Self-assembled nanoparticles for photothermal therapy

Abstract

Described herein are cyclometallated iron (II) complexes as photothermal transduction agents. The disclosed complexes exhibit high structural robustness and significant absorption in the near infrared (NIR) and visible light regions. The described complexes can be self-assembled to form metal supramolecular particles which have excellent photo-thermal properties and can target tumors through the EPR effect. For example, the Fe NPs disclosed herein have strong near-infrared (NIR) absorbance, high photothermal conversion efficiency of at least 30% (e.g., about 60%) under near-infrared (e.g., 808 nm) laser irradiation, and / or excellent photothermal stability. The Fe NP may be coated with a coating agent (e.g., bovine serum albumin) to form a coated Fe NP, which may further enhance tumor accumulation and biocompatibility of the metal supramolecular particles in vivo. The excellent photo-thermal performance of the Fe NP enables the Fe NP to solve the problem of low photo-thermal conversion efficiency related to most existing photo-thermal materials.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 593,831, filed on October 27, 2023, the disclosure of which is incorporated herein by reference. Technical Field

[0003] The present invention relates generally to the field of iron (II) complexes, particles formed therefrom (eg, metallosupramolecular particles), and methods of use thereof. Background Art

[0004] Conventional treatments, including chemotherapy, radiotherapy or surgery, are always accompanied by severe side effects. Unlike conventional therapies, photothermal therapy (PTT) causes less damage to normal tissues around the tumor because skin, tissues and hemoglobin have poor absorption in the near-infrared (NIR) region. Basically, PTT agents can convert absorbed light energy into thermal energy to induce cellular thermal effects, such as protein denaturation cells, mitochondrial damage or membrane destruction, thereby ablating cancer cells. It is also important that PTT agents have good photothermal properties, photothermal stability, as well as biocompatibility and biosafety. Organic dyes, polymer materials and inorganic nanoparticles have been widely explored as potential photosensitizers (PS) for this purpose. However, despite their photothermal properties, their applications are limited due to poor photothermal stability, unsatisfactory biosafety and potential long-term damage. In addition, precise imaging is usually required to provide tumor location and monitor nanoparticle accumulation in tumor tissue. This information helps determine the best time for treatment. Therefore, the development of new PTT agents is urgent for anticancer research and application.

[0005] In recent years, transition metal complexes have made remarkable achievements in the clinical treatment of neuropathies, tumor therapy and diabetes. These putative systems should exhibit good biosafety properties, thanks to their high stability, photostability and thermostability. They should also allow simultaneous imaging of the target disease state. Fe polypyridine complexes are generally non-luminescent or exhibit extremely short-lived charge transfer (CT) excited states, which limits their use as substitutes or supplements for heavy metal (e.g., Ir, Ru, Pt, etc.) complexes in photophysical / chemical applications. Although Fe is an ideal element due to its high abundance and biocompatibility, molecular Fe(II) (polypyridine) complexes for photothermal therapy studies have not been reported. The scarcity of such reports on Fe(II) complexes is believed to be related to their overall structural instability (especially in biological environments) and low absorption properties in the low-energy visible or NIR regions.

[0006] There is still a need to develop iron(II) complexes as photosensitizers for photothermal therapy.

[0007] It was therefore an object of the present invention to provide iron(II) complexes.

[0008] It is a further object of the present invention to provide particles (eg, metallosupramolecular particles) formed from iron (II) complexes.

[0009] It is a further object of the present invention to provide methods of using iron (II) complexes and particles formed therefrom (eg, metallosupramolecular particles) in photothermal therapy (eg, for treating cancer). Summary of the invention

[0010] Described herein are cyclometallated iron(II) complexes (also referred to herein as "complexes" or "Fe(II) complexes") as photothermal transducers. The disclosed complexes exhibit high structural robustness due to the strengthened Fe-L bonds. In addition, the disclosed complexes have a narrow energy gap caused by the higher metal-based HOMO, which allows them to have significant absorption in the near infrared (NIR) and visible regions (e.g., as demonstrated by using UV-vis spectroscopy).

[0011] The described complexes can self-assemble to form metal supramolecular particles (also referred to herein as "Fe nanoparticles" or "Fe NPs"), for example, through non-covalent interactions. The Fe NPs formed by the complexes have excellent photothermal properties and can target tumors through the EPR effect. For example, the Fe NPs disclosed herein have strong near-infrared (NIR) absorbance, have a high photothermal conversion efficiency of at least 30% (e.g., about 60%), which is significantly higher than commercial gold nanorods (21.0%), Cu2-xSe (22%), and Cu9S5 (25.7%); and / or have excellent photothermal stability under near-infrared (e.g., 808nm) laser irradiation (e.g., a decrease in photothermal conversion efficiency of less than 10% in at least 4 cycles of NIR irradiation).

[0012] In some forms, the Fe NPs are coated with a coating agent, such as bovine serum albumin (BSA), to form coated FeNPs. The coating agent can associate with the Fe NPs by any suitable interaction, such as an electrostatic interaction. Coating with a coating agent can further enhance the tumor accumulation and biocompatibility of the metal supramolecular particles in vivo, as shown, for example, by the following: mice treated with coated Fe NPs have a photothermal effect for an appropriate period of time (e.g., about 5 min, about 6 min, about 10 min, about 20 min, etc.) under 808 nm laser irradiation compared to mice treated with uncoated Fe NPs. For example, the in vivo photothermal effect exhibited by the coated Fe NPs (e.g., mice treated with coated Fe NPs for about 5 to about 20 min under 808 nm laser irradiation) is at least 1.5 times, at least 2 times, 1.5 to 10 times, 1.5 to 5 times, or 1.5 to 3 times stronger than the in vivo photothermal effect of uncoated Fe NPs (e.g., mice treated with uncoated Fe NPs for the same period of time as mice treated with coated Fe NPs at the same dose and the same laser irradiation). See, e.g., the examples described below Fig.13F The excellent photothermal properties of Fe NPs enable them to address the low photothermal conversion efficiency associated with most existing photothermal materials, such as those described above.

[0013] Also disclosed are methods for treating cancer using Fe NPs and coated Fe NPs in photothermal therapy. Generally, the method comprises the step of administering a composition comprising Fe NPs and / or coated Fe NPs to a subject in need thereof. After the administering step, laser irradiation is applied to the subject or a target area of ​​the subject in need of treatment. Generally, after the laser irradiation step, the volume and / or weight of the subject's tumor is reduced by at least 30% compared to the tumor before treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figures 1A-1E Complex C ( Figure 1A ), complex J( Figure 1B ), complex P( Figure 1C )、Complex Q( Figure 1D ) and complex S( Figure 1E ). Counterions and hydrogen atoms have been removed for clarity.

[0015] Figure 2 The UV-vis absorption spectrum of complex CG in CH3CN is shown.

[0016] Figure 3 The UV-vis absorption spectrum of complex HK in CH3CN is shown.

[0017] Figures 4A-4D It shows that the complex O in CH3CN ( Figure 4A ) and complex Q in CH3CN ( Figure 4B ), complex R in DCM ( Figure 4C ) and complex S in CH3CN ( Figure 4D )’s UV-vis absorption spectrum.

[0018] Figure 5 The cyclic voltammogram of the complex CO in CH3CN is shown.

[0019] Figure 6 Shown is the cyclic voltammogram of complex Q in DCM.

[0020] Fig. 7A Shown is the fs-TA spectrum of complex F recorded in MeCN with 455 nm excitation. Figure 7B The kinetic curve of TA intensity at a wavelength of 470 nm is shown.

[0021] Fig. 8A Shown is the fs-TA spectrum of complex C recorded in MeCN with 266 nm excitation. Figure 8B The kinetic curve of TA intensity at a wavelength of 420 nm is shown. Figure 8C The fs-TA spectrum of complex K in MeCN is shown. Fig.8D The kinetic fit of complex K at 595 nm is shown.

[0022] Fig.9A and 9B Shown is the fs-TA spectrum of complex G recorded in MeCN with 455 nm excitation. Fig. 9C The kinetic curve of TA intensity at a wavelength of 500 nm is shown.

[0023] Fig.10 The differential absorption spectrum of complex C upon single electron reduction in 0.1 M MeCN solution of (TBA)PF6 is shown.

[0024] Fig.11 The differential absorption spectrum of complex G upon single electron reduction in 0.1 M MeCN solution of (TBA)PF6 is shown.

[0025] Figures 12A-12E Characterization of Fe(II)-BQ-Bphen2 complex nanoparticles is shown. Fig. 12A is a schematic diagram showing the nanoparticle preparation process. Figures 12B-12E The UV-vis absorption spectrum of Fe(II)-BQ-Bphen2 complex nanoparticles is shown ( Fig. 12B)、Dynamic light scattering (DLS) of Fe(II)-BQ-Bphen2 complex nanoparticles in H2O ( Fig. 12C )、ζ(zeta) potential of Fe(II)-BQ-Bphen2 complex nanoparticles ( Fig.12D ) and Fe(II)-BQ-Bphen2 complex nanoparticles ( Fig.12E , the two figures above) and Fe(II)-BQ-Bphen2 complex nanoparticles coated with BSA ( Fig.12E , the two figures below) of TEM images. Fig.12F Shown is the change in UV-vis absorbance of Fe NPs (uncoated) in pH 7.4 PBS over time. Figure 12G It shows the Fig.12F Shown are graphs of the UV-vis data showing the stability of Fe NPs over time. Fig.12H Shown is the change in UV-vis absorbance of BSA-coated Fe NPs in pH 7.4 PBS over time. Fig.12I It shows the Fig.12H Shown are graphs of the UV-vis data for the stability of BSA-coated Fe NPs over time.

[0026] Figures 13A-13E The photothermal effect of Fe(II)-BQ-Bphen2 complex nanoparticles was shown. Fig.13A The power density of three near-infrared laser irradiations (808 nm, 0.20.5 and 1 W / cm 2 ) under the temperature rise. Fig. 13B It is a graph showing the temperature increase of Fe(II)-BQ-Bphen2 complex nanoparticles with different concentrations after irradiation with 808 nm laser (1.0 W / cm) for 12 min. Fig. 13C Figure 2 is a graph showing the steady-state heating curve of Fe(II)-BQ-Bphen2 complex nanoparticles irradiated with laser (100 μg / mL, 1.0 W / cm2) in aqueous solution. -2 Photothermal effect of Fe NP aqueous dispersion (100 ppm) under 808 laser irradiation and laser off after 22 min of irradiation. The time constant of heat transfer of the system was determined to be τs = 473.13 s by applying the linear time data from the cooling period (after 22 minutes) to the negative natural logarithm of the driving force temperature obtained from the cooling stage of the curve. Fig.13D Figure 2 shows the nanoparticle solution after four irradiation and cooling cycles (100 μg / mL, 1 W / cm 2 ) during the temperature change. Fig.13EGraph showing the photothermal curves of mouse tumors during 808 nm laser irradiation for 6 min 1 hour after intravenous injection of PBS, Fe(II)-BQ-Bphen2 complex nanoparticles (10 mg / kg), or BSA-coated Fe(II)-BQ-Bphen2 complex nanoparticles (10 mg / kg) via the tail vein. Fig.13F Photothermal images of tumors on mice treated with PBS, Fe(II)-BQ-Bphen2 complex nanoparticles (10 mg / kg), or BSA-coated Fe(II)-BQ-Bphen2 complex nanoparticles (10 mg / kg) are shown. These images are from top to bottom with Fig.13E The temperature data of the light thermal curve from top to bottom corresponds to the temperature data of the light thermal curve from top to bottom.

[0027] Figures 14A-14F In vitro phototherapy efficacy and cellular uptake of Fe-NPs are shown. Figures 14A-14B Shown are the results of 808 nm laser irradiation in 4T1 cells ( Fig.14A ) and NCI H460 cells ( Fig. 14B ) Fe-NP dose-dependent cell viability, mean ± SD (n = 4). Unpaired, two-sided t-test *p < 0.05, **p < 0.01 and ***p < 0.001. Figures 14C-14D Propidium iodide and Hoechst staining were used to determine the Fig. 14C ) and NCI H460 cells ( Fig.14D ) were used to count dead and whole cells using a high-throughput microscopy system. Fig.14E is a graph showing the fluorescence intensity of ROS generation in 4T1 cells under different treatment conditions using a microplate reader (Ex 490 nm, Em 525 nm). 2 Irradiation was performed for 10 min. Fig.14F is shown with or without 808nm laser irradiation (1W / cm 2 Figure 3 is a graph of flow cytometric analysis of apoptosis in 4T1 cells treated with vehicle, Fe-NPs (25 μM, 50 μM, and 100 μM) for 10 min.

[0028] Figures 15A-15C It is a graph showing the anti-tumor effect of Fe NP. Fig.15A is a schematic diagram showing the method of treatment of 4T1 tumor-bearing mice. Fig. 15B Figure 2 shows Fe NPs injected via tail vein during treatment with PBS, Fe-NPs (10 mg / kg), and then irradiated with 808 nm (0.5 W / cm 2 ) Tumor volume of nude mice bearing 4T1 xenografts after irradiation for 6 min. Fig. 15C is a graph showing comparison of 4T1 tumor weights and digital images of corresponding 4T1 tumors after 16 days of treatment (n=5). Mean values ​​and error bars are defined as mean and sd, respectively. P values ​​were calculated using a two-tailed Student's t-test (***P<0.005, *P<0.05) by comparing other groups with Fe-NPs with laser irradiation.

[0029] Figures 16A-16O is a bar graph showing the evaluation of the following standard hematological markers and blood biochemistry analysis: White Blood Cells (WBC) ( Fig.16A )、Red blood cells (RBC) Fig. 16B )、Hemoglobin (HGB) ( Fig. 16C )、cran( Fig.16D )、mcv( Fig.16E )、rdw-cv( Fig.16F )、HCT( Figure 16G ),lymph( Fig.16H )、PLT( Fig.16I )、PCT( Fig.16J )、ALT( Figure 16K )、AST( Figure 16L )、ALP( Figure 16M )、Bun( Fig.16N )、Crea( Fig.16O ).

[0030] Figures 17A-17F is a graph showing a mild PTT-induced immune response. Fig.17A The results show that the use of mild power 808nm laser treatment (0.3W / cm 2 ) Method for treating 4T1 tumor-bearing mice. Fig. 17B Shown are the body weight changes of mice under different treatments. Fig. 17C and 17D Figure 2 shows DC maturation induced by mild PTT in 4T1 tumor-bearing mice gated on CD11+ DC cells (CD80 expression: Fig. 17C ; CD86 expression: Fig.17D ). Cells in tumors were collected on day 15 after various treatments for evaluation by flow cytometry after staining with CD11c+, CD80, and CD86. Data represent mean ± SEM (n = 6 biologically independent samples). Fig.17E and 17F Is to show CD4( Fig.17E ) and CD8( Fig.17F ). Comparison of two groups was followed by unpaired Student's t-test (two-tailed). *P<0.05, **P<0.01 and ***P<0.001. DETAILED DESCRIPTION OF THE INVENTION

[0032] I. Definitions

[0033] It should be understood that, unless otherwise stated, the disclosed compounds, compositions and methods are not limited to specific synthetic methods, specific analytical techniques or specific reagents, and can therefore vary. It should also be understood that the terminology used herein is for the purpose of describing specific forms and embodiments only, and is not intended to be limiting.

[0034] As used herein, "substituted" refers to all permissible substituents of the compounds or functional groups described herein. In the broadest sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Illustrative substituents include, but are not limited to, halogens, hydroxyl groups, or any other organic group containing any number of carbon atoms (preferably 1-14 carbon atoms), and optionally contain one or more heteroatoms, such as oxygen, sulfur or nitrogen groups, in a straight chain, branched or ring structure format. Representative substituents include substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, halogen, hydroxy, alkoxy, phenoxy, aryloxy, silyl, thiol, alkylthio, substituted alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, substituted or unsubstituted carbonyl, carboxyl, amino, amide, oxo, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphanyl, phosphoryl, phosphonyl, amino acid. Such substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, halogen, hydroxy, alkoxy, phenoxy, aryloxy, silyl, thiol, alkylthio, substituted alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, substituted or unsubstituted carbonyl, carboxyl, amino, amide, oxo, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphino, phosphoryl, phosphonyl and amino acid may be further substituted.

[0035] The heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. It is understood that "substitution" or "substituted" includes the implicit proviso that such substitution is in accordance with the permissible valences of the substituted atom and the substituent, and that such substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation (e.g., rearrangement, cyclization, elimination, etc.).

[0036] As used herein, "alkyl" refers to a saturated aliphatic group, including straight chain alkyl groups, branched chain alkyl groups, and cycloalkyl groups (alicyclic). In some forms, a straight chain or branched chain alkyl group has 30 or fewer carbon atoms in its backbone (e.g., a straight chain is C1-C 30 , the branch chain is C3-C 30 ), 20 or less, 15 or less, or 10 or less.Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, etc. Similarly, cycloalkyl is based on non-aromatic carbocyclic rings composed of at least three carbon atoms, for example, non-aromatic monocyclic or non-aromatic polycyclic rings containing 3-30 carbon atoms, 3-20 carbon atoms or 3-10 carbon atoms in its ring structure, and there are 5, 6 or 7 carbons in the ring structure.Cycloalkyl containing polycyclic ring systems can have two or more non-aromatic rings, wherein two or more carbons are common to two adjacent rings (i.e., "condensed cycloalkyl ring").Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

[0037] "Substituted alkyl" refers to an alkyl moiety having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can be any of the above substituents, such as halogen (e.g., fluorine, chlorine, bromine or iodine), hydroxy, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (e.g., thioester, thioacetate or thioformate), aryl, alkoxy, aralkyl, phosphonium, phosphino, phosphonyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, oxo, sulfhydryl, thiol, alkylthio, silyl, sulfinyl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aromatic or heteroaromatic moieties. -NRR', wherein R and R' are independently hydrogen, alkyl or aryl, and wherein the nitrogen atom is optionally quaternized; -SR, wherein R is phosphonyl, sulfinyl, silyl, hydrogen, alkyl or aryl; -CN; -NO2; -COOH; carboxylate; -COR, -COOR or -CON(R)2, wherein R is hydrogen, alkyl or aryl; imino, silyl, ether, haloalkyl (e.g., -CF3, -CH2-CF3, -CCl3); -CN; -NCOCOCH2CH2; -NCOCOCHCH; and -NCS; and combinations thereof.

[0038] It will be appreciated by those skilled in the art that the moiety substituted on the hydrocarbon chain itself may be substituted if appropriate. For example, the substituents of substituted alkyl groups may include halogen, hydroxyl, nitro, thiol, amino, aralkyl, azido, imino, amide, phosphonium, phosphino, phosphoryl (including phosphonates and phosphinates), oxo, sulfonyl (including sulfates, sulfonamido, sulfamoyl and sulfonates) and silyl groups, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates and esters), haloalkyl, -CN, etc. Cycloalkyl groups may be substituted in the same manner.

[0039] Unless the number of carbons is otherwise specified, "lower alkyl" as used herein refers to an alkyl group as defined above, but having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths.

[0040] As used herein, "heteroalkyl" refers to a linear or branched or cyclic carbon-containing alkyl group or a combination thereof containing at least one heteroatom on the carbon backbone. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, wherein nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term "heterocycloalkyl" is a cycloalkyl group as defined above, wherein at least one carbon atom of the ring is replaced by a heteroatom (such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus).

[0041] As used herein, the term "alkenyl" is a hydrocarbon group having 2 to 24 carbon atoms and a structural formula containing at least one carbon-carbon double bond. Alkenyl groups include straight chain alkenyl groups, branched alkenyl groups, and cycloalkenyl groups. Cycloalkenyl groups are based on non-aromatic carbocyclic rings composed of at least three carbon atoms and at least one carbon-carbon double bond, such as non-aromatic monocyclic or non-aromatic polycyclic rings containing 3-30 carbon atoms and at least one carbon-carbon double bond, 3-20 carbon atoms and at least one carbon-carbon double bond, or 3-10 carbon atoms and at least one carbon-carbon double bond in its ring structure, and having 5, 6 or 7 carbons and at least one carbon-carbon double bond in the ring structure. Cycloalkenyl groups containing polycyclic ring systems may have two or more non-aromatic rings, wherein two or more carbons are common to two adjacent rings (i.e., "fused cycloalkenyl rings") and contain at least one carbon-carbon double bond. Asymmetric structures such as (AB)C=C(C'D) are intended to include E and Z isomers. This can be inferred from the structural formula herein, where an asymmetric olefin is present, or it can be explicitly indicated by the bond symbol C. The term "alkenyl" as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkenyl" and "substituted alkenyl," the latter referring to alkenyl moieties having one or more substituents replacing hydrogen on one or more carbons of the hydrocarbon backbone. The term "alkenyl" also includes "heteroalkenyl."

[0042] The term "substituted alkenyl" refers to an alkenyl moiety having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents may be any of the above substituents, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphonium, phosphino, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, oxo, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclic, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl and combinations thereof.

[0043] As used herein, "heteroalkenyl" refers to a linear or branched or cyclic carbon-containing alkenyl group or a combination thereof containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, wherein nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term "heterocycloalkenyl group" is a cycloalkenyl group in which at least one carbon atom of the ring is replaced by a heteroatom (such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus).

[0044] As used herein, the term "alkynyl group" is a hydrocarbon group having 2 to 24 carbon atoms and a structural formula containing at least one carbon-carbon triple bond. Alkynyl groups include straight chain alkynyl groups, branched chain alkynyl groups, and cycloalkynyl groups. Cycloalkynyl groups are non-aromatic carbon-based rings consisting of at least three carbon atoms and at least one carbon-carbon triple bond, such as 3-30 carbon atoms and at least one carbon-carbon triple bond, 3-20 carbon atoms and at least one carbon-carbon triple bond, or 3-10 carbon atoms and at least one carbon-carbon triple bond in its ring structure, and non-aromatic monocyclic or non-aromatic polycyclic rings having 5, 6 or 7 carbons and at least one carbon-carbon triple bond in the ring structure. Cycloalkynyl groups containing polycyclic ring systems can have two or more non-aromatic rings, wherein two or more carbons are common to two adjacent rings (i.e., "fused alkynyl rings") and contain at least one carbon-carbon triple bond. Asymmetric structures such as (AB)C≡C(C"D) are intended to include both E and Z isomers. This may be inferred in the formulae herein where an asymmetric alkyne is present, or it may be explicitly indicated by the bond symbol C. The term "alkynyl" as used throughout the specification, examples and claims is intended to include both "unsubstituted alkynyls" and "substituted alkynyls", the latter referring to alkynyl moieties having one or more substituents replacing hydrogen on one or more carbons of the hydrocarbon backbone. The term "alkynyl" also includes "heteroalkynyls".

[0045] The term "substituted alkynyl" refers to an alkynyl moiety having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can be any of the substituents described above, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphonium, phosphino, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

[0046] As used herein, "heteroalkynyl" refers to a linear or branched or cyclic carbon-containing alkynyl group or a combination thereof containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, wherein nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term "heterocycloalkynyl group" is a cycloalkynyl group in which at least one carbon atom of the ring is replaced by a heteroatom (such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus).

[0047] As used herein, "aryl" refers to a C4-C 26The term "aryl" refers to a ring system which is a fused ring system which contains one aromatic ring and optionally one or more non-aromatic rings. Examples of aryl groups are benzene, tetralin, indane, and the like.

[0048] The term "substituted aryl" refers to an aryl group in which one or more hydrogen atoms on one or more aromatic rings are replaced with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, alkoxy, carbonyl (e.g., ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, imino, alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl (e.g., CF3, -CH2-CF3, -CCl3), -CN, aryl, heteroaryl, and combinations thereof.

[0049] "Heterocycle" and "heterocyclyl" are used interchangeably and refer to a cyclic group attached through a ring carbon or nitrogen atom of a monocyclic or polycyclic ring system containing 3-30 ring atoms, 3-20 ring atoms, 3-10 ring atoms, or 5-6 ring atoms, wherein the polycyclic ring system contains one or more non-aromatic rings and optionally one or more aromatic rings, wherein at least one non-aromatic ring contains carbon and 1 to 4 heteroatoms, each heteroatom selected from non-peroxidized oxygen, sulfur and N(Y), wherein Y is absent or is H, O, C1-C 10 Alkyl, phenyl or benzyl and optionally contain 1-3 double bonds and optionally substituted by one or more substituents.Heterocyclic radical is different from heteroaryl according to definition.Heterocycle can be heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl etc., such as piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, dihydrofuran and [2,3-b] tetrahydrofuran, morpholinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pyranyl, 2H-pyrrolyl, 4H-quinolizinyl, quinuclidinyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl.Heterocyclic radical can be optionally substituted by one or more substituents as defined above for alkyl and aryl.

[0050] The term "heteroaryl" refers to a C3-C 26The invention relates to a fused ring system of an aromatic ring or a ring containing an aromatic ring and optionally one or more non-aromatic rings, wherein one or more carbon atoms on the aromatic ring structure have been replaced by heteroatoms. Suitable heteroatoms include, but are not limited to, oxygen, sulfur and nitrogen. Examples of heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, etc. Examples of heteroaryl rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, hexazinyl, decahydroquinolinyl, 2H,6H-1, 5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolyl, 1,2, 3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl The term "heteroaryl" refers to any of the following: 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, and xanthenyl. One or more rings may be substituted as defined below for "substituted heteroaryl".

[0051] The term "substituted heteroaryl" refers to a heteroaryl radical in which one or more hydrogen atoms on one or more heteroaryl rings are replaced with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, alkoxy, carbonyl (e.g., ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, imino, alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl (e.g., CF3, -CH2-CF3, -CCl3), -CN, aryl, heteroaryl, and combinations thereof.

[0052] The term "polyaryl" refers to a fused ring system comprising two or more aromatic rings and optionally one or more non-aromatic rings. Examples of polyaryl groups are naphthalene, anthracene, phenanthrene, When the fused ring system contains two or more aromatic rings and optionally one or more non-aromatic rings, wherein one or more carbon atoms in the two or more aromatic ring structures have been replaced by heteroatoms, the fused ring system may be referred to as a "polyheteroaryl". When the fused ring system contains two or more aromatic rings and optionally one or more non-aromatic rings, wherein one or more carbon atoms in the fused ring system have been replaced by heteroatoms, it may be referred to as a "heteropolyaryl".

[0053] The term "substituted polyaryl" refers to polyaryl groups in which one or more aryl groups are substituted with one or more substituents, including but not limited to halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof. When referring to polyheteroaryl groups, the chemical moiety may be referred to as a "substituted polyheteroaryl".

[0054] The term "ring", "cyclic ring" or "cyclic group" refers to a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted polycyclic ring (e.g., those formed by a monocyclic ring system or a fused ring system), such as a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted cycloalkynyl, or a substituted or unsubstituted heterocyclyl, which, where geometric constraints permit, has 3 to 30 carbon atoms. Substituted cycloalkyl, cycloalkenyl, cycloalkynyl and heterocyclyl are substituted as defined above for alkyl, alkenyl, alkynyl, or heterocyclyl, respectively.

[0055] As used herein, the term "aralkyl" is an aryl or heteroaryl group having an alkyl, alkynyl or alkenyl group as defined above attached to an aromatic group (eg, aryl, heteroaryl, polyaryl or polyheteroaryl). An example of an aralkyl group is a benzyl group.

[0056] The terms "alkoxyl" or "alkoxy", "aroxy" or "aryloxy" generally describe a radical of the formula -OR v A compound represented by v Including but not limited to substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic radical, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, phosphonium, phosphino, phosphono, sulfinyl, silyl, thiol, amide and amino. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy etc. "lower alkoxy" groups are alkoxy groups containing 1 to 6 carbon atoms. "Ether" is two functional groups covalently linked by oxygen, as defined below. Thus, an alkyl substituent that makes an alkyl group an ether is or is similar to an alkoxy group, for example, represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -O-arakyl, -O-aryl, -O-heteroaryl, -O-polyaryl, -O-polyheteroaryl, -O-heterocyclyl, etc.

[0057] The term "substituted alkoxy" refers to an alkoxy group having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the alkoxy backbone. Such substituents can be any of the above substituents, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphonium, phosphino, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, oxo, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclic, alkylaryl, haloalkyl, -CN, aryl, heteroaryl and combinations thereof.

[0058] As used herein, the term "ether" is a 2 OA 1 Indicates that A 2 and A 1 It may independently be a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, a phosphonium group, a phosphino group, a phosphonyl group, a sulfinyl group, a silyl group, a thiol group, a substituted or unsubstituted carbonyl group, an alkoxy group, an amide group or an amino group as described above.

[0059] As used herein, the term "polyether" is represented by the formula:

[0060]

[0061] Among them A 3 It may independently be a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, phosphonium, phosphino, substituted or unsubstituted carbonyl, alkoxy, amide or amino as described above; g may be a positive integer from 1 to 30.

[0062] The term "phenoxy" is art-recognized and refers to a radical of the formula -OR v A compound wherein R v It is C6H5 (ie -O-C6H5). Those skilled in the art will recognize that phenoxy is a type of aryloxy.

[0063] The term "substituted phenoxy" refers to a phenoxy group as defined above having one or more substituents replacing one or more hydrogen atoms on one or more carbons of a phenyl ring. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphonium, phosphino, phosphino, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclic, alkylaryl, haloalkyl, -CN, aryl, heteroaryl and combinations thereof.

[0064] The terms "aroxy" and "aryloxy" used interchangeably herein are represented by -O-aryl or -O-heteroaryl, wherein aryl and heteroaryl are as defined herein.

[0065] The terms "substituted aroxy" and "substituted aryloxy" used interchangeably herein represent an -O-aryl or -O-heteroaryl group having one or more substituents replacing one or more hydrogen atoms on one or more ring atoms of the aryl and heteroaryl groups as defined herein. Such substituents can be any of the substituents described above, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphonium, phosphino, phosphino, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

[0066] As used herein, the term "amino" includes the following groups

[0067]

[0068] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, wherein independently of E, R x , R xi and R xiiEach independently represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aralkyl group (e.g., a substituted or unsubstituted alkylaryl group, a substituted or unsubstituted arylalkyl group), a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, a substituted or unsubstituted heterocyclic group, a hydroxyl group, an alkoxy group, a phosphonium group, a phosphino group, a phosphono group, a sulfinyl group, a silyl group, a thiol group, an amide group, an amino group, or -(CH2) m -R"'; R"' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphonium group, a phosphine group, an amide group or an amino group; and m is 0 or an integer from 1 to 8. The term "quaternary amino group" also includes groups in which nitrogen, R x , R xi and R xii The N + A group forming a heterocyclyl or heteroaryl group having 3 to 14 atoms in the ring structure. It is understood by those skilled in the art that the E groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethylene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0069] The terms "amide" or "amido" are used interchangeably to refer to both "unsubstituted amide" and "substituted amide" and are represented by the following general formula:

[0070]

[0071] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, or substituted or unsubstituted heterocyclyl, wherein R and R' independently of E each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted aralkyl. substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl group (e.g., substituted or unsubstituted alkylaryl group, substituted or unsubstituted arylalkyl group), substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted polyaryl group, substituted or unsubstituted polyheteroaryl group, substituted or unsubstituted heterocyclic group, hydroxyl group, alkoxyl group, phosphonium group, phosphino group, phosphono group, sulfinyl group, silyl group, thiol group, amide group, amino group or -(CH2) m -R"', or R and R' together with the N atom to which they are attached form a heterocyclic ring having 3 to 14 atoms in the ring structure; R"' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphonium group, a phosphine group, an amide group or an amino group; and m is zero or an integer ranging from 1 to 8. In some forms, when E is oxygen, a carbamate is formed. Those skilled in the art understand that the E groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethylene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0072] As used herein, "carbonyl" is art-recognized and includes moieties that can be represented by the following general formula:

[0073]

[0074] wherein X is a bond or represents oxygen or sulfur, and R represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g. substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxy, alkoxy, phosphonium, phosphino, amide, amino, or -(CH2) m-R", or a pharmaceutically acceptable salt thereof; E" is absent, or E" is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl; R' represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxy, alkoxy, phosphonium, phosphino, amide, amino, or -(CH2) m -R"; R" represents a hydroxyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphonium group, a phosphine group, an amide group or an amino group; and m is 0 or an integer ranging from 1 to 8. Such substituents can be any of the substituents described above, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphonium, phosphino, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof. Those skilled in the art understand that the "E" groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethylene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl). When X is oxygen and R is as defined above, the moiety is also referred to as a carboxyl group. When X is oxygen and R is hydrogen, the formula represents a "carboxylic acid." When X is oxygen and R' is hydrogen, the formula represents a "format." When X is oxygen and R or R' is not hydrogen, the formula represents an "ester." In general, when the oxygen atom of the above formula is replaced by a sulfur atom, the formula represents a "thiocarbonyl" group. When X is sulfur and R or R' is not hydrogen, the formula represents a "thioester." When X is sulfur and R is hydrogen, the formula represents a "thioformic acid." When X is sulfur and R' is hydrogen, the formula represents a "thioformate." When X is a bond and R is not hydrogen, the above formula represents a "ketone." When X is a bond and R is hydrogen, the above formula represents an "aldehyde."

[0075] The term "phosphino" is represented by the formula

[0076]

[0077] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, wherein independently of E, R vi and R vii Each independently represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclic group, hydroxyl, alkoxyl, phosphonium, phosphino, phosphono, sulfinyl, silyl, thiol, amide, amino, or -(CH2) m -R"', or R vi and R vii Together with the P atom to which they are attached, they form a heterocyclic ring having 3 to 14 atoms in the ring structure; R'' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphonium group, a phosphine group, an amide group or an amino group; and m is 0 or an integer ranging from 1 to 8. Such substituents can be any of the substituents described above, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl) group, , alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl and combinations thereof. It is understood by those skilled in the art that the E groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethylene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0078] The term "phosphonium" is represented by the formula

[0079]

[0080] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, wherein independently of E, R vi , R vii and R viii Each independently represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclic group, hydroxyl, alkoxyl, phosphonium, phosphino, phosphono, sulfinyl, silyl, thiol, amide, amino, or -(CH2) m -R"', or R vi , R vii and R viii The P +The atoms together form a heterocyclic ring having 3 to 14 atoms in the ring structure; R'' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphonium group, a phosphino group, an amide group or an amino group; and m is 0 or an integer ranging from 1 to 8. Such substituents can be any of the substituents described above, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxy alkyl, alkyl, alkyl, alkylene ...

[0081] The term "phosphono" is represented by the formula

[0082]

[0083] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, oxygen, alkoxy, aryloxy, or substituted alkoxy or substituted aryloxy, wherein independently E, R vi and R vii independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxy, alkoxy, phosphonium, phosphino, phosphono, sulfinyl, silyl, thiol, amide, amino or -(CH2) m-R"', or R vi and R vii Together with the P atom to which they are attached, they form a heterocyclic ring having 3 to 14 atoms in the ring structure; R'' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphonium group, a phosphine group, an amide group or an amino group; and m is 0 or an integer ranging from 1 to 8. Such substituents can be any of the substituents described above, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl) group, , alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl and combinations thereof. It is understood by those skilled in the art that the E groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethylene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0084] The term "phosphoryl" defines a phosphonyl group wherein E is absent, oxygen, alkoxy, aryloxy, substituted alkoxy or substituted aryloxy, as defined above and independently of E, R vi and R vii R is independently hydroxy, alkoxy, aryloxy, substituted alkoxy or substituted aryloxy, as defined above. As will be appreciated by those of ordinary skill in the art, when E is oxygen, the phosphoryl group cannot be attached to another chemical species, such as to form an oxygen-oxygen bond or other unstable bond. vi and R viiWhen substituted, the substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those skilled in the art that the E groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethylene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0085] The term "sulfinyl group" is represented by the formula

[0086]

[0087] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, wherein R, independently of E, represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxy, alkoxy, phosphonium, phosphino, phosphono, silyl, thiol, amide, amino, or -(CH2) m-R"', or E and R together with the S atom to which they are attached form a heterocyclic ring having 3 to 14 atoms in the ring structure; R"' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphonium group, a phosphine group, an amide group or an amino group; and m is 0 or an integer ranging from 1 to 8. Such substituents can be any of the substituents described above, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl and combinations thereof. It is understood by those skilled in the art that the E groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethylene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0088] The term "sulfonyl" is represented by the formula

[0089]

[0090] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, wherein R, independently of E, represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), substituted or unsubstituted aryl , substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxyl, phosphonium, phosphino, amide, amino, or -(CH2)mR"', or E and R together with the S atom to which they are attached form a heterocyclic ring having 3 to 14 atoms in the ring structure; R"' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxyl, phosphonium, phosphino, amide or amino; and m is 0 or an integer ranging from 1 to 8. Such substituents can be any of the substituents described above, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl and combinations thereof. It is understood by those skilled in the art that the E groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethylene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0091] The term "sulfonic acid" refers to a sulfonyl group as defined above, wherein R is hydroxy and E is absent or E is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, or substituted or unsubstituted heteroaryl. Such substituents can be any of the substituents described above, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl and combinations thereof. It is understood by those skilled in the art that the E groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethylene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0092] The term "sulfate" refers to a sulfonyl group as defined above, wherein E is absent, oxygen, alkoxy, aryloxy, substituted alkoxy or substituted aryloxy, all as defined above, and R is independently hydroxy, alkoxy, aryloxy, substituted alkoxy or substituted aryloxy, all as defined above. As will be appreciated by those of ordinary skill in the art, when E is oxygen, sulfate cannot be connected to another chemical species, such as to form an oxygen-oxygen bond or other unstable bonds. Such substituents can be any of the substituents described above, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl and combinations thereof. It is understood by those skilled in the art that the E groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethylene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0093] The term "sulfonate" refers to a sulfonyl group as defined above, wherein E is oxygen, alkoxy, aryloxy, substituted alkoxy or substituted aryloxy, all as defined above, and R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, -(CH2) m -R"', R"' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, an aryl group, a cycloalkyl ring, a cycloalkenyl ring, a heterocycle, an amide group, an amino group, or a polycycle; and m is zero or an integer ranging from 1 to 8. As will be appreciated by those of ordinary skill in the art, when E is oxygen, the sulfonate cannot be linked to another chemical species, for example to form an oxygen-oxygen bond or other unstable bonds. Such substituents can be any of the substituents described above, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl and combinations thereof. It is understood by those skilled in the art that the E groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethylene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0094] The term "sulfamoyl" refers to a sulfonamide or a sulfonamide represented by the formula

[0095]

[0096] wherein E is absent, or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, wherein R and R' independently of E each independently represent hydrogen, substituted or unsubstituted alkyl ... substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl (e.g. substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclic group, hydroxyl, alkoxy, phosphonium, phosphino, amide, amino or -(CH2) m -R"', or R and R' together with the N atom to which they are attached form a heterocyclic ring having 3 to 14 atoms in the ring structure; R"' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphonium group, a phosphine group, an amide group or an amino group; and m is 0 or an integer ranging from 1 to 8. Such substituents can be any of the substituents described above, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl and combinations thereof. It is understood by those skilled in the art that the E groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethylene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0097] The term "silyl group" as used herein is represented by the formula -SiRR'R", wherein R, R' and R" can independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted carbonyl, phosphonium, phosphino, phosphono, sulfinyl, thiol, amide, amino, alkoxy or oxo as described above. Such substituents can be any of the substituents described above, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

[0098] The term "thiol" is used interchangeably and is represented by -SR, where R can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted carbonyl, phosphonium, phosphino, amido, amino, alkoxy, oxo, phosphono, sulfinyl, or silyl as described above. Such substituents can be any of the substituents described above, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

[0099] The disclosed compounds and substituent groups can independently have two or more of the groups listed above. For example, if the compound or substituent group is a straight chain alkyl group, one hydrogen atom of the alkyl group can be substituted by a hydroxyl group, an alkoxy group, etc. Depending on the selected group, the first group can be incorporated into the second group, or the first group can be suspended (i.e., connected) to the second group. For example, for the phrase "an alkyl group comprising an ester group", the ester group can be introduced into the main chain of the alkyl group. Alternatively, the ester can be connected to the main chain of the alkyl group. The nature of the selected group will determine whether the first group is embedded in or attached to the second group.

[0100] The compounds and substituents may independently be substituted with substituents as described above in the definition of "substituted".

[0101] Numerical ranges disclose each possible number that such a range can reasonably cover, and any sub-ranges and combinations of sub-ranges covered therein, respectively. For example, in a given carbon range of C3-C9, the range also discloses C3, C4, C5, C6, C7, C8, and C9, and any sub-ranges (e.g., C4-C6) between these numbers, and any possible range combinations that may be between these values. In yet another example, a given temperature range may be about 25°C to 30°C, wherein the range also discloses temperatures that may be independently selected from about 25, 26, 27, 28, 29, and 30°C, and any ranges (e.g., 26 to 28°C) between these numbers, and any possible range combinations between these values.

[0102] The use of the term "about" is intended to describe a value above or below the stated value, and the term "about" modifies the value within a range of about + / - 10%. When the term "about" is used before a numerical range (i.e., about 1-5) or before a series of numbers (i.e., about 1, 2, 3, 4, etc.), unless otherwise indicated, it is intended to modify both ends of the numerical range and / or each number listed in the entire series.

[0103] The disclosed compounds and substituent groups can independently have two or more of the groups listed above. For example, if the compound or substituent group is a straight chain alkyl group, one hydrogen atom of the alkyl group can be substituted by a hydroxyl group, an alkoxy group, etc. Depending on the selected group, the first group can be incorporated into the second group, or the first group can be suspended (i.e., connected) to the second group. For example, for the phrase "an alkyl group comprising an ester group", the ester group can be introduced into the main chain of the alkyl group. Alternatively, the ester can be connected to the main chain of the alkyl group. The nature of the selected group will determine whether the first group is embedded in or attached to the second group.

[0104] The compounds and substituents may independently be substituted with substituents as described above in the definition of "substituted".

[0105] II. Composition

[0106] Cyclometallated iron(II) complexes (also referred to herein as "complexes," "Fe(II) complexes," or "compounds") and particles formed from these complexes have been developed. The complexes and particles formed from them are suitable for use as photothermal transduction agents. The disclosed complexes exhibit high structural robustness and significant absorption in the near infrared (NIR) and / or visible regions (e.g., absorption at a wavelength of at least 670 nm), for example as demonstrated by using UV-vis spectroscopy. Without being bound by any theory, it is believed that the high structural robustness of the disclosed complexes is due to enhanced Fe-L bonds, while the absorption in the NIR and / or visible regions is due to a narrower energy gap caused by a higher metal-based HOMO. In addition, the disclosed complexes have a spectral density of at least 1 ps. 3 MLCT excited state lifetime (also referred to herein as "excited state lifetime" or "lifetime"), which is measured using fs-TA spectroscopy combined with UV-vis spectroelectrochemistry. In some forms, the complexes tested are 3 The MLCT excited state lifetime is at least 2 orders of magnitude higher than the lifetime of conventional polypyridyl Fe(II) complexes, for example, about 2 orders of magnitude higher than the lifetime of conventional polypyridyl Fe(II) complexes. 3 The MLCT excited state lifetime (e.g., close to the ns state) is promising for photocatalytic applications involving excited state electrons or energy transfer processes. In addition, such lifetimes do not exhibit appreciable photoluminescence quantum yields, which is advantageous for photothermal conversion because luminescence does not serve as the primary excited state decay pathway that limits the photothermal quantum efficiency. The cyclometallated structures of the disclosed complexes can lead to strong field effects. Such strong ligand fields can be coupled with longer lifetimes relative to the strong ligand fields of conventional polypyridyl Fe(II) complexes. 3 Directly related to MLCT lifespan.

[0107] Metal supramolecular particles (also referred to herein as "Fe nanoparticles" or "Fe NPs") can be formed by self-assembly of the disclosed complexes, for example, by non-covalent interactions. The Fe NPs formed by the complexes have excellent photothermal properties and can target tumors by an enhanced permeability retention (EPR) effect. For example, the Fe NPs disclosed herein have strong near-infrared (NIR) absorbance, with a high photothermal conversion efficiency of at least 30% (e.g., about 60%, measured using an 808nm laser irradiated at 1.0W / cm for about 20min, e.g., 22min), which is significantly higher than commercial gold nanorods (21.0%), Cu2-xSe (22%), and Cu9S5 (25.7%); and / or excellent photothermal stability under near-infrared (e.g., 808nm) laser irradiation (e.g., in at least 4 cycles of laser irradiation-cooling, the decrease in photothermal conversion efficiency is less than 10%, wherein each laser irradiation lasts at least 5min).

[0108] The Fe NPs can be coated with a coating agent, such as bovine serum albumin (BSA), to form coated Fe NPs. The coating agent can associate with the Fe NPs by any suitable interaction (covalent or non-covalent, such as electrostatic interaction). Coating with a coating agent can further enhance tumor accumulation and biocompatibility of the metal supramolecular particles in vivo, for example, as shown by the following: mice treated with coated Fe NPs have a photothermal effect for an appropriate period of time (e.g., about 5 min, about 6 min, about 10 min, about 20 min, etc.) under 808 nm laser irradiation compared to mice treated with uncoated Fe NPs. For example, the in vivo photothermal effect displayed by the coated Fe NPs (e.g., mice treated with coated Fe NPs, lasting about 5 to about 20 min under 808 nm laser irradiation) is at least 1.5 times, at least 2 times, 1.5 to 10 times, 1.5 to 5 times, or 1.5 to 3 times stronger than the in vivo photothermal effect of uncoated Fe NPs (e.g., mice treated with uncoated Fe NPs, at the same dose as mice treated with coated Fe NPs and under the same laser irradiation for the same time). The excellent photothermal properties of Fe NPs enable it to solve the problem of low photothermal conversion efficiency associated with most existing photothermal materials (e.g., those described above).

[0109] A. Iron(II) complexes

[0110] The cyclometallated iron (II) complexes disclosed herein are photothermal agents with high quantum efficiency. The photothermal quantum efficiency of the Fe nanoparticles disclosed in the present invention is higher than that of the reported nanoparticles formed by molecular metal complexes, such as those described in Xu, Y., et al., Nat Commun. 2022 13(1): 2009; Yao, Y., et al., Journal of the American Chemical Society, 2022 144(16): 7346-7356. These are suitable for use as photosensitizers in cancer photothermal therapy. When compared with the benchmark [Fe II (bpy)3] 2+ The disclosed complexes exhibit a large σ-donor effect of the cyclometallated donor when compared to the disclosed complexes and are stable in air. In addition, the disclosed complexes exhibit absorption in the near infrared and visible light regions (e.g., from about 200 nm to about 1100 nm, such as from about 600 nm to about 850 nm, from about 600 nm to about 1100 nm, from about 700 nm to about 850 nm, or from about 700 nm to about 1100 nm), and extended 3 MLCT lifetime (e.g., at least 1 ps, such as about 2.59 ps), which is better than the benchmark [Fe(bpy)3] 2+ The complex is at least one order of magnitude longer. In certain forms, the iron complex can be a monocyclometallated tri(bidentate)[Fe II (ppy)(N^N)2] + , [Fe II (BQ)(N^N)2] + (ppy = 2-(pyridin-2-yl)benzene-1-anion, BQ = benzo[h]quinoline-10-anion) and [Fe II (ppy)(tpy)Cl](tpy=2,2':6',2"-terpyridine) complex.

[0111] In certain forms, the disclosed iron (II) complexes may have the structure of Formula I or Formula I':

[0112]

[0113] Wherein: (i) X1, X4, X5, X6, X7 and X9 can independently be carbon or nitrogen, X can be an anion (e.g., PF6 - , Cl - ,OTf - etc.); (ii) each ----- may not exist or be a single bond, each may be absent or may be a double bond; (iii) R1, R'1, R2, R'2, R3 and R'3, when present, may independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted alkylaryl; (iv) R4, R'4, R5, R'5, R6, R'6, R7, R'7, R8, R'8, R9 and R'9 may independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted ring, substituted or unsubstituted heterocycle, halide, amino, amide, thiol, hydroxyl, cyano, nitro, carbonyl , or alkoxy; (v) R"4, R"'4, R"5, R"6, R"7, R"'7, R"8, R"'8, R"9 and R"'9, when present, can independently be hydrogen, halide, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted ring (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl), or substituted or unsubstituted heterocycle; and (vi) when substituents are present, the substituents can independently be unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted heteropolyaryl, unsubstituted alkylaryl, unsubstituted ring, unsubstituted heterocycle, halide, amino, amide, thiol, hydroxyl, cyano, nitro, carbonyl, or alkoxy.

[0114] In some forms, the iron (II) complex may have the structure of Formula II or Formula II':

[0115]

[0116]

[0117] Wherein: (i) X1, X4, X5, X6, X7 and X9 can independently be carbon or nitrogen, X can be an anion (e.g., PF6 - , Cl - ,OTf - etc.); (ii) each ----- may not exist or be a single bond, each (iii) R1, R'1, R2, R'2, R3 and R'3, when present, may independently be hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; (iv) R4, R'4, R5, R'5, R6, R'6, R7, R'7, R8, R'8, R9 and R'9 may independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, or halide; and (v) when substituents are present, the substituents are independently unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted heteropolyaryl, unsubstituted alkylaryl, unsubstituted ring (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl), unsubstituted heterocycle, halide, amino, amide, thiol, hydroxyl, cyano, nitro, carbonyl, or alkoxy.

[0118] In some forms, the iron (II) complex may have the structure of Formula III or Formula III':

[0119]

[0120]

[0121] Wherein: (i) X1, X4, X5, X6, X7 and X9 can be independently carbon or nitrogen, X can be an anion (e.g. PF6 - , Cl - ,OTf - R4, R'4, R"4, R"'4, R5, R'5, R"5, R6, R'6, R"6, R7, R'7, R"7, R"'7, R8, R'8, R"8, R9, R'9, R"9 and R"'9 can independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, or halide; and (iii) when substituents are present, the substituents are independently unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted heteropolyaryl, unsubstituted alkylaryl, unsubstituted ring (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl), unsubstituted heterocycle, halide, amino, amide, thiol, hydroxyl, cyano, nitro, carbonyl, or alkoxy.

[0122] In some forms, for any formula described herein, X1, X5 and X6 may be carbon, and X4, X7 and X9 may be nitrogen. In some forms, for any formula described herein, X1, X9, X5 and X6 may be carbon, and X4 and X7 may be nitrogen. In some forms, for any formula described herein, X4, X7 and X5 may be carbon, and X1, X9 and X6 may be nitrogen.

[0123] In some forms, for any formula described herein, R1, R'1, R2, R'2, R3 and R'3, when present, can independently be hydrogen, unsubstituted alkyl, or unsubstituted aryl. In some forms, for any formula described herein, R4, R'4, R5, R'5, R6, R'6, R7, R'7, R8, R'8, R9 and R'9 can independently be hydrogen, unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, or halide. In some forms, for any formula described herein, R"4, R"'4, R"5, R"6, R"7, R"'7, R"8, R"'8, R"9 and R"'9, when present, can independently be hydrogen, unsubstituted heteroaryl, or halide.

[0124] In some forms, the iron (II) complex may have the structure of Formula IV:

[0125]

[0126] wherein (i) X1 and X9 can independently be carbon or nitrogen; (ii) Y1, Y2, Y3 and Y4 can independently be phosphorus, halogen, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; (iii) R8, R'8, R"8, R"'8, R9, R'9, R"9, R 18 (when present) and R 19 (when present) can independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, or halide; and (iv) when substituents are present, the substituents can independently be unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted heteropolyaryl, unsubstituted alkylaryl, unsubstituted ring (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl), unsubstituted heterocycle, halide, amino, amide, thiol, hydroxy, cyano, nitro, carbonyl, or alkoxy.

[0127] In some forms, the iron (II) complex may have the structure of Formula V:

[0128]

[0129] wherein (i) X1 and X9 can independently be carbon or nitrogen; (ii) Y1, Y2, Y3 and Y4 can independently be phosphorus or halogen; (iii) R8, R'8, R"8, R"'8, R9, R'9, R"9, R 18 (when present) and R 19(when present) may independently be hydrogen, substituted or unsubstituted alkyl, or a halide; and (iv) when substituents are present, the substituents may independently be unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted heteropolyaryl, unsubstituted alkylaryl, unsubstituted ring (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl), unsubstituted heterocycle, halide, amino, amide, thiol, hydroxy, cyano, nitro, carbonyl, or alkoxy.

[0130] In some forms, X1 can be nitrogen and X9 can be carbon. In some forms, Y1, Y2, Y3 and Y4 can independently be trialkylphosphine (e.g., trimethylphosphine) or halogen. In some forms, R8, R'8, R"8, R"'8, R9, R'9 and R"9 can independently be hydrogen or unsubstituted alkyl. R"8 and R"9 can independently be hydrogen. In some forms, R 18 and R 19 (when present) may independently be hydrogen or unsubstituted alkyl.

[0131] In some forms, the iron (II) complex may have the structure of Formula VI:

[0132]

[0133] wherein (i) X1, X4, X7 and X9 can independently be carbon or nitrogen; (ii) Y1 can be phosphorus, halogen, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; (iii) R4, R'4, R"4, R"'4, R6, R'6, R"6, R"'6, R7, R'7, R"7, R8, R'8, R"8, R"'8, R9, R'9, R"9, R 18 (when present) and R 19 (when present) may independently be hydrogen, substituted or unsubstituted alkyl, or a halide; and (iv) when substituents are present, the substituents may independently be unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted heteropolyaryl, unsubstituted alkylaryl, unsubstituted ring (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl), unsubstituted heterocycle, halide, amino, amide, thiol, hydroxy, cyano, nitro, carbonyl, or alkoxy.

[0134] In some forms, the iron (II) complex may have the structure of Formula VII:

[0135]

[0136] wherein (i) X1, X4, X7 and X9 can independently be carbon or nitrogen; (ii) Y1 can be phosphorus or a halogen; (iii) R4, R'4, R"4, R"'4, R6, R'6, R"6, R"'6, R7, R'7, R"7, R8, R'8, R"8, R"'8, R9, R'9 and R"9 can independently be hydrogen, substituted or unsubstituted alkyl, or a halide; and (iv) when substituents are present, the substituents can independently be unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted heteropolyaryl, unsubstituted alkylaryl, unsubstituted ring (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl), unsubstituted heterocycle, halide, amino, amide, thiol, hydroxyl, cyano, nitro, carbonyl, or alkoxy.

[0137] In some forms, X1, X4 and X9 may be nitrogen, and X7 may be carbon. In some forms, Y1 may be a halogen (e.g., fluorine, chlorine or bromine). In some forms, R4, R'4, R"4, R"'4, R6, R'6, R"6, R"'6, R7, R'7, R"7, R8, R'8, R"8, R"'8, R9, R'9 and R"9 may independently be hydrogen or unsubstituted alkyl. In some forms, R"8 and R"9 may independently be hydrogen. In some forms, R 18 and R 19 (when present) may independently be hydrogen or unsubstituted alkyl.

[0138] For any formula described herein, the alkyl group (when present) can be a straight chain alkyl group, a branched chain alkyl group, or a cyclic alkyl group (monocyclic or polycyclic). The terms "cyclic alkyl group" and "cycloalkyl group" are used interchangeably herein. Exemplary alkyl groups include straight chain C1-C 30 Alkyl, branched C4-C 30 Alkyl, cyclic C3-C 30 Alkyl, straight chain C1-C 20 Alkyl, branched C4-C 20 Alkyl, cyclic C3-C 20 Alkyl, straight chain C1-C 10 Alkyl, branched C4-C 10 Alkyl, cyclic C3-C 10 Alkyl, linear C1-C6 alkyl, branched C4-C6 alkyl, cyclic C3-C6 alkyl, linear C1-C4 alkyl, cyclic C3-C4 alkyl, for example linear C1-C 10C1-C9, C1-C8, C1-C7, C1-C6, C1-C5, C1-C4, C1-C3 or C1-C2 alkyl groups, branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5 or C3-C4 alkyl groups, or cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5 or C3-C4 alkyl groups. The cyclic alkyl group can be a monocyclic or polycyclic alkyl group, for example, C4-C 30 、C4-C 25 、C4-C 20 、C4-C 18 、C4-C 16 、C4-C 15 、C4-C 14 、C4-C 13 、C4-C 12 、C4-C 10 , C4-C9, C4-C8, C4-C7, C4-C6 or C4-C5 monocyclic or polycyclic alkyl group.

[0139] For any formula described herein, alkenyl (when present) can be straight chain alkenyl, branched chain alkenyl, or cyclic alkenyl (monocyclic or polycyclic). The terms "cyclic alkenyl" and "cycloalkenyl" are used interchangeably herein. Exemplary alkenyl groups include straight chain C2-C 30 Alkenyl, branched C4-C 30 Alkenyl, cyclic C3-C 30 Alkenyl, straight chain C2-C 20 Alkenyl, branched C4-C 20 Alkenyl, cyclic C3-C 20 Alkenyl, straight chain C2-C 10 Alkenyl, branched C4-C 10 Alkenyl, cyclic C3-C 10 alkenyl, straight-chain C2-C6 alkenyl, branched-chain C4-C6 alkenyl, cyclic C3-C6 alkenyl, straight-chain C2-C4 alkenyl, cyclic C3-C4 alkenyl, for example straight-chain C2-C 10 C2-C9, C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-C3 alkenyl groups, branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkenyl groups, or cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkenyl groups. The cyclic alkenyl group can be a monocyclic or polycyclic alkenyl group, for example, C4-C 30 、C4-C 25 、C4-C 20 、C4-C 18 、C4-C16 、C4-C 15 、C4-C 14 、C4-C 13 、C4-C 12 、C4-C 10 , C4-C9, C4-C8, C4-C7, C4-C6 or C4-C5 monocyclic or polycyclic alkenyl group.

[0140] For any formula described herein, the alkynyl group (when present) can be a straight chain alkynyl group, a branched chain alkynyl group, or a cyclic alkynyl group (monocyclic or polycyclic). The terms "cyclic alkynyl group" and "cycloalkynyl group" are used interchangeably herein. Exemplary alkynyl groups include straight chain C2-C 30 Alkynyl, branched C4-C 30 Alkynyl, cyclic C3-C 30 Alkynyl, straight chain C2-C 20 Alkynyl, branched C4-C 20 Alkynyl, cyclic C3-C 20 Alkynyl, straight chain C2-C 10 Alkynyl, branched C4-C 10 Alkynyl, cyclic C3-C 10 Alkynyl, straight chain C2-C6 alkynyl, branched chain C4-C6 alkynyl, cyclic C3-C6 alkynyl, straight chain C1-C4 alkynyl, cyclic C3-C4 alkynyl, for example straight chain C2-C 10 C2-C9, C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-C3 alkynyl groups, branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkynyl groups, or cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkynyl groups. The cyclic alkynyl group can be a monocyclic or polycyclic alkynyl group, for example, C4-C 30 、C4-C 25 、C4-C 20 、C4-C 18 、C4-C 16 、C4-C 15 、C4-C 14 、C4-C 13 、C4-C 12 、C4-C 10 , C4-C9, C4-C8, C4-C7, C4-C6 or C4-C5 monocyclic or polycyclic alkynyl group.

[0141] For any of the formulae described herein, the aryl group (when present) can be C4-C 30 Aryl, C4-C 20 Aryl, C4-C 12Aryl, C4-C 11 Aryl, C4-C9 aryl, C5-C 30 Aryl, C5-C 20 Aryl, C5-C 12 Aryl, C5-C 11 Aryl, C5-C9 aryl, C6-C 20 Aryl, C6-C 12 Aryl, C6-C 11 It should be understood that the aryl group can be a heteroaryl group, such as a C4-C 30 Heteroaryl, C4-C 20 Heteroaryl, C4-C 12 Heteroaryl, C4-C 11 Heteroaryl, C4-C9 heteroaryl, C5-C 30 Heteroaryl, C5-C 20 Heteroaryl, C5-C 12 Heteroaryl, C5-C 11 Heteroaryl, C5-C9 heteroaryl, C6-C 30 Heteroaryl, C6-C 20 Heteroaryl, C6-C 12 Heteroaryl, C6-C 11 For any of the formulas described herein, the polyaryl group may be C8-C 30 Polyaryl, C8-C 20 Polyaryl, C8-C 12 Polyaryl, C8-C 11 Polyaryl, C 10 -C 30 Polyaryl, C 10 -C 20 Polyaryl, C 10 -C 12 Polyaryl, C 10 -C 11 Polyaryl or C 12 -C 20 It should be understood that the aryl group can be a polyheteroaryl group, such as C 10 -C 30 Polyheteroaryl, C 10 -C 20 Polyheteroaryl, C 10 -C 12 Polyheteroaryl, C 10 -C 11 Polyheteroaryl or C 12 -C 20 Polyheteroaryl.

[0142] Exemplary iron (II) complexes are presented below.

[0143]

[0144]

[0145] Additional exemplary iron(II) complexes are presented below.

[0146]

[0147] The photophysical properties of the iron (II) complexes disclosed herein can be evaluated by absorption wavelength and / or excited state lifetime. Techniques for measuring the absorption wavelength and lifetime of iron (II) complexes are known. For example, the absorption wavelength of the iron (II) complex can be directly measured from the absorption spectrum. For example, the excited state lifetime of the iron (II) complex can be measured using fs-TA spectroscopy in combination with UV-vis spectroelectrochemistry. fs-TA spectroscopy can detect the UV-vis absorption of the transiently present excited states (ESAs) of the iron complexes under light excitation, with lifetimes as low as several hundred femtoseconds, and monitor their evolution over time. Analyzing the kinetics and absorption characteristics of the ESAs, combined with UV-vis spectroelectrochemistry (wherein the absorption of electrochemically generated redox derivatives is obtained), the electronic structure of the excited states can be elucidated.

[0148] In some forms, the iron (II) complex disclosed herein can have an absorption at a wavelength of at least 600 nm, ranging from 600 nm to about 1100 nm, 600 nm to about 1000 nm, 600 nm to about 850 nm, about 650 nm to about 1100 nm, about 650 nm to about 1000 nm, about 650 nm to about 850 nm, about 700 nm to about 1100 nm, about 700 nm to about 1000 nm, or about 700 nm to about 850 nm, such as about 800 nm, obtained according to the absorption spectrum of the iron (II) complex as described above. For example, the iron (II) complex of formula I, I', II, II', III and III' can have absorption in the wavelength range of 600 nm to about 850 nm or about 700 nm to about 850 nm. For example, the iron (II) complex of formula IV can have absorption in the wavelength range of 600 nm to about 1100 nm or about 700 nm to about 1100 nm. For example, the iron (II) complex of formula V can have absorption in the wavelength range of 600 nm to about 850 nm or about 700 nm to about 850 nm. For example, the iron (II) complex of formula VI or VII (e.g., complex R) can have absorption in the wavelength range of 600 nm to about 1100 nm or about 700 nm to about 1100 nm.

[0149] In some forms, the iron (II) complexes disclosed herein can have a spectral distribution of at least 1 ps, at least 2 ps, or at least 2.5 ps (e.g., about 2.59 ps) obtained by fs-TA spectroscopy combined with UV-vis spectroelectrochemistry. 3 MLCT excited state lifetime. In some forms, the disclosed complexes have lifetimes that are at least 2 orders of magnitude higher than the lifetimes of conventional polypyridyl Fe(II) complexes, such as about 2 orders of magnitude higher than the lifetimes of conventional polypyridyl Fe(II) complexes. 3 The MLCT excited state lifetime (e.g., approaching the ns state) is promising for photocatalytic applications involving excited state electrons or energy transfer processes. In addition, such lifetimes do not exhibit appreciable photoluminescence quantum yields, which is advantageous for photothermal conversion because luminescence does not serve as the primary excited state decay pathway that limits the photothermal quantum efficiency. The cyclometallated structures of the disclosed complexes can lead to strong field effects. Such strong ligand fields are usually associated with longer lifetimes relative to the strong ligand fields of conventional polypyridyl Fe(II) complexes. 3 Directly related to MLCT lifespan.

[0150] B. Nanoparticles

[0151] The visible-NIR absorbing iron (II) complexes disclosed herein can self-assemble to form nanoparticles (i.e., "Fe nanoparticles" or "Fe NPs"), typically through non-covalent interactions between the iron (II) complexes. The Fe nanoparticles disclosed herein combine the flexibility of metal supramolecular self-assembly with the advantages of near-infrared (NIR) absorbance, and have a high photothermal conversion efficiency of at least 30% (e.g., about 60.6%, measured using 808 nm laser irradiation at 1.0 W / cm for about 20 min, e.g., 22 min), and excellent photothermal stability under NIR laser irradiation (e.g., 808 nm) laser irradiation (e.g., the photothermal conversion efficiency decreases by less than 10% in at least 4 cycles of laser irradiation-cooling, wherein each laser irradiation lasts at least 5 min). The photothermal conversion efficiency of Fe NPs can be calculated using known methods, such as the method described in Roper, DK, et al., The Journal of Physical Chemistry C, 2007, 111 (9), 3636-3641. For example, the photothermal conversion efficiency (η) of Fe NPs can be calculated using the following formula:

[0152]

[0153] Where h(mW / (m 2 ·℃)) is the heat transfer coefficient, S(m 2 ) is the surface area of ​​the container, and T maxis the equilibrium temperature, T surr is the ambient temperature of the surrounding environment. max -T surr It can be determined based on the temperature-time diagram of the photothermal effect of Fe NPs, see, for example, the following examples Fig. 13C For example, according to Fig. 13C Determined T max -T surr is 51.3℃. Dis (mW) represents the heat from the light absorbed by the cuvette wall (e.g., 8.80 mW in the example), which can be measured using a quartz cuvette containing an aqueous solution without Fe NPs. I is the incident laser power (1 W), and A 808 is the absorbance of supra-CND at 808 nm (0.579).

[0154] To obtain hS, use the maximum system temperature T max Introduce θ:

[0155]

[0156] And the sampling system time constant τs:

[0157]

[0158] According to the following expression:

[0159] t=-t s ln(θ) (4)

[0160] τs can be determined first, and then hS can be derived. For example, in the following example, τs is determined to be 473.13 s, so hS is derived to be 9.91 mW / °C (substituting m=1 g and C=4.2 J / g·K in formula (3)).

[0161] Finally, the photothermal conversion efficiency (η) of Fe NPs can be calculated according to Equation 1 shown above.

[0162] In some forms, the photothermal conversion efficiency is significantly higher than those currently available, such as gold nanorods: 21.0%, Cu2-xSe: 22% and Cu9S5: 25.7% (Wang, S., et al., Advanced Materials, 2016, 28(38), 8379-8387; Hessel, CM, et al., Nano Letters, 2011, 11(6), 2560-2566; and Tian, ​​Q., et al., ACS Nano, 2011, 5(12), 9761-9771). Without being bound by any theory, it is believed that the dd state energy level of the iron (II) complex forming the particle is lower, allowing it to convert more energy from light to heat, thereby achieving enhanced photothermal conversion efficiency.

[0163] The average diameter of the disclosed Fe nanoparticles is generally less than 200 nm, which allows them to target tumors through an enhanced permeability retention (EPR) effect. For example, the disclosed Fe nanoparticles have an average morphological diameter ranging from about 50 nm to about 150 nm or about 80 nm to about 100 nm, as measured using a transmission electron microscope in a solid form. For example, the disclosed Fe nanoparticles have an average hydrodynamic diameter ranging from about 60 nm to about 200 nm, such as about 90 nm, as measured using dynamic light scattering in an aqueous solvent (e.g., water).

[0164] In addition, the disclosed Fe nanoparticles have excellent tumor-targeted photothermal efficacy, as well as good in vitro and in vivo biosafety, as demonstrated by the data shown in the following examples. In some forms, the Fe NPs are coated with a coating agent, such as bovine serum albumin ("BSA"). The coating agent can be associated with the Fe NPs by any suitable interaction, such as an electrostatic interaction.

[0165] Coating with a coating agent can further enhance the tumor accumulation and biocompatibility of the metal supramolecular particles in vivo, for example, as indicated by the following: compared with mice treated with uncoated Fe NPs, mice treated with coated Fe NPs have a photothermal effect under 808 nm laser irradiation for an appropriate period of time (such as about 5 min, about 6 min, about 10 min, about 20 min, etc.). For example, the in vivo photothermal effect shown by the coated Fe NPs (e.g., mice treated with coated Fe NPs, under 808 nm laser irradiation for about 5 to about 20 min) is at least 1.5 times, at least 2 times, 1.5 to 10 times, 1.5 to 5 times, or 1.5 to 3 times stronger than the in vivo photothermal effect of uncoated Fe NPs (e.g., mice treated with uncoated Fe NPs, at the same dose as mice treated with coated Fe NPs and under the same laser irradiation for the same time). See, for example, the following examples described in Fig.13F The excellent photothermal properties of Fe NPs enable them to address the low photothermal conversion efficiency associated with most existing photothermal materials, such as those described above.

[0166] Other examples of coating agents suitable for coating Fe nanoparticles include, but are not limited to, polyalkylene or copolymers thereof (e.g., F-127, DSPE-PEG (2000)) and polysaccharides (e.g., hyaluronic acid), and combinations thereof.

[0167] In some forms, the disclosed Fc nanoparticles further comprise a targeting portion capable of binding to a target biological substance (e.g., a target tumor cell) to improve the cellular uptake, tumor targeting, and / or intratumoral retention time of the nanoparticles. The targeting portion can be attached to the surface of the Fc nanoparticle or to the coating of the coated Fc nanoparticle. Typically, the targeting portion is arranged to expose it to the surrounding environment. Exemplary targeting portions suitable for the disclosed nanoparticles include, but are not limited to, antibodies, antibody fragments, antibody mimetics, affibodies, nucleic acids, oligonucleotides, aptamers, peptides, steroids, histidine tags, NTA-Ni, and tyrosine kinase inhibitors and combinations thereof.

[0168] In some forms, the disclosed Fe nanoparticles further comprise an active agent, such as one or more anticancer agents. The active agent can be encapsulated in the Fe nanoparticles or coated Fe nanoparticles, embedded in the coating of the coated Fe nanoparticles, or associated with the surface of the Fe nanoparticles or coated Fe nanoparticles. Examples of anticancer agents that can be used for nanoparticles include, but are not limited to, temozolomide, carmustine, bevacizumab, procarbazine, lomustine, vincristine, gefitinib, erlotinib, cisplatin, carboplatin, oxaliplatin, 5-fluorouracil, gemcitabine, tegafur, raltitrexed, methotrexate, cytarabine, hydroxyurea, doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, vinblastine, vindesine, vinorelbine, taxane paclitaxel, paclitaxel, docetaxel, etoposide, teniposide, amsacrine, topotecan, camptothecin, bortezomib, anagrelide, tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, fulvestrant, bicalutamide, flutamide, nilutamide, cyproterone acetate, goserelin, leuprolide, buserelin, megestrol acetate, anastrozole, letrozole, vorozole, exemestane, finasteride, horse Mastastat, trastuzumab, cetuximab, dasatinib, imatinib, comprestatin, thalidomide, azacitidine, azathioprine, capecitabine, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, doxifluridine, epothilone, irinotecan, nitrogen mustard, mercaptopurine, mitoxantrone, pemetrexed, thioguanine, valrubicin and / or lenalidomide or a combination thereof, such as cyclophosphamide, methotrexate, 5-fluorouracil (CMF); doxorubicin, cyclophosphamide (AC); nitrogen mustard, long Vinblastine, procarbazine, prednisolone (MOPP); doxorubicin (sdriamycin), bleomycin, vinblastine, dacarbazine (ABVD); cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP); bleomycin, etoposide, cisplatin (BEP); epirubicin, cisplatin, 5-fluorouracil (ECF); epirubicin, cisplatin, capecitabine (ECX); and methotrexate, vincristine, doxorubicin, cisplatin (MVAC); and combinations thereof. Additional anticancer agents are described in U.S. Pat. No. 10,393,736, the disclosure of which is incorporated herein by reference in its entirety.

[0169] C. Pharmaceutical compositions containing Fe NPs or coated Fe NPs

[0170] Disclosed are pharmaceutical compositions containing a plurality of Fe nanoparticles or coated Fe nanoparticles described herein in a form suitable for in vitro or in vivo application (e.g., administration to a mammal). The pharmaceutical composition may comprise one or more pharmaceutically acceptable carriers and / or one or more pharmaceutically acceptable excipients. For example, the pharmaceutical composition may be in the form of a liquid, such as a solution or suspension, and contain a plurality of the disclosed Fe nanoparticles or coated Fe nanoparticles in an aqueous medium, and optionally one or more suitable excipients for liquid compositions. Optionally, the pharmaceutical composition is in solid form and contains a plurality of the disclosed Fe nanoparticles or coated Fe nanoparticles and one or more suitable excipients for solid compositions.

[0171] 1. Carriers and excipients

[0172] Suitable pharmaceutically acceptable carriers and excipients are generally recognized as safe (GRAS) and can be administered to an individual without causing undesirable biological side effects or unwanted interactions.

[0173] Representative carriers and excipients include solvents (including buffers), diluents, pH adjusters, preservatives, antioxidants, suspending agents, wetting agents, viscosity modifiers, tonicity agents, stabilizers, and combinations thereof.

[0174] Excipients may be added to liquid or solid pharmaceutical compositions (for in vivo or in vitro use) to aid sterility, stability (e.g., shelf life), integration, and to adjust and / or maintain the pH or isotonicity of the Fe nanoparticles or coated Fe nanoparticles in the pharmaceutical composition, such as diluents, pH adjusters, preservatives, antioxidants, suspending agents, wetting agents, viscosity modifiers, tonicity agents, and stabilizers, and combinations thereof.

[0175] Fe nanoparticles or coated Fe nanoparticles for administration to a subject (e.g., a mammal) in need thereof can be dissolved or suspended in a suitable carrier to form a liquid pharmaceutical preparation, such as sterile saline, phosphate buffered saline (PBS), balanced salt solution (BSS), viscous gel or other pharmaceutically acceptable carriers for administration. The pharmaceutical preparation can also be a sterile solution, suspension or emulsion in a non-toxic, parenterally acceptable diluent or solvent.

[0176] 2. Form for administration

[0177] The plurality of disclosed Fe nanoparticles or coated Fe nanoparticles can be formulated into pharmaceutical compositions in liquid form or solid form as liquid preparations or solid preparations for oral administration or parenteral administration (e.g., intramuscular injection, intravenous injection, intraperitoneal administration, and subcutaneous administration) to a subject.

[0178] a. Oral Compositions

[0179] Pharmaceutical compositions containing a variety of the disclosed Fe nanoparticles or coated Fe nanoparticles can be provided in a form suitable for oral administration to a subject (e.g., a mammal) (i.e., an oral composition). Oral administration can involve swallowing so that the Fe nanoