more particularly 0, 1, 2, or 3. In particular aspects, p or t independently is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. In some aspects of the present disclosure, q is an integer selected from 0 to 50 such as 0 to 25, or 0 to 20, or 0 to 15, or 0 to 10, or 0 to 9, or 0 to 8, or 0 to 7, or 0 to 6, or 0 to 5, or 0 to 4, or 0 to 3, or 0 to 2. In particular aspects, q is either 0 or is 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6).

[0118] In some aspects of the disclosure, Y is a moiety that is provided by reacting two clickable functional groups. In such aspects, m typically is zero and thus no Z group is present. In some aspects, Y comprises a ring formed by a cycloaddition reaction between (i) an alkyne and an azide; (ii) a tetrazine and a trans-cyclooctene; (iii) an azide and a dibenzocyclooctyne (DBCO); or (iv) an azide and a bicyclo[6.1.0]nonyne. In some aspects, Y comprises a triazole, a cycloocta[d]pyridazine, a cycloocta[d]triazole, a triazole- functionalized DBCO, or the like. In particular aspects of the present disclosure, the phthalocyanine core can be functionalized with an alkyne, dibenzocyclooctyne, or bicyclo[6.1.0]nonyne, and a separate moiety comprising the VLP-binding moiety can be functionalized with an azide. In yet other aspects, the phthalocyanine core can be functionalized with an azide, and a separate moiety comprising the VLP-binding moiety can be functionalized with a terminal or di-substituted alkyne, dibenzocyclooctyne, or a bicyclo[6.1.0]nonyne group. In yet additional aspects, the phthalocyanine core can be functionalized with a tetrazine, and a separate moiety comprising the VLP-binding moiety - 28 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01can be functionalized with a trans-cyclooctene group. In yet other aspects, the phthalocyanine core can be functionalized with a trans-cyclooctene group, and a separate moiety comprising the VLP-binding moiety can be functionalized with a tetrazine. In exemplary aspects, the phthalocyanine core is functionalized with an alkyne or an azide and the separate moiety comprising the VLP-binding moiety is functionalized with an azide (if the phthalocyanine core is functionalized with an alkyne) or an alkyne (if the phthalocyanine core is functionalized with an azide).

[0119] Those in the art recognize, particularly with the benefit of the present disclosure, reaction conditions that can be used to facilitate bond formation between the clickable functional groups described above. In some aspects of the disclosure, the reaction conditions can include using copper-mediated catalysis or ruthenium-mediated catalysis. In yet other aspects of the disclosure, the reaction conditions can comprise incubating the functionalized phthalocyanine core with the separate moiety comprising the VLP-binding moiety at physiological pH. In some such aspects of the disclosure, the reaction can be carried out under a pH ranging from 6.5 to 8, such as 7 to 8, or 7 to 7.5 and a buffer can be used.

[0120] In other aspects of the disclosure, Y is a group having a structure of -CH=CH-[Q1]s- wherein s is 1 or 0. When s is 1, Q1is aromatic, -C(=O)Y’-, or -S(=O)2Y’, and (i) the aromatic group is selected from an aryl (e.g., phenyl, naphthyl, anthracenyl, or the like) or a heteroaryl group (e.g., a pyridinyl, furanyl, pyrroyl, thiophenyl, indolyl, benzofuranyl, carbazoyl, quinolinyl, isoquinolinyl, imidazoyl, oxazoyl, pyrazoyl, pyriazinyl, pyrimidinyl, and the like); or (ii) Y’ of -C(=O)Y’- and / or -S(=O)2Y’ is O or -NH, -N(CN), -NCF3, -NSO2Me, -NSO2CF3, - NSO2NH2, or -NSO2NMe2. In particular aspects wherein Y is -CH=CH-Aromatic-, the aromatic group is a phenyl group or a pyridyl group. In aspects wherein Y is -CH=CH- Aromatic-, m can be zero or 1 and typically is 1. In aspects wherein m is 1, Z is present and is a heteroatom selected from oxygen, sulfur, or nitrogen. In particular aspects, Z is oxygen.

[0121] In yet other aspects of the disclosure, Y is a group having a structure according to -C C-Q2, wherein Q2 is –(CH2)uC(=O)Y’-, wherein u is an integer selected from 1 to 10, suchas 1 to 8, or 1 to 6 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) and Y’ is O or NH. In some suchaspects,

[0122] In aspects of the disclosure, G is not present. In other aspects, G is present and is selected from chloro, bromo, fluoro, iodo, or Linker-X, wherein the linker and X groups of Linker-X are as defined herein for Formula I and other formulas of the disclosure. In some particular aspects, G is positioned ortho to the Linker-X group illustrated in Formula I. In - 29 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01some aspects of the disclosure, G is Linker-X and this Linker-X group comprises a linker and an X group that are both the same as the linker and X groups of the Linker-X group illustrated in Formula I. In yet some other aspects of the disclosure, G is Linker-X and this Linker-X group comprises a linker that is the same as the linker of the Linker-X group illustrated in Formula I and an X group that is different from X of the Linker-X group illustrated in Formula I. In yet other aspects of the disclosure, G is Linker-X and this Linker- X group comprises a linker that is different from the linker of the Linker-X group illustrated in Formula I and an X group that is the same as X of the Linker-X group illustrated in Formula I. In yet additional aspects, G is Linker-X and this Linker-X group comprises a linker and an X group that are both different from the linker and X groups of the Linker-X group illustrated in Formula I.

[0123] In aspects of the disclosure, each of R1a, R2a, R3a, R1b, R2b, and R3b, independently and for each occurrence is selected from hydrogen, hydroxyl, ether, thiol, thioether, NH2, or amine; or (i) R1aand R1bjoin together, with the carbon atoms to which they are attached, to form a phenyl ring, (ii) R2aand R2bjoin together, with the carbon atoms to which they are attached, to form a phenyl ring, and (iii) R3aand R3bjoin together, with the carbon atoms to which they are attached, to form a phenyl ring. In such aspects, the phenyl ring can be unsubstituted or unsubstituted with substituents described in definitions provided herein.

[0124] In some aspects, L is selected from -(CH2)4, -Si(Me)2(CH2)3-, -Si(Et)2(CH2)3-, - Si(iPr)2(CH2)3-, -Si(Ph)2(CH2)3-, -C(=O)(CH2)3-, or -PhCH2-, wherein any CH2 group of the L group is attached to the quaternary amine of Formula I or Formula II.

[0125] In some aspects, compounds of Formula I can have a structure according one of Formulas IA or IB, shown below. In any aspects, the Si(R5)2(CH2)3groups illustrated in the formulas can be replaced with a -(CH2)4-, -C(=O)(CH2)3-, or -PhCH2- group.- 30 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0126] In some aspects, compounds according to Formula I and Formula IA can have structures according to Formula IA(i), Formula IA(ii), Formula IA(iii), or Formula IA(iv), wherein ring A is either an aryl ring, a heteroaryl ring, or a ring system provided by coupling clickable functional groups as described herein. Each of R1a, R2a, R3a, R1b, R2b, R3b, R5, X, G, Z, Q1, Q2, m, n, p, q, and s is as described above for any of the preceding formulas. In particular aspects of Formula IA(i) or Formula IA(ii), ring A is a ring system selected from a phenyl ring, a triazole, a cycloocta[d]pyridazine, a cycloocta[d]triazole, or a triazole- functionalized DBCO. In some particular aspects, the alkene group attached to ring A is present or is absent, as represented by the option of 1 or 0 in the formulas. When present, the alkene group is bound to ring A which typically is phenyl or pyridyl. In some such aspects, Z is present and is a heteroatom (e.g., O). When the alkene group is absent, ring A typically is a triazole, a cycloocta[d]pyridazine, a cycloocta[d]triazole, or a triazole- functionalized DBCO. In any aspects, the Si(R5)2(CH2)3groups illustrated in the formulas can be replaced with a -(CH2)4-, -C(=O)(CH2)3-, or -PhCH2- group. In some aspects, each R5independently is methyl, ethyl, ipropyl, or phenyl. The dashed bonds in the formulas below are intended to indicate that a G group can be present (and bound to the carbon to which the dashed bond is attached) or that a G group is not present (and the carbon to which the dashed bond is attached is instead attached to a hydrogen atom). In particular aspects, Q1is -C(=O)NH- or -S(=O)2NH- wherein the C or S atoms are bound to the alkene group of Formula IA(iii). In particular aspects, G is chloro, iodo, bromo, or comprises the same linker and X combination as shown in any of Formula IA(i), Formula IA(ii), Formula IA(iii), or Formula IA(iv). - 31 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 32 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0127] In some aspects, compounds according to Formula IA and / or Formula IA(i) can have structures according to Formulas IA(i)(a)-IA(i)(i). With reference to Formulas IA(i)(a)- IA(i)(i), each of R1a, R2a, R3a, R1b, R2b, R3b, R5, X, G, Z, Y’, n, p, and q is as described above for any of the preceding formulas and Z’ is N or CH. In particular aspects of Formula IA(i)(a), Formula IA(i)(c), Formula IA(i)(e), Formula IA(i)(f), Formula IA(i)(g), Formula IA(i)(h), Formula IA(i)(i), X is an activated ester (or a precursor thereto, such as a carboxylic acid or a carboxylate having a formula –C(O)O-M+, wherein M is a monovalent counterion), an azide, or an alkyne; G is chloro, iodo, bromo, or comprises the same linker and X combination as shown in any of Formulas IA(i)(a)-IA(i)(i); each R5independently is methyl, ethyl, ipropyl, or phenyl; n is an integer selected from 0 to 3 (such as 0, 1, 2, or 3); p is an integer selected from 0 to 21 (such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21); and q is an integer selected from 0 to 6 (such as 0, 1, 2, 3, 4, 5, or 6). In particular aspects of Formula IA(i)(b) or Formula IA(i)(d), Z is oxygen, Z’ is CH or N, X is an activated ester (or a precursor thereto, such as a carboxylic acid or a carboxylate having a formula – C(O)O-M+, wherein M is a monovalent counterion), an azide, or an alkyne; p is an integer selected from 0 to 21 (such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21); and q is an integer selected from 0 to 6 (such as 0, 1, 2, 3, 4, 5, or 6). In any aspects, the Si(R5)2(CH2)3groups illustrated in the formulas can be replaced with a -(CH2)4-, -C(=O)(CH2)3-, or -PhCH2- group. The dashed bonds in the formulas below are intended toindicate that a G group can be present (and bound to the carbon to which the dashed bond is attached) or that a G group is not present (and the carbon to which the dashed bond is attached is instead attached to a hydrogen atom).- 33 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 34 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 35 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0128] In some aspects, compounds according to Formula I and Formula IB can have structures according to Formula IB(i) or Formula IB(ii), wherein ring A is either an aryl ring, heteroaryl ring, or a ring system provided by coupling clickable functional groups as described herein. Each of R1a, R2a, R3a, R1b, R2b, R3b, R5, X, G, Z, m, n, p, and q is as described above for any of the preceding formulas. In some particular aspects, the alkene group attached to ring A is present or is absent. When present, the alkene group is typically bound to ring A which is phenyl or pyridyl. In some such aspects, Z is present and is a heteroatom (e.g., O). When the alkene group is absent, ring A typically is a triazole, a cycloocta[d]pyridazine, a cycloocta[d]triazole, or a triazole-functionalized DBCO. In any aspects, the Si(R5)2(CH2)3 groups illustrated in the formulas can be replaced with a -(CH2)4-, -C(=O)(CH2)3-, or -PhCH2- group. Additional compounds can have Formulas according to Formulas IA(i)-IA(iv) wherein the core comprises the fused naphthalene ring system shown in Formulas IB(i) and IB(ii). The dashed bonds in Formula IB(i) and IB(ii) are intended to indicate that a G group can be present (and bound to the carbon to which the dashed bond is attached) or that a G group is not present (and the carbon to which the dashed bond is attached is instead attached to a hydrogen atom). In particular aspects, G is chloro, iodo, bromo, or comprises the same linker and X combination as shown in Formula IB(i) or Formula IB(ii). In some aspects, each R5independently is methyl, ethyl, ipropyl, or phenyl.- 36 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0129] In some aspects, compounds according to Formula IB(i) can have structures according to Formulas IB(i)(a)-IB(i)(d). With reference to Formulas IB(i)(a)-IB(i)(d), each of R1a, R2a, R3a, R1b, R2b, R3b, R5, X, G, Z, n, p, and q is as described above for any of the preceding formulas and Z’ is CH or N. In particular aspects of Formula IB(i)(a) and Formula IB(i)(c), X is an activated ester (or a precursor thereto, such as a carboxylic acid or a carboxylate having a formula –C(O)O-M+, wherein M is a monovalent counterion), an azide, or an alkyne; n is an integer selected from 0 to 3 (such as 0, 1, 2, or 3); G is bromo, chloro, iodo, or comprises the same linker and X combination as shown in Formulas IB(i)(a)-IB(i)(d); each R5independently is methyl, ethyl, ipropyl, or phenyl; p is an integer selected from 0 to 21 (such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21); and q is an integer selected from 1 to 6 (such as 1, 2, 3, 4, 5, or 6). In particular aspects of Formula IB(i)(b) and Formula IB(i)(d), Z is oxygen, Z’ is CH or N, X is an activated ester (or a precursor thereto, such as a carboxylic acid or a carboxylate having a formula –C(O)O-M+, wherein M is a monovalent counterion), an azide, or an alkyne; p is an integer selected from 0 to 21 (such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21); and q is an integer selected from 1 to 6 (such as 1, 2, 3, 4, 5, or 6). In any such aspects, the Si(R5)2(CH2)3 groups illustrated in the formulas can be replaced with a -(CH2)4-, - C(=O)(CH2)3-, or -PhCH2- group. Additional compounds can have Formulas according to Formulas IA(i)(a)-IA(i)(i) wherein the core comprises the fused naphthalene ring system shown in Formulas IB(i)(a)-IB(i)(d). The dashed bonds in the formulas below are intended to indicate that a G group can be present (and bound to the carbon to which the dashed bond is attached) or that a G group is not present (and the carbon to which the dashed bond is attached is instead attached to a hydrogen atom). In particular aspects, G is chloro, iodo, bromo, or comprises the same linker and X combination as shown in any of Formulas IB(i)(a)-IB(i)(d).- 37 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0130] In some other aspects of the disclosure, the compounds can be dimers having a structure according to Formula II. In some aspects, compounds according to Formula II can have structures according to Formula IIA, Formula IIB, or Formula IIC. Each of R1a, R3a, R1b, R3b, R5, X, Z, Q1, m, n, p, q, and s is as described above for any of the preceding formulas. In particular aspects of Formula IIA or Formula IIB, ring A is a ring system selected from a phenyl ring, a pyridyl ring, a triazole, a cycloocta[d]pyridazine, a cycloocta[d]triazole, or a triazole-functionalized DBCO. In some particular aspects, the alkene group attached to ring A is present or is absent. When present, the alkene group is bound to ring A which typically - 38 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01is phenyl or pyridyl. In some such aspects, Z is present and is a heteroatom (e.g., O). When the alkene group is absent, ring A typically is a triazole, a cycloocta[d]pyridazine, a cycloocta[d]triazole, or a triazole-functionalized DBCO. In any aspects, the Si(R5)2(CH2)3 groups illustrated in the formulas can be replaced with a -(CH2)4-, -C(=O)(CH2)3-, or -PhCH2- group. In some aspects of Formula IIC, s is 1 and Q1is -C(=O)Y’ or -S(=O)2Y’, wherein Y’ is O or NH, -N(CN), -NCF3, -NSO2Me, -NSO2CF3, -NSO2NH2, or -NSO2NMe2. In some other aspects of Formula IIC, s is 0. In some aspects, the linker group of Formula IIA, IIB, and IIC can comprise a formula according to any of Formulas IA(i)-IA(iv) or Formulas IA(i)(a)-IA(i)(i).- 39 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0131] In some aspects, compounds according to Formula IIA can have structures according to Formulas IIA(i) or IIA(ii), Formula IIB can have structures according to Formulas IIB(i) and IIB(ii), and Formula IIC can have structures according to Formulas IIC(i), IIC(ii), IIC(iii), and IIC(iv). In some aspects, the linker group of Formulas IIA(i), IIA(ii), IIB(i) or IIB(ii) can comprise a formula according to any of Formulas IA(i)-IA(iv) or Formulas IA(i)(a)-IA(i)(i). With reference to Formulas IIA(i), IIA(i), IIB(i), IIB(ii), IIC(i), IIC(ii), IIC(iii), and IIC(iv), each of R1a, R3a, R1b, R3b, R5, X, Z, Z’, Y’, n, p, and q is as described above for any of the preceding formulas. In particular aspects of Formula IIA(i) or Formula IIB(i), X is an activated ester (or a precursor thereto, such as a carboxylic acid or a carboxylate having a formula –C(O)O-M+, wherein M is a monovalent counterion), an azide, or an alkyne; n is an integer selected from 0 to 3 (such as 0, 1, 2, or 3); p is an integer selected from 0 to 21 (such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21); and q is an integer selected from 1 to 6 (such as 1, 2, 3, 4, 5, or 6). In particular aspects of Formula IIA(ii) or IIB(ii), Z is oxygen, Z’ is CH or N, X is an activated ester (or a precursor thereto, such as a carboxylic acid or a carboxylate having a formula –C(O)O-M+, wherein M is a monovalent counterion), an azide, or an alkyne; p is an integer selected from 0 to 21 (such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21); and q is an integer selected from 1 to 6 (such as 1, 2, 3, 4, 5, or 6). In particular aspects of Formula IIC(i) and IIC(iii), Y’ is O or -NH, -N(CN), - NCF3, -NSO2Me, -NSO2CF3, -NSO2NH2, or -NSO2NMe2. In any aspects, the Si(R5)2(CH2)3groups illustrated in the formulas can be replaced with a -(CH2)4-, -C(=O)(CH2)3-, or -PhCH2- group. - 40 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 41 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 42 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01^^^^^ ^^^^^ ^^^^^^^^^^^ ^ ^ ^^^^^^^ ^^^^ ^^^^^^^ ^^^ ^ ^ ^^ ^^ ^ ^ ^^ ^^ ^- 43 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0132] Exemplary compounds according to aspects of the disclosure are illustrated below.With reference to any of the below-illustrated species, it is to be understood that the present disclosure also contemplates the same compounds but with the linker groups attached at the alpha carbon instead of the beta carbon as illustrated below, unless otherwise stated. Additionally, the present disclosure also contemplates the same compounds, but wherein any sodium salt form of the illustrated terminal ester group is present as another salt form (e.g., including any M+species, wherein M is a metal) or as the protonated carboxylic acid form. In any of the exemplary compounds shown below, the Si(R5)2(CH2)3groups (where R5is Me, Et, iPr, or Ph) illustrated in the formulas can be replaced with a -(CH2)4-, -C(=O)(CH2)3-, or -PhCH2- group.-44 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01 Na Na Na Na-45 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01SO3Na O Si SO3Na Na- 46 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01 O SO3Na N O O Si SO3Na Na Na-47 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01-48 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01NaO SO3Na O O Si SO3Na aNaNa NaNa- 49 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01O SO3Na O N O Si SO3Na aNaNa- 50 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01SO3Na O O Si SO3Na NaNaNa Na Na- 51 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01O SO3Na N O OSO3Naa a Na Na- 52 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01SO3Na O O Si SO3Na a Na Na Na Na a a- 53 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01O SO3Na N O O Si SO3Na Naa a Na Na a a- 54 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01O SO3Na N O O Si SO3Na Na Na- 55 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01O NOO O Na Na Na Na- 56 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01SO3Na O O Si SO3Na NaNa Na Na Na- 57 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01SO3Na O O Si SO3Na Naaa 3Na 3Na a a- 58 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01ONa O O3S N N SO3Na NaNaNa Na Na- 59 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01ONa O NaNa Na Na- 60 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01O ONa NaNaNa Na- 61 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01O O N Na Na Na Na NaNa- 62 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01O N O Na NaNa Na- 63 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01N3Na Na Na Na- 64 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01O N Na NaNa Na- 65 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01ONa O Na Na N Na Na- 66 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01NaO O NaNa Na Na- 67 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01O ONN a a Na Na

[0133] VLP-compound conjugates according to the present disclosure can comprise compounds according to any of the formulas described herein wherein the X group is a VLP- binding moiety that has been bound to the corresponding VLP to which it is designed to bind. In such aspects of the disclosure, the X group and the VLP are bound via a chemical bond, typically a covalent bond. In particular aspects, the X group and the VLP are bound such that a covalent bond is formed between atoms of the X group and atoms of a functional group of the VLP, such as a functional group of an amino acid group of the VLP. In certain - 68 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01aspects of the disclosure, the X group is an activated ester (e.g., an NHS ester), the VLP comprises an amine group (e.g., NH2), and the covalent bond is formed between the carbonyl of the activated ester and the nitrogen atom of the amine group, thereby forming an amide bond. In exemplary aspects of the disclosure the VLP becomes bound to the compound via a covalent bond between a primary amine of a surface amino acid of the VLP and a carbonyl group of an activated ester group of the compound. Those in the art, with the benefit of the present disclosure will recognize how VLP-compound conjugates are formed for compounds having other X groups and / or biomolecules having other functional groups. These additional types of chemical conjugations also are contemplated by the present disclosure.

[0134] In aspects of the disclosure, the ratio of the compound to VLP may vary. In some aspects, the ratio of VLP:compound is 1:10 to 1:1000, 1:10 to 1:500, 1:50 to 1:500, or 1:50 to 1:1000. In some aspects, a VLP-compound conjugate may comprise 10 to 1000 compounds according to the formulas described herein. In some aspects, the ratio of VLP:compound is 1:10, 1:15, 1:20, 1:25, 1:50, 1:75, 1:100, 1:150, 1:200, 1:250, 1:300, 1:350, 1:400, 1:450, 1:500, 1:550, 1:600, 1:650, 1:700, 1:750, 1:800, 1:850, 1:900, 1:950 or 1:1000. In some aspects, the VLP may comprise 10, 15, 20, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 compounds according to the formulas described herein. In some aspects, the VLP may comprise more than 1000 such compounds, or fewer than 10 such compounds.

[0135] In some aspects, more than one compound according to formulas described herein may be conjugated to a single capsid protein. For example, a single capsid protein (e.g., L1 or L2 capsid protein) may be conjugated to 1 to 5 (e.g., 1, 2, 3, 4 or 5) such compounds. Thus, more than one amino acid of a capsid protein may be conjugated to a compound of the disclosure. In some aspects, a single capsid protein may be conjugated to 1 to 2, 1 to 3, or 2 to 3 compounds. Thus, a compound according to the disclosure may be conjugated to 1, 2, 3, 4 or 5 different amino acids (e.g., lysine, arginine and / or histidine, or other amino acid) of a single capsid protein.

[0136] VLP-compound conjugates according to the present disclosure can have structures satisfying any one of Formulas I, IA, IB, IA(i), IA(ii), IA(i)(a), IA(i)(b), IA(i)(c), IA(i)(d), IB(i), IB(ii), IB(i)(a), IB(i)(b), IB(i)(c), IB(i)(d), IIA, IIB, IIA(i), IIA(ii), IIB(i), or IIB(ii), wherein X is replaced with X’, wherein X’ comprises the VLP bound to the compound. In some aspects, X’ is {Core}-linker–C(=O)-VLP, {Core}-linker-S-VLP, or {Core}-linker-NH-VLP. - 69 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0137] In some aspects, the capsid proteins of the VLP-compound conjugates are papillomavirus capsid proteins. For example, in some aspects, the papillomavirus capsid proteins are non-human papillomavirus capsid proteins, such as bovine, murine, canine, leporine, or macaque or rhesus papillomavirus capsid proteins. In some embodiments, the virus-like particles comprise human papillomavirus capsid proteins and do not cross-react with human papillomavirus (HPV) 16, HPV 18 or other pre-existing antibodies specific induced by HPV prophylactic vaccines.

[0138] VLPs in accordance with the present disclosure may have a modified immunogenicity and / or antigenicity with respect to the wild-type papillomavirus VLPs. The VLPs may, for example, be assembled from capsomers having a variant capsid protein with modified immunogenicity and / or antigenicity. A variant capsid protein with “modified immunogenicity and / or antigenicity” is one that is modified naturally or synthetically (e.g., mutated, substituted, deleted, pegylated or inserted) at an amino acid to reduce or prevent recognition of the capsid protein by pre-existing (e.g., endogenous) viral serotype-specific antibodies. A variant capsid protein may be a human papillomavirus (HPV) L1 variant, a non- human papillomavirus L1 variant, or a papillomavirus L1 variant based on a combination of amino acids from different HPV serotypes. For example, an L1 variant with modified immunogenicity and / or antigenicity may be a recombinant protein based on HPV serotype 16 and HPV serotype 31.

[0139] In some aspects, the virus-like particles comprise papilloma L1 or L1 / L2 proteins (e.g., of human or other mammalian species). In some aspects, the L1 or L1 / L2 VLPs do not cross-react with neutralizing antibodies to human papillomavirus (HPV) 16, HPV 18 or pre- existing antibodies specific for other HPVs. However, in some aspects, the virus-like particles comprise human papillomavirus capsid proteins of HPV16. In some aspects, a VLP is a papillomavirus VLP. The VLP may be a human papillomavirus VLP. In other aspects, the VLP is a non-human papillomavirus VLP. Examples of non-human VLPs include those derived from, without limitation, bovine papillomaviruses, murine papillomaviruses, leporine papillomaviruses, canine papillomaviruses, and macaque or rhesus papillomavirus particles. In some embodiments, the VLPs are human or other mammalian papillomavirus viral-like nanoparticles (e.g., type 1 viral-like nanoparticles) (e.g., assembled from BPV L1 capsid proteins or a combination of BPV L1 and BPV L2 capsid proteins). In capsids of nonhuman mammalian types, the capsids may facilitate transducing human cells with a marker gene plasmid and thus can be used in aspects involving pseudovirions transferring cytotoxic or immune modifying genes. - 70 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0140] In some aspects, the photosensitive molecules are conjugated to surface-exposed peptides of capsid proteins.

[0141] In some aspects, the virus-like particles comprise L1 capsid proteins or a combination of L1 and L2 capsid proteins. In some embodiments, the virus-like particles consist of L1 capsid proteins.

[0142] Other suitable capsid proteins are described in U.S. Pat. No.10,117,947 and are incorporated herein by reference.

[0143] In some aspect, the VLP-compound conjugates are in the form of nanoparticles. The nanoparticles contain one or two types of capsid proteins from papillomavirus. In some embodiments, the capsid proteins are modified. Capsid proteins typically self-assemble into “empty” proto-capsids approximately 55 nm in diameter (e.g., spherical-like particles containing a hollow core). After maturation of the proto-capsids to form viral-like nanoparticles (virus-like particles), viral-like nanoparticles are then chemically conjugated with the compound. In some aspect, each nanoparticle comprises 12-72 capsomers with each capsomer containing 5 molecules of L1 capsid protein (e.g., 55-56 kD each) and 1 molecule of L2 capsid protein (e.g., 52 kD each). In some aspects, each nanoparticle comprises 12-72 capsomers with each capsomer containing only L1 capsid proteins (e.g., 5 molecules of L1 protein per capsomer). In some aspects, a fraction of the L1 capsomers in the VLPs are associated with L2.

[0144] To produce nanoparticles of VLP-compound conjugates, mammalian cells, such as 293T cells (e.g., HEK293F cells) may be grown (e.g., in suspension culture) and transiently transfected with a nucleic acid (e.g., bi-cistronic plasmid DNA) encoding BPV or HPV L1 (or L1 and L2) capsid proteins. This induces the formation of proto-capsids. Following cell mass recovery and disruption, the proto-capsids may be subjected to host DNA clearance with benzonase treatment and a subsequent maturation process in vitro to form stable viral-like nanoparticles. Following purification, the viral-like nanoparticles may be chemically conjugated with a compound according to the formulas described herein to produce the photosensitive nanoparticles. However, papillomavirus VLPs can alternatively be produced in other cell production systems including recombinant baculovrus infected cells, Saccharomyces cerevisiae, Pichia, Hansenula polymorpha, and E. coli. In conjugates comprising the compounds and VLPs, the conjugates can have structures satisfying any one of Formulas I, IA, IB, IA(i), IA(ii), IA(i)(a), IA(i)(b), IA(i)(c), IA(i)(d), IA(i)(e), IA(i)(f), IA(i)(g), IA(i)(h), IA(i)(i), IB(i), IB(ii), IB(i)(a), IB(i)(b), IB(i)(c), IB(i)(d), IIA, IIB, IIC, IIA(i), IIA(ii), IIB(i), IIB(ii), IIC(i), IIC(ii), IIC(iii), IIC(iv), wherein X is replaced with X’, wherein X’ comprises the - 71 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01VLP bound to the compound. In some aspects, X’ is {Core}-linker–C(=O)-VLP, {Core}- linker-S-VLP, or {Core}-linker-NH-VLP.

[0145] Methods

[0146] Compounds of the present disclosure can be made according to methods described herein. In some aspects, the method comprises preparing a phthalocyanine core precursor compound having a structure according to Formula III, wherein R4is selected from halogen or a group having a structure according to a formula {Core}-(CR2)n-CFG, wherein “CFG” is a clickable functional group as described herein, “Core” represents the attachment to the phthalocyanine core, and R, R1a, R1b, R2a, R2b, R3a, R3b, R5, and n are as described herein for any of the preceding formulas. In some aspects, the halogen can be selected from Br, Cl, F, or I, with representative examples being Br or I. In some aspects, the CFG group is an azide or alkyne.

[0147] In particular aspects of the present disclosure, the phthalocyanine core precursor can be selected from the structures according to Formulas IIIA-IIIC, shown below. While beta-position attachment is indicated for the R4groups of the below-structures, aspects of the present disclosure also contemplate compounds with alpha-attachment, unless otherwise indicated. - 72 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0148] In representative aspects of the disclosure, the phthalocyanine core precursor can be made using a phthalonitrile (or a naphthalene-2,3-dicarbonitrile) starting material comprising an R4group. The starting material is exposed to ammonia in the presence of methanol to form an R4-functionalized isoindoline-1,3-diimine (or an R4-functionalized 1H- benzo[f]isoindole-1,3(2H)-diimine) ring system, which can then be combined with one or - 73 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01more other isoindoline-1,3-diimine (or 1H-benzo[f]isoindole-1,3(2H)-diimine) ring systems, which can comprise R1a, R2a, R3a, R1b, R2b, and R3bgroups as described herein, in the presence of SiCl4 and quinoline to form an SiCl2-containing complex. In some aspects, the SiCl2-containing complex can be converted to the phthalocyanine core precursor comprising an amine-terminated alkoxy group (e.g., O-[CH)2]4NH2). In some other aspects, the SiCl2- containing complex can be converted to an Si(OH)2complex after treatment with sodium hydroxide or ammonia, which can then be converted to the phthalocyanine core precursor after treatment with an amine-terminated siloxy reagent (e.g., 3- (methoxydimethylsilyl)propan-1-amine, 3-(diethyl(methoxy)silyl)propan-1-amine, 3- (diisopropyl(methoxy)silyl)propan-1-amine, or 3-(methoxydiphenylsilyl)propan-1-amine). Representative examples of a method for making a phthalocyanine core precursor are shown below in Schemes 1-12.- 74 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 75 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 76 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 77 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 78 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 79 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 80 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 81 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 82 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 83 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0149] After the phthalocyanine core precursor is obtained, it can be converted to the desired compound by performing a click chemistry reaction (wherein the phthalocyanine core precursor comprises an R4group that comprises a clickable functional group), or a palladium-catalyzed carbon-carbon cross coupling reaction (wherein the phthalocyanine core precursor comprises an R4group that is a halogen, such as bromo). Representative methods for making the compounds are illustrated below in Schemes 13-32. Conditions suitable for performing a click chemistry reaction are recognizable to those in the art with the benefit of the present disclosure. In some aspects, the click chemistry reaction comprises a copper-catalyzed azide-alkyne cycloaddition, such as described in Schemes 13-24. Conditions suitable for performing a palladium-catalyzed carbon-carbon cross coupling reaction also are recognizable to those in the art with the benefit of the present disclosure. In some aspects, the palladium-catalyzed carbon-carbon cross coupling is a Heck reaction, such as described in Schemes 25 and 27-32. In yet other aspects, the palladium-catalyzed carbon-carbon cross coupling is a Sonogashira reaction, such as described in Scheme 26.- 84 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 85 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 86 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 87 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 88 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 89 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 90 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 91 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 92 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01^ ^ ^^ ^ ^ ^ ^ ^ ^ ^^^^^^^^ ^ ^^ ^ ^^^^ ^ ^^- 93 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01^ ^^ ^ ^^^^ ^ ^ ^ ^'"^^ ^ ^ ^^^ ^- 94 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 95 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 96 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0150] Also disclosed is a method of producing VLP-compound conjugates according to the present disclosure wherein the VLP is a viral-like nanoparticle. The method comprises transiently transfecting cells with a nucleic acid that encodes one or more capsid proteins, thereby forming proto-capsids; collecting the proto-capsids and subjecting the proto-capsids to a maturation process in vitro, thereby forming stable viral-like nanoparticles; and - 97 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01chemically conjugating the viral-like nanoparticles to one or more compounds according to the present disclosure.

[0151] Methods of using the compounds and VLP-compound conjugates according to aspects of the present disclosure also are described. The VLP-compound conjugates and / or compounds described herein can be used in in vivo, ex vivo, or in vitro methods. The present disclosure also provides methods of administering, to a subject having a tumor, a tumor-targeting VLP-compound conjugate. In some aspects, administration can comprise administering, to a subject having a tumor, a tumor-targeting VLP comprising about 50 to about 1000 (e.g., 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000) compounds according to formulas of the present disclosure. In some aspects, the subject is a mammal, such as a human.

[0152] The mode of administration can be by injection, infusion, implantation, topical administration, or by any other means typically used to deliver VLPs. In some aspects, hollow needles, coated needles, mini-needles or micro-needles are used, depending on the area of injection.

[0153] Examples of reagents that may be used to deliver VLP-compound conjugates of the present disclosure include, without limitation, water, physiological saline, balanced salt solutions (such as PBS / EDTA), aqueous dextrose, sesame oil, glycerol, ethanol, combinations thereof, or the like, as a vehicle. The carrier and composition can be sterile, and the formulation suits the mode of administration.

[0154] Photosensitive compounds of the VLP-compound conjugates of the disclosure can be activated at a suitable wavelength. In some aspects, activating the photosensitive compounds renders them cytotoxic or able to produce a cytotoxic molecule. Suitable wavelengths include, without limitation, ultraviolet wavelengths, visible wavelengths, infrared wavelengths and near infrared wavelengths. In some aspects, the photosensitive molecules are activated and become cytotoxic at a wavelength of 650 nm to 1100 nm. Suitable wavelengths for photosensitive molecule activation will depend on the particular compound used.

[0155] After administering the one or more VLP-compound conjugates or one or more compounds, the sample or the subject is irradiated. Irradiation can comprise irradiating the whole sample / subject or a targeted portion of the sample / subject. In particular aspects, irradiating comprises exposing a targeted portion of the sample or the subject to light. The targeted portion typically comprises the VLP-compound conjugate or the compound. In - 98 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01some aspects, the light used for irradiation is infrared, near-infrared, or ultraviolet light. In particular aspects, the light is near-infrared.

[0156] In some particular aspects, irradiation is carried out under conditions that permit killing of a target, for example irradiation at a wavelength of 650 nm to 1100 nm at a dose of at least 1 J cm-2. In one example, there is at least 10 minutes, at least 30 minutes, at least 1 hour, at least 4 hours, at least 8 hours, at least 12 hours, or at least 24 hours (such as 1 to 4 hours, 30 minutes to 1 hour, 10 minutes to 60 minutes, or 30 minutes to 8 hours) in between contacting the cell with the VLP-compound conjugate (or the compound) and the irradiation. The NIR excitation light wavelength allows penetration of at least several centimeters into tissues. For example, by using fiber-coupled laser diodes with diffuser tips, NIR light can be delivered within several centimeters of otherwise inaccessible tumors located deep to the body surface. In addition to treating solid cancers, circulating tumor cells can be targeted since they can be excited when they traverse superficial vessels (for example using NIR LED wearable devices known to those in the art with the benefit of the present disclosure).

[0157] In some aspects, the method can also include contacting the target or target cell with one or more additional therapeutic agents. In some aspects, there is a time-period following irradiation during which uptake of additional therapeutic agents can be enhanced. In some aspects of the disclosure, the time-period is approximately 8 hours after irradiation at a wavelength of 650 nm to 1100 nm at a dose of at least 10 J cm-2, at least 20 J cm-2, at least 30 J cm-2, at least 40 J cm-2, at least 50 J cm-2, at least 70 J cm-2, at least 80 J cm-2or at least 100 J cm-2, such as at least 10 to 100 J cm-2. Thus, one or more additional therapeutic agents can be contacted with the cell contemporaneously or sequentially with the PIT. In one example, the additional therapeutic agents are administered after the irradiation, for example, about 0 to 8 hours after irradiating the cell (such as at least 10 minutes, at least 30 minutes, at least 60 minutes, at least 2 hours, at least 3 hours, at least 4, hours, at least 5 hours, at least 6 hours, or at least 7 hours after the irradiation, for example no more than 10 hours, no more than 9 hours, or no more than 8 hours, such as 1 hour to 10 hours, 1 hour to 9 hours 1 hour to 8 hours, 2 hours to 8 hours, or 4 hours to 8 hours after irradiation). In another example, the additional therapeutic agents are administered just before the irradiation (such as about 10 minutes to 120 minutes before irradiation, such as 10 minutes to 60 minutes or 10 minutes to 30 minutes before irradiation).

[0158] In some examples, combining the method according to the present disclosure with an additional therapy, enhances the effectiveness of the treatment of the tumor. For example, combining the disclosed method according to the present disclosure with the additional therapy can result in a tumor volume that is less than the tumor volume would be if - 99 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01it were treated with either the VLP-compound conjugate / PIT method according to the present disclosure alone or the additional therapy alone, that is, there is a synergistic effect. In one example, the volume of a tumor treated with the combination therapy is at least 2-fold, at least 3-fold, at least 4-fold, or even at least 5-fold smaller than the volume of a tumor treated with either the disclosed method alone or the additional therapy alone (for example after at least 7 days, at least 10 days, at least 14 days, at least 30 days, at least 60 days, at least 90 days, or at least 120 days after the treatment). In one example, the volume of a tumor treated with the combination therapy is at least 5-fold, at least 6-fold, at least 7-fold, or even at least 10-fold smaller than the volume of a control untreated tumor (for example after at least 7 days, at least 10 days, at least 14 days, at least 30 days, at least 60 days, at least 90 days, or at least 120 days after the treatment). In another or additional example, combining the disclosed method with the additional therapy (such as anti-neoplastic agents) can increase the survival time of a subject having a tumor relative to the survival time of the subject if the tumor was treated with either the disclosed method alone or the additional therapy alone, that is, there is a synergistic effect. In one example, the survival time of a subject having a tumor treated with the combination therapy is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, or at least 10-fold longer than survival time of a subject having a tumor treated with either the disclosed method alone or the additional therapy alone (for example after a specified period of time, such as at least 14 days, at least 30 days, at least 60 days, at least 90 days, at least 120 days, at least 6 months, at least 12 months, at least 24 months, or at least 5 years after the treatment, more subjects treated with the combination therapy will be alive than if treated with either therapy alone). In one example, the survival time of a subject having a tumor treated with the combination therapy is at least 5-fold, at least 10-fold, at least 15-fold, or even at least 20- fold greater than the survival time of a subject having an untreated tumor (for example after at least 7 days, at least 10 days, at least 14 days, at least 30 days, at least 60 days, at least 90 days, at least 120 days after the treatment at least 6 months, at least 12 months, at least 24 months, or at least 5 years after the treatment, more subjects treated with the combination therapy will be alive than if untreated).

[0159] Exemplary additional therapeutic agents include anti-neoplastic agents, such as chemotherapeutic and anti-angiogenic agents or therapies, such as radiation therapy. In one example the agent is a chemotherapy immunosuppressant (such as Rituximab, steroids) or a cytokine (such as GM-CSF). Chemotherapeutic agents are known in the art (see for example, Slapak and Kufe, Principles of Cancer Therapy, Chapter 86 in Harrison's Principles of Internal Medicine, 14th edition; Perry et al., Chemotherapy, Ch.17 in Abeloff, Clinical Oncology 2nd ed., 2000 Churchill Livingstone, Inc; Baltzer and Berkery. (eds): - 100 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01Oncology Pocket Guide to Chemotherapy, 2nd ed. St. Louis, Mosby-Year Book, 1995; Fischer Knobf, and Durivage (eds): The Cancer Chemotherapy Handbook, 4th ed. St. Louis, Mosby-Year Book, 1993). Exemplary chemotherapeutic agents that can be used with the methods provided herein include but are not limited to, carboplatin, cisplatin, paclitaxel, docetaxel, doxorubicin, epirubicin, topotecan, irinotecan, gemcitabine, iazofurine, gemcitabine, etoposide, vinorelbine, tamoxifen, valspodar, cyclophosphamide, methotrexate, fluorouracil, mitoxantrone, Doxil (liposome encapsulated doxiorubicine) and vinorelbine. In some examples, the additional therapeutic agent is conjugated to (or otherwise associated with) a nanoparticle, such as one at least 1 nm in diameter (for example at least 10 nm in diameter, at least 30 nm in diameter, at least 100 nm in diameter, at least 200 nm in diameter, at least 300 nm in diameter, at least 500 nm in diameter, or at least 750 nm in diameter, such as 1 nm to 500 nm, 1 nm to 300 nm, 1 nm to 100 nm, 10 nm to 500 nm, or 10 nm to 300 nm in diameter). Other therapeutic agents that can be used in combination with VLP-compound conjugates and / or compounds according to the present disclosure are as described in U.S. Pat. Pub. No.2024 / 0101685, the relevant portion of which is incorporated herein by reference. In yet some additional aspects, the VLP-compound conjugates can be used in conjunction with immune checkpoint inhibitors (or “ICIs”, such as PD1, CTL4m mAbs, and the like). In such aspects, the ICIs can exhibit synergy with antitumor immune responses generated by the VLP-compound conjugates.

[0160] The methods can be used to kill cells in vitro, for example by incubating cells of a sample with the VLP-compound conjugate or compound according to the present disclosure and, optionally, one or more therapeutic agents in culture, or in vivo, for example, by administering one or more VLP-compound conjugates or compounds and, optionally, one or more therapeutic agents to the subject. For example, a subject to be treated can be administered a therapeutically effective amount of one or more VLP-compound conjugates or compounds, followed by irradiating the subject (or a tumor or tumor cell in the subject) with a therapeutic dose of irradiation and administration of one or more additional therapeutic agents (such as within about 8 hours of the irradiation).

[0161] In one example, contacting target cells with one or more VLP-compound conjugates according to the present disclosure followed by irradiation and administration of an additional therapeutic agent kills the target cells that express a cell surface protein that specifically binds to the VLP of the VLP-compound conjugate. For example, the disclosed methods can kill at least 10%, for example at least 20%, at least 40%, at least 50%, at least 80%, at least 90%, or more of the treated cells relative to the absence of treatment with one or more VLP- - 101 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01compound conjugates followed by irradiation and optional administration of one or more therapeutic agents.

[0162] In one example, administration of one or more VLP-compound conjugates according to the present disclosure to a subject having a tumor, in combination with irradiation and optional administration of one or more therapeutic agents, kills cells thereby treating the tumor. For example, the disclosed methods can decrease the size or volume of a tumor, slow the growth of a tumor, decrease or slow metastasis of the tumor (for example by reducing the number of metastases or decreasing the volume or size of a metastasis), or combinations thereof. For example, the disclosed methods can reduce tumor cell size or volume and / or a metastatic tumor cell volume (or number of metastatic tumors), such as by at least 10%, for example by at least 20%, at least 40%, at least 50%, at least 80%, at least 90%, or more, relative to the absence of administration of one or more VLP-compound conjugates followed by irradiation. In addition, the disclosed methods can result in a decrease in the symptoms associated with a tumor and / or a metastatic tumor. In one example, administration of the disclosed VLP-compound conjugates slows the growth of a tumor, such as by at least 10%, for example by at least 20%, at least 40%, at least 50%, at least 80%, at least 90%, or more, relative to the absence of administration of the VLP- compound conjugate followed by irradiation. Methods of monitoring tumor volume / size / metastasis are routine in the art. In some examples, the disclosed methods can increase a subject’s (such as a subject with a tumor or who has had a tumor previously removed) survival time, for example relative the absence of administration of one or more VLP-compound conjugates, irradiation, and administration of one or more therapeutic agents, such as an increase of at least 20%, at least 40%, at least 50%, at least 80%, at least 90%, or more. For example, the disclosed methods can increase a subject’s survival time by at least 3 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months or more, relative to average survival time in the absence of administration of a VLP-compound conjugate, irradiation, and administration of one or more therapeutic agents.

[0163] Administration of therapeutically effective amounts of VLP-compound conjugates according to the present disclosure, followed by therapeutically effective doses of irradiation and optional administration of one or more therapeutic agents are capable of selectively killing tumor cells in vivo, and are capable of decreasing the weight or volume of a tumor in vivo. By selective killing of tumor cells relative to normal cells is meant that the methods are capable of killing tumor cells more effectively than normal cells. - 102 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0164] The disclosed methods can be used to treat fixed tumors in the body as well as tumors in the circulation (e.g., leukemia cells, metastases, circulating tumor cells); however, circulating cells, by their nature, cannot be exposed to light for very long. Thus, if the cell to be killed is one that is circulating throughout the body, the methods can be accomplished by using a device that can be worn, or that covers parts of the body. Such devices are known to those in the art with the benefit of the present disclosure.

[0165] In some examples, the method further includes monitoring the therapy, such as killing of tumor cells. In such examples, the VLP-compound conjugate is contacted with the cells and the cells irradiated as described above. However, a lower dose of the VLP- compound conjugate and NIR light can be used (as cell killing may not be required, just monitoring of the therapy). In one example, the amount of VLP-compound conjugate administered for monitoring is at least 2-fold less (such as at least 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-fold less than the therapeutic dose). In one example, the amount of the VLP-compound conjugate administered for monitoring is at least 20% or at least 25% less than the therapeutic dose. In one example, the amount of NIR light used for monitoring is at least 1 / 1000 or at least 1 / 10,000 of the therapeutic dose. This permits detection of the cells being treated. For example, by using such methods, the size of the tumor and metastases can be monitored.

[0166] In some examples, the method is useful during surgery, such as endoscopic procedures. For example, after the VLP-compound conjugate is contacted with the cells and the cells irradiated as described above, this not only results in cell killing, but permits a surgeon or other medical care provider to visualize the margins of a tumor, and help ensure that resection of the tumor (such as a tumor of the skin, breast, lung, colon, or prostate) is complete and that the margins are clear. In some examples, a lower dose of the VLP- compound conjugate can be used for visualization, such as at least 2-fold less (such as at least 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-fold less than the therapeutic dose).

[0167] In some aspects of the present disclosure, the target cell can be a cell that is not desired or whose growth is not desired, such as a tumor cell. The cells can be growing in culture, or present in a mammal to be treated, such as a patient with cancer. Any target cell can be treated with aspects of the method according to the present disclosure.

[0168] In one example, the tumor cell is a cancer cell, such as a cell in a patient with cancer. Exemplary cells that can be killed with the disclosed methods include cells of the following tumors: a liquid tumor such as a leukemia, including acute leukemia (such as acute lymphocytic leukemia, acute myelocytic leukemia, and myeloblastic, promyelocytic, - 103 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01myelomonocytic, monocytic and erythroleukemia), chronic leukemias (such as chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia), polycythemia vera, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, Waldenstrdm's macroglobulinemia, heavy chain disease). In another example the cell is a solid tumor cell, such as sarcomas and carcinomas, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, and other sarcomas, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, hepatocellular carcinomna, lung cancer, colorectal cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma (for example adenocarcinoma of the pancreas, colon, ovary, lung, breast, stomach, prostate, cervix, or esophagus), sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, Wilms' tumor, cervical cancer, testicular tumor, bladder carcinoma, CNS tumors (such as a glioma, astrocytoma, medulloblastoma, craniopharyogioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma and retinoblastoma).

[0169] In some aspects of the present disclosure, the disclosed methods are used to treat a subject who has a tumor, such as a tumor described herein. In some examples, the tumor has been previously treated, such as surgically or chemically removed, and the disclosed methods are used subsequently to kill any remaining undesired tumor cells that may remain in the patient.

[0170] The disclosed methods can be used to treat any mammalian subject, such as a human, who has a tumor, such as a cancer, or has had such previously removed or treated. Subjects in need of the disclosed therapies can include human subjects having cancer, wherein the cancer cells comprise heparan sulfate proteoglycans (HSPGs) on their surface. The VLPs of the VLP-compound conjugates of the present disclosure comprise a high number of heparin binding sites on the capsid proteins (e.g., L1). For example, the disclosed methods can be used as initial treatment for cancer either alone, or in combination with radiation or other chemotherapy. The disclosed methods can also be used in patients who have failed previous radiation or chemotherapy. Thus, in some examples, the subject is one who has received other therapies, but those other therapies have not provided a desired therapeutic response. The disclosed methods can also be used in patients with localized and / or metastatic cancer. - 104 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0171] In some examples the method includes selecting a subject that will benefit from the disclosed therapies, such as selecting a subject having a tumor that expresses proteins (such as a tumor-specific protein) that can specifically bind to a VLP-compound conjugate according to the present disclosure.

[0172] Overview of Several Aspects

[0173] Disclosed herein is a conjugate comprising: a virus-like particle compound; and a compound having a structure according to Formula I or Formula II as described herein, wherein: X is a biomolecule-binding moiety or a precursor thereto; the Linker has a structure according to a formula {Core}-(CR2)n-Y-(Z)m-(CR2)p[O(CR2)t]q-{X}, wherein {Core} represents attachment to the phthalocyanine core and {X} represents attachment to X; each R, independently for each occurrence, is selected from hydrogen, halogen, aliphatic, heteroaliphatic, or aromatic; Y is selected from (i) a functional group produced from a reaction between two clickable functional groups; (ii) -CH=CH-[Q1]s-, wherein s is 1 or 0 and Q1is selected from aromatic or -C(=O)Y’- or -S(=O)2Y’,, wherein Y’ is NR” or O, wherein R”is H, -CN, CF3, or a sulfonyl group; or (iii) -C C-Q2, wherein Q2 is –(CH2)uC(=O)Y’-, whereinu is an integer selected from 1 to 10, Y’ is NR” or O, wherein R” is H, -CN, CF3, or a sulfonyl group; Z is a heteroatom; m is 1 or 0; each of n, p, and t independently is selected from an integer ranging from 0 to 50; and q is an integer selected from 0 to 50; G, if present, is selected from halogen (such as chloro, bromo, fluoro, or iodo) or Linker-X (wherein the linker group and the X group are selected from definitions provided herein); each of R1a, R2a, R3a, R1b, R2b, and R3bindependently is selected from hydrogen, aliphatic, halogen, heteroaliphatic, aromatic, thiol, hydroxyl, or amine; or (i) R1aand R1bjoin together, with the carbon atoms to which they are attached, to form a 6-membered aromatic ring, (ii) R2aand R2bjoin together, with the carbon atoms to which they are attached, to form a six-membered aromatic ring, (iii) R3aand R3bjoin together, with the carbon atoms to which they are attached, to form a six-membered aromatic ring, or (iv) any combination of two or more of (i)- (iii); and L is selected from -(CH2)r-, -Si(R5)2(CH2)r-, -C(=O)(CH2)r-, or -Ph(CH2)r-, wherein each R5independently is aliphatic or aryl, r is an integer selected from 1 to 5 and wherein any CH2group of the L group is attached to the quaternary amine of Formula I or Formula II.

[0174] In any or all of the above aspects, the compound has a structure according to Formula IA or Formula IB as disclosed herein.

[0175] In any or all aspects, the compound has a structure according to any one of Formulas IA(i) - Formula IA(iv) as described herein, wherein ring A is a ring system selected - 105 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01from a phenyl ring, a pyridyl ring, a triazole, a cycloocta[d]pyridazine, a cycloocta[d]triazole, or a triazole-functionalized DBCO.

[0176] In any or all aspects, the compound has a structure according to one of Formulas IA(i)(a), IA(i)(b), IA(i)(c), IA(i)(d), A(i)(e), IA(i)(f), IA(i)(g), IA(i)(h), or IA(i)(i) as described herein.

[0177] In any or all of the above aspects, the compound has a structure according to Formula IB(i) or Formula IB(ii) as disclosed herein wherein ring A is a ring system selected from a phenyl ring, a triazole, a cycloocta[d]pyridazine, a cycloocta[d]triazole, or a triazole- functionalized DBCO.

[0178] In any or all of the above aspects, wherein the compound has a structure according to one of Formulas IB(i)(a), IB(i)(b), IB(i)(c), or IB(i)(d) as disclosed herein.

[0179] In any or all aspects, G is present and is selected from chloro, bromo, fluoro, iodo, or Linker-X, wherein the linker and X groups of Linker-X are as defined herein.

[0180] In any or all aspects, G is positioned ortho to the Linker-X group of Formula I.

[0181] In any or all aspects, L is -(CH2)4, -Si(Me)2(CH2)3-, -Si(Et)2(CH2)3-, -Si(iPr)2(CH2)3-, or -Si(Ph)2(CH2)3-.

[0182] In any or all of the above aspects, the compound has a structure according Formula IIA or Formula IIB as disclosed herein wherein ring A is a ring system selected from a phenyl ring, a triazole, a cycloocta[d]pyridazine, a cycloocta[d]triazole, or a triazole-functionalized DBCO.

[0183] In any or all aspects, the compound has a structure according to one of Formulas IIA(i), IIA(ii), IIB(i), IIB(ii), IIC(i), IIC(ii), IIC(iii), or IIC(iv) as described herein.

[0184] In any or all of the above aspects, X is comprises a carbonyl group.

[0185] In any or all of the above aspects, the carbonyl group is provided by an activated ester that facilitates binding with the VLP.

[0186] In any or all of the above aspects, Y comprises a ring formed between (i) an alkyne and an azide; (ii) a tetrazine and a trans-cyclooctene; (iii) an azide and a dibenzocyclooctyne (DBCO); or (iv) an azide and a bicyclo[6.1.0]nonyne. - 106 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0187] In any or all of the above aspects, Y comprises a ring formed between an alkyne and an azide.

[0188] In any or all of the above aspects, the ring formed between the alkyne and the azide is a triazole.

[0189] In any or all of the above aspects, m is zero and the Linker has a structure according to a formula {Core}-(CR2)n-Y-(CR2)p-{X} or {Core}-(CR2)n-Y-(CR2)p[O(CR2)t]q-{X}, wherein each R is H, n is an integer selected from 0, 1, 2, or 3, p is an integer selected from zero to 21, t is 2, q is an integer selected from 1 to 6, and Y is a 1,2,3-triazole.

[0190] In any or all aspects, m is 1 and the Linker has a structure according to a formula {Core}-(CR2)n-Y-(Z)m-(CR2)p-{X}, wherein each R is H, n is an integer selected from 0, 1, 2, or 3, p is an integer selected from zero to 21, Y is -CH=CH-Ph- or -CH=CH-Pyridyl-, and m is 0.

[0191] In any or all aspects, m is 1 and the Linker has a structure according to a formula {Core}-(CR2)n-Y-(Z)m-(CR2)p-{X}, wherein each R is H, n is an integer selected from 0, 1, 2, or 3, p is an integer selected from zero to 21, Y is -CH=CH-Ph- or -CH=CH-Pyridyl-, Z is O, and m is 1.

[0192] In any or all aspects, m is zero and the Linker has a structure according to a formula {Core}-(CR2)n-Y-(CR2)p-{X}, wherein each R is H, n is an integer selected from 0, 1, 2, or 3, p is an integer selected from zero to 21, and wherein Y is -CH=CH-C(=O)Y’ or -CH=CH- S(=O)2Y’, wherein Y’ is O or -NH, -N(CN), -NCF3, -NSO2Me, -NSO2CF3, -NSO2NH2, or - NSO2NMe2.

[0193] In any or all aspects, m is zero and the Linker has a structure according to a formula {Core}-(CR2)n-Y-(CR2)p-{X}, wherein each R is H, n is an integer selected from 0, 1, 2, or 3, pis an integer selected from zero to 21, and wherein Y is -C C(CH2)2C(=O)NH-(CH2)t-,wherein t is an integer selected from 1 to 10.

[0194] In any or all of the above aspects, each of n and m is zero and the Linker has a structure according to -CH=CH-(CR2)p-, -CH=CH-C(O)O-(CR2)p, or -CH=CH-C(O)NR”- (CR2)p-.

[0195] In any or all of the above aspects, the compound is a compound according to any exemplary compounds disclosed herein.

[0196] In any or all of the above aspects, the VLP is a tumor-targeting papilloma VLP. - 107 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0197] In any or all of the above aspects, the VLP comprises papillomavirus capsid proteins.

[0198] In any or all of the above aspects, the papillomavirus capsid proteins are non-human mammalian papillomavirus capsid proteins, selected from bovine, murine, canine, leporine, or macaque or rhesus papillomavirus capsid proteins.

[0199] In any or all of the above aspects, the VLP comprises human papillomavirus (HPV) L1 capsid proteins.

[0200] In any or all of the above aspects, the HPV L1 capsid proteins comprise modified HPV L1 capsid proteins, relative to wild-type HPV L1 capsid proteins, and wherein the modified HPV L1 capsid proteins do not cross-react with neutralizing antibodies to HPV 16 or HPV 18.

[0201] In any or all of the above aspects, the modified HPV L1 capsid proteins comprise a combination of modified HPV L1 capsid proteins and wild-type HPV L2 capsid proteins.

[0202] In any or all of the above aspects, the tumor-targeting papillomavirus-like particle has reduced immunogenicity and / or antigenicity relative to a virus-like particle comprising wild-type HPV L1 capsid proteins.

[0203] In any or all of the above aspects, the compound is covalently conjugated to papillomavirus capsid proteins of the VLP.

[0204] In any or all of the above aspects, the compound is conjugated to a lysine residue of papillomavirus capsid proteins of the VLP.

[0205] In any or all of the above aspects, a plurality of compounds having a structure according to Formula I or Formula II are conjugated to the VLP.

[0206] In any or all of the above aspects, the compound does not compromise binding of the VLP to a surface of a tumor cell, or wherein the compound does not compromise binding of the VLP to heparan sulfate proteoglycans on a surface of a tumor cell.

[0207] Also disclosed is a method for treating a subject or sample using NIR-PIT, comprising: administering a conjugate according to any or all of the above aspects, or a pharmaceutically acceptable composition thereof, to the subject or the sample; and irradiating the conjugate by application of light to a targeted portion of the subject or the sample. - 108 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0208] In any or all of the above aspects, the light is applied (i) in a quantity sufficient to produce fluorescence of the conjugate, (ii) in a quantity sufficient to induce killing of a target or a target cell present in the subject or the sample, or a combination of (i) and (ii).

[0209] In any or all of the above aspects, the light is light of a wavelength ranging from 650 nm to 1100 nm.

[0210] In any or all of the above aspects, the light is applied at a dose of at least 1 J / cm2.

[0211] In any or all of the above aspects, administering is carried out using intravenous administration.

[0212] Examples Example 1

[0213] In this example, factors affecting the reaction for forming compounds of the present disclosure were evaluated by synthesizing silicon phthalocyanine dyes with various functional groups in various substitution positions (e.g., mono- / di-functional groups, such as methyl groups, methoxy groups and halogens, at 6 / ^ positions). To identify an effective design and efficient synthetic processes of A3B-type asymmetric phthalocyanine dyes with the linker, silicon phthalocyanine dyes with sulfonate groups as axial ligands were synthesized as model compounds because these dyes can be purified with reverse-phase HPLC and are soluble in polar organic solvents, such as methanol. Therefore, these dyes can be characterized by NMR and MS (Schemes 33 and 34). Further, the quantitative analysis by peak area of HPLC can be performed. - 109 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 110 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0214] General procedure for making Compounds 12–14: A dibromobenzene derivative (1 eq) and CuCN (5 eq) were dissolved in dimethylformamide (15 mL) and the mixture was - 111 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01stirred at 160 °C under an Ar atmosphere for 2.5-3 hours. After cooling, CH2Cl2was added to the reaction mixture and the precipitate was filtered. After the filtrate was evaporated, CH2Cl2 was added to the residue and the suspension was filtered. The filtrate was washed with H2O, dried over Na2SO4, filtered and evaporated. The crude product was purified with silica gel column chromatography to afford the pure product.

[0215] Compound 12: Yield, 70%.1H NMR (400 MHz, CDCl3): 72.63 (s, 3H), 7.57–7.66 (m, 3H). HRMS (ESI+) m / z: calcd for C9H6N2Na: 165.0423 [M+Na]+; found: 165.0415.

[0216] Compound 13: Yield, 39%.1H NMR (400 MHz, CDCl3): 73.92 (s, 3H), 7.19 (dd, J = 2.6, 8.7 Hz, 1H), 7.27 (d, J = 2.6 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H). HRMS (ESI+) m / z: calcd for C9H6N2NaO: 181.0372 [M+Na]+; found: 181.0367.

[0217] Compound 14: Yield, 67%.1H NMR (400 MHz, CDCl3): 72.38 (s, 6H), 7.56 (s, 2H). HRMS (ESI+) m / z: calcd for C10H8N2Na: 179.0580 [M+Na]+; found: 179.0575.

[0218] Procedure for making Compound 15: 2.0 mol / L NH3in MeOH (30 mL, 60 mmol) was added to compound 1 (1.01 g, 6.92 mmol) and the mixture was stirred at 60 °C under an Ar atmosphere for 3 hours. After cooling, H2O was added to the reaction mixture. After MeOH was evaporated, the precipitate was collected, washed with H2O and dried. The filtrate was extracted with AcOEt and the organic layer was dried over Na2SO4, filtered and evaporated. The crude product combined with the precipitate and the extract was purified with silica gel column chromatography to afford the pure product (0.243 g, 1.49 mmol, y.22%).1H NMR (400 MHz, CD3OD): 77.35 (ddd, J = 0.9, 7.8, 9.5 Hz, 1H), 7.65 (dt, J = 4.5, 7.8 Hz, 1H), 7.70 (td, J = 0.9, 7.8 Hz, 1H). HRMS (ESI+) m / z: calcd for C8H7FN3: 164.0619 [M+H]+; found: 164.0590.

[0219] General procedure for making Compounds 16–25: 2.0 mol / L NH3 in MeOH (10–100 mL) was added to the starting material (1 eq) and NaOMe (1 eq), and the mixture was stirred at 60 °C under an Ar atmosphere for 1.5–6 hours. The solvent was evaporated, and the crude product was washed with H2O or purified with silica gel column chromatography to afford the pure product.

[0220] Compound 16: Yield, 97%.1H NMR (400 MHz, CD3OD): 77.62 (dd, J = 0.6, 4.1 Hz, 2H), 7.84 (t, J = 4.1 Hz, 1H). HRMS (ESI+) m / z: calcd for C8H7ClN3: 180.0323 [M+H]+; found: 180.0330. - 112 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0221] Compound 17: Yield, 74%.1H NMR (400 MHz, CD3OD): 72.66 (s, 3H), 7.39 (d, J = 7.5 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H). HRMS (ESI+) m / z: calcd for C9H10N3: 160.0869 [M+H]+; found: 160.0877.

[0222] Compound 18: Synthesized from compound 3. Yield, 42%.1H NMR (400 MHz, CD3OD): 74.03 (s, 3H), 7.49 (dd, J = 0.7, 7.7 Hz, 1H), 7.54 (dd, J = 0.7, 8.8 Hz, 1H), 7.79 (dd, J = 7.7, 8.8 Hz, 1H). HRMS (ESI+) m / z: calcd for C9H10N3O: 176.0818 [M+H]+; found: 176.0811.

[0223] Compound 19: Yield, 55%.1H NMR (400 MHz, CD3OD): 77.65 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1), 7.91 (s, 1H). HRMS (ESI+) m / z: calcd for C8H7ClN3: 180.0323 [M+H]+; found: 180.0326.

[0224] Compound 20: Yield, 95%.1H NMR (400 MHz, CD3OD): 77.76 (dd, J = 0.6, 8.0 Hz, 1H), 7.80 (dd, J = 1.6, 8.0 Hz, 1H), 8.05 (dd, J = 0.6, 1.6 Hz, 1H). HRMS (ESI+) m / z: calcd for C8H7BrN3: 223.9818 [M+H]+; found: 223.9830.

[0225] Compound 21: Yield, 99%.1H NMR (400 MHz, CD3OD): 72.48 (s, 3H), 7.43 (qd, J = 0.7, 7.7 Hz, 1H), 7.62 (t, J = 0.7 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H). HRMS (ESI+) m / z: calcd for C9H10N3: 160.0869 [M+H]+; found: 160.0876.

[0226] Compound 22: Yield, 94%.1H NMR (400 MHz, CD3OD): 73.92 (s, 3H), 7.14 (dd, J = 2.1, 8.4 Hz, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H). HRMS (ESI+) m / z: calcd for C9H10N3O: 176.0818 [M+H]+; found: 176.0824.

[0227] Compound 23: Yield, 95%.1H NMR (400 MHz, CD3OD): 78.03 (s, 2H). HRMS (ESI+) m / z: calcd for C8H6Cl2N3: 213.9933 [M+H]+; found: 213.9899.

[0228] Compound 24: Yield, 63%.1H NMR (400 MHz, CD3OD): 72.40 (s, 6H), 7.62 (s, 2H). HRMS (ESI+) m / z: calcd for C10H12N3: 174.1026 [M+H]+; found: 174.1010.

[0229] Compound 25: Yield, 97%.1H NMR (400 MHz, CD3OD): 73.94 (s, 6H), 7.50 (s, 2H). HRMS (ESI+) m / z: calcd for C10H12N3O2: 206.0924 [M+H]+; found: 206.0903.

[0230] General procedure for making Compounds 26–36, 42, and 91: A mono / di- substituted 1,3-diiminoisoindoline compound (1 mmol, 1 eq), 1,3-diiminoisoindoline (3 mmol, 3 eq) and SiCl4(2 or 6 mmol, 2 or 6 eq) were dissolved in quinoline (3 mL) and the mixture was stirred at 210 °C under an Ar atmosphere for 2 hours. After cooling, 1 mol / L NaOHaq (3 mL) was added to the mixture and the reaction solution was stirred at 120 °C for 1 hour. The - 113 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01precipitate was collected, washed with MeOH and dried. The crude product was used for the next step without further purification.

[0231] Procedure for making Compound 39: Compound 37 (2.01 g, 17.9 mmol) and fumaronitrile (2.81 g, 35.9 mmol) were dissolved in CH2Cl2 (20 mL) and boron trifluoride diethyl ether complex (3.81 g, 26.9 mmol) was slowly dropped to the mixture. After the reaction solution was heated at 70 °C under an Ar atmosphere, m-chloroperoxybenzoic acid (30% H2O, 8.91 g, 36.1 mmol) in CH2Cl2 (50 mL) was slowly added to the reaction solution over 40 minutes. Then, the solution was stirred at 70 °C for 1 hour. Saturated NaHCO3aq was added to the solution, following additional stirring for 10 minutes. The organic layer was separated, washed with H2O, dried over Na2SO4, filtered and evaporated. The residue and o-toluic acid (27 mg, 0.20 mmol) were dissolved in 1,2-dichloroethane (12 mL) and the mixture was irradiated with microwave (repeated 45 times in the following cycle: 140 °C, 60 s, 400 W / 100 °C, 10 s, 0 W). After that, the solvent was evaporated and the crude product was purified with silica gel column chromatography to afford the pure product (0.588 g, 3.76 mmol, y.21%).1H NMR (400 MHz, CDCl3): 72.57 (s, 6H), 7.45 (s, 2H). HRMS (ESI+) m / z: calcd for C10H8N2Na: 179.0580 [M+Na]+; found: 179.0574.

[0232] Procedure for making Compound 40: 2.0 mol / L NH3in MeOH (30 mL, 60 mmol) was added to compound 39 (0.474 g, 3.03 mol) and NaOMe (0.169 g, 3.12 mmol), and the mixture was stirred at 60 °C under an Ar atmosphere for 30 hours. The solvent was evaporated and the crude product was purified with silica gel column chromatography to afford the pure product (0.290 g, 1.67 mmol, y.55%).1H NMR (400 MHz, CD3OD): 72.62 (s, 6H), 7.28 (s, 2H). HRMS (ESI+) m / z: calcd for C10H12N3: 174.1026 [M+H]+; found: 174.0998.

[0233] General procedure making ^ / ^-X-SiPc-NH2compounds: A crude silicon phthalocyanine dihydroxide derivative (0.15 mmol, 1 eq) and (3- aminopropyl)dimethylethoxysilane (1.5 mmol, 10 eq) were dissolved in pyridine (100 mL) and the mixture was stirred at 150 °C under an Ar atmosphere for 5 hours. After cooling, the solvent was evaporated and the residue was azeotropic dried with toluene. The crude product was suspended with H2O / EtOH = 2:1 solution or H2O / MeOH = 10:1 solution, washed and dried. The mixture of A4-type and A3B-type silicon phthalocyanines was used for the next step without further purification, if the generation of A3B-type silicon phthalocyanine was confirmed by NMR.

[0234] General procedure for making ^ / ^-X-SiPc compounds: A mixture of A4-type and A3B-type silicon phthalocyanines (70–100 mg, 1 eq), 1,3-propanesultone (50 eq) and iPr2EtN (65 eq) were dissolved in MeOH (5 mL) and the mixture was stirred at 50 °C under an Ar - 114 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01atmosphere for 27–31 hours. The reaction solution was concentrated and the residue was purified with reverse-phase HPLC (eluent A: 0.1 M triethylamine acetate solution, eluent B: CH3CN). The product was desalted with a Sep-Pak C18 cartridge and cation-exchange resin, affording 6 / ^-X-SiPc as a sodium salt. Repurification was performed as needed. In HPLC purification, the intermediate with the five axial ligands was also collected and subjected to the same reaction again to afford additional 6 / ^-X-SiPc. HPLC analysis of the reaction solution was performed 26.5 hours after the start of the reaction, and the production ratio of A4-type and A3B-type phthalocyanines was calculated from the peak area ratio at the wavelength of peak top of each compound.

[0235] ^-Cl-SiPc: Yield, 4.0% (4 steps).1H NMR (400 MHz, CD3OD): 7 −2.78 (s, 12H), −2.18 (t, J = 8.4 Hz, 4H), −0.85–−0.77 (m, 4H), 1.66–1.74 (m, 12H), 2.03 (t, J = 8.0 Hz, 4H), 2.71 (t, J = 6.8 Hz, 12H), 2.77–2.82 (m, 12H), 8.44 (t, J = 7.5 Hz, 1H), 8.48–8.55 (m, 7H), 9.69–9.71 (m, 1H), 9.77–9.82 (m, 6H). HRMS (ESI−) m / z: calcd for C60H75ClN10Na2O20S6Si3: 806.1143 [M−2Na]2−; found: 806.1101.

[0236] ^-Me-SiPc: Yield, 8.4% (4 steps).1H NMR (400 MHz, CD3OD): 7 −2.79 (s, 12H), −2.16 (t, J = 8.4 Hz, 4H), −0.93–−0.84 (m, 4H), 1.66–1.74 (m, 12H), 2.01 (t, J = 8.3 Hz, 4H), 2.71–2.79 (m, 24H), 4.08 (s, 3H), 8.30 (d, J = 7.4 Hz, 1H), 8.40 (t, J = 7.4 Hz, 1H), 8.49–8.54 (m, 6H), 9.65–9.70 (m, 2H), 9.77–9.80 (m, 5H). HRMS (ESI−) m / z: calcd for C61H78N10Na2O20S6Si3: 796.1416 [M−2Na]2−; found: 796.1370.

[0237] ^-Cl-SiPc: Yield, 7.4% (4 steps).1H NMR (400 MHz, CD3OD): 7 −2.78 (s, 12H), −2.19 (t, J = 8.4 Hz, 4H), −0.86–−0.77 (m, 4H), 1.67–1.74 (m, 12H), 2.02 (t, J = 8.2 Hz, 4H), 2.73 (t, J = 6.8 Hz, 12 H), 2.77–2.81 (m, 12H), 8.46 (dd, J = 1.8, 8.2 Hz, 1H), 8.51–8.54 (m, 6H), 9.72 (dd, J = 0.5, 1.8 Hz, 1H), 9.73–9.80 (m, 7H). HRMS (ESI−) m / z: calcd for C60H75ClN10Na2O20S6Si3: 806.1143 [M−2Na]2−; found: 806.1095.

[0238] ^-Br-SiPc: Yield, 0.3% (4 steps).1H NMR (400 MHz, CD3OD): 7 −2.78 (s, 12H), −2.19 (t, J = 8.7 Hz, 4H), −0.85–−0.77 (m, 4H), 1.67–1.74 (m, 12H), 2.02 (t, J = 8.2 Hz, 4H), 2.73 (t, J = 6.8 Hz, 12 H), 2.77–2.81 (m, 12H), 8.51–8.55 (m, 6H), 8.61 (dd, J = 1.7, 8.2 Hz, 1H), 9.68 (dd, J = 0.4, 8.2 Hz, 1H), 9.76–9.80 (m, 6H), 9.88 (dd, J = 0.4, 1.7 Hz, 1H). HRMS (ESI−) m / z: calcd for C60H75BrN10Na2O20S6Si3: 828.0890 [M−2Na]2−; found: 828.0841.

[0239] ^-Me-SiPc: Yield, 9.0% (4 steps).1H NMR (400 MHz, CD3OD): 7 −2.79 (s, 12H), −2.15 (t, J = 8.4 Hz, 4H), −1.01–−0.93 (m, 4H), 1.67–1.75 (m, 12H), 2.01 (t, J = 8.2 Hz, 4H), 2.75–2.79 (m, 24H), 3.13 (s, 3H), 8.36 (dd, J = 0.7, 7.9 Hz, 1H), 8.50–8.53 (m, 6H), 9.6 (s, - 115 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-011H), 9.66 (d, J = 7.9 Hz, 1H), 9.77–9.80 (m, 6H). HRMS (ESI−) m / z: calcd for C61H78N10Na2O20S6Si3: 796.1416 [M−2Na]2−; found: 796.1371.

[0240] ^-diCl-SiPc: Yield, 3.9% (4 steps).1H NMR (400 MHz, CD3OD): 7 −2.77 (s, 12H), −2.21 (t, J = 8.4 Hz, 4H), −0.78–−0.69 (m, 4H), 1.66–1.74 (m, 12H), 2.03 (t, J = 8.2 Hz, 4H), 2.71 (t, J = 6.7 Hz, 12H), 2.78–2.82 (m, 12H), 8.52–8.55 (m, 6H), 9.76–9.80 (m, 6H), 9.88 (s, 2H). HRMS (ESI−) m / z: calcd for C60H74Cl2N10Na2O20S6Si3: 823.0948 [M−2Na]2−; found: 823.0906.

[0241] ^-diMe-SiPc: Yield, 5.5% (4 steps).1H NMR (400 MHz, CD3OD): 7 −2.79 (s, 12H), −2.11 (t, J = 8.4 Hz, 4H), −1.04–−0.96 (m, 4H), 1.68–1.76 (m, 12H), 2.01 (t, J = 8.1 Hz, 4H), 2.75–2.79 (m, 24H), 3.04 (s, 6H), 8.49–8.52 (m, 6H), 9.56 (s, 2H), 9.76–9.80 (m, 6H). HRMS (ESI−) m / z: calcd for C62H80N10Na2O20S6Si3: 803.1494 [M−2Na]2−; found: 803.1452.

[0242] ^-diMe-SiPc: Yield, 3.5% (4 steps).1H NMR (400 MHz, CD3OD): 7 −2.78 (s, 12H), −2.19 (t, J = 8.4 Hz, 4H), −0.86–−0.78 (m, 4H), 1.64–1.72 (m, 12H), 2.01 (t, J = 8.2 Hz, 4H),2.69 (t, J = 6.8 Hz, 12H), 2.75–2.80 (m, 12H), 4.05 (s, 6H), 8.19 (s, 2H), 8.49–8.51 (m, 6H), 9.65–9.67 (m, 2H), 9.77–9.80 (m, 4H). HRMS (ESI−) m / z: calcd for C62H80N10Na2O20S6Si3: 803.1494 [M−2Na]2−; found: 803.1449.

[0243] As a result of the analysis of the reaction products, A3B-type asymmetric phthalocyanine dyes were prepared, with some specific examples exhibiting a level of decomposition (labeled as “decomp” in Table 1). Table 1: Analysis of reaction products from phthalocyanine condensation reaction with various isoindolines as a starting material

[0000] n some exampes, p t aocyanne dyes wt 6- uoro and 6 / -met oxy groups exhibited levels of decomposition, whereas phthalocyanine dyes with α-Cl, α-Me, ^-Cl, ^-Br - 116 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01and 6 / ^-methyl groups were successfully synthesized. Without being limited to a single theory, it currently is believed that these results suggests that: (i) an alkylated conjugation linker would be tolerated by the harsh conditions used for the phthalocyanine ring condensation reaction; and (ii) a synthetic route of linker extension by coupling reaction using ^-brominated phthalocyanines as a starting material would be effective. Example 2

[0245] With the above concepts determined in Example 1 in mind, various A3B-type asymmetric phthalocyanine dyes with linker groups were designed. In some examples, A3B- type asymmetric phthalocyanine compounds with an alkyne directly conjugated to the ring (compound 49 in Scheme 35) was synthesized. From this compound, synthesis of various compound species with linkers of various lengths having either a carboxylic acid (or a carboxylate) or NHS ester terminus was achieved using click chemistry reactions (Scheme 35). - 117 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0246] Compound 45 was made using the general procedure described in Example 1. Compound 45: Yield, 95%.1H NMR (400 MHz, CD3OD): 71.16 (s, 21H), 7.68 (dd, J = 1.3, - 118 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-017.8 Hz, 1H), 7.84 (dd, J = 0.8, 7.8 Hz, 1H), 7.98 (dd, J = 0.8, 0.13 Hz, 1H). HRMS (ESI+) m / z: calcd for C19H27N3NaSi: 348.1867 [M+Na]+; found: 348.1855.

[0247] Procedure for making Compound 44: Compound 43 (1.56 g, 6.16 mmol), (triisopropylsilyl)acetylene (2.25 g, 12.3 mmol), PdCl2(PPh3)2 (94 mg, 0.13 mmol), CuI (120 mg, 0.63 mmol) and NEt3 (1.27 g, 12.6 mmol) were dissolved in tetrahydrofuran (25 mL) and the mixture was stirred at room temperature for 13 hours. Then, saturated NH4Claq was added to the reaction mixture, which was extracted with AcOEt. The organic layer was washed with saturated NaClaq, dried over Na2SO4, filtered and evaporated. The crude product was purified with silica gel column chromatography to afford the pure product (1.84 g, 5.97 mmol, y.97%).1H NMR (400 MHz, CDCl3): 71.12–1.15 (s, 21H), 7.73–7.78 (m, 2H), 7.85 (dd, J = 0.8, 1.4 Hz, 1H). HRMS (ESI+) m / z: calcd for C19H24N2NaSi: 331.1601 [M+Na]+; found: 331.1591.

[0248] General procedure for making Compound 46: An 6 / ^-substituted 1,3- diiminoisoindoline derivative (1 eq), 1,3-diiminoisoindoline (3 eq) and SiCl4 (6 eq) were dissolved in quinoline (1.5–8 mL) and the mixture was stirred at 210 °C under an Ar atmosphere for 2 hours. After cooling, NH4OH (5–30 mL) was added to the mixture and the reaction solution was stirred at 80 °C for 1 hour. The precipitate was collected, washed with MeOH and dried. The crude product was used for the next step without further purification.

[0249] General procedure for making Compound 47: A crude silicon phthalocyanine dihydroxide derivative (1 eq) and (3-aminopropyl)dimethylethoxysilane (10 eq) were dissolved in pyridine (100–250 mL) and the mixture was stirred at 150 °C under an Ar atmosphere for 5–8 hours. After cooling, the solvent was evaporated and the residue was azeotropic dried with toluene. The crude product was suspended with H2O / MeOH = 10:1 solution, washed and dried. The crude product was used for the next step without further purification.

[0250] General procedure for making Compound 48: A crude phthalocyanines (1 eq), 1,3- propanesultone (50 eq) and iPr2EtN (50–65 eq) were dissolved in MeOH (7–25 mL) and the mixture was stirred at 50 °C under an Ar atmosphere for 27–28 hours. The reaction solution was concentrated and the residue was purified with reverse-phase HPLC (eluent A: 0.1 M triethylamine acetate solution, eluent B: CH3CN). The product was desalted with a Sep-Pak C18 cartridge and cation-exchange resin, affording the pure product as a sodium salt. In HPLC purification, the intermediate with the five axial ligands was also collected and subjected to the same reaction again to afford additional product. - 119 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0251] Compound 48: Yield, 6.8% (4 steps).1H NMR (400 MHz, CD3OD): 7 −2.77 (s, 12H), −2.19 (t, J = 8.4 Hz, 4H), −0.83–−0.75 (m, 4H), 1.36 (s, 21H), 1.66–1.74 (m, 12H), 2.03 (t, J = 8.2 Hz, 4H), 2.73 (t, J = 6.7 Hz, 12H), 2.76–2.81 (m, 12H), 8.49–8.54 (m, 7H), 9.71 (t, J = 1.0 Hz, 1H), 9.73–9.80 (m, 7H). HRMS (ESI−) m / z: calcd for C71H96N10Na2O20S6Si4: 879.2005 [M−2Na]2−; found: 879.1961.

[0252] General procedure for making Compound 49: An A3B-type silicon phthalocyanine with triisopropylsilyl group (1 eq) and AgF (10 eq) were dissolved in MeOH (3–8 mL), and the mixture was stirred at room temperature under an Ar atmosphere in the dark for 2–18.5 hours. Then, saturated NH4Claq (3 mL) was added to the reaction solution, following additional stirring for 10 minutes. The reaction solution was concentrated and the residue was purified with reverse-phase HPLC (eluent A: 0.1 M triethylamine acetate solution, eluent B: CH3CN). The product was desalted with a Sep-Pak C18 cartridge and cation-exchange resin, affording the pure product as a sodium salt.

[0253] Compound 49: Yield, 83%.1H NMR (400 MHz, CD3OD): 7 −2.78 (s, 12H), −2.17 (t, J = 8.4 Hz, 4H), −0.88–−0.80 (m, 4H), 1.67–1.74 (m, 12H), 2.02 (t, J = 8.2 Hz, 4H), 2.72–2.81 (m, 24H), 4.09 (s, 1H), 8.51–8.55 (m, 7H), 9.74–9.80 (m, 8H). HRMS (ESI−) m / z: calcd for C62H76N10Na2O20S6Si3: 801.1338 [M−2Na]2−; found: 801.1296.

[0254] General procedure for click reaction installation of linker group: An A3B-type silicon phthalocyanine with alkyne (1 eq), azido compound (3 eq), tris[(1-benzyl-1H-1,2,3-triazol-4- yl)methyl]amine (0.1 eq), CuSO4 (5 eq) and sodium ascorbate (10 eq) were dissolved in H2O / tBuOH / CH3CN (2:2:1), and the mixture was stirred at room temperature in the dark for 5.5–19.5 hours. The crude product was purified with reverse-phase HPLC (eluent A: 0.1 M triethylamine acetate solution, eluent B: CH3CN). The product was desalted with a Sep-Pak C18 cartridge and cation-exchange resin, affording the pure product as a sodium salt.

[0255] ^-Tz-IR700C2COOH: Yield, 80%.1H NMR (400 MHz, CD3OD): 7 −2.76 (s, 12H), −2.15 (t, J = 8.4 Hz, 4H), −0.88–−0.81 (m, 4H), 1.67–1.74 (m, 12H), 2.03 (t, J = 8.1 Hz, 4H), 2.72–2.81 (m, 24H), 5.26 (s, 2H), 8.51–8.54 (m, 6H), 9.01 (dd, J = 1.3, 8z, 1H), 9.05 (s, 1H), 9.78–9.82 (m, 7H), 10.20 (dd, J = 0.7, 1.3 Hz, 1H). HRMS (ESI−) m / z: calcd for C64H78N13Na3O22S6Si3: 862.6360 [M−2Na]2−; found: 862.6313.

[0256] ^-Tz-IR700C3COOH: Yield, 94%.1H NMR (400 MHz, CD3OD): 7 −2.76 (s, 12H), −2.15 (t, J = 8.3 Hz, 4H), −0.88–−0.80 (m, 4H), 1.67–1.74 (m, 12H), 2.03 (t, J = 8.1 Hz, 4H), 2.72–2.81(m, 24H), 3.02 (t, J = 7.2 Hz, 2H), 4.91 (t, J = 7.3 Hz, 2H), 8.52–8.54 (m, 6H), 8.98 - 120 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01(dd, J = 1.3, 8.0 Hz, 1H), 9.09 (s, 1H), 9.78–9.82 (m, 7H), 10.17 (s, 1H). HRMS (ESI−) m / z: calcd for C65H80N13Na3O22S6Si3: 869.6439 [M−2Na]2−; found: 869.6394.

[0257] ^-Tz-IR700C3SE: HRMS (ESI−) m / z: calcd for C69H84N14Na2O24S6Si3: 907.1611 [M−2Na]2−; found: 907.1563.

[0258] ^-Tz-IR700C6COOH: Yield, 65%.1H NMR (400 MHz, CD3OD): 7 −2.76 (s, 12H), −2.14 (t, J = 8.4 Hz, 4H), −0.93–−0.85 (m, 4H), 1.57–1.63 (m, 2H), 1.67–1.74 (m, 12H), 1.78–1.85 (m, 2H), 2.02 (t, J = 8.2 Hz, 4H), 2.17–2.25 (m, 2H), 2.29 (t, J = 7.4 Hz, 2H), 2.73– 2.80 (m, 24H), 4.69 (t, J = 7.4 Hz, 2H), 8.52–8.54 (m, 6H), 9.01 (dd, J = 1.4, 8.0 Hz, 1H), 9.17 (s, 1H), 9.78–9.83 (m,7H), 10.19 (s, 1H). HRMS (ESI−) m / z: calcd for C68H86N13Na3O22S6Si3: 890.6673 [M−2Na]2−; found: 890.6628.

[0259] ^-Tz-IR700C6SE: HRMS (ESI−) m / z: calcd for C72H90N14Na2O24S6Si3: 928.1845 [M−2Na]2−; found: 928.1797.

[0260] ^-Tz-IR700C10COOH: Yield, 84%.1H NMR (400 MHz, CD3OD): 7 −2.76 (s, 12H), −2.12 (t, J = 8.4 Hz, 4H), −0.97–−0.88 (m, 4H), 1.38–1.45 (m, 6H), 1.50–1.57 (m, 4H), 1.63– 1.75 (m, 14H), 2.02 (t, J = 8.2 Hz, 4H), 2.16–2.24 (m, 4H), 2.74–2.80 (m, 24H), 4.68 (t, J = 7.3 Hz, 2H), 8.52–8.55 (m, 6H), 9.03 (dd, J = 1.4, 8.0 Hz, 1H), 9.20 (s, 1H), 9.78–9.87 (m, 7H), 10.19 (s, 1H). HRMS (ESI−) m / z: calcd for C72H94N13Na3O22S6Si3: 918.6986 [M−2Na]2−; found: 918.6943.

[0261] ^-Tz-IR700C10SE: HRMS (ESI−) m / z: calcd for C76H98N14Na2O24S6Si3: 956.2158 [M−2Na]2−; found: 956.2110.

[0262] General procedure for making succinimidyl ester compounds: An A3B-type silicon phthalocyanine with carboxylate at the end of linker (1 eq), di(N-succinimidyl) carbonate (50 eq) and excess NEt3were dissolved in dimethyl sulfoxide, and the mixture was stirred at room temperature under an Ar atmosphere in the dark for 6–16 hours. Then, Et2O was added to the reaction solution to generate the precipitate, which was collected and dried. The product was used for the antibody labeling without further purification. If the succinimidyl ester compounds were not or not easily formed in this condition, HATU, N- hydroxysuccinimide and iPr2EtN were used instead of di(N-succinimidyl) carbonate and NEt3.

[0263] General procedure for making Compounds 57 and 59: A bromofatty acid compound (1 eq) and NaN3(1.1 eq) were dissolved in dimethyl sulfoxide (20 mL), and the mixture was stirred at room temperature under an Ar atmosphere for 13.5–14 hours. After addition of - 121 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01H2O, the reaction mixture was extracted with AcOEt. The organic layer was washed with H2O and saturated NaClaq, dried over Na2SO4, filtered, evaporated and dried. The product was used for the next step without further purification.

[0264] Compound 57: Yield, 66%.1H NMR (400 MHz, CD3OD): 72.55 (t, J = 6.3 Hz, 2H), 3.54 (t, J = 6.3 Hz, 2H). HRMS (ESI−) m / z: calcd for C3H4N3O2: 114.0309 [M−H]−; found: 114.0298.

[0265] Compound 59: Yield, 97%.1H NMR (400 MHz, CD3OD): 71.34–1.40 (m, 10H), 1.55–1.62 (m, 4H), 2.28 (t, J = 7.4 Hz, 2H), 3.28 (t, J = 6.9 Hz, 2H). HRMS (ESI−) m / z: calcd for C10H18N3O2: 212.1405 [M−H]−; found: 212.1399.

[0266] General procedure for making Compounds 50–53: An azido fatty acid compound (1 eq) and NaHCO3(1 eq) were dissolved in H2O (10 mL), and the mixture was stirred at room temperature for 10 minutes. Then, the solvent was evaporated and the residue was dried. The product was used for the next step without further purification.

[0267] Compound 50: Yield 95%.1H NMR (400 MHz, CD3OD): 73.65 (s, 2H). HRMS (ESI+) m / z: calcd for C2H2N3Na2O2: 145.9937 [M+Na]+; found: 145.9928.

[0268] Compound 51: Yield, 96%.1H NMR (400 MHz, CD3OD): 72.40 (t, J = 6.9 Hz, 2H), 3.49 (t, J = 6.9 Hz, 2H). HRMS (ESI+) m / z: calcd for C3H4N3Na2O2: 160.0093 [M+Na]+; found: 160.0085.

[0269] Compound 52: Yield, 96%.1H NMR (400 MHz, CD3OD): 71.37–1.45 (m, 2H), 1.57– 1.66 (m, 4H), 2.16 (t, J = 7.6 Hz, 2H), 3.28 (t, J = 7.0 Hz, 2H). HRMS (ESI+) m / z: calcd for C6H10N3Na2O2: 202.0563 [M+Na]+; found: 202.0555.

[0270] Compound 53: Yield, 97%.1H NMR (400 MHz, CD3OD): 71.33–1.40 (m, 10H), 1.55–1.61 (m, 4H), 2.15 (t, J = 7.6 Hz, 2H), 3.27 (t, J = 6.9 Hz, 2H). HRMS (ESI+) m / z: calcd for C10H18N3Na2O2: 258.1189 [M+Na]+; found: 258.1180. Example 3

[0271] In this example, compounds comprising a terminal azide (N3) group were prepared according to the methods described below and as summarized in Scheme 36. - 122 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0272] Procedure for making Compound 61: Compound 60 (1.22 g, 4.06 mmol) and NaN3 (1.02 g, 15.8 mmol) were dissolved in dimethylformamide (6 mL), and the mixture was stirred at room temperature under an Ar atmosphere for 12 hours. Then, H2O was added to the reaction solution, which was extracted with CH2Cl2. The organic layer was washed with H2O, dried over Na2SO4, filtered and evaporated. The crude product was purified with silica gel column chromatography to afford the pure product (0.796 g, 3.55 mmol, y.87%).1H NMR (400 MHz, CDCl3): 71.30–1.38 (m, 12H), 1.56–1.63 (m, 4H), 3.26 (t, J = 7.0 Hz, 4H).

[0273] Procedure for making ^-Tz-IR700C10N3: Compound 49 (4.5 mg, 2.78mol), compound 61 (8.0 mg, 368mol), tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (0.7 mg, 1.38mol), CuSO4·5H2O (3.8 mg, 158mol) and sodium ascorbate (6.2 mg, 318mol) were dissolved in H2O / tBuOH / CH3CN (0.3 mL / 0.3 mL / 0.15 mL), and the mixture was stirred at room temperature in the dark for 12.5 hours. The crude product was purified with reverse- phase HPLC (eluent A: 0.1 M triethylamine acetate solution, eluent B: CH3CN). The product was desalted with a Sep-Pak C18 cartridge and cation-exchange resin, affording the pure product as a sodium salt (4.2 mg, 2.28mol, y.82%).1H NMR (400 MHz, CD3OD): 7 −2.76 (s, 12H), −2.14–−2.10 (m, 4H), −0.97–−0.87 (m, 4H), 1.40–1.45 (m, 8H), 1.52–1.62 (m, 6H), 1.67–1.75 (m, 12H), 2.02 (t, J = 8.3 Hz, 4H), 2.16–2.22 (m, 2H), 2.74–2.80 (m, 24H), 3.28 (t, J = 6.9 Hz, 2H), 4.69 (t, J = 7.2 Hz, 2H), 8.51–8.55 (m, 6H), 9.05 (dd, J = 1.4, 8.0 Hz, 1H), 9.24 (s, 1H), 9.78–9.81 (m, 5H), 9.83–9.88 (m, 2H), 10.19 (s, 1H). HRMS (ESI−) m / z: calcd for C72H96N16Na2O20S6Si3: 913.2213 [M−2Na]2−; found: 913.2171. Example 4

[0274] In this example, compounds with a terminal alkyne were synthesized, the terminal alkyne providing a clickable functional group for preparing the linker group. The alkyne was then reacted with a coupling partner comprising another clickable functional group (an azide) - 123 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01to provide a compound with a triazole-based linker. The methods used for this example are detailed below and summarized in Scheme 37.- 124 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0275] General procedure for making Compound 63: A dibromotoluene derivative (1 eq), N- bromosuccinimide (1 eq) and benzoyl peroxide (75% in H2O, 0.2 eq) were dissolved in CCl4(10–15 mL), and the mixture was stirred at 80 °C under an Ar atmosphere for 2.5 hours. Then, 10% NaHCO3aq was added to the reaction solution, which was extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified with silica gel column chromatography to afford the product.

[0276] Compound 63: Compound 63 could not be separated from the dibromo compound by column purification. The purity was about 80%. The mixture was used for the next step.1H NMR (400 MHz, CDCl3): 74.38 (s, 2H), 7.19 (dd, J = 2.1, 8.2 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 2.1 Hz, 1H).

[0277] General procedure for making Compounds 64: 1.6 mol / L nBuLi (in hexane, 1–1.5 eq) was slowly dropped to (triisopropylsilyl)acetylene (1–1.5 eq) in tetrahydrofuran (6 mL) at −78 °C under an Ar atmosphere, and the mixture was stirred at −78 °C for 1.5 hours. A benzyl bromide derivative (1 eq) dissolved in tetrahydrofuran (2 mL) was added to the reaction mixture, which was stirred at −78 °C for 30 minutes. The reaction mixture was further stirred at room temperature for 1 hour, as needed. The solution was evaporated, and the residue was purified with silica gel column chromatography to afford the product. - 125 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0278] Compound 64: Compound 64 could not be separated from the by-products by column purification. The purity was about 70%. The mixture was used for the next step.1H NMR (400 MHz, CDCl3): 71.00–1.03 (m, 21H), 2.54 (t, J = 7.0 Hz, 2H), 2.77 (t, J = 7.0 Hz, 2H), 7.05 (dd, J = 2.1, 8.2 Hz, 1H), 7.50–7.52 (m, 2H).

[0279] Procedure for making Compound 65: Deoxygenated dimethylacetamide (1 mL) was added to a crude compound 64 (199 mg), Zn(CN)2 (81.7 mg, 0.70 mmol), Pd2(dba)3 (10.8 mg, 128mol) and 1,1’-bis(diphenylphosphino)ferrocene (9.9 mg, 188mol) under an Ar atmosphere, and the mixture was stirred at 120 °C for 2 hours. Then, CH2Cl2was added to the reaction solution and the precipitate was filtered. The filtrate was evaporated and the crude product was purified with silica gel column chromatography to afford the pure product (78.8 mg, 0.23 mmol).1H NMR (400 MHz, CDCl3): 70.99–1.03 (m, 21H), 2.63 (t, J = 6.8 Hz, 2H), 2.94 (t, J = 6.8 Hz, 2H), 7.62 (dd, J = 1.6, 8.1 Hz, 1H), 7.72–7.74 (m, 2H). HRMS (ESI+)m / z: calcd for C21H28N2NaSi: 359.1914 [M+Na]+; found: 359.1904.

[0280] Compound 66 was made using the general procedure described in Example 1. Compounds 67, 68, 69, 70, 71, 73, and ^-TzEt-IR700C8COOH were made according to the procedure described by Example 2. ^-TzEt-IR700C8SE was made according to the general procedure for making the succinimidyl ester compounds described in Example 2.

[0281] Compound 66: Yield, 89%.1H NMR (400 MHz, CD3OD): 70.92–0.97 (s, 21H), 2.68 (t, J = 7.0 Hz, 2H), 2.98 (t, J = 7.0 Hz, 2H), 7.54 (dd, J = 1.4, 7.7 Hz, 1H), 7.75 (d, J = 1.4 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H). HRMS (ESI+) m / z: calcd for C21H32N3Si: 354.2360 [M+H]+; found: 354.2353.

[0282] Compound 69: Yield, 4.6% (4 steps).1H NMR (400 MHz, CD3OD): 7 −2.78 (s, 12H), −2.15 (t, J = 8.4 Hz, 4H), −0.98–−0.90 (m, 4H), 1.01 (s, 21H), 1.67–1.75 (m, 12H), 2.01 (t, J = 8.2 Hz, 4H), 2.74–2.80 (m, 24H), 3.12 (t, J = 6.7 Hz, 2H), 3.61 (t, J = 6.7 Hz, 2H), 8.42 (dd, J = 1.3, 7.9 Hz, 1H), 8.50–8.53 (m, 6H), 9.67–9.70 (m, 2H), 9.75–9.81 (m, 6H). HRMS (ESI−) m / z: calcd for C73H100N10Na2O20S6Si4: 893.2162 [M−2Na]2−; found: 893.2115.

[0283] Compound 70: Yield, 81%.1H NMR (400 MHz, CD3OD): 7 −2.79 (s, 12H), −2.13 (t, J = 8.4 Hz, 4H), −1.00–−0.92 (m, 4H), 1.67–1.74 (m, 12H), 2.01 (t, J = 8.5 Hz, 4H), 2.48 (t, J = 2.6 Hz, 1H), 2.75–2.78 (m, 24H), 3.02 (dt, J = 2.6, 7.2 Hz, 2H), 3.61 (t, J = 7.2 Hz, 2H), 8.44 (dd, J = 1.3, 7.9 Hz, 1H), 8.50–8.53 (m, 6H), 9.67 (s, 1H), 9.70 (d, J = 7.9 Hz, 1H), 9.77–9.82 (m, 6H). HRMS (ESI−) m / z: calcd for C64H80N10Na2O20S6Si3: 815.1494 [M−2Na]2−; found: 815.1451. - 126 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0284] Compound 71: Yield, 89%.1H NMR (400 MHz, CD3OD): 71.34–1.41 (m, 6H), 1.55– 1.62 (m, 4H), 2.15 (t, J = 7.6 Hz, 2H), 3.27 (t, J = 6.9 Hz, 2H). HRMS (ESI+) m / z: calcd for C8H14N3Na2O2: 230.0876 [M+Na]+; found: 230.0867.

[0285] Compound 73: Yield, 97%.1H NMR (400 MHz, CD3OD): 71.35–1.42 (m, 6H), 1.56– 1.63 (m, 4H), 2.29 (t, J = 7.4 Hz, 2H), 3.28 (t, J = 6.9 Hz, 2H). HRMS (ESI−) m / z: calcd for C8H14N3O2: 184.1092 [M−H]−; found: 184.1085.

[0286] ^-TzEt-IR700C8COOH: Yield, 75%.1H NMR (400 MHz, CD3OD): 7 −2.79 (s, 12H), −2.13 (t, J = 8.4 Hz, 4H), −1.00–−0.92 (m, 4H), 1.33–1.41 (m, 6H), 1.59–1.63 (m, 2H), 1.68– 1.75 (m, 12H), 1.93–1.96 (m, 2H), 2.02 (t, J = 8.1 Hz, 4H), 2.18 (t, J = 7.6 Hz, 2H), 2.75–2.79 (m, 24H), 3.53 (t, J = 8.0 Hz, 2H), 3.77 (t, J = 8.0 Hz, 2H), 4.42 (t, J = 7.2 Hz, 2H), 8.02 (s, 1H), 8.37 (dd, J = 1.2, 7.9 Hz, 1H), 8.51–8.53 (m, 6H), 9.64 (s, 1H), 9.67 (d, J = 7.9 Hz, 1H), 9.76–9.81 (m, 6H). HRMS (ESI−) m / z: calcd for C72H94N13Na3O22S6Si3: 918.6986 [M−2Na]2−; found: 918.6943.

[0287] ^-TzEt-IR700C8SE: HRMS (ESI−) m / z: calcd for C76H98N14Na2O24S6Si3: 956.2158 [M−2Na]2−; found: 956.2110. Example 5

[0288] In this example, compounds comprising a styrene-like linker group were prepared using a Heck reaction with ^-Br SiPc-NH2 and styrene having a linker as detailed below and summarized in Scheme 38. - 127 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0289] Procedure for making Compound 75: Compound 74 (4-Vinylphenol, 2.39 g, 19.9 mmol), methyl 6-bromohexanoate (3.80 g, 18.2 mmol) and potassium carbonate (7.03 g, 50.8 mmol) were dissolved in acetone (15 mL), and the mixture was refluxed for 14 hours. After the addition of 1 M HCl and brine, the reaction mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by - 128 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01silica gel column chromatography (eluent: hexane / CH2Cl2, 5 / 1 to 0 / 1) to give 75 (3.76 g, 15.1 mmol, y.76%) as a colorless oil.1H NMR (400 MHz, CDCl3): δ 7.33 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.65 (dd, J = 17.6, 10.9 Hz, 1H), 5.60 (dd, J = 17.6, 0.9 Hz, 1H), 5.11 (dd, J = 10.9, 0.9 Hz, 1H), 3.96 (t, J = 6.4 Hz, 2H), 3.67 (s, 3H), 2.35 (t, J = 7.5, 2H), 1.83– 1.76 (m, 2H), 1.74–1.66 (m, 2H), 1.54–1.48 (m, 2H). HRMS (ESI+) m / z: calcd for C15H21O3: 249.1485 [M+H]+; found: 249.1484.

[0290] Procedure for making Compound 76: β-Br-SiPc-NH2(331 mg) and bis(tri-tert- buthylphosphine)palladium (Pd[P(tBu)3]2) (12.0 mg, 67 µmol) were dissolved in toluene (12 mL), and the mixture was stirred at room temperature under an Ar atmosphere. N- methyldicyclohexylamine (Cy2NMe) (175 mg, 896 µmol) and compound 75 (365 mg, 1.47 mmol) were added, and the mixture was stirred at 100 °C for 24 hours. The crude product was extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and evaporated to afford 76 (585 mg), which was used in the next step without further purification.

[0291] Procedure for making Compound 77: Compound 76 (368 mg), 1,3-propanesultone (2.21 g, 18.1 mmol), and N,N-diisopropylethylamine (3.17 g, 24.5 mmol) were dissolved in MeOH (18 mL), and the mixture was stirred at 50 °C for 48 hours under an Ar atmosphere. The product was purified by an HPLC system with a reverse-phase column, using eluent A (H2O, 0.1 M triethylammonium acetate) and eluent B (CH3CN) (A / B = 70 / 30 to 0 / 100 in 50 min. The product was desalted with a Sep-Pak C18 cartridge and cation-exchange resin, affording the product (17.1 mg, 9.1 µmol, y.0.5% in 4 steps as a sodium salt).1H NMR (400 MHz, CD3OD): δ 9.90–9.88 (m, 2H), 9.80–9.78 (m, 6H), 9.73 (d, J = 8.1 Hz, 1H), 8.73 (d, J = 8.1 Hz, 1H), 8.55–8.52 (m, 7H), 7.89 (d, J = 8.7 Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 4.12 (t, J = 6.3 Hz, 2H), 3.71 (s, 3H), 2.82–2.77 (m, 24H), 2.44 (t, J = 7.4, 2H), 2.07–2.03 (m, 4H), 1.93– 1.86 (m, 2H), 1.79–1.72 (m, 14H), 1.64–1.58 (m, 2H), −0.85–−0.93 (m, 4H), −2.08–−2.12 (m, 4H), −2.74 (s, 12H). HRMS (ESI−) m / z: calcd for C75H94N10Na2O23S6Si3: 912.1966 [M−2Na]2−; found: 912.1927.

[0292] Procedure for making Styrl-IR700 C6COOH: Compound 77 (12.6 mg, 6.7 µmol) was dissolved in CH3CN containing 20 vol% of H2O (1 mL). Triethylamine (75.0 mg, 741 µmol) was added followed by the lithium bromide (183 mg, 2.11 mmol). The mixture was stirred vigorously at room temperature for 24 hours. The product was purified by an HPLC system with a reverse-phase column, using eluent A (H2O, 0.1 M triethylammonium acetate) and eluent B (CH3CN) (A / B = 70 / 30 to 50 / 50 in 50 min, 50 / 50 to 0 / 100 in 5 min. The product was desalted with a Sep-Pak C18 cartridge and cation-exchange resin, affording the product (8.3 - 129 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01mg, 4.4 µmol, y.66% as a sodium salt).1H NMR (400 MHz, CD3OD): δ 9.89–9.87 (m, 2H), 9.81–9.79 (m, 6H), 9.73 (d, J = 8.2 Hz, 1H), 8.74 (d, J = 8.2 Hz, 1H), 8.57–8.52 (m, 7H), 7.88 (d, J = 7.1 Hz, 2H), 7.08 (d, J = 7.1 Hz, H), 4.12 (t, J = 6.5 Hz, 2H), 2.81–2.78 (m, 24H), 2.27 (t, J = 7.5, 2H), 2.06–2.04 (m, 4H), 1.93–1.87 (m, 2H), 1.76–1.71 (m, 14H), 1.64–1.57 (m, 2H), −0.92–−0.94 (m, 4H), −2.06–−2.10 (m, 4H), −2.74 (s, 12H). HRMS (ESI−) m / z: calcd for C74H91N10Na3O23S6Si3: 916.1792 [M−2Na]2−; found: 916.1760.

[0293] Procedure for making Styrl-IR700 C6SE: Styrl-IR700 C6COOH (3.8 mg, 2.0 µmol), N,N’-disuccinimidyl carbonate (17.2 mg, 67 µmol) and triethylamine (32.0 mg, 316 µmol) were dissolved in dry dimethyl sulfoxide (770 µL) at room temperature under Ar atmosphere, and the mixture was stirred at room temperature for 26 hours. After addition of Et2O (40 mL) to the reaction mixture, precipitation occurred. The precipitates were collected and washed by Et2O (40 mL) to afford Styrl-IR700 C6SE (9.5 mg), which was used in the conjugation reaction to Cetuximab without further purification. HRMS (ESI−) m / z: calcd for C78H95N11Na2O25S6Si3: 953.6970 [M−2Na]2−; found: 953.6930. Example 6

[0294] In this example, a compound comprising a triazole-containing linker in combination with a PEG linker is described. The compound was made according to the method described in detail below and summarized in Scheme 39.- 130 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0295] Compounds 79, ^-Tz-IR700PEG6COOH, and ^-Tz-IR700PEG6SE were made according to the methods described in Example 2.

[0296] ^-Tz-IR700PEG6COOH: Yield, 90%.1H NMR (400 MHz, CD3OD): 7 −2.76 (s, 6H), −2.76 (s, 6H), −2.15–−2.11 (m, 4H), −0.94–−0.88 (m, 4H), 1.67–1.75 (m, 12H), 2.02 (t, J = 8.4 Hz, 4H), 2.46 (t, J = 6.5 Hz, 2H), 2.74–2.80 (m, 24H), 3.64–3.66 (m, 12H), 3.72–3.79 (m, 8H), 3.83–3.85 (m, 2H), 4.19 (t, J = 5.1 Hz, 2H), 4.90 (t, J = 5.1 Hz, 2H), 8.51–8.55 (m, 6H), 9.06 (dd, J = 1.3, 8.0Hz, 1H), 9.27 (s, 1H), 9.78–9.80 (m, 5H), 9.83–9.87 (m, 2H), 10.20 (s, 1H). HRMS (ESI−) m / z: calcd for C77H104N13Na3O28S6Si3: 1001.7225 [M−2Na]2−; found: 1001.7182.

[0297] ^-Tz-IR700PEG6SE: HRMS (ESI−) m / z: calcd for C81H108N14Na2O30S6Si3: 1039.2397 [M−2Na]2−; found: 1039.2349.

[0298] Compound 79: Yield, 98%.1H NMR (400 MHz, CD3OD): 72.46 (t, J = 6.5 Hz, 2H), 3.40 (t, J = 4.8 Hz, 2H), 3.63–3.68 (m, 22H), 3.71 (t, J = 9.3 Hz, 2H). HRMS (ESI+) m / z: calcd for C15H28N3Na2O8: 424.1666 [M+Na]+; found: 424.1654. Example 7

[0299] In this example, a compound comprising the Linker group at the alpha position is made. The compound was made according to the method described in detail below and summarized in Scheme 40. - 131 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0300] Procedure for making Compound 83: Deoxygenated dimethylforamide (3 mL) was added to compound 82 (393 mg, 0.884 mmol), Zn(CN)2(257 mg, 2.19 mmol) and Pd(PPh3)4(523 mg, 0.453 mmol) under an Ar atmosphere, and the mixture was stirred at 130 °C for 6 hours. Then, 8% NH4OH was added to the reaction solution, which was extracted with CH2Cl2. The organic layer was washed with H2O, dried over Na2SO4, filtered and evaporated. The residue was purified with silica gel column chromatography to afford the - 132 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01pure product. (87 mg, 0.258 mmol, y.29%).1H NMR (400 MHz, CDCl3): 70.98–0.99 (m, 21H), 2.71 (t, J = 6.8 Hz, 2H), 3.12 (t, J = 6.8 Hz, 2H), 7.63 (t, J = 7.7 Hz, 1H), 7.68 (dd, J = 1.5, 7.7 Hz, 1H), 7.72 (dd, J = 1.5, 7.7 Hz, 1H). HRMS (ESI+) m / z: calcd for C21H28N2NaSi: 359.1914 [M+Na]+; found: 359.1903.

[0301] Compound 84 was made according to the method described in Example 1. Compounds 85, 86, 87, 88, and 6-TzEt-IR700C8COOH were made according to the method described in Example 2. Compounds 81 and 82 were made according to the method described in Example 4.

[0302] Compound 81: Yield, 78%.1H NMR (400 MHz, CDCl3): 74.65 (s, 2H), 7.17 (t, J = 7.8 Hz, 1H), 7.40 (dd, J = 1.6, 7.8 Hz, 1H), 7.59 (dd, J = 1.6, 7.8 Hz, 1H).

[0303] Compound 82: Yield, 16%.1H NMR (400 MHz, acetone-d6): 71.01–1.04 (m, 21H), 2.67 (t, J = 7.1 Hz, 2H), 3.09 (t, J = 7.1 Hz, 2H), 7.26 (t, J = 7.8 Hz, 1H), 7.43 (dd, J = 1.6, 7.8 Hz, 1H), 7.61 (dd, J = 1.6, 7.8 Hz, 1H).

[0304] Compound 84: Yield, 50%.1H NMR (400 MHz, CD3OD): 70.91–0.98 (s, 21H), 2.73 (t, J = 6.7 Hz, 2H), 3.33 (t, J = 6.7 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.51 (dd, J = 1.2, 7.4 Hz, 1H), 7.68 (dd, J = 1.2, 7.4 Hz, 1H). HRMS (ESI+) m / z: calcd for C21H32N3Si: 354.2360 [M+H]+; found: 354.2363.

[0305] Compound 87: Yield, 7.6% (4 steps).1H NMR (400 MHz, CD3OD): 7 −2.77 (s, 12H), −2.15 (t, J = 8.4 Hz, 4H), −0.90–−0.82 (m, 4H 115–117 m 21H 166–173 (m, 12H),2.01 (t, J = 8.3 Hz, 4H), 2.72 (t, J = 6.7 Hz, 12H), 2.76–2.80 (m, 12H), 3.63 (t, J = 7.4 Hz, 2H), 4.75 (t, J = 7.4 Hz, 2H), 8.35 (d, J = 6.5 Hz, 1H), 8.38–8.46 (m, 2H), 8.49–8.54 (m, 5H), 9.68–9.73 (m, 2H), 9.78–9.81 (m, 5H). HRMS (ESI−) m / z: calcd for C73H100N10Na2O20S6Si4: 893.2162 [M−2Na]2−; found: 893.2113.

[0306] Compound 88: Yield, 95%.1H NMR (400 MHz, CD3OD): 7 −2.77 (s, 12H), −2.16 (t, J = 8.4 Hz, 4H), −0.89–−0.81 (m, 4H), 1.66–1.74 (m, 12H), 2.02 (t, J = 8.2 Hz, 4H), 2.63 (t, J = 2.5 Hz, 1H), 2.72 (t, J = 6.7 Hz, 12H), 2.76–2.81 (m, 12H), 3.46 (dt, J = 2.5, 7.6 Hz, 2H), 4.76 (t, J = 7.6 Hz, 2H), 8.34 (d, J = 6.8 Hz, 1H), 8.42 (t, J = 7.5 Hz, 1H), 8.48–8.54 (m, 6H), 9.72 (dd, J = 0.8, 7.5 Hz, 1H), 9.78–9.82 (m, 6H). HRMS (ESI−) m / z: calcd for C64H80N10Na2O20S6Si3: 815.1494 [M−2Na]2−; found: 815.1454.

[0307] ^-TzEt-IR700C8COOH: Yield, 71%.1H NMR (400 MHz, CD3OD): 7 −2.76 (s, 12H), −2.15 (t, J = 8.4 Hz, 4H), −0.90–−0.81 (m, 4H), 1.40–1.48 (m, 6H), 1.66–1.74 (m, 14H), 2.00–2.04 (m, 6H), 2.21 (t, J = 7.6 Hz, 2H), 2.72 (t, J = 6.8 Hz, 12H), 2.76–2.80 (m, 12H), - 133 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-013.95 (t, J = 7.9 Hz, 2H), 4.52 (t, J = 7.2 Hz, 2H), 4.98 (t, J = 7.9 Hz, 2H), 8.07 (s, 1H), 8.25 (d, J = 7.1 Hz, 1H), 8.35–8.40 (m, 2H), 8.46–8.54 (m, 5H), 9.42 (d, J = 7.6 Hz, 1H), 9.71 (dd, J = 0.6, 7.6 Hz, 1H), 9.75–9.80 (m, 5H). HRMS (ESI−) m / z: calcd for C72H94N13Na3O22S6Si3: 918.6986 [M−2Na]2−; found: 918.6946.

[0308] α-TzEt-IR700C8SE: HRMS (ESI−) m / z: calcd for C76H98N14Na2O24S6Si3: 956.2158 [M−2Na]2−; found: 956.2113. Example 8

[0309] In this example, a compound comprising a β-alkyne linker group installed via a Sonogashira coupling was prepared using the method detailed below and summarized in Scheme 41. - 134 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01^ ^ ^ ^ ^ ^ ^ ^^^^ ^^^^^^Scheme 41

[0310] Procedure for making ^-alkyne-IR700C7COOH: A solution of Pd(OAc)2 (0.05 mg, 0.228mol) and CuI (0.05 mg, 0.268mol) in CH3CN (0.1 mL) were added to a solution of ^-I- SiPc (3.4 mg, 1.98mol) and P(m-C6H4SO3Na)3(0.4 mg, 0.708mol) in H2O (1 mL). Then, NEt3(0.1 mL) and a solution of compound 92 (4.1 mg, 268mol) in CH3CN (0.1 mL) were - 135 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01added to the mixture, which was stirred at room temperature in the dark for 12.5 hours. The crude product was purified with reverse-phase HPLC (eluent A: 0.1 M triethylamine acetate solution, eluent B: CH3CN). The product was desalted with a Sep-Pak C18 cartridge and cation-exchange resin, affording the pure product as a sodium salt (3.5 mg, 1.98mol, y. 96%).1H NMR (400 MHz, CD3OD): 7 −2.78 (s, 12H), −2.18–−2.13 (m, 4H), −0.93–−0.85 (m, 4H), 1.40–1.50 (m, 4H), 1.62–1.75 (m, 16H), 2.02 (t, J = 8.2 Hz, 4H), 2.16 (t, J = 7.6 Hz, 2H), 2.74–2.80 (m, 26H), 3.01 (t, J = 7.4 Hz, 2H), 3.35 (t, J = 7.2 Hz, 2H), 8.44 (dd, J = 1.0, 8.3 Hz, 1H), 8.51–8.54 (m, 6H), 9.69–9.71 (m, 2H), 9.76–9.80 (m, 6H).

[0311] ^-alkyne-IR700C7SE: HRMS (ESI−) m / z: calcd for C76H96N12Na2O25S6Si3: 949.2024 [M−2Na]2−; found: 949.1977.

[0312] Procedure for making Compound 94: N, N’-Dicyclohexylcarbodiimide (0.421 g, 2.04 mmol) was added to the solution of compound 93 (0.201 g, 2.05 mmol) and N- hydroxysuccinimide (0.262 g, 2.15 mmol) in tetrahydrofuran (5 mL) at 0 °C, and the mixture was stirred at 0 °C under an Ar atmosphere for 1 hour. Then, the reaction solution was further stirred at room temperature for 1 hour. The precipitate was filtered and the filtrate was evaporated. The crude product was purified with silica gel column chromatography to afford the pure product (0.336 g, 1.72 mmol, y.84%).1H NMR (400 MHz, CDCl3): 72.05 (t, J = 2.7 Hz, 1H), 2.62 (dt, J = 2.7, 7.4 Hz, 2H), 2.84 (s, 4H), 2.88 (t, J = 7.4 Hz, 2H). HRMS (ESI+)m / z: calcd for C9H10NO4: 196.0604 [M+H]+; found: 196.0595.

[0313] Procedure for making Compound 92: A solution of 7-aminoheptanoic acid (68 mg, 0.47 mmol) and NEt3 (101 mg, 1.00 mmol) in H2O (1 mL) was added to a solution of compound 94 (59 mg, 0.30 mmol) in CH3CN (1.5 mL), and the mixture was stirred at room temperature for 12.5 hours. The CH3CN was evaporated and the residue was acidified to pH3 with 3 mol / L HClaq. Then, the solution was extracted with AcOEt, and the organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified with silica gel column chromatography to afford the pure product (58 mg, 0.26 mmol, y.86%).1H NMR (400 MHz, CD3OD): 71.35–1.38 (m, 4H), 1.48–1.57 (m, 6H), 1.59–1.64 (m, 6H), 2.26 (t, J = 2.6 Hz, 1H), 2.29 (t, J = 7.4 Hz, 2H), 2.36 (dt, J = 1.2, 7.1 Hz, 2H), 2.44–2.48 (m, 2H), 3.15– 3.20 (m, 2H), 8.00 (br, 1H). HRMS (ESI−) m / z: calcd for C12H18NO3: 224.1292 [M−H]−; found: 224.1286.

[0314] Compounds 90, and ^-I-SiPc were made according to the procedure described in Example 1. - 136 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0315] Compound 90: Yield, 99%.1H NMR (400 MHz, CD3OD): 77.64 (dd, J = 0.5, 7.9 Hz, 1H), 8.01 (dd, J = 1.4, 7.9 Hz, 1H), 8.27 (dd, J = 0.5, 1.4 Hz, 1H). HRMS (ESI+) m / z: calcd for C8H7IN3: 271.9679 [M+H]+; found: 271.9631.

[0316] ^-I-SiPc: Yield, 2.1% (4 steps).1H NMR (400 MHz, CD3OD): 7 −2.78 (s, 12H), −2.20 (t, J = 8.4 Hz, 4H), −0.83–−0.75 (m, 4H), 1.67–1.74 (m, 12H), 2.03 (t, J = 8.2 Hz, 4H), 2.73 (t, J = 6.8 Hz, 12 H), 2.77–2.81 (m, 12H), 8.51–8.54 (m, 6H), 8.61 (dd, J = 1.4, 8.1 Hz, 1H), 9.53 (d, J = 8.1 Hz, 1H), 9.76–9.79 (m, 6H), 10.08 (d, J = 0.8 Hz, 1H). HRMS (ESI−) m / z: calcd for C60H75IN10Na2O20S6Si3: 852.0821 [M−2Na]2−; found: 852.0782. Example 9

[0317] In this example, compounds with alkene-containing linkers were prepared. The compounds were made according to the method detailed below and summarized in Scheme 42. ^ ^ ^ ^^ ^^ ^ ^ ^ ^ ^ ^ ^ ^^^^- 137 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0318] Procedure for making Compound 101: ^-Br-SiPc-NH2(412 mg) and bis(tri-tert- buthylphosphine)palladium (Pd[P(tBu)3]2) (18.5 mg, 35.2 µmol) were dissolved in dioxane (17 mL), and the mixture was stirred at room temperature under an Ar atmosphere. N- methyldicyclohexylamine (Cy2NMe) (592 mg, 3.04 mmol) and methyl 10-undecenoate (457 mg, 2.30 mmol) were added, and the mixture was stirred at 100 °C for 24 hours. The crude product was extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and evaporated to afford 1 (1039 mg), which was used in the next step without further purification.

[0319] Procedure for making Compound 102: Compound 101 (1000 mg), 1,3- propanesultone (2.90 g, 23.8 mmol), and N,N-diisopropylethylamine (5.18 g, 40.0 mmol) were dissolved in MeOH (15 mL), and the mixture was stirred at 70 °C for 3 hours under microwave irradiation. This operation was repeated 5 times. The product was purified by an HPLC system with a reverse-phase column, using eluent A (H2O, 0.1 M triethylammonium acetate) and eluent B (CH3CN) (A / B = 70 / 30 to 0 / 100 in 50 min. The product was desalted with a Sep-Pak C18 cartridge and cation-exchange resin, affording the product (7.5 mg, 4.1 µmol, y.0.2% in 4 steps as a sodium salt).1H NMR (400 MHz, CD3OD): 79.74–9.62 (m, 6H), 9.60–9.57 (m, 2H), 8.47–8.41 (m, 7H), 7.12 (d, J = 15.9 Hz, 1H), 7.03–6.98 (m, 1H), 3.58 (s, 3H), 2.71–2.65 (m, 24H), 2.50–2.44 (m, 2H), 2.28 (t, J = 7.4, 2H), 1.95–1.91 (m, 4H), 1.67–1.57 (m, 12H), 1.51–1.20 (m, 12H), −0.97–−0.99 (m, 4H), −2.21–−2.25 (m, 4H), −2.86 (s, 12H). LRMS (ESI−) m / z: [M+2H−4Na]2−calcd for C72H98N10O22S6Si3, 865; found, 866.

[0320] Procedure for making IR700-alkene-COOH: Compound 102 (5.8 mg, 3.1 µmol) was dissolved in CH3CN containing 30 vol% of H2O (1.4 mL). Triethylamine (60.0 mg, 593 µmol) was added followed by the lithium bromide (181 mg, 2.08 mmol). The mixture was stirred vigorously at room temperature for 24 hours. The product was purified by an HPLC system with a reverse-phase column, using eluent A (H2O, 0.1 M triethylammonium acetate) and eluent B (CH3CN) (A / B = 70 / 30 to 50 / 50 in 50 min, 50 / 50 to 0 / 100 in 5 min. The product was desalted with a Sep-Pak C18 cartridge and cation-exchange resin, affording the product (2.8 mg, 1.5 µmol, y.48% as a sodium salt).1H NMR (400 MHz, CD3OD): 79.72–9.55 (m, 6H), 9.57–9.55 (m, 2H), 8.46–8.39 (m, 7H), 7.09 (d, J = 15.8 Hz, 1H), 7.01–6.94 (m, 1H), 2.69– 2.64 (m, 24H), 2.47–2.42 (m, 2H), 2.10 (t, J = 7.7, 2H), 1.93–1.89 (m, 4H), 1.67–1.61 (m, 12H), 1.49–1.34 (m, 8H), 1.20–1.19 (m, 4H), −1.02–−1.05 (m, 4H), −2.21–−2.25 (m, 4H), −2.87 (s, 12H). LRMS (ESI−) m / z: [M+3H−5Na]2−calcd for C71H96N10O22S6Si3, 858; found, 859. - 138 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01Procedure for making IR700-alkene-SE: IR700-alkene-COOH (1.0 mg, 0.5 µmol), N,N’- disuccinimidyl carbonate (3.3 mg, 13 µmol) and triethylamine (10.0 mg, 99 µmol) were dissolved in dry dimethyl sulfoxide (500 µL) at room temperature under Ar atmosphere, and the mixture was stirred at room temperature for 21 hours. After addition of Et2O (40 mL) to the reaction mixture, precipitation occurred. The precipitates were collected and washed by Et2O (40 mL) to afford IR700-alkene-SE (9.2 mg), which was used in the conjugation reaction to Cetuximab without further purification. LRMS (ESI−) m / z: [M+2H−4Na]2−calcd for C75H99N11O24S6Si3, 907; found, 907. Example 10

[0321] In this example, compounds comprising alkoxy groups within the phthalocyanine core were prepared according to the method described below and summarized in Scheme 43.- 139 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0322] Compound 101: Compound 45 (0.331 g, 1.02 mmol), 1,3-diiminoisoindoline (0.440 g, 3.03 mmol) and SiCl4 (1.02 g, 6.03 mmol) were dissolved in quinoline (3 mL) and the mixture was stirred at 210^ under an Ar atmosphere for 2 h. After cooling, MeOH was added to the mixture and the precipitate was collected, washed with MeOH and dried (0.490 g). The crude product was used for the next step without further purification.

[0323] Compound 102: Crude compound 101 (0.204 g) and 4-amino-1-butanol (70 mg, 0.785 mmol) was dissolved in toluene (50 mL). NaH (20 mg, 0.829 mmol) was added to the solution, and the reaction mixture was stirred at 130^ under an Ar atmosphere for 7 h. After evaporation, the crude product was suspended with H2O / MeOH = 10 / 1 solution, washed and dried (0.168 g). The mixture of A4-type and A3B-type silicon phthalocyanines was used for the next step without further purification.

[0324] Compound 103: A mixture of A4-type and A3B-type silicon phthalocyanines (162 mg), 1,3-propanesultone (1.13 g, 9.23 mmol) and iPr2EtN (1.52 g, 11.8 mmol) were dissolved in MeOH (10 mL) and the mixture was stirred at 50^ under an Ar atmosphere for 20.5 h. The reaction solution was concentrated and the residue was purified with reverse- phase HPLC (eluent A: 0.1 M triethylamine acetate solution, eluent B: CH3CN). Repurification was performed. The product was desalted with a Sep-Pak C18 cartridge and cation-exchange resin, affording compound 103. In HPLC purification, the intermediate reacted with five 1,3-propanesultone was also collected and subjected to the same reaction again to afford additional compound 103 (totally 5.3 mg, 3.088mol, 0.8% (3 steps)).1H NMR (400 MHz, CD3OD): 7 −1.94–−1.88 (m, 4H), −1.46–−1.39 (m, 4H), −0.91–−0.83 (m, 4H), 1.36–1.47 (m, 37H), 2.55 (t, J = 6.6 Hz, 12H), 2.58–2.63 (m, 12H), 8.50–8.55 (m, 7H), 9.73– 9.75 (m, 2H), 9.76–9.80 (m, 6H). HRMS (ESI−) m / z: calcd for C69H88N10Na2O20S6Si2: 835.1923 [M−2Na]2−; found: 835.1942.

[0325] Compound 104: Compound 104 was synthesized according to general procedure of deprotection reaction of triisopropylsilyl group. Yield 86%.1H NMR (400 MHz, CD3OD): 7 −1.92 (t, J = 5.8 Hz, 4H), −1.45–−1.38 (m, 4H), −0.94–−0.87 (m, 4H), 1.35–1.47 (m, 16H), 2.56 (t, J = 6.6 Hz, 12H), 2.58–2.63 (m, 12H), 4.08 (s, 1H), 8.51–8.55 (m, 7H), 9.74 (dd, J = 0.7, 7.9 Hz, 1H), 9.76–9.81 (m, 7H). HRMS (ESI−) m / z: calcd for C60H68N10Na2O20S6Si: 757.1256 [M−2Na]2−; found: 757.1265.

[0326] ^-Tz-IR700C10COOH-alk: ^-Tz-IR700C10COOH-alk was synthesized according to general procedure of click reaction. Yield 90%.1H NMR (400 MHz, CD3OD): 7 −1.89 (t, J = 5.7 Hz, 4H), −1.41–−1.35 (m, 4H), −0.98–−0.9(m, 4H), 1.36–1.48 (m, 22H), 1.52–1.58 (m, 4H), 1.61–1.69 (m, 2H), 2.19 (t, J = 7.6 Hz, 4H), 2.55–2.63 (m, 24H), 4.67 (t, J = 7.4 Hz, 2H), - 140 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-018.52–8.55 (m, 6H), 9.02 (dd, J = 1.4, 8.0 Hz, 1H), 9,15 (s, 1H), 9.78–9.86 (m, 5H), 9.82–9.86 (m, 2H), 10.2 (dd, J = 0.8, 1.4 Hz, 1H). HRMS (ESI−) m / z: calcd for C70H86N13Na3O22S6Si: 874.6904 [M−2Na]2−; found: 874.6927.

[0327] ^-Tz-IR700C10SE-alk: ^-Tz-IR700C10SE-alk was synthesized according to general procedure of synthesis of succinimidyl ester compounds. Example 11

[0328] In this example, compounds comprising a naphthylene ring system within the phthalocyanine core were prepared according to the method described below and as summarized in Scheme 44. - 141 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0329] Compound 106: Compound 105 (0.513 g, 2.00 mmol), (triisopropylsilyl)acetylene (0.726 g, 3.98 mmol), PdCl2(PPh3)2 (15.7 mg, 22.48mol) and CuI (4.4 mg, 23.18mol) were dissolved in tetrahydrofuran (10 mL) under an Ar atmosphere. Then, iPr2EtN (0.521 g, 4.03 mmol) were added to the solution and the mixture was stirred at 80^ for 8.5 h. After that, saturated NH4Claq was added to the reaction mixture, which was extracted with AcOEt. The organic layer was washed with saturated NaClaq, dried over Na2SO4, filtered and evaporated. The crude product was purified with silica gel column chromatography to afford - 142 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01the pure product (0.307 g, 0.856 mmol, y.43%).1H NMR (400 MHz, CDCl3): 71.16–1.18 (m, 21H), 7.80 (dd, J = 1.5, 8.6 Hz, 1H), 7.91 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 0.6 Hz, 1H), 8.28 (s, 1H), 8.31 (s, 1H). HRMS (ESI+) m / z: calcd for C23H26N2NaSi: 381.1758 [M+Na]+; found: 381.1747.

[0330] Compound 107: Compound 107 was synthesized according to general procedure of synthesis of substituted 1,3-diiminoisoindoline derivatives. Yield 99%.1H NMR (400 MHz, CD3OD): 71.19 (s, 21H), 7.65 (dd, J = 1.6, 8.6 Hz, 1H), 8.04 (d, J = 8.6 Hz, 1H), 8.17 (d, J = 0.7 Hz, 1H), 8.30 (s, 1H), 8.31 (s, 1H). HRMS (ESI+) m / z: calcd for C23H30N3Si: 376.2204 [M+H]+; found: 376.2198.

[0331] Compound 108: Compound 108 was synthesized according to general procedure of synthesis of A3B-type silicon phthalocyanine dihydroxide derivatives (compound 46, 67, 85).

[0332] Compound 109: Compound 109 was synthesized according to general procedure of addition reaction of axial ligands to A3B-type silicon phthalocyanine dihydroxide derivatives (compound 47, 68, 86).

[0333] Compound 110: Compound 110 was synthesized according to general procedure of alkyl sulfonation of A3B-type silicon phthalocyanine derivatives (compound 48, 69, 87). Yield 3.8% (4 steps).1H NMR (400 MHz, CD3OD): 7 −2.67 (s, 12H), −2.03 (t, J = 8.3 Hz, 4H), −0.91–−0.82 (m, 4H), 1.30 (s, 21H), 1.66–1.74 (m, 12H), 2.04 (t, J = 8.3 Hz, 4H), 2.73–2.79 (m, 24H), 8.00 (dd, J = 1.4, 8.5 Hz, 1H), 8.47–8.53 (m, 6H), 8.85 (d, J = 8.5 Hz, 1H), 8.99 (s, 1H), 9.73–9.76 (m, 4H), 9.79–9.83 (m, 2H), 10.3 (t, J = 2.7 Hz, 2H)HRMS (ESI−) m / z: calcd for C75H98N10Na2O20S6Si4: 904.2083 [M−2Na]2−; found: 904.2112.

[0334] Compound 111: Compound 110 was synthesized according to general procedure of deprotection reaction of triisopropylsilyl group. Yield 89%.1H NMR (400 MHz, CD3OD): 7 −2.68 (s, 12H), −2.02 (t, J = 8.4 Hz, 4H), −0.93–−0.84 (m, 4H), 1.66–1.74 (m, 12H), 2.04 (t, J = 8.2 Hz, 4H), 2.73–2.77 (m, 24H), 3.90 (s, 1H), 8.02 (dd, J = 1.5, 8.5 Hz, 1H), 8.49 (dd, J = 2.8, 5.7 Hz, 2H), 8.52 (dd, J = 2.8, 5.7 Hz, 4H), 8.86 (d, J = 8.7 Hz, 1H), 9.04 (s, 1H), 9.73– 9.76 (m, 4H), 9.81–9.84 (m, 2H), 10.3 (s, 2H). HRMSESI−) m / z: calcd for C66H78N10Na2O20S6Si3: 826.1416 [M−2Na]2−; found: 826.1442.

[0335] ^-Tz-naph-IR700C10COOH: ^-Tz-naph-IR700C10COOH was synthesized according to general procedure of click reaction. Yield 85%.1H NMR (400 MHz, CD3OD): 7 −2.66 (s, 12H), −2.01 (t, J = 8.4 Hz, 4H), −0.92–−0.83 (m, 4H), 1.37–1.42 (m, 6H), 1.48–1.52 (m, 4H), 1.62–1.74 (m, 14H), 2.05 (t, J = 8.2 Hz, 4H), 2.09–2.15 (m, 2H), 2.20 (t, J = 7.5 Hz, 2H), 2.74–2.78 (m, 24H), 4.61 (t, J = 7.3 Hz, 2H), 8.48 (dd, J = 2.9, 5.8 Hz, 2H), 8.51–8.53 - 143 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01(m, 4H), 8.58 (dd, J = 1.5, 8.6 Hz, 2H), 8.87 (s, 1H), 8.97 (d, J = 8.9 Hz, 1H), 9.31 (s, 1H), 9.73–9.76 (m, 4H), 9.81–9.84 (m, 2H), 10.3 (s, 1H), 10.4 (s, 1H). HRMS (ESI−) m / z: calcd for C76H96N13Na3O22S6Si3: 943.7065 [M−2Na]2−; found: 943.7097.

[0336] ^-Tz-naph-IR700C10SE: ^-Tz-naph-IR700C10SE was synthesized according to general procedure of synthesis of succinimidyl ester compounds. HRMS (ESI−) m / z: calcd for C80H100N14Na2O24S6Si3: 981.2237 [M−2Na]2−; found: 981.2271. Example 12

[0337] In this example, compounds comprising chloro or iodo substituents attached to the phthalocyanine core in addition to a Linker-X group were prepared according to the method described below and summarized in Scheme 45. - 144 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01Scheme 45

[0338] Compound 113: Compound 112 (6.00 g, 40.8 mmol) and I2(10.4 g, 41.1 mmol) were dissolved in fuming H2SO4(30%, 20 mL) and the reaction mixture was stirred at 100^ - 145 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01for 41 h. The mixture was poured into ice and the precipitate was collected, washed with 2% K2CO3aq and saturated NaNO2aq, and dried. The crude product was purified with silica gel column chromatography (7.13 g). In some examples, the product still contained unknown impurities, but was used for the next step without further purification. In other examples, the compound was purified and the following characterization data were obtained: HRMS (ESI−) m / z: calcd for C8H2I2NO2: 397.8180 [M−H]−; found: 397.8197.

[0339] Compound 114: Compound 113 (4.90 g) was suspended in NH4OH (60 mL) and the mixture was stirred at 60^ for 1.5 h. Then, the precipitate was collected, wash with cold H2O and MeOH, and dried to afford the product (3.21 g, 7.71 mmol, 27% (2 steps)).1H NMR (400 MHz, DMSO-d6): 77.43 (br, 2H), 7.84 (br, 2H), 7.92 (s, 2H). HRMS (ESI+) m / z: calcd for C8H6I2N2NaO2: 438.8411 [M+Na]+; found: 438.8394.

[0340] Compound 115: Compound 114 (1.01 g, 2.43 mmol) was dissolved in pyridine (35 mL) and dioxane (15 mL) under an Ar atmosphere and POCl3 (2.2 mL, 23.5 mmol) was slowly added dropwise to the solution at 0^. Then, the reaction mixture was stirred at room temperature for 11 h. H2O was added to the mixture at 0^, followed by extraction with AcOEt. The organic layer was washed with H2O and saturated NaClaq, dried over Na2SO4, filtered and evaporated. The crude product was purified with silica gel column chromatography to afford the pure product (0.694 g, 1.83 mmol, 75%).1H NMR (400 MHz, CDCl3): 78.22 (s, 2H). HRMS (ESI−) m / z: calcd for C8HI2N2: 378.8235 [M−H]−; found: 378.8241.

[0341] Compound 116, 117: Compound 115 (0.703 g, 1.85 mmol), (triisopropylsilyl)acetylene (0.511 g, 2.80 mmol), Pd(PPh3)4 (0.104 g, 90.08mol), CuI (34.2 mg, 1808mol) and NEt3 (0.579 g, 5.72 mmol) were dissolved in tetrahydrofuran (12 mL) and the mixture was stirred at 60^ under an Ar atmosphere for 18 h. Then, saturated NH4Claq was added to the mixture, followed by extraction with AcOEt. The organic layer was washed with saturated NaClaq, dried over Na2SO4, filtered and evaporated. The crude product was purified with silica gel column chromatography. For complete separation of compound 116 and compound 117, additional column chromatography was performed two times to afford pure compound 116 (87.5 mg, 0.201 mmol, 11%) and compound 117 (91.2 mg, 0.187 mmol, 10%).1H NMR (400 MHz, CDCl3): 71.14–1.19 (m, 21H), 7.77 (d, J = 0.3 Hz, 1H), 8.26 (d, JR (400 MHz, CDCl3): 71.12–1.15 (m, 42H), 7.83 (s, 2H) for compound 117. HRMS (ESI+) m / z: calcd for C19H23IN2NaSi: 457.0567 [M+H]+; found: 457.0555 for compound 116. HRMS (ESI+) m / z: calcd for C30H44N2NaSi2: 511.2935 [M+Na]+; found: 511.2922 for compound 117. - 146 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0342] Compound 118: Compound 118 was synthesized according to general procedure of synthesis of substituted 1,3-diiminoisoindoline derivatives. Yield 96%.1H NMR (400 MHz, CD3OD): 71.21 (s, 21H), 8.00 (d, J = 0.5 Hz, 1H), 8.41 (d, J = 0.5 Hz, 1H). HRMS (ESI+) m / z: calcd for C19H27IN3Si: 452.1014 [M+H]+; found: 452.1003.

[0343] Compound 119, 120: Compound 119 was synthesized according to general procedure of synthesis of A3B-type silicon phthalocyanine dihydroxide derivatives (compound 46, 67, 85) except for chemical equivalent of SiCl4 (2.8 eq). Compound 120 was obtained as a reaction byproduct. The mixture was used as is for the next step.

[0344] Compound 121, 122: Compound 121 and compound 122 were synthesized according to general procedure of addition reaction of axial ligands to A3B-type silicon phthalocyanine dihydroxide derivatives (compound 47, 68, 86). The mixture was used as is for the next step.

[0345] Compound 123, 124: Compound 123 and compound 124 were synthesized according to general procedure of alkyl sulfonation of A3B-type silicon phthalocyanine derivatives (compound 48, 69, 87) except for chemical equivalent of 1,3-propanesultone (40 eq). In some examples, reverse-phase HPLC was performed, but compound 123 and compound 124 could not be separated. The mixture was used as is for the next step. In other examples, the compounds could be separated and the following characterization data were obtained: HRMS (ESI−) m / z: calcd for C71H95IN10Na2O20S6Si4: 942.1488 [M−2Na]2−; found: 942.1517 for compound 123. HRMS (ESI−) m / z: calcd for C71H95ClN10Na2O20S6Si4: 896.1810 [M−2Na]2−; found: 896.1838 for compound 124.

[0346] Compound 125, 126: Compound 125 and compound 126 were synthesized according to general procedure of deprotection reaction of triisopropylsilyl group. Yield 2.7% (5 steps) for compound 126. Compound 125 still contained unknown impurities after reverse- phase HPLC purification.1H NMR (400 MHz, CD3OD): 7 −2.76 (s, 12H), −2.20 (t, J = 8.4 Hz, 4H), −0.78–−0.70 (m, 4H)1.66–1.74 (m, 12H), 2.03 (t, J = 8.2 Hz, 4H), 2.72 (t,J = 6.7 Hz, 12H), 2.78–2.82 (m, 12H), 4.42 (s, 1H), 8.50–8.55 (m, 6H), 9.75–9.80 (m, 7H), 9.87 (s, 1H). HRMS (ESI−) m / z: calcd for C62H75IN10Na2O20S6Si3: 864.0821 [M−2Na]2−; found: 864.0850 for compound 125. HRMS (ESI+) m / z: calcd for C62H75ClN10Na2O20S6Si3: 818.1143 [M−2Na]2−; found: 818.1171 for compound 126.

[0347] ^-I-Tz-IR700C10COOH: ^-I-Tz-IR700C10COOH was synthesized according to general procedure of click reaction except for chemical equivalent of azido compound (1 eq). Yield 1.0% (6 steps).1H NMR (400 MHz, CD3OD): 7 −2.75 (s, 12H), −2.18 (t, J = 8.4 Hz, - 147 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-014H), −0.80–−0.72 (m, 4H), 1.39–1.46 (m, 6H), 1.50–1.57 (m, 4H), 1.64–1.75 (m, 14H), 2.04 (t, J = 8.1 Hz, 4H), 2.16–2.22 (m, 4H), 2.72 (t, J = 6.7 Hz, 12H), 2.78–2.83 (m, 12H), 4.70 (t, J = 7.2 Hz, 2H), 8.50–8.55 (m, 6H), 8.91 (s, 1H), 9.72–9.74 (m, 1H), 9.77–9.81 (m, 5H), 9.88 (d, J = 0.4 Hz, 1H), 10.3 (d, J = 0.4 Hz, 1H). HRMS (ESI−) m / z: calcd for C72H93IN13Na3O22S6Si3: 981.6469 [M−2Na]2−; found: 981.6506.

[0348] ^-Cl-Tz-IR700C10COOH: ^-Cl-Tz-IR700C10COOH was synthesized according to general procedure of click reaction. Yield 95%.1H NMR (400 MHz, CD3OD): 7 −2.75 (s, 12H), −2.18 (t, J = 8.4 Hz, 4H), −0.80–−0.71 (m, 4H), 1.39–1.45 (m, 6H), 1.50–1.58 (m, 4H), 1.64–1.74 (m, 14H), 2.04 (t, J = 8.1 Hz, 4H), 2.15–2.22 (m, 4H), 2.71 (t, J = 6.7 Hz, 12H), 2.78–2.83 (m, 12H), 4.69 (t, J = 7.4 Hz, 2H), 8.51–8.55 (m, 6H), 9.01 (s, 1H), 9.75–9.81 (m, 6H), 9.87 (s, 1H), 10.3 (s, 1H). HRMS (ESI−) m / z: calcd for C72H93ClN13Na3O22S6Si3: 935.6791 [M−2Na]2−; found: 935.6828.

[0349] ^-I-Tz-IR700C10SE: ^-I-Tz-IR700C10SE was synthesized according to general procedure of synthesis of succinimidyl ester compounds. HRMS (ESI−) m / z: calcd for C76H97IN14Na2O24S6Si3: 1019.1642 [M−2Na]2−; found: 1019.1684.

[0350] ^-Cl-Tz-IR700C10SE: ^-Cl-Tz-IR700C10SE was synthesized according to general procedure of synthesis of succinimidyl ester compounds. HRMS (ESI−) m / z: calcd for C76H97ClN14Na2O24S6Si3: 973.1964 [M−2Na]2−; found: 973.2006. Example 13

[0351] In this example, compounds comprising a bromo substituent attached to the phthalocyanine core in addition to a Linker-X group were prepared according to the method described below and summarized in Scheme 46. - 148 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01Scheme 46

[0352] Compound 128: Compound 127 (5.13 g, 22.7 mmol) and I2 (5.75 g, 22.7 mmol) were dissolved in fuming H2SO4 (10 mL) and the mixture was stirred at 90^ for 45 h. Then, - 149 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01the reaction mixture was poured into ice and the precipitate was collected, washed with 2% K2CO3aq, saturated NaNO2aq and H2O, and dried (10.2 g). In some examples, the product contained unknown impurities, but was used for the next step. In other examples, the following characterization data were obtained: HRMS (ESI−) m / z: calcd for C8H2BrINO2: 349.8319 [M−H]−; found: 349.8325.

[0353] Compound 129: Compound 128 (10.2 g) was suspended in NH4OH (80 mL) and the mixture was stirred at 60^ for 1.5 h. Then, the precipitate was collected, wash with cold H2O and MeOH, and dried to afford the product (5.40 g, 14.6 mmol, 65% (2 steps)).1H NMR (400 MHz, DMSO-d6): 77.45 (br, 2H), 7.75 (s, 1H), 7.85 (br, 2H), 7.96 (s, 1H). HRMS (ESI+) m / z: calcd for C8H6BrIN2NaO2: 390.8550 [M+Na]+; found: 390.8547.

[0354] Compound 130: Compound 129 (5.16 g, 14.0 mmol) was dissolved in pyridine (100 mL) and dioxane (40 mL) under an Ar atmosphere and POCl3(5 mL, 53.5 mmol) was slowly added dropwise to the solution at 0^. Then, the reaction mixture was stirred at room temperature for 5 h. H2O was added to the mixture at 0^. After evaporation, the residue was dissolved in AcOEt and the organic layer was washed with H2O and saturated NaClaq, dried over Na2SO4, filtered and evaporated. The crude product was purified with silica gel column chromatography to afford the pure product (1.62 g, 4.87 mmol, 35%).1H NMR (400 MHz, CDCl3): 78.00 (s 1H) 8.26 (s 1H). HRMS (ESI−) m / z: calcd for C8HBrIN2: 330.8373[ ] o pou o pou ( . g, . o), ( sopopylsilyl)acetylene (0.824 g, 4.52 mmol), PdCl2(PPh3)2 (41.7 mg, 59.48mol), CuI (60.6 mg, 3188mol) and NEt3 (0.625 g, 6.18 mmol) were dissolved in tetrahydrofuran (15 mL) and the mixture was stirred under an Ar atmosphere at room temperature for 12 h and at 60^ for 6.5 h. Then, saturated NH4Claq was added to the mixture, followed by extraction with AcOEt. The organic layer was washed with saturated NaClaq, dried over Na2SO4, filtered and evaporated. The crude product was purified with silica gel column chromatography to afford the pure product (0.821 g, 2.12 mmol, 64%).1H NMR (400 MHz, CDCl3): 71.14–1.16 (m, 21H), 7.85 (d, J = 0.3 Hz, 1H), 8.02 (d, J = 0.3 Hz, 1H). HRMS (ESI+) m / z: calcd for C19H23BrN2NaSi: 409.0706 [M+Na]+; found: 409.0694.

[0356] Compound 132: Compound 132 was synthesized according to general procedure of synthesis of substituted 1,3-diiminoisoindoline derivatives. Yield 99%.1H NMR (400 MHz, CD3OD): 71.19 (s, 21H), 8.04 (d, J = 0.3 Hz, 1H), 8.16 (d, J = 0.3 Hz, 1H). HRMS (ESI+) m / z: calcd for C19H27BrN3Si: 404.1152 [M+H]+; found: 404.1145. - 150 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0357] Compound 133: Compound 133 was synthesized according to general procedure of synthesis of A3B-type silicon phthalocyanine dihydroxide derivatives (compound 46, 67, 85) except for chemical equivalent of SiCl4 (2.6 eq).

[0358] Compound 134: Compound 134 was synthesized according to general procedure of addition reaction of axial ligands to A3B-type silicon phthalocyanine dihydroxide derivatives (compound 47, 68, 86).

[0359] Compound 135: Compound 135 was synthesized according to general procedure of alkyl sulfonation of A3B-type silicon phthalocyanine derivatives (compound 48, 69, 87). Compound 125 still contained unknown impurities after reverse-phase HPLC purification. In some examples, the following characterization data were obtained: HRMS (ESI−) m / z: calcd for C71H95BrN10Na2O20S6Si4: 918.1558 [M−2Na]2−; found: 918.1597.

[0360] Compound 136: Compound 136 was synthesized according to general procedure of deprotection reaction of triisopropylsilyl group. Yield 0.4% (5 steps).1H NMR (400 MHz, CD3OD): 7 −2.76 (s, 12H), −2.21 (t, J = 8.4 Hz, 4H), −0.75–−0.67 (m, 4H), 1.66–1.74 (m, 12H), 2.04 (t, J = 8.2 Hz, 4H), 2.71 (t, J = 6.7 Hz, 12H), 2.78–2.82 (m, 12H), 4.41 (s, 1H), 8.51–8.55 (m, 6H), 9.75–9.80 (m, 6H), 9.85 (s, 1H), 9.97 (d, J = 0.4 Hz, 1H). HRMS (ESI−) m / z: calcd for C62H75BrN10Na2O20S6Si3: 840.0890 [M−2Na]2−; found: 840.0922.

[0361] ^-Br-Tz-IR700C10COOH: ^-Br-Tz-IR700C10COOH was synthesized according to general procedure of click reaction. Yield 67%.1H NMR (400 MHz, CD3OD): 7 −2.75 (s, 12H), −2.18 (t, J = 8.4 Hz, 4H), −0.79–−0.72 (m, 4H), 1.40–1.46 (m, 6H), 1.50–1.58 (m, 4H), 1.67–1.74 (m, 14H), 2.04 (t, J = 8.1 Hz, 4H), 2.17–2.22 (m, 4H), 2.71 (t, J = 6.7 Hz, 12H), 2.79–2.83 (m, 12H), 4.69 (t, J = 7.3 Hz, 2H), 8.50–8.55 (m, 6H), 9.00 (s, 1H), 9.73–9.76 (m, 1H), 9.77–9.81 (m, 5H), 10.1 (d, J = 0.3 Hz, 1H), 10.1 (s, 1H). HRMS (ESI−) m / z: calcd for C72H93BrN13Na3O22S6Si3: 9539 [M−2Na]2−; found: 957.6579.

[0362] ^-Br-Tz-IR700C10SE: ^-Br-Tz-IR700C10SE was synthesized according to general procedure of synthesis of succinimidyl ester compounds. HRMS (ESI−) m / z: calcd for C76H97BrN14Na2O24S6Si3: 995.1711 [M−2Na]2−; found: 995.1746. Example 14

[0363] In this example, compounds comprising two linker groups and two X groups were prepared according to the method described below and summarized in Scheme 47. - 151 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01Scheme 47

[0364] Compound 137: Compound 137 was synthesized according to general procedure of synthesis of substituted 1,3-diiminoisoindoline derivatives. Yield 99%.1H NMR (400 MHz, CD3OD): 71.18 (s, 42H), 8.04 (s, 2H). HRMS (ESI+) m / z: calcd for C30H47N3NaSi2: 528.3201 [M+Na]+; found: 528.3189.

[0365] Compound 138: Compound 138 was synthesized according to general procedure of synthesis of A3B-type silicon phthalocyanine dihydroxide derivatives (compound 46, 67, 85).

[0366] Compound 139: Compound 139 was synthesized according to general procedure of addition reaction of axial ligands to A3B-type silicon phthalocyanine dihydroxide derivatives (compound 47, 68, 86). - 152 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0367] Compound 140: A crude compound 139 (0.217 g), 1,3-propanesultone (1.11 g, 9.05 mmol) and iPr2EtN (1.45 g, 11.2 mmol) were dissolved in MeOH (10 mL) and the mixture was stirred at 50^ under an Ar atmosphere for 24 h. Then, AgF (224 mg, 1.76 mmol) was added to the reaction mixture and the mixture was stirred at room temperature under an Ar atmosphere in the dark for 3.5 h. Saturated NH4Claq (1 mL) was added to the mixture and the mixture was stirred at room temperature in the dark for 10 min. The reaction solution was concentrated and the residue was purified with reverse-phase HPLC (eluent A: 0.1 M triethylamine acetate solution, eluent B: CH3CN). The product was desalted with a Sep-Pak C18 cartridge and cation-exchange resin, affording the pure product as a sodium salt (5.3 mg, 3.178mol, 1.4% (5 steps)).1H NMR (400 MHz, CD3OD): 7 −2.76 (s, 12H), −2.21 (t, J = 8.4 Hz, 4H), −0.76–−0.67 (m, 4H), 1.66–1.73 (m, 12H), 2.03 (t, J = 8.2 Hz, 4H), 2.71 (t, J = 6.7 Hz, 12H), 2.78–2.82 (m, 12H), 3.35 (s, 2H), 8.48 (dd, J = 2.9, 5.8 Hz, 1H), 8.51–8.55 (m, 5H), 9.75–9.80 (m, 6H), 9.82 (s, 2H). HRMS (ESI−) m / z: calcd for C64H76N10Na2O20S6Si3: 813.1338 [M−2Na]2−; found: 813.1367.

[0368] ^-diTz-IR700C10COOH: ^-diTz-IR700C10COOH was synthesized according to general procedure of click reaction. Yield 51%.1H NMR (400 MHz, CD3OD): 7 −2.74 (s, 12H), −2.13 (t, J = 8.3 Hz, 4H), −0.89–−0.81 (m, 4H), 1.40–1.46 (m, 12H), 1.49–1.54 (m, 8H), 1.64–1.75 (m, 16H), 2.03 (t, J = 8.1 Hz, 4H), 2.07–2.14 (m, 4H), 2.21 (t, J = 7.6 Hz, 4H), 2.74 (t, J = 6.7 Hz, 12H), 2.78–2.82 (m, 12H), 4.60 (t, J = 7.3 Hz, 4H), 8.32 (s, 2H), 8.51– 8.55 (m, 6H), 9.77–9.82 (m, 6H), 10.0 (s, 2H). HRMS (ESI−) m / z: calcd for C84H112N16Na4O24S6Si3: 1048.2635 [M−2Na]2−; found: 1048.2675.

[0369] ^-diTz-IR700C10SE: ^-diTz-IR700C10SE was synthesized according to general procedure of synthesis of succinimidyl ester compounds. HRMS (ESI−) m / z: calcd for C92H120N18Na2O28S6Si3: 1123.2979 [M−2Na]2−; found: 1123.3022. Example 15

[0370] In this example, compounds comprising ethyl-substituted silyl groups within the phthalocyanine core were prepared according to the method described below and summarized in Scheme 48. - 153 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01^^'"&?^^ ^^^^^ ^^^ 9^ ^^^^^ ^^ ^^^^ ^^^^^ ^^^^ ^^ ^ ^< ^:'"^^ )&^^ &^^ :< ^ ^^^ ^^^ ^^^ ^^^^^^^ ^^^^^^

[0371] Compound 142: Compound 141 (2.01 g, 8.26 mmol) was dissolved in tetrahydrofuran (30 mL) under an Ar atmosphere. EtMgBr (3 M in Et2O, 6.9 mL, 20.7 mmol) was added to the solution and the mixture was stirred at 60^ for 3 h. AcOEt was added to the reaction mixture and the organic layer was washed with H2O and saturated NaClaq, dried over Na2SO4, filtered and evaporated. The crude product was purified with silica gel column chromatography to afford the pure product (1.25 g, 5.23 mmol, 63%).1H NMR (400 MHz, CDCl3): 70.60–0.66 (m, 4H), 0.71–0.76 (m, 2H), 0.97 (t, J = 7.9 Hz, 6H), 1.87–1.95 - 154 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01(m, 2H), 3.41 (t, J = 7.0 Hz, 2H), 3.47 (s, 3H). HRMS (ESI+) m / z: calcd for C8H19BrNaOSi: 261.0281 [M+Na]+; found: 261.0272.

[0372] Compound 143: Compound 143 was synthesized according to general procedure of synthesis of azido fatty acid compounds (compound 57, 59, 73). Yield 92%.1H NMR (400 MHz, CDCl3): 70.60–0.68 (m, 6H), 0.98 (t, J = 7.9 Hz, 6H), 1.62–1.70 (m, 2H), 3.26 (t, J = 7.0 Hz, 2H), 3.47 (s, 3H). HRMS (ESI+) m / z: calcd for C8H19N3NaOSi: 224.1195 [M+Na]+; found: 224.1181.

[0373] Compound 144: Compound 143 (0.752 g, 3.73 mmol) was dissolved in MeOH (8 mL) and tetrahydrofuran (2.5 mL). NiCl2(0.147 g, 1.13 mmol) was added to the solution at 0^. Then, NaBH4(0.276 g, 7.30 mmol) was added portionwise to the mixture and the reaction mixture was stirred at 0^ for 20 min and room temperature for 40 min under an Ar atmosphere. The mixture was filtered and the filtrate was evaporated. The residue was suspended with CH2Cl2 and the mixture was filtered again. The filtrate was evaporated and dried to afford the pure product (0.503 g, 2.87 mmol, 77%).1H NMR (400 MHz, CDCl3): 7 0.59–0.65 (m, 6H), 0.97 (t, J = 7.9 Hz, 6H), 1.45–1.53 (m, 2H), 2.68 (t, J = 6.9 Hz, 2H), 3.47 (s, 3H). HRMS (ESI+) m / z: calcd for C8H22NOSi: 176.1465 [M+H]+; found: 176.1457.

[0374] Compound 145: Compound 145 was synthesized according to general procedure of addition reaction of axial ligands to A3B-type silicon phthalocyanine dihydroxide derivatives (compound 47, 68, 86) except that compound 144 was used instead of (3- aminopropyl)dimethylethoxysilane.

[0375] Compound 146: Compound 146 was synthesized according to general procedure of alkyl sulfonation of A3B-type silicon phthalocyanine derivatives (compound 48, 69, 87). Yield 8.2% (4 steps).1H NMR (400 MHz, CD3OD): 7 −2.39–−2.21 (m, 12H), −1.20–−1.15 (m, 12H), −0.75–−0.67 (m, 4H), 1.37 (s, 21H), 1.72–1.80 (m, 12H), 2.07 (t, J = 8.1 Hz, 4H), 2.76 (t, J = 6.7 Hz, 12H), 2.85–2.89 (m, 12H), 8.49–8.55 (m, 7H), 9.69–9.75 (m, 2H), 9.77–9.81 (m, 6H). HRMS (ESI−) m / z: calcd for C75H104N10Na2O20S6Si4: 907.2318 [M−2Na]2−; found: 907.2349.

[0376] Compound 147: Compound 147 was synthesized according to general procedure of deprotection reaction of triisopropylsilyl group. Yield 61%.1H NMR (400 MHz, CD3OD): 7 −2.39–−2.24 (m, 12H), −1.18 (dt, J = 2.1, 7.9 Hz, 12H), −0.76–−0.68 (m, 4H), 1.73–1.81 (m, 12H), 2.06 (t, J = 8.2 Hz, 4H), 2.76 (t, J = 6.8 Hz, 12H), 2.85–2.89 (m, 12H), 4.09 (s, 1H), 8.51–8.55 (m, 7H), 9.75 (dd, J = 0.6, 7.9 Hz, 1H), 9.76–9.80 (m, 7H). HRMS (ESI−) m / z: calcd for C66H84N10Na2O20S6Si3: 829.1651 [M−2Na]2−; found: 829.1683. - 155 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0377] ^-Tz-IR700C10COOH-diEtSi: ^-Tz-IR700C10COOH-diEtSi was synthesized according to general procedure of click reaction. Yield 83%.1H NMR (400 MHz, CD3OD): 7 −2.41–−2.22 (m, 12H), −1.15 (dt, J = 1.3, 8.0 Hz, 12H), −0.84–−0.75 (m, 4H), 1.39–1.45 (m, 6H), 1.50–1.58 (m, 4H), 1.61–1.69 (m, 2H), 1.73–1.81 (m, 12H), 2.06 (t, J = 8.2 Hz, 4H), 2.14–2.22 (m, 4H), 2.77 (t, J = 6.9 Hz, 12H), 2.85–2.89 (m, 12H), 4.68 (t, J = 7.4 Hz, 2H), 8.52–8.56 (m, 6H), 9.03 (dd, J = 1.4, 8.0 Hz, 1H), 9.18 (s, 1H), 9.79–9.81 (m, 5H), 9.82–9.87 (m, 2H), 10.2 (dd, J = 0.8, 1.2 Hz, 1H). HRMS (ESI−) m / z: calcd for C76H102N13Na3O22S6Si3: 946.7299 [M−2Na]2−; found: 946.7336.

[0378] ^-Tz-IR700C10SE-diEtSi: ^-Tz-IR700C10SE-diEtSi was synthesized according to general procedure of synthesis of succinimidyl ester compounds. HRMS (ESI−) m / z: calcd for C80H106N14Na2O24S6Si3: 984.2471 [M−2Na]2−; found: 984.2508. Example 16

[0379] In this example, compounds comprising iso-propyl-substituted silyl groups within the phthalocyanine core were prepared according to the method described below and summarized in Scheme 49. - 156 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01^^ ^^"^^2&^^ ^^^^ ^^^ 9^ ^^^^^^^^ ^^ ^^ ^^ ^^ ^ ^^ ^^ ^ ^^^ ^^ ^ ^^!-!^#^^%^^^ ^^ ^-^^^^^^ )&^^ &^^ < ^ ^^^^ : ^^^ ^^^ ^^^Scheme 49

[0380] Compound 149: Compound 148 (2.58 g, 17.1 mmol), allyl bromide (1.68 g, 13.9 mmol) and H2PtCl6(4.4 mg, 8.508mol) were dissolved in cyclohexane (15 mL) and the mixture was stirred at 100^ under an Ar atmosphere for 11 h. The reaction mixture was evaporated and dried. The crude product was used as is for the next step without further purification.

[0381] Compound 150: Compound 149 was dissolved in pyridine (10 mL) at 0^ and MeOH (1.6 mL, 39 mmol) was added dropwise to the solution. The reaction mixture was stirred at - 157 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01room temperature under an Ar atmosphere for 6.5 h. The precipitate was filtered and the filtrate was evaporated. The residue was azeotropic dried with toluene, and the crude product was purified with silica gel column chromatography to afford the product (0.883 g). Compound 150 still contained unknown impurities, but was used for the next step. In some examples, the following characterization data were obtained: HRMS (ESI+) m / z: calcd for C10H23BrNaOSi: 289.0594 [M+Na]+; found: 289.0587.

[0382] Compound 151: Compound 151 was synthesized according to general procedure of synthesis of azido fatty acid compounds (compound 57, 59, 73). Yield 14% (3 steps).1H NMR (400 MHz, CDCl3): 70.67–0.71 (m, 2H), 1.03–1.05 (m, 14H), 1.66–1.73 (m, 2H), 3.26 (t, J = 6.9 Hz, 2H), 3.52 (s, 3H). HRMS (ESI+) m / z: calcd for C10H23N3NaOSi: 252.1503 [M+Na]+; found: 252.1496.

[0383] Compound 152: Compound 151 (442 mg, 1.93 mmol) was dissolved in MeOH (4.5 mL) and tetrahydrofuran (1.5 mL). NiCl2 (84.6 mg, 0.653 mmol) was added to the solution at 0^. NaBH4 (161 mg, 4.25 mmol) was added portionwise to the mixture and the reaction mixture was stirred at 0^ for 20 min and room temperature for 40 min under an Ar atmosphere. Then, the mixture was filtered and the filtrate was evaporated. The residue was suspended with CH2Cl2 was the mixture was filtered again. The filtrate was evaporated and dried to afford the product (0.319 g, 1.57 mmol, 81%).1H NMR (400 MHz, CDCl3): 70.62– 0.66 (m, 2H), 1.04 (s, 14H), 1.54 (br, 2H), 2.71 (br, 2H), 3.52 (s, 3H). HRMS (ESI+) m / z: calcd for C10H26NOSi: 204.1778 [M+H]+; found: 204.1751.

[0384] Compound 153: Compound 153 was synthesized according to general procedure of addition reaction of axial ligands to A3B-type silicon phthalocyanine dihydroxide derivatives (compound 47, 68, 86 of Examples 2, 4, and 7, respectively) except that compound 152 was used instead of (3-aminopropyl)dimethylethoxysilane.

[0385] Compound 154: Compound 154 was synthesized according to general procedure of alkyl sulfonation of A3B-type silicon phthalocyanine derivatives (compound 48, 69, 87, Examples 2, 4, and 7, respectively). Yield 9.7% (4 steps).1H NMR (400 MHz, CD3OD): 7 −2.70–−2.65 (m, 4H), −1.81–−1.73 (m, 4H), −1.28 (dd, J = 1.3, 7.4 Hz, 12H), −1.18 (dd, J = 1.3, 7.4 Hz, 12H), −0.25–−0.16 (m, 4H), 1.30 (t, J = 7.3 Hz, 3H), 1.37 (s, 18H), 1.76–1.83 (m, 12H), 2.02–2.09 (m, 4H), 2.72 (t, J = 6.6 Hz, 12H), 2.97–3.01 (m, 12H), 8.48 (dd, J = 1.3, 8.0 Hz, 1H), 8.49–8.53 (m, 6H), 9.66–9.70 (m, 2H), 9.72–9.76 (m, 6H). HRMS (ESI+) m / z: calcd for C10H26NOSi: 204.1778 [M+H]+; found: 204.1751. - 158 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0386] Compound 155: Compound 155 was synthesized according to general procedure of deprotection reaction of triisopropylsilyl group (such as shown in Examples 2, 4, and 7). Yield 56%.1H NMR (400 MHz, CD3OD): 7 −2.69 (t, J = 8.5 Hz, 4H), −1.81–−1.74 (m, 4H), −1.28 (d, J = 7.4 Hz, 12H), −1.19 (d, J = 7.4 Hz, 12H), −0.25–−0.17 (m, 4H), 1.77–1.84 (m, 12H), 2.05 (t, J = 8.1 Hz, 4H), 2.73 (t, J = 6.7 Hz, 12H), 2.98–3.02 (m, 12H), 4.10 (s, 1H), 8.51–8.53 (m, 7H), 9.70 (dd, J = 0.7, 8.0 Hz, 1H), 9.72–9.76 (m, 7H). HRMS (ESI−) m / z: calcd for C70H92N10Na2O20S6Si3: 857.1964 [M−2Na]2−; found: 857.1994.

[0387] ^-Tz-IR700C10COOH-diPrSi: ^-Tz-IR700C10COOH-diPrSi was synthesized according to general procedure of click reaction (such as shown in Examples 2, 4, and 7). Yield 74%.1H NMR (400 MHz, CD3OD): 7 −2.63 (t, J = 8.5 Hz, 4H), −1.82–−1.75 (m, 4H), −1.25 (dd, J = 1.1, 7.4 Hz, 12H), −1.17 (d, J = 7.4 Hz, 12H), −0.30–−0.21 (m, 4H), 1.39–1.45 (m, 6H), 1.51–1.58 (m, 4H), 1.62–1.69 (m, 2H), 1.76–1.83 (m, 12H), 2.05 (t, J = 8.0 Hz, 4H), 2.16–2.22 (m, 4H), 2.72 (t, J = 6.7 Hz, 12H), 2.97–3.01 (m, 12H), 4.68 (t, J = 7.4 Hz, 2H), 8.52 (dd, J = 2.9, 5.8 Hz, 6H), 8.99 (dd, J = 1.4, 8.0 Hz, 1H), 9.13 (s, 1H), 9.75 (dd, J = 2.9, 5.8 Hz, 5H), 9.78–9.82 (m, 2H), 10.2 (dd, J = 0.8, 1.2 Hz, 1H). HRMS (ESI−) m / z: calcd for C80H110N13Na3O22S6Si3: 974.7612 [M−2Na]2−; found: 974.7650.

[0388] ^-Tz-IR700C10SE-diPrSi: ^-Tz-IR700C10SE-diPrSi was synthesized according to general procedure of synthesis of succinimidyl ester compounds, such as shown in Examples 2, 4, and 7). HRMS (ESI−) m / z: calcd for C84H114N14Na2O24S6Si3: 1012.2784 [M−2Na]2−; found: 1012.2823. Example 17

[0389] In this example, compounds comprising phenyl-substituted silyl groups within the phthalocyanine core were prepared according to the method described below and summarized in Scheme 50. - 159 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01^^^^&?^^^^ ^^ ^^^^ ^^ ^^ ^ ^^ ^^^^ ^ ^^ ^^ ^^ 9^ ^^^^^^ ^^^ ^ ^^^ ^< : ) ^ ^^^' & &^^ < ^ ^^"^^ ^ : ^^^ ^^^ ^^^ ^^^^^^^ ^^^^^^Scheme 50

[0390] Compound 156: Compound 141 (2.99 g, 12.3 mmol) was dissolved in tetrahydrofuran (25 mL) under an Ar atmosphere. PhMgBr (3 M in Et2O, 9 mL, 27 mmol) was added to the solution and the mixture was stirred at 60^ for 3 h. AcOEt was added to the reaction mixture and the organic layer was washed with H2O and saturated NaClaq, dried over Na2SO4, filtered and evaporated. The crude product was purified with silica gel column chromatography to afford the pure product (3.38 g, 10.1 mmol, 82%).1H NMR (400 MHz, CDCl3): 71.26–1.30 (m, 2H), 1.93–2.00 (m, 2H), 3.41 (t, J = 6.8 Hz, 2H), 3.54 (s, 3H), 7.37– - 160 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-017.46 (m, 6H), 7.57–7.59 (m, 4H). HRMS (ESI+) m / z: calcd for C16H19BrNaOSi: 357.0281 [M+Na]+; found: 357.0269.

[0391] Compound 157: Compound 157 was synthesized according to general procedure of synthesis of azido fatty acid compounds (compound 57, 59, 73, such as in Examples 2 and 4). Yield quant.1H NMR (400 MHz, CDCl3): 71.17–1.21 (m, 2H), 1.67–1.75 (m, 2H), 3.26 (t, J = 6.9 Hz, 2H), 3.54 (s, 3H), 7.37–7.44 (m, 6H), 7.57–7.59 (m, 4H). HRMS (ESI+) m / z: calcd for C16H19N3NaOSi: 320.1190 [M+Na]+; found: 320.1179.

[0392] Compound 158: Compound 157 (904 mg, 3.04 mmol) was dissolved in MeOH (9 mL) and tetrahydrofuran (3 mL). NiCl2(127 mg, 0.976 mmol) was added to the solution at 0^. NaBH4(234 mg, 6.1 mmol) was added portionwise to the mixture and the reaction mixture was stirred at 0^ for 20 min and room temperature for 40 min under an Ar atmosphere. Then, the mixture was filtered and the filtrate was evaporated. The residue was suspended with CH2Cl2 was the mixture was filtered again. The filtrate was evaporated and dried to afford the product (576 mg, 2.12 mmol, 70%).1H NMR (400 MHz, CDCl3): 71.15 (t, J = 8.4 Hz, 2H), 1.52–1.59 (m, 2H), 2.69 (br, 2H), 3.54 (s, 3H), 7.36–7.43 (m, 6H), 7.57–7.60 (m, 4H). HRMS (ESI+) m / z: calcd for C16H22NOSi: 272.1465 [M+H]+; found: 272.1456.

[0393] Compound 159: Compound 159 was synthesized according to general procedure of addition reaction of axial ligands to A3B-type silicon phthalocyanine dihydroxide derivatives (compound 47, 68, 86, such as in Examples 2, 4, and 7, respectively) except that compound 179 was used instead of (3-aminopropyl)dimethylethoxysilane.

[0394] Compound 160: Compound 160 was synthesized according to general procedure of alkyl sulfonation of A3B-type silicon phthalocyanine derivatives (compound 48, 69, 87, such as in Examples 2, 4, and 7, respectively). Yield 4.5% (4 steps).1H NMR (400 MHz, CD3OD): 7 −1.73–−1.64 (m, 4H), −0.85–−0.65 (m, 4H), 1.39 (s, 21H), 1.42–1.50 (m, 12H), 2.52–2.61 (m, 24H), 4.80 (t, J = 6.6 Hz, 8H), 6.36–6.41 (m, 8H), 6.74–6.81 (m, 4H), 8.47–8.56 (m, 7H), 9.52 (s, 1H), 9.55–9.58 (m, 1H), 9.62–9.46 (m, 2H), 9.66–9.69 (m, 1H), 9.71–9.78 (m, 3H). HRMS (ESI−) m / z: calcd for C91H104N10Na2O20S6Si4: 1003.2318 [M−2Na]2−; found: 1003.2354.

[0395] Compound 161: Compound 161 was synthesized according to general procedure of deprotection reaction of triisopropylsilyl group, such as shown in Examples 2, 4, and 7, respectively. Yield 55%.1H NMR (400 MHz, CD3OD): 7 −1.70–−1.65 (m, 4H), −0.83–−0.75 (m, 4H), 1.43–1.51 (m, 12H), 1.72 (t, J = 8.3 Hz, 4H), 2.53–2.57 (m, 12H), 2.60 (t, J = 6.8 Hz, 12H), 4.11 (s, 1H), 4.80 (td, J = 1.6, 7.7 Hz, 8H), 6.38 (dt, J = 1.1, 7.7 Hz, 8H), 6.75–6.80 - 161 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01(m, 4H), 8.50–8.56 (m, 7H), 9.59 (dd, J = 0.6, 7.9 Hz, 1H), 9.63–9.75 (m, 7H). HRMS (ESI−) m / z: calcd for C82H84N10Na2O20S6Si3: 925.1651 [M−2Na]2−; found: 925.1687.

[0396] ^-Tz-IR700C10COOH-diPhSi: ^-Tz-IR700C10COOH-diPhSi was synthesized according to general procedure of click reaction, such as shown in Examples 2, 4, and 7, respectively. Yield 96%.1H NMR (400 MHz, CD3OD): 7 −1.63 (t, J = 7.3 Hz, 4H), −0.88– −0.75 (m, 4H), 1.43–1.50 (m, 18H), 1.53–1.62 (m, 4H), 1.63–1.72 (m, 6H), 2.17–2.21 (m, 4H), 2.51–2.56 (m, 12H), 2.61 (t, J = 6.9 Hz, 12H), 4.69 (t, J = 7.4 Hz, 2H), 4.80 (td, J = 1.2, 7.8 Hz, 8H), 6.38 (dt, J = 1.0, 7.8 Hz, 8H), 6.73–6.79 (m, 4H), 8.51–8.55 (m, 6H), 9.01 (dd, J = 1.4, 8.0 Hz, 1H), 9.19 (s, 1H), 9.67–9.73 (m, 7H), 10.1 (dd, J = 0.8, 1.2 Hz, 1H). HRMS (ESI−) m / z: calcd for C92H102N13Na3O22S6Si3: 1042.7299 [M−2Na]2−; found: 1042.7340.

[0397] ^-Tz-IR700C10SE-diPhSi: ^-Tz-IR700C10SE-diPhSi was synthesized according to general procedure of synthesis of succinimidyl ester compounds, such as shown in Examples 2, 4, and 7, respectively. HRMS (ESI−) m / z: calcd for C96H106N14Na2O24S6Si3: 1080.2471 [M−2Na]2−; found: 1080.2514. Example 18

[0398] In this example, compounds comprising a pyridyl-containing linker group were prepared using a Heck reaction with ^-Br SiPc-NH2 and a pyridine comprising a linker as detailed below and summarized in Scheme 51. - 162 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01^ ^ ^ ^^ ^ ^ ^ ^ ^ ^^^^Scheme 51

[0399] Procedure for making Compound 163: Compound 162 (2-bromo-5-hydroxypiridine, 2.10 g, 12.1 mmol), methyl 6-bromohexanoate (2.32 g, 11.1 mmol) and potassium carbonate (4.51 g, 32.7 mmol) were dissolved in acetone (20 mL), and the mixture was refluxed for 14 hours. After the addition of 1 M HCl and brine, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate, 3 / 1 to 2 / 1) to give compound 163 (3.19 g, 10.6 mmol, y.95%) as a colorless oil.1H NMR (400 MHz, - 163 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01CDCl3) 78.03 (d, J = 3.0 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.09 (dd, J = 8.7, 3.0 Hz, 1H), 3.98 (t, J = 6.4 Hz, 2H), 3.67 (s, 3H), 2.35 (t, J = 7.4 Hz, 2H), 1.85–1.78 (m, 2H), 1.74–1.67 (m, 2H), 1.54–1.47 (m, 2H). LRMS (ESI+) m / z: [M+H]+calcd for C12H16BrNO3302.0392; found 302. HRMS (ESI+) m / z: calcd for C12H16BrNO3: 302.0386 [M+H]+; found: 302.0382.

[0400] Procedure for making Compound 164: Compound 163 (1.52 g, 5.1 mmol), vinylboronic acid pinacol ester (1.25 g, 8.1 mmol), cesium fluoride (2.29 g, 15.1 mmol) and bis(triphenylphosphine)palladium(II) dichloride (76 mg, 506 µmmol) were dissolved in dioxane / H2O (10 mL / 5 mL), and the mixture was stirred at 80 °C under an Ar atmosphere for 21 hours. After the addition of brine, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate, 1 / 0 to 3 / 1) to give compound 164 (565 mg, 2.27 mmol, y.45%) as a colorless oil.1H NMR (400 MHz, CDCl3) 7 8.23 (d, J = 2.8 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.13 (dd, J = 8.6, 2.8 Hz, 1H), 6.77 (dd, J = 17.5, 10.9 Hz, 1H), 6.02 (dd, J = 17.5, 1.3 Hz, 1H), 5.35 (dd, J = 10.9, 1.3 Hz, 1H), 4.01 (t, J = 6.4 Hz, 2H), 3.68 (s, 3H), 2.36 (t, J = 7.4 Hz, 2H), 1.86–1.78 (m, 2H), 1.75–1.67 (m, 2H), 1.55–1.47 (m, 2H). LRMS (ESI+) m / z: [M+H]+calcd for C14H20NO3250.1443; found 250. HRMS (ESI+) m / z: calcd for C14H20NO3: 250.1438 [M+H]+; found: 250.1449.

[0401] Compound 165: Compound 165 was synthesized by the same method as compound 76.

[0402] Compound 166: Compound 166 was synthesized by the same method as compound 77. LRMS (ESI): m / z calc. for C74H95N11O23S6Si3 [M+2H−4Na]2−, 890.71225; found, 891. HRMS (ESI−) m / z: calcd for C74H93N1N O23S6Si3: 912.6942 [M−2Na]2−; found: 912.6976.

[0403] Pyr-IR700 C6COOH: Pyr-IR700 C6COOH was synthesized by the same method as Styrl-IR700 C6COOH (y.0.26% in 5 steps).1H NMR (400 MHz, CD3OD): 79.83 (s, 1H), 9.75–9.73 (m, 1H), 9.69–9.66 (m, 5H), 9.64 (d, J = 8.1 Hz, 1H), 8.63 (d, J = 8.1 Hz, 1H), 8.44–8.40 (m, 6H), 8.26 (d, J = 2.9 Hz, 1H), 8.09 (d, J = 16.1 Hz, 1H), 7.87 (d, J = 16.1 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.7, 2.9, 1H), 4.08 (t, J = 6.5 Hz, 2H), 2.69–2.64 (m, 24H), 2.15 (t, J = 7.5 Hz, 2H), 1.93–1.89 (m, 4H), 1.84–1.78 (m, 2H), 1.68–1.58 (m, 14H), 1.53–1.45 (m, 2H), −1.01–−1.03 (m, 4H), −2.21–−2.25 (m, 4H), −2.87 (s, 12H). LRMS (ESI): m / z calc. for C73H93N11O23S6Si3[M+3H−5Na]2−, 884.70445; found, 884. HRMS (ESI−) m / z: calcd for C73H90N11Na3O23S6Si3: 916.6774 [M−2Na]2−; found: 916.6810. - 164 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0404] Pyr-IR700 C6SE: Pyr-IR700 C6SE was synthesized by the same method as Styrl- IR700 C6SE. LRMS (ESI): m / z calc. for C77H96N12O25S6Si3 [M+2H−4Na]2−, 932.21265; found, 933. HRMS (ESI−) m / z: calcd for C73H90N11Na3O23S6Si3: 916.6774 [M−2Na]2−; found: 916.6810. Example 19

[0405] In this example, compounds comprising an amide-containing linker group were prepared using a Heck reaction with ^-Br SiPc-NH2 and an amide-terminated linker group as detailed below and summarized in Scheme 52. ^ ^^ ^ ^ ^ ^^^^^ ^ ^'"^^^^^- 165 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0406] Procedure for making Compound 168: Thionyl chloride (6 mL, 82.2 mmol) was added dropwise to a stirred solution of compound 167 (7-aminoheptanoid acid, 2.31 mg, 15.9 mmol) and methanol (17 mL) at 0 °C. The resulting solution was then warmed to room temperature and stirred for 3 hours. The solvent and thionyl chloride were then removed under reduced pressure. Compound 168 (3.05 g, 15.6 mmol, y.98%) were isolated as a white solid.1H NMR (400 MHz, MeOD) 73.67 (s, 3H), 2.82 (t, J = 7.5 Hz, 2H), 2.25 (t, J = 7.3 Hz, 2H), 1.59–1.50 (m, 4H), 1.36–1.24 (m, 4H). LRMS (ESI+) m / z: [M−Cl]+calcd for C8H18NO2160.1338; found 160. HRMS (ESI+) m / z: calcd for C8H18NO2: 160.1332 [M−Cl]+; found: 160.1339.

[0407] Procedure for making Compound 169: Acryloyl chloride (10.2 g, 11.1 mmol) was added dropwise to the stirred ice-cold dispersion of compound 168 (1.08 g, 5.5 mmol) and triethylamine (2.54 g, 25.1 mmol) in CH3CN (7.5 mL). The resulting solution was then warmed to room temperature and stirred overnight. After the addition of brine, the reaction mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and evaporated to give compound 169 (1.05 g, 4.92 mmol, y.89%) as a yellow oil.1H NMR (400 MHz, MeOD) 76.23 (d, J = 8.3 Hz, 1H), 6.22 (d, J = 3.7 Hz, 1H), 5.65 (dd, J = 8.3, 3.7 Hz, 1H), 3.67 (s, 3H), 3.29–3.22 (m, 2H), 2.34 (d, J = 7.4, 2H), 1.67–1.52 (m, 4H), 1.42–1.31 (m, 4H). LRMS (ESI+) m / z: [M+H]+calcd for C11H20NO2214.1443; found 214. HRMS (ESI+) m / z: calcd for C11H20NO3: 214.1438 [M+H]+; found: 214.1434.

[0408] Compound 170: Compound 170 was synthesized by the same method as compound 101.

[0409] Compound 171: Compound 171 was synthesized by the same method as compound 102. LRMS (ESI−) m / z: [M+2H−4Na]2−calcd for C71H95N11O23S6Si3, 872.71225; found, 873. HRMS (ESI−) m / z: calcd for C71H93N11Na2O23S6Si3: 894.6942 [M−2Na]2−; found: 894.6982.

[0410] IR700-Amd-COOH: IR700-Amd-COOH was synthesized by the same method as IR700-alkene-COOH (y.0.32% in 5 steps).1H NMR (400 MHz, CD3OD): 79.90 (s, 1H), 9.76–9.74 (m, 1H), 9.70–9.65 (m, 6H), 8.61 (d, J = 8.1 Hz, 1H), 8.47–8.40 (m, 6H), 8.13 (d, J = 15.7 Hz, 1H), 7.39 (d, J = 15.7, 1H), 3.36 (t, J = 7.7 Hz, 2H), 2.70–2.65 (m, 24H), 2.14 (t, J = 7.6 Hz, 2H), 1.93–1.89 (m, 4H), 1.66–1.60 (m, 16H), 1.47–1.37 (m, 4H), −1.02 (m, 4H), −2.21–−2.25 (m, 4H), −2.87 (s, 12H). LRMS (ESI−) m / z: [M+3H−5Na]2−calcd for C70H93N11O23S6Si3, 865.7045; found, 866. HRMS (ESI−) m / z: calcd for C70H90N11Na3O23S6Si3: 898.6774 [M−2Na]2−; found: 898.6816. - 166 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0411] IR700-Amd-SE: IR700-Amd-SE was synthesized by the same method as IR700- alkene-SE. LRMS (ESI−) m / z: [M+2H−4Na]2−calcd for C74H96N12O25S6Si3, 914.21265; found, 915. HRMS (ESI−) m / z: calcd for C74H94N12Na2O25S6Si3: 936.1946 [M−2Na]2−; found: 936.1991. Example 20

[0412] In this example, compounds comprising a sulfonamide-containing linker group were prepared using a Heck reaction with ^-Br SiPc-NH2 and a sulfonamide-terminated linker group as detailed below and summarized in Scheme 53. ^ ^ ^^ ^^ ^ ^ ^ ^ ^'"^^^^^- 167 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0413] Procedure for making Compound 172: The solution of 2-chloroethanesulfonyl chloride (795 mg, 4.9 mmol) in CH2Cl2 (10 mL) was added dropwise to the stirred ice-cold dispersion of compound 168 (597 mg, 3.1 mmol) and triethylamine (1.15 g, 11.4 mmol) in CH2Cl2 (20 mL). The resulting solution was then warmed to room temperature and stirred overnight. Then it was evaporated at reduced pressure, the residue was triturated with water, acidified to pH 3, and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate, 1 / 0 to 2 / 1) to give compound 172 (678 mg, 2.72 mmol, y.89%).1H NMR (400 MHz, MeOD) 76.64 (dd, J = 16.6, 10.0 Hz, 1H), 6.13 (d, J = 16.6 Hz, 1H), 5.96 (d, J = 16.6 Hz, 1H), 3.67 (s, 3H), 2.94 (t, 7.0 Hz, 2H), 2.34 (t, 7.4 Hz, 2H), 1.67–1.60 (m, 2H), 1.58–1.51 (m, 2H), 1.43–1.31 (m, 4H). LRMS (ESI+) m / z: [M+H]+calcd for C10H20NO4S 250.1113; found 250. HRMS (ESI+) m / z: calcd for C10H20NO4S: 250.1108 [M+H]+; found: 250.1107.

[0414] Compound 173: Compound 173 was synthesized by the same method as compound 101.

[0415] Compound 174: Compound 174 was synthesized by the same method as compound 102. LRMS (ESI−) m / z: [M+2H−4Na]2−calcd for C70H95N11O24S7Si3, 890.69575; found, 891. HRMS (ESI−) m / z: calcd for C70H93N11Na2O24S7Si3: 912.6777 [M−2Na]2−; found: 912.6820.

[0416] IR700-SA-COOH: IR700-SA-COOH was synthesized by the same method as IR700-alkene-COOH (y.0.08% in 5 steps).1H NMR (400 MHz, CD3OD): 79.90 (s, 1H), 9.75–9.66 (m, 7H), 8.61 (d, J = 8.2 Hz, 1H), 8.45–8.41 (m, 6H), 8.05 (d, J = 15.5 Hz, 1H), 7.71 (d, J = 15.5, 1H), 2.70–2.62 (m, 26H), 2.25 (t, J = 7.4 Hz, 2H), 1.94–1.90 (m, 4H), 1.63– 1.34 (m, 20H), −0.94–−0.99 (m, 4H), −2.25–−2.29(m, 4H), −2.88 (s, 12H). LRMS (ESI−) m / z: [M+3H−5Na]2−calcd for C69H93N11O24S7Si3, 883.6880; found, 884. HRMS (ESI−) m / z: calcd for C69H90N11Na3O24S7Si3: 916.6609 [M−2Na]2−; found: 916.6649.

[0417] IR700-SA-SE: IR700-SA-SE was synthesized by the same method as IR700-alkene- SE. LRMS (ESI−) m / z: [M+2H−4Na]2−calcd for C73H96N12O26S7Si3, 932.1961; found, 933. HRMS (ESI−) m / z: calcd for C73H94N12Na2O26SM−2Na]2−; found: 954.1826. Example 21

[0418] In this example, compounds comprising a PEG linker group were prepared using a Heck reaction with ^-Br SiPc-NH2 and a PEG linker group as detailed below and summarized in Scheme 54. - 168 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01^^ ^ ^ ^ ^^ "^+ ^ "^+ ^ ^^^^^^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^^^)&^^^^^^^^^^^^^^^^Scheme 54

[0419] Procedure for making Compound 176: Compound 175 (PEG3-carboxylic acid tert- butyl ester, 2.35 g, 10.0 mmol) was slowly added to a stirred suspension of NaH (90%; 325 mg, 12.2 mmol) in dry THF (17 mL) under an Ar atmosphere at 0 °C. after stirring for 30 min, the solution was allowed to warm up to room temperature. Allyl bromide (1.89 g, 15.6 mmol) was added dropwise, and the resulting suspension was stirred at room temperature for 2 hours. The reaction was quenched by adding water and the organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate, 10 / 1) to give compound 176 (1.05 g, 3.81 mmol, y.38%).1H NMR (400 MHz, CDCl3) 75.92 (ddt, J = 17.2, 10.4, 5.7 Hz, 1H), 5.27 (ddt, J = 17.2, 1.7, 1.Hz, 1H), 5.18 (ddt, J = 10.4, 1.7, 1.4, 1H), 4.02 (dt, J = 5.7, 1.4 Hz, 2H), - 169 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-013.71 (t, J = 6.6 Hz, 2H), 3.67–3.59 (m, 8H), 2.50 (t, J = 6.6 Hz, 2H), 1.45 (s, 9H). LRMS (ESI+) m / z: [M+Na]+calcd for C14H26NaO5297.1678; found 297. HRMS (ESI−) m / z: calcd for C73H94N12Na2O26S7Si3: 954.1781 [M−2Na]2−; found: 954.1826.

[0420] Procedure for making Compound 177: Compound 176 (290 mg, 1.06 mmol) was dissolved in CH2Cl2 (7 mL). Trifluoroacetic acid (2.6 mL) was added and the solution was stirred at room temperature for 3 hours. Once the reaction was finished, the solution was co- evaporated with toluene three times (20 mL each) to remove trifluoroacetic acid and solvent. After drying under vacuum, compound 177 (231 mg, 1.06 mmol, y. quant) was directly used in next step without further purification.1H NMR (400 MHz, CDCl3) 75.92 (ddt, J = 17.2, 10.4, 5.8 Hz, 1H), 5.28 (ddt, J = 17.2, 1.6, 1.4 Hz, 1H), 5.17 (ddt, J = 10.4, 1.6, 1.4, 1H), 4.04 (dt, J = 5.8, 1.4 Hz, 2H), 3.79 (t, J = 6.1 Hz, 2H), 3.70–3.61 (m, 8H), 2.66 (t, J = 6.1 Hz, 2H). LRMS (ESI+) m / z: [M+H]+calcd for C10H19O5219.1232; found 219. HRMS (ESI+) m / z: calcd for C10H19O5: 219.1227 [M+H]+; found: 219.1221.

[0421] Procedure for making Compound 178: To the compound 177 (653 mg, 3.0 mmol) were added CH2Cl2(8 mL), ethanol (350 µL, 6 mmol) and DMAP (48 mg, 393 µmol). After cooling the solution to 0 °C, DCC (710 mg, 3.4 mmol) was added. The mixture was stirred at 0 °C for 5 min and then at room temperature for 4 hours. The reaction mixture was extracted with CH2Cl2, washed with 0.5 M HCl and saturated NaHCO3 solution sequentially. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate, 10 / 1 to 10 / 2) to give compound 178 (690 mg, 2.80 mmol, y.94%).1H NMR (400 MHz, CDCl3) 75.92 (ddt, J = 17.2, 10.4, 5.7 Hz, 1H), 5.27 (ddt, J = 17.2, 1.7, 1.5 Hz, 1H), 5.18 (ddt, J = 10.4, 1.7, 1.5, 1H), 4.15 (q, J = 7.1 Hz, 2H), 4.02 (dt, J = 5.7, 1.5 Hz, 2H), 3.76 (t, J = 6.5 Hz, 2H), 3.67– 3.59 (m, 8H), 2.59 (t, J = 6.5 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H). LRMS (ESI+) m / z: [M+H]+calcd for C12H23O5247.1545; found 247. HRMS (ESI+) m / z: calcd for C12H23O5: 247.1540 [M+H]+; found: 247.1534.

[0422] Compound 179: Compound 179 was synthesized by the same method as compound 101.

[0423] Compound 180: Compound 180 was synthesized by the same method as compound 102. LRMS (ESI−) m / z: [M+2H−4Na]2−calcd for C72H98N10O25S6Si3 , 889.2174; found, 890.

[0424] IR700-PEG-COOH: IR700-PEG-COOH was synthesized by the same method as IR700-alkene-COOH (y.0.15% in 5 steps).1H NMR (400 MHz, CD3OD): 79.75–9.66 (m,- 170 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-017H), 9.61 (d, J = 8.1 Hz, 1H), 8.52 (dd, J = 8.1, 1.2 Hz, 1H), 8.46–8.40 (m, 6H), 7.36 (d, J = 16.0 Hz, 1H), 7.05 (dt, J = 16.0, 5.8 Hz, 1H), 4.44 (d, J = 5.8 Hz, 2H), 3.80–3.61 (m, 10H), 2.74–2.64 (m, 24H), 2.42 (t, J = 6.8 Hz, 2H), 1.94–1.90 (m, 4H), 1.64–1.60 (m, 12H), −1.00– −1.03 (m, 4H), −2.21–−2.25 (m, 4H), −2.87 (s, 12H). LRMS (ESI−) m / z: [M+3H−5Na]2−calcd for C70H94N10O25S6Si3[M+3H−5Na]2−, 875.20175; found, 876. HRMS (ESI−) m / z: calcd for C70H91N10Na3O25S6Si3: 908.1747 [M−2Na]2−; found: 908.1784.

[0425] IR700-PEG-SE: IR700-PEG-SE was synthesized by the same method as IR700- alkene-SE. LRMS (ESI−) m / z: [M+2H−4Na]2−calcd for C74H97N11O27S6Si3, 923.7099; found, 924. HRMS (ESI−) m / z: calcd for C74H95N11Na2O27S6Si3: 945.6919 [M−2Na]2−; found: 945.6963. Example 22

[0426] In this example, compounds comprising an amide PEG linker group were prepared using a Heck reaction with ^-Br SiPc-NH2 and an amide PEG linker group as detailed below and summarized in Scheme 55. - 171 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01Scheme 55

[0427] Procedure for making Compound 182: Compound 181 ((Boc-amino)-PEG3-C2- carboxylic acid, 282 mg, 0.9 mmol) was dissolved in CH2Cl2(4.5 mL). Trifluoroacetic acid (2.2 mL) was added and the solution was stirred at room temperature for 2 hours. Once the reaction was finished, the solution was co-evaporated with toluene three times (20 mL each) to remove trifluoroacetic acid and solvent. After drying under vacuum, crude compound 182 (361 mg) was directly used in next step without further purification. LRMS (ESI+) m / z: [M+H]+calcd for C9H20NO5222.1341; found 222. HRMS (ESI+) m / z: calcd for C9H20NO5: 222.1336 [M+H]+; found: 222.1317. - 172 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0428] Procedure for making Compound 183: Thionyl chloride (4.1 mL, 56.2 mmol) was added dropwise to a stirred solution of crude compound 182 (1.56 g) and methanol (6 mL) at 0 °C. The resulting solution was then warmed to room temperature and stirred for 4 hours. The solvent and thionyl chloride were then removed under reduced pressure. Compound 183 (1010 mg, 3.72 mmol, y.97.8% (2 steps)) were isolated as a white solid.1H NMR (400 MHz, MeOD) 73.80–3.66 (m, 12H), 3.65 (s, 3H), 3.15 (t, J = 5.06 Hz, 2H), 2.62 (t, J = 6.10 Hz, 2H). LRMS (ESI+) m / z: [M−Cl]+calcd for C10H22NO5236.1498; found 236. HRMS (ESI+) m / z: calcd for C10H22NO5: 236.1425 [M−Cl]+; found: 236.1469.

[0429] Procedure for making Compound 184: Acryloyl chloride (791 mg, 8.7 mmol) was added dropwise to the stirred ice-cold dispersion of compound 183 (982 mg, 3.6 mmol) and triethylamine (1.79 g, 17.7 mmol) in CH3CN (6 mL). The resulting solution was then warmed to room temperature and stirred overnight. After the addition of brine, the reaction mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and evaporated to give compound 184 (430 mg, 1.49 mmol, y.41%) as a yellow oil.1H NMR (400 MHz, CDCl3) 76.42 (br, 1H), 6.30 (dd, J = 17.0, 1.6 Hz, 1H), 6.14 (dd, J = 17.0, 10.2 Hz, 1H), 5.63 (dd, J = 10.2, 1.6 Hz, 1H), 3.77 (t, J = 6.4 Hz, 2H), 3.69 (s, 3H), 3.64–3.51 (m, 12H), 2.61 (t, 2H). LRMS (ESI+) m / z: [M+H]+calcd for C13H24NO6290.1604; found 290. HRMS (ESI+) m / z: calcd for C13H24NO6: 290.1598 [M+H]+; found: 290.1593.

[0430] Compound 185: Compound 185 was synthesized by the same method as compound 101.

[0431] Compound 186: Compound 186 was synthesized by the same method as compound 102. LRMS (ESI−) m / z: [M+2H−4Na]2−calcd for C73H99N11O26S6Si3, 910.7203; found, 911. HRMS (ESI−) m / z: calcd for C73H97N11Na2O26S6Si3: 932.7022 [M−2Na]2−; found: 932.7067.

[0432] IR700-Amd-PEG-COOH: IR700-Amd-PEG-COOH was synthesized by the same method as IR700-alkene-COOH (y.0.10% in 5 steps).1H NMR (400 MHz, CD3OD): 79.91 (s, 1H), 9.75–9.73 (m, 1H), 9.67–9.63 (m, 6H), 8.53 (d, J = 8.2 Hz, 1H), 8.43–8.39 (m, 6H), 8.12 (d, J = 15.7 Hz, 1H), 7.44 (d, J = 15.7, 1H), 3.68–3.51 (m, 14H), 2.67–2.60 (m, 24H), 2.38 (t, J = 6.7 Hz, 2H), 1.92–1.87 (m, 4H), 1.64–1.58 (m, 12H), −1.04–−1.06 (m, 4H), −2.24–−2.28 (m, 4H),−2.89 (s, 12H). LRMS (ESI−) m / z: [M+3H−5Na]2−calcd for C72H97N11O26S6Si3, 903.71245; found, 904. HRMS (ESI−) m / z: calcd for C72H94N11Na3O26S6Si3: 936.6854 [M−2Na]2−; found: 936.6897. - 173 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0433] IR700-Amd-PEG-SE: IR700-Amd-PEG-SE was synthesized by the same method as IR700-alkene-SE. LRMS (ESI−) m / z: [M+2H−4Na]2−calcd for C76H100N12O28S6Si3, 952.22065; found, 953. HRMS (ESI−) m / z: calcd for C76H98N12Na2O28S6Si3: 974.2026 [M−2Na]2−; found: 974.2068. Example 23

[0434] In this example, dimer precursor compounds were made. The compounds were made according to the method detailed below and summarized in Schemes 56 and 57. Results from analyzing these compounds using IR spectroscopy are shown in FIG.1.

[0435] Procedure for making Compound 96: Compound 95 (1,2,4,5-tetracyanobenzene, 1.00 g, 5.61 mmol) and NaOMe (128 mg, 2.37 mmol) was stirred at room temperature in 2 mol / L ammonia methanol solution (50 mL) for 1 hour. The product was insoluble in methanol and precipitated out to afford compound 96 (843 mg, y.71%), and dried in vacuo.1H NMR (400 MHz, CD3OD): δ 7.83 (s, 2H), LRMS (ESI+) m / z: [M+H]+calcd for C10H9N6, 213; found, 213.

[0436] Procedure for making Compound 97: Compound 96 (103 mg, 484 µmol), SiCl4 (833 mg, 4.90 mmol) and 1,3-diiminoisoindoline (686 mg, 4.72 mmol) were dissolved in quinoline (10 mL), and the mixture was refluxed for 2 hours under an Ar atmosphere. After the mixture was cooled to room temperature, 1 mol / L NaOHaq (10 mL) was added, and the mixture was refluxed for 1 hour. The product was recovered by filtration, washed with MeOH, and dried in vacuo to afford compound 97 (591 mg). The crude product was used for the next step without further purification. - 174 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0437] Procedure for making Compound 98: Compound 97 (199 mg) and 3- aminopropyldimethylethoxysilane (327 mg, 2.03 mmol) were dissolved in pyridine (80 mL), and the mixture was refluxed for 6 hours under Ar atmosphere. The reaction mixture was concentrated by rotary evaporation. The residue was diluted, filtered, washed with a H2O / EtOH solution (2:1), and dried in vacuo to afford compound 98 (205 mg). The crude product was used for the next step without further purification.

[0438] Procedure for making Di-SiPc (Xdye-2): Compound 98 (101 mg), 1,3- propanesultone (978 mg, 8.01 mmol), and N,N-diisopropylethylamine (1.13 g, 8.74 mmol) were dissolved in MeOH (6 mL), and the mixture was stirred at 50 °C for 48 hours under an Ar atmosphere. The product was purified by an HPLC system with a reverse-phase column, using eluent A (H2O, 0.1 M triethylammonium acetate) and eluent B (CH3CN) (A / B = 70 / 30 to 50 / 50 in 40 min, 50 / 50 to 0 / 100 in 5 min. The product was desalted with a Sep-Pak C18 cartridge and cation-exchange resin, affording the product (3.4 mg, 1.1 µmol, y.1.4% in 3 steps as a sodium salt).1H NMR (400 MHz, CD3OD): δ 11.76 (s, 2H), 10.06 (d, J = 7.5 Hz, 12H), 9.74–9.69 (m, 8H), 8.56 (t, J = 7.5 Hz, 4H), 8.48 (t, J = 7.7 Hz, 4H), 8.43 (dd, J = 8.5, 2.9 Hz, 4H), 2.70–2.66 (m, 24H), 2.59 (t, J = 6.7 Hz, 24H), 1.97–1.93 (m, 8H), 1.57–1.55 (m, 24H), −0.77–−0.78 (m, 8H), −2.16–−2.21 (m, 8H), −2.72 (s, 24H). HRMS (ESI−) m / z: calcd for C114H146N20Na4O40S12Si6: 769.6221 [M−4Na]4−; found: 769.6166.

[0439] Procedure for making Compound 99: Compound 96 (101 mg, 475 µmol), SiCl4 (670 mg, 3.94 mmol) and 1,3-diiminobenz[f]isoindoline (737 mg, 3.78 mmol) were dissolved in - 175 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01quinoline (10 mL), and the mixture was refluxed for 2 hours under an Ar atmosphere. After the mixture was cooled to room temperature, 1 mol / L NaOHaq (10 mL) was added, and the mixture was refluxed for 1 hour. The product was recovered by filtration, washed with MeOH, and dried in vacuo to afford compound 99 (801 mg). The crude product was used for the next step without further purification.

[0440] Procedure for making Compound 100: Compound 99 (396 mg) and 3- aminopropyldimethylethoxysilane (480 mg, 2.97 mmol) were dissolved in pyridine (100 mL), and the mixture was refluxed for 8 hours under Ar atmosphere. The reaction mixture was concentrated by rotary evaporation. The residue was diluted, filtered, washed with a H2O / EtOH solution (1:1), and dried in vacuo to afford compound 100 (333 mg). The crude product was used for the next step without further purification.

[0441] Procedure for making Di-SiNPc (Xdye-3): Compound 100 (204 mg), 1,3- propanesultone (1.64 g, 13.4 mmol), and N,N-diisopropylethylamine (1.88 g, 14.5 mmol) were dissolved in MeOH (10 mL), and the mixture was stirred at 50 °C for 48 hours under an Ar atmosphere. The product was purified by an HPLC system with a reverse-phase column, using eluent A (H2O, 0.1 M triethylammonium acetate) and eluent B (CH3CN) (A / B = 70 / 30 to 50 / 50 in 40 min, 50 / 50 to 0 / 100 in 5 min. The product was desalted with a Sep-Pak C18 cartridge and cation-exchange resin, affording the product (2.8 mg, 0.8 µmol, y.0.6% in 3 steps as a sodium salt).1H NMR (400 MHz, CD3OD): δ 11.64 (s, 2H), 10.59 (s, 4H), 10.30 (s, 4H), 10.28 (s, 4H), 9.07 (d, J = 8.1 Hz, 4H), 8.85–8.81 (m, 8H), 8.04–7.96 (m, 8H), 2.61– 2.53 (m, 48H), 2.04–2.00 (m, 8H), 1.53–1.45 (m, 24H), −0.57–−0.63 (m, 8H), −1.77–−1.81 (m, 8H), −2.36 (s, 24H). HRMS (ESI−) m / z: calcd for C138H158N20Na4O40S12Si6: 844.6455 [M−4Na]4−; found: 844.6400. Example 24

[0442] The procedure of chemical conjugation of VLPs (e.g., viral-like nanoparticles containing a combination of variant HPV16 / 31 L1 proteins and HPV L2 proteins) to a compound of the present disclosure is as follows. Typically, solutions of VLPs are maintained at a concentration of 1 mg / ml in PBS, pH=7.2 and 0.3 to 0.5 M NaCl. The compound to be conjugated with the VLP is dissolved in DMSO at a concentration of 5 mg / ml and stored frozen. Different ratios of VLP:compound can be achieved by mixing different amounts of the compound to a fixed amount of VLP, such as 1 ml of 1 mg / ml solution in PBS. Example 25 - 176 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0443] SK-OV-3 cells in suspension are treated under the following conditions: no VLP (e.g., viral-like nanoparticles containing a combination of variant HPV16 / 31 L1 proteins and HPV L2 proteins), VLP conjugated to a compound of the disclosure, or the same VLP conjugates incubated in the presence of HSPG. Following incubation, these cultures are subjected to light (e.g., 4 joules 690 or 6nm near-infrared light). A parallel set of non-light irradiated cells are used as a control. Following irradiation, the cultures are assessed for the extent of cell death. Cell death can be abrogated in the presence of HSPG, indicating that VLP binding to the cell is facilitates conjugate-mediated cell death. Example 26

[0444] SK-OV-3 cells in suspension are treated with differing concentrations of VLP (e.g., viral-like nanoparticles containing a combination of variant HPV16 / 31 L1 proteins and HPV L2 proteins) that are conjugated with differing amounts of a compound according to the disclosure. VLP without conjugation to a compound is used as a control. Following incubation, these cultures are subjected to light (e.g., 0 or 16 joules 690 or 680 nm near- infrared light). Following the light treatment, the extent of cell death is assessed. Cell death can be dependent on both the presence of the compound and light treatment. Example 27

[0445] SKOV-3 ovarian cancer cells are plated on a 24-well plate and treated with two different concentrations of VLP conjugates (e.g., 2.5 µg and 0.25 µg) for 1 h at 37 °C. Upon binding, the cells are washed, followed by treatment with light (e.g., 4 joules 690 nm near- infrared light). Cell death is determined upon enzymatic estimation of LDH release (determined by measuring absorbance at 490 nm). Three different molar ratios of VLP:compound can be tested, e.g., 1:500, 1:1000 and 1:2000, respectively. Detergent- mediated cell lysis is used as a positive control. Example 28

[0446] Ocular melanoma cell line (92.1; HER2-) in suspension are exposed to varying dilutions of either Herceptin® antibody conjugated to a compound alone or a VLP-compound conjugate. Parallel cultures are then assessed for agent binding or cell death in the absence or presence of 16 joules of light (e.g., 16 joules 690 nm near-infrared light). In the absence of light, there is should be no cell death. - 177 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01Example 29

[0447] SK-OV-3 cells (HER2-) in suspension are exposed to varying dilutions of either Herceptin® antibodies or a VLP-compound conjugate. Parallel cultures re then assessed for Herceptin® or VLP binding or cell death in the absence or presence of light (e.g., 16 joules 690 nm near-infrared light). The resulting data can establish that the VLPs conjugated to IR700 (PsV-IR700) are more potent that the Herceptin® conjugated to IR700 (Herceptin- IR700). Example 30

[0448] Samples of serum containing different antibodies are tested for the ability to inhibit VLP-compound conjugates binding to the 92.1 ocular melanoma cell line. Native serum conditions should exhibit no activity that neutralizes VLP binding. Observed blocking activity can be specific for virus serotype. That is, only human papillomavirus-like particles conjugated to a compound of the disclosure should be neutralized with serum containing HPV16 antibodies. Bovine papillomavirus-like particles (or other non-human mammalian papillomavirus-like particles) conjugated to a compound of the disclosure should not be neutralized by serum containing HPV16-specific antibodies.

[0449] Similarly, neutralizing titers are determined by serial dilution of sera containing antibodies against either HPV16 or BPV. Antibodies against HPV16 should neutralize only HPV16. Antibodies against BPV should neutralize only BPV. Thus, there is neither cross- reactivity of HVP16 antibodies against BPV nor BPV antibodies against HPV16. Example 31

[0450] In this example, the binding of viral-like nanoparticles containing human papillomavirus 16 (HPV16) capsid proteins, variant HPV16 / 31 L1 capsid proteins, and bovine papillomavirus (BPV) capsid proteins (or other non-human mammalian papillomavirus capsid proteins) to various types of cancer cells is evaluated. In addition, viral-like nanoparticles containing L1 and L2 capsid proteins, or only L1 capsid proteins, are tested to determine if there was a dependence on L2 for viral-like nanoparticle binding to cancer cells. Binding of BPV viral-like nanoparticles and HPV viral-like nanoparticles is shown to be comparable.

[0451] A large panel of cell lines is screened, which can include: miscellaneous cell lines (e.g., 293TT, HaCaT, PAM-212 and TC-1), cervical cell lines (e.g., HeLa, SiHa, CaSki and C-33A), ovarian cell lines (e.g., MOSEC, SHIN-3, SK-OV-3, WF-3, ES-2, A2780, OVCAR-3 - 178 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01and OVCAR-4), melanoma cell lines (e.g., B16F10, SKMEL-2, SKMEL-5, SKMEL-28 and UACC), ocular melanoma cell lines (e.g., 92.1, MKT-BR, OCM-1 and UW-1), lung cell lines (e.g., NCI-H23, NCI-H322M, NCI-H460 and NCI-H522), head and neck cell lines (e.g., CAL- 33 (HPV-), FaDu (HPV-), HSC-3 (HPV-), SNU-1076 (HPV-), UM-SCC-47 (HPV+), UPCI- SSC-90 (HPV+) and UPCI-SCC-154 (HPV+), and bladder cell lines (e.g., 5637, J82, RT112, SCaBER, SVHUC, T24, UMUC-3, UMUC-5). Viral-like nanoparticles are conjugated to AlexaFluor488 to allow for easy and direct analysis of viral-like nanoparticle binding to the cell surface. AlexaFluor488 is attached to the viral-like nanoparticle using N- Hydroxysuccinimide (NHS)-ester chemistry, which does not interfere with binding. Each of the viral-like nanoparticles can be tested at a concentration of 10 µg / ml, 1 µg / ml and 0.1 µg / ml.

[0452] Cells are trypsinized to remove them from the plastic surface of tissue culture plates, washed and allowed to recover for 4 hours at 37 °C. in growth media on a rocking platform. The cells are then washed, counted and placed into a 96-well round bottom plate at 1x105cells / well in phosphate buffered saline (PBS) / 2% fetal bovine serum (FBS). The viral-like nanoparticles are added to the cells in a final volume of 100 µl PBS / 2% FBS. Viral-like nanoparticles pre-incubated with heparin (1 mg / ml, 1 hour, 4 °C.) are also added to wells as controls. The cells and viral-like nanoparticles are then incubated for 1 hour at 4 °C. (in the dark), washed twice with PBS / 2% FBS and fixed with 4% paraformaldehyde for 15 minutes at room temperature. Cells are finally washed again and resuspended in 200 µl PBS / 2% FBS and analyzed on a BD FACS CANTOTMII (BD Biosciences, San Jose, Calif.) using BD FACSDIVATM(BD Biosciences, San Jose, Calif.) and FlowJo software. All viral-like nanoparticles, regardless of their serotype or makeup (L1 versus L1 / L2) should bind to cancer cells in the binding assay. Moreover, heparin competes for binding, demonstrating that viral-like nanoparticle binding is specific and HSPG dependent. Example 32

[0453] In this example, tumor localization and time course of clearance of viral-like nanoparticles following intravenous injection into tumor-bearing animals is assessed. Purified viral-like nanoparticles are prepared by labeling viral-like nanoparticles (e.g., viral- like nanoparticles containing a combination of variant HPV16 / 31 L1 proteins and HPV L2) with a compound of the disclosure at a viral-like nanoparticle:compound ratio of 1:500. The photosensitive viral-like nanoparticles are purified by density gradient ultracentrifugation using OPTIPREPRMDensity Gradient Medium. Tumors are generated in albino C57B116 mice by subcutaneous injection of 2x105TC-1 cancer cells in 100 µl of PBS. After about two - 179 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01weeks, animals are randomized into treatment groups. Tumor-bearing animals receive, by intravenous injection, either PBS or 200 µg of the photosensitive viral-like nanoparticles in a volume of 100 µl.12-24 hours following injection, the animals are euthanized. Following euthanasia, tumor tissue is harvested and imaged for fluorescence of the compound, indicating presence of the photosensitive viral-like nanoparticles. Example 33

[0454] In this example, tumor localization and time course of clearance of viral-like nanoparticles following intravenous injection into tumor-bearing animals is assessed. Purified viral-like nanoparticles are labeled with a compound of the disclosure and purified by density gradient ultracentrifugation using OPTIPREPTMDensity Gradient Medium. Tumors are generated in albino C57Bl / 6 mice by subcutaneous injection of 2x105TC-1 cancer cells in 100 µl of PBS. After about 2 weeks, 200 µg of the photosensitive viral-like nanoparticles are delivered by intravenous injection in a volume of 100 µl. Tumors are harvested at the following time points following photosensitive viral-like nanoparticle injection: T=1, 2, 4, 8, 12, 24, 48 and 72 hours. Upon harvest, fragments of tumors are frozen for microscopic assessment. For this microscopic assessment, tissue sections are further stained. Rabbit polyclonal sera against HPV16 is used in conjunction with a suitable secondary antibody. Blood vessels are co-stained with a rat anti-CD31 antibody and an anti-rat suitable secondary antibody. Nuclei are highlighted with DAPI. Example 34

[0455] In this example, tumor viability 24 hours after a single treatment is evaluated. This example establishes guidelines for long-term in vivo studies. Animals can be randomized such that an even distribution of large and small tumors are within each group of n=3 in the saline-treated groups and n=5 in the VLP-compound conjugate groups. Viral-like nanoparticles are administered intravenously 12 hours prior to light treatment. One hundred microgram (100 µg) and 200 µg doses are evaluated. Light treatment can include 25 J (62.3 s at 400 mW) or 50 J (125 s at 400 mW). After 24 hours, tumors are harvested and processed using collagenase and DNase to generate a single cell suspension. BD LIVE / DEADTMyellow stain is then applied, and cells are placed through a FACS CANTOTMII. Data are reported as percentage of dead cells as indicated by a shift in fluorescence in the Pacific orange channel. - 180 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01

[0456] A single dose of 200 µg of the VLP-compound conjugate can be capable of killing the majority of the tumor cells after treatment with light. This example establishes light dosage information for in vivo studies. Example 35

[0457] The TC-1 tumor model offers the ability to examine anti-tumor immune induction upon treatment with viral-like nanoparticles in immune competent animals. The TC-1 tumor line was developed from C57Bl / 6 lung epithelial cells immortalized with HPV16 oncogenes E6 and E7 as well as a mutated gene expressing c-Ha-Ras (Lin K Y, et al., Cancer Research.56(1):21-6, 1996). These cells can be implanted subcutaneously or, for studying metastatic models, they can be injected intravenously to seed cells in the lungs. For nearly twenty years these cells have been used to test E6 and E7 therapeutic vaccine efficacy. E7 has a distinctive MHC class I epitope on the C57Bl / 6 background that has been shown to be protective if a CD8 T-cell response can be elicited against it (H-2D.sup.b, aa 49-57 RAHYNIVTF (SEQ ID NO: 3)) (Feltkamp M C, et al. European Journal of Immunology.23(9):2242-9, 1993). These responses are detected by both tetramer staining and re-stimulation of cells with the peptide followed by intracellular cytokine staining.

[0458] Animals are inoculated subcutaneously with 2x105TC-1 cells in 100 µl of PBS. Approximately two weeks after inoculating, animals are randomized into six groups: (1) no treatment controls, (2) 100 µg viral-like nanoparticles (containing a combination of variant HPV16 / 31 L1 proteins and HPV L2 proteins labeled with a compound of the disclosure) without light controls, (3) PBS with 50 J / cm2light controls, (4) 200 µg viral-like nanoparticles with 50 J / cm2light, (5) 100 µg n viral-like nanoparticles with 50 J / cm2light and (6) 50 µg viral-like nanoparticles with 50 J / cm2light. Mice receive PBS or viral-like nanoparticles by intravenous injection of a 100 µl volume, and light is applied to the tumor 12 hours later using a laser. Tumors are harvested 24 hours later, digested to generate a single cell suspension, and stained with a viability stain to measure the percentage of dead cells.

[0459] Survival Study: Animals are inoculated subcutaneously with 2x105TC-1 cells in 100 µl of PBS. Approximately two to three weeks after inoculating, animals are randomized into the treatment group (25 µg viral-like nanoparticles) and the placebo group (PBS only). Mice receive two rounds of treatment, three days apart. A treatment is considered a single intravenous injection of 100 µl of either 25 µg of viral-like nanoparticles or sterile PBS, followed 12 hours later by light treatment (e.g., 50 J / cm2using a laser. Tumor volumes are - 181 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01measured every 3-4 days, and animals are euthanized when their tumors reached a size>1500 mm3.

[0460] Immunology Study: For the immunological readout, blood is collected on day 0 (prior to first treatment), day 10 and day 17. Red blood cells are lysed and the remaining cells are split into two, one half stained for cell surface markers (CD62L, CD127, CD103, CD69, CD4, CD8, CD3, H2-D.sup.6E7(49-57) tetramer). The other half is re-stimulated for 4.5 hours with HPV16 E7 peptide 49-57 followed by staining with antibodies against CD4, CD8 and IFN-gamma as well as a viability dye to discriminate live cells. Example 36

[0461] The effects of photosensitive viral-like nanoparticles (e.g., viral-like nanoparticles containing a combination of variant HPV16 / 31 L1 proteins and HPV L2 proteins conjugated to a compound of the present disclosure) at the histological level are assessed using a murine xenograft model. Briefly, 1.5x10692.1 uveal melanoma cells are implanted into the subcutaneous space of the hind flank of nu / nu mice. The tumors are allowed to reach approximately 200 mm3, at which time the animals are treated with an intravenous injection of 200 µg of photosensitive viral-like nanoparticles. Twelve hours following the injection of photosensitive viral-like nanoparticles, the tumor site is irradiated with light (e.g., 50 J / cm2of 690 nm near-infrared light). After an additional 24 hours, the animals are euthanized, the tumor tissue is excised, fixed in formalin, paraffin embedded and processed for standard histological examination. Upon examination at higher magnification, the cells of the photosensitive viral-like nanoparticle-treated tumors can show a dramatic loss of cytoplasm compared to the control treated tumor. And, the extent of necrosis can be evaluated to confirm whether the light penetrates through the entire depth of tumor tissue. Example 37

[0462] In this example, the anti-cancer activity of the photosensitive viral-like nanoparticle is evaluated in an orthotopic xenograft model of uveal melanoma. In this model, human uveal melanoma cells are implanted into the choroidal space of immunosuppressed rabbits and allowed to grow. When tumors are observable by fundoscopy, the animals are assigned to treatment or control groups. In both cases, the animals are followed by fundoscopy and ultrasound for progressive tumor growth or response to treatment. Following termination of the study, the tumor-bearing eyes are also examined by gross and histopathology. Evidence of tumor necrosis can confirm that the disclosed VLP-compound conjugates can treat uveal melanoma tumors. A suitable schedule and experimental design used for this example can - 182 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01be adapted from that disclosed by U.S. Pat. No.10,117,947, the relevant portion of which is incorporated herein by reference. Example 38

[0463] In this example, photosensitive viral-like nanoparticles (e.g., viral-like nanoparticles containing a combination of variant HPV16 / 31 L1 proteins and HPV L2 proteins conjugated to a compound of the present disclosure) potency can be assayed by an in vitro cell killing assay. Uveal melanoma cells (e.g., cell line OCM-1 or 92.1) are harvested by routine methods using a solution of EDTA and trypsin. Once removed from the tissue culture plastic, the cells are suspended in complete growth media and are allowed to recover for approximately 30 minutes at 37 °C. During this recovery period, serial dilutions of the photosensitive viral-like nanoparticle are made (e.g., 2000 pM, 600 pM, 200 pM, 60 pM, 20 pM, 6 pM, 2 pM and 0.6 pM) in PBS+2% fetal bovine serum. Following the recovery period, the cells are counted, centrifuged and suspended in PBS+2% FBS to a cell density of 3x106 / ml. An equal volume of cell suspension is added to the viral-like nanoparticle dilutions to yield 1.5x106cells per ml in the appropriate concentration (e.g., 1000 pM, 300 pM, 100 pM, 30 pM, 10 pM, 3 pM, 1 pM and 0.3 pM) of viral-like nanoparticle. These conditions are incubated on ice for about 1.5 to 2 hours.

[0464] Following this incubation, the tubes are centrifuged to collect the cells and the cells are subsequently washed twice with PBS+2% FBS, without the photosensitive viral-like nanoparticles. After the final centrifugation, the cells are suspended in 200 µl of PBS+2% FBS. A 100 µl of each sample is removed and transferred to the well of a 96-well plate. Each sample is then irradiated with light (e.g., 25 J / cm2(600 mW, 43 seconds) of near infrared light (689 nm) using a Coherent Opal Photoactivator ophthalmic laser. Following the irradiation, the sample of cells is then transferred to a new tube. Both the light irradiated and non-irradiated samples are placed at 37 °C. for an additional 1 to 2 hours.

[0465] Following this incubation, a final 20 µl sample of cells is mixed 1:1 with AOPI stain (Acridine Orange and Propidium Iodide) and the viability of the cells is evaluated using a Nexcelom Cellometer Auto 2000. Example 39

[0466] In this example, head & neck cancer cells are implanted in the dorsal lateral flank of nu / nu mice. Tumors are allowed to grow for two weeks. Once the tumor reaches an average size of 150 mm3, the animals are randomized into 6 study groups (7 animals per group), as follows: Saline; photosensitive viral-like nanoparticles (HPV16 / 31 L1 / L2; 200 µg dose); - 183 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01Saline+NIR light (50 J / cm2); photosensitive viral-like nanoparticles (200 µg dose)+NW light (50 J / cm2); photosensitive viral-like nanoparticles (100 µg dose)+NIR light (50 J / cm2); and photosensitive viral-like nanoparticles (50 µg dose)+NIR light (50 J / cm2). Dosing and NIR light treatment are performed every three days. Tumor measurements are recorded every 3- 5 days. Example 40

[0467] In this example, VLP-compound conjugates are evaluated for activity against ocular melanoma. The VLP-compound conjugate is administered to a subject having (i) a clinical diagnosis of primary indeterminate lesion or small choroidal melanoma (IL / CM), (ii) no evidence of metastatic disease confirmed by imaging, and that is (iii) treatment naïve for IL / CM and does not have an active ocular disease. One or more subjects falling into the groups indicated in Table 1 are exposed to the protocol detailed therein. In each group, the treatment involves administering a VLP-compound conjugate via suprachoroidal administration using with a suprachoroidal microinjector and corresponding laser treatment with a PDT laser. The following are then measured over a 52-week time frame: (i) treatment-related adverse events and treatment-related serious adverse events; (ii) within- subject difference of historical tumor thickness growth rate and post-treatment growth rate; and (iii) time to reach tumor progression. Participant Protocol Group d- 184 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01Example 41

[0468] In this example, compound ^-Tz IR700C10SE was conjugated to cetuximab, an antibody for EGFR, to obtain an antibody-compound conjugate to establish that compounds disclosed herein can be conjugated through chemistry described herein. Such conjugation is also accomplished with VLPs as described herein using methods for conjugating with activated esters, such as that present in compound ^-Tz IR700C10SE and other compounds of the present disclosure. In vitro PIT was then performed with this antibody-compound conjugate using A431 cells to evaluate the ability to use the compounds to induce cell death.

[0469] A431 cells were incubated in DMEM on a 3.5 cm glass bottom dish. Next day, cells were washed with DMEM phenol red (-) and incubated with 5 ug / mL (final) ^-Tz IR700C10SE or IR700 in DMEM phenol red (-) for 1 hour at 37 °C. Then, cells were washed with DMEM phenol red (-) and set on an upright microscope. Cells were irradiated with 690 nm LED light for 5 minutes (0.026 W / cm2, 7.8 J / cm2) and microscopic images were taken (see FIG.2) after 5 minutes, 15 minutes, and 30 minutes. As can be seen by the results in FIG.2, particularly the zoomed images in the bottom row, blebs were formed to induce cell death using the biomolecule-compound conjugate within 5 minutes following irradiation. Example 42

[0470] In this example, three compounds of the present disclosure with different linker lengths were evaluated in comparison with IR700. Antibody-compound conjugates comprising compounds ^-Tz IR700C3SE, ^-Tz IR700C6SE, and ^-Tz IR700C10SE were formed by coupling compounds ^-Tz IR700C3COOH, ^-Tz IR700C6COOH, and ^-Tz IR700C10COOH with cetuximab. In vitro PIT was then performed with these antibody- compound conjugates using A431 cells.

[0471] A431 cells were incubated in DMEM on a 3.5 cm glass bottom dish. Next day, cells were washed with DMEM phenol red (-) and incubated with 5 ug / mL (final) of the antibody- compound conjugate or IR700 in DMEM phenol red (-) for 1 hour at 37 °C. Then, cells were washed with DMEM phenol red (-) and set on an upright microscope. Cells were irradiated with LED light (690 nm). LED light irradiation was conducted for 5 minutes (0.026 W / cm2, 7.8 J / cm2) and microscopic images were taken of the cells at each time-period of 10 minutes, 30 minutes, and 60 minutes. As can be seen in FIG.3 (wherein “ADR” represents antibody:dye ratio), the antibody-compound conjugates exhibited induction of cell death. - 185 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01Example 43

[0472] In this example, photolysis evaluations were conducted to determine the photo- response for aspects of compounds disclosed herein. A solution of each compound (5 µM) in 0.1 M sodium phosphate buffer (pH 7.0) containing 1 mM DTT was prepared in a vial. The solution was bubbled with Ar through the septum cap of the sealed vial before being irradiated with a laser MLL-III-690 (Changchun New Industries Optoelectronics Technology Co., Ltd, Changchun, China) (690 nm, 50 mW cm2) for 1.4–6.4 min (5–20 J cm2). The irradiated solution was analyzed by HPLC (eluent A (H2O, 0.1 M triethylammonium acetate) / eluent B (CH3CN) = 80 / 20 to 0 / 100 in 10 min for all compounds). The detection wavelength was 680 nm. Sulfo-Cyanine5.5 was used as an internal standard. The power densities were measured with an optical power meter PM200 (Thorlabs Inc., Newton, NJ, USA). All the experiments were carried out at room temperature. Results for compounds Pyr-IR700 C6-COOH, Styrl-IR700 C6-COOH, IR700-alkene-COOH, IR700-PEG-COOH, IR700-SA-COOH, IR700-Amd-PEG-COOH, and IR700-Amd-COOH are shown in FIG.4.

[0473] In view of the many possible embodiments to which the principles of the present disclosure may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the present disclosure and should not be taken as limiting the scope of the disclosure. Rather, the scope is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims. - 186 -

Claims

4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01We claim:

1. A conjugate comprising: a virus-like particle compound; and a compound having a structure according to Formula I or Formula IIwherein: X is a VLP-binding moiety or a precursor thereto; the Linker has a structure according to a formula {Core}-(CR2)n-Y-(Z)m- (CR2)p[O(CR2)t]q-{X}, wherein {Core} represents attachment to the phthalocyanine core and {X} represents attachment to X; each R, independently for each occurrence, is selected from hydrogen, halogen, aliphatic, heteroaliphatic, or aromatic; - 187 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01Y is selected from (i) a functional group produced from a reaction between two clickable functional groups; (ii) -CH=CH-[Q1]s-, wherein s is 1 or 0 and Q1is selected from aromatic, -C(=O)Y’-, or -S(=O)2Y’, wherein Y’ is NR” or O, wherein R” is H, -CN, CF3, or a sulfonyl group; or (iii) -C C-Q2, wherein Q2 is –(CH2)uC(=O)Y’-, wherein u is an integer selected from 1 to 10, Y’ is NR” or O, wherein R” is H, -CN, CF3, or a sulfonyl group; Z is a heteroatom; m is 1 or 0; each of n, p, and t independently is selected from an integer ranging from 0 to 50; and q is an integer selected from 0 to 50; G, if present, is selected from halogen or Linker-X, wherein the linker group and the X group are as defined above; each of R1a, R2a, R3a, R1b, R2b, and R3bindependently is selected from hydrogen, aliphatic, halogen, heteroaliphatic, aromatic, thiol, hydroxyl, or amine; or (i) R1aand R1bjoin together, with the carbon atoms to which they are attached, to form a 6-membered aromatic ring, (ii) R2aand R2bjoin together, with the carbon atoms to which they are attached, to form a six-membered aromatic ring, (iii) R3aand R3bjoin together, with the carbon atoms to which they are attached, to form a six-membered aromatic ring, or (iv) any combination of two or more of (i)-(iii); and L is selected from -(CH2)r-, -Si(R5)2(CH2)r-, -C(=O)(CH2)r-, or -Ph(CH2)r-, wherein each R5independently is aliphatic or aryl, r is an integer selected from 1 to 5 and wherein any CH2group of the L group is attached to the quaternary amine of Formula I or Formula II.

2. The conjugate of claim 1, wherein the compound has a structure according to Formula IA or Formula IB- 188 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-013. The conjugate of claim 1 or claim 2, wherein the compound has a structure according to Formula IA(i) - Formula IA(iv)- 189 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01wherein ring A is a ring system selected from a phenyl ring, a pyridyl ring, a triazole, a cycloocta[d]pyridazine, a cycloocta[d]triazole, or a triazole-functionalized DBCO.

4. The conjugate of any one of claims 1-3, wherein the compound has a structure according to one of of Formulas IA(i)(a), IA(i)(b), IA(i)(c), IA(i)(d), IA(i)(e), IA(i)(f), IA(i)(g), IA(i)(h), or IA(i)(i)- 190 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 191 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01. - 192 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-015. The conjugate of claim 1, wherein the compound has a structure according to Formula IB(i) or Formula IB(ii)wherein ring A is a ring system selected from a phenyl ring, a triazole, a cycloocta[d]pyridazine, a cycloocta[d]triazole, or a triazole-functionalized DBCO.

6. The conjugate according to claim 1 or claim 5, wherein the compound has a structure according to one of Formulas IB(i)(a), IB(i)(b), IB(i)(c), or IB(i)(d)- 193 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-017. The compound according to any one of claims 1-6, wherein G is present and is selected from chloro, bromo, fluoro, iodo, or Linker-X, wherein the linker and X groups of Linker-X are as defined for claim 1.

8. The compound according to any one of claims 1-7, wherein G is positioned ortho to the Linker-X group of Formula I. - 194 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-019. The compound according to any one of claims 1-8, wherein L is -(CH2)4, - Si(Me)2(CH2)3-, -Si(Et)2(CH2)3-, -Si(iPr)2(CH2)3-, or -Si(Ph)2(CH2)3-.

10. The conjugate according to claim 1, wherein the compound has a structure according Formula IIA, Formula IIB, or Formula IIC- 195 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01wherein ring A is a ring system selected from a phenyl ring, a triazole, a cycloocta[d]pyridazine, a cycloocta[d]triazole, or a triazole-functionalized DBCO.

11. The compound according to claim 1 or claim 10, wherein the compound has a structure according to one of Formulas II(A)(i), IIA(ii), IIB(i), IIB(ii), IIC(i), IIC(ii), IIC(iii), or IIC(iv)- 196 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 197 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01- 198 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01^ ^^ ^^ ^ ^ ^^ ^^ ^. - 199 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-0112. The conjugate of any one of claims 1-11, wherein X is comprises a carbonyl group.

13. The conjugate of claim 12, wherein the carbonyl group is provided by an activated ester that facilitates binding with the VLP.

14. The conjugate of any one of claims 1-11, wherein Y comprises a ring formed between (i) an alkyne and an azide; (ii) a tetrazine and a trans-cyclooctene; (iii) an azide and a dibenzocyclooctyne (DBCO); or (iv) an azide and a bicyclo[6.1.0]nonyne.

15. The conjugate of any one of claims 1-12, wherein Y comprises a ring formed between an alkyne and an azide.

16. The conjugate of claim 15, wherein the ring formed between the alkyne and the azide is a triazole.

17. The conjugate of any one of claims 1, 2, or 12-16, wherein m is zero and the Linker has a structure according to a formula {Core}-(CR2)n-Y-(CR2)p-{X} or {Core}-(CR2)n-Y- (CR2)p[O(CR2)t]q-{X}, wherein each R is H, n is an integer selected from 0, 1, 2, or 3, p is an integer selected from zero to 21, t is 2, q is an integer selected from 1 to 6, and Y is a 1,2,3- triazole.

18. The conjugate of any one of claims 1, 2, or 12-16, wherein m is 1 and the Linker has a structure according to a formula {Core}-(CR2)n-Y-(Z)m-(CR2)p-{X}, wherein each R is H, n is an integer selected from 0, 1, 2, or 3, p is an integer selected from zero to 21, Y is -CH=CH-Ph- or -CH=CH-Pyridyl-, and m is 0.

19. The conjugate of any one of claims 1, 2, or 12-16, wherein m is 1 and the Linker has a structure according to a formula {Core}-(CR2)n-Y-(Z)m-(CR2)p-{X}, wherein each R is H, n is an integer selected from 0, 1, 2, or 3, p is an integer selected from zero to 21, Y is -CH=CH-Ph- or -CH=CH-Pyridyl-, Z is O, and m is 1.

20. The conjugate of any one of claims 1, 2, or 12-16, wherein m is zero and the Linker has a structure according to a formula {Core}-(CR2)n-Y-(CR2)p-{X}, wherein each R is H, n is an integer selected from 0, 1, 2, or 3, p is an integer selected from zero to 21, and - 200 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01 wherein Y is -CH=CH-C(=O)Y’ or -CH=CH-S(=O)2Y’ wherein Y’ is O or -NH, -N(CN), -NCF3, -NSO2Me, -NSO2CF3, -NSO2NH2, or -NSO2NMe2.. s 1, 2, or 12-16, wherein m is zero and theLinker has a structure according to a formula {Core}-(CR2)n-Y-(CR2)p-{X}, wherein each R is H, n is an integer selected from 0, 1, 2, or 3, p is an integer selected from zero to 21, andwherein Y is -C C(CH2)2C(=O)NH-(CH2)t-, wherein t is an integer selected from 1 to 10.

22. The compound of any one of claims 1, 2, or 12-16, wherein each of n and m is zero and the Linker has a structure according to -CH=CH-(CR2)p-, -CH=CH-C(O)O-(CR2)p, or -CH=CH-C(O)NR”-(CR2)p-.

23. The conjugate of any one of claims 1-16, wherein the compound is ; ; ;- 201 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01 Na Na ; a a ;- 202 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01SO3Na O Si SO3Na Na;- 203 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01 O SO3Na N O O Si SO3Na NaNa ;- 204 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01 ; a a ;- 205 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01SO3Na O Si N SO3Na 3Na3Na ; NaNa ; Na Na;- 206 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01O SO3Na O O Si SO3Na a a ; a a ;- 207 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01SO3Na O O Si SO3Na Na ; a a ;- 208 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01SO3Na O O Si SO3Na a ; Na Na ;- 209 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01O SO3Na N O O Si SO3Na a ; a a ; ; a a ;- 210 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01SO3Na O O Si SO3Na ; a a ; ; a Na ;- 211 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01SO3Na O O Si SO3Na ; NaNa ;- 212 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01SO3Na O O O Si SO3Na ; a a ; a a ;- 213 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01SO3Na O Si SO3Na ; ; Na Na- 214 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01SO3Na O Si SO3Na 3Na ; a a ; a a ;- 215 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01NaO O N Na Na; Na Na; Na Na;- 216 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01ONa O NaNa ; Na Na ;- 217 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01O ONa NaNa; NaNa ; Na Na ;- 218 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01O N O NaNa ; Na Na ;- 219 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01O N O Na Na ; Na Na ;- 220 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01O N Na Na; NaNa;- 221 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01ONa O Na Na ; ;- 222 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01NaO O NaNa ; NaNa ;- 223 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01O ONN Na Na NaNa .

24. The conjugate of any one of claims 1-23, wherein the VLP is a tumor- targeting papilloma VLP.

25. The conjugate of any one of claims 1-24, wherein the VLP comprises papillomavirus capsid proteins. - 224 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-0126. The conjugate of claim 25, wherein the papillomavirus capsid proteins are non-human mammalian papillomavirus capsid proteins, selected from bovine, murine, canine, leporine, or macaque or rhesus papillomavirus capsid proteins.

27. The conjugate of any one of claims 1-25, wherein the VLP comprises human papillomavirus (HPV) L1 capsid proteins.

28. The conjugate of claim 27, wherein the HPV L1 capsid proteins comprise modified HPV L1 capsid proteins, relative to wild-type HPV L1 capsid proteins, and wherein the modified HPV L1 capsid proteins do not cross-react with neutralizing antibodies to HPV 16 or HPV 18.

29. The conjugate of claim 28, wherein the modified HPV L1 capsid proteins comprise a combination of modified HPV L1 capsid proteins and wild-type HPV L2 capsid proteins.

30. The conjugate of claim 29, wherein the tumor-targeting papillomavirus-like particle has reduced immunogenicity and / or antigenicity relative to a virus-like particle comprising wild-type HPV L1 capsid proteins.

31. The conjugate of any one of claims 1-30, wherein the compound is covalently conjugated to papillomavirus capsid proteins of the VLP.

32. The conjugate of any one of claims 1-31, wherein the compound is conjugated to a lysine residue of papillomavirus capsid proteins of the VLP.

33. The conjugate of any one of claims 1-32, wherein a plurality of compounds having a structure according to Formula I or Formula II are conjugated to the VLP.

34. The conjugate of any one of claims 1-32, wherein the compound does not compromise binding of the VLP to a surface of a tumor cell, or wherein the compound does not compromise binding of the VLP to heparan sulfate proteoglycans on a surface of a tumor cell.

35. A method for treating a subject or sample using NIR-PIT, comprising: - 225 -4239-114561-02 09 / 03 / 25 E-137-2024-1-PC-01administering a conjugate according to any one of claims 1-34, or a pharmaceutically acceptable composition thereof, to the subject or the sample; and irradiating the conjugate by application of light to a targeted portion of the subject or the sample.

36. The method of claim 35, wherein the light is applied (i) in a quantity sufficient to produce fluorescence of the conjugate, (ii) in a quantity sufficient to induce killing of a target or a target cell present in the subject or the sample, or a combination of (i) and (ii).

37. The method of claim 35 or claim 36, wherein the light is light of a wavelength ranging from 650 nm to 1100 nm.

38. The method of any one of claims 35-37, wherein the light is applied at a dose of at least 1 J / cm2.

39. The method of any one of claims 35-38, wherein administering is carried out using intravenous administration, intratumor administration, peritumor administration, or via injection into the choroidal space. - 226 -

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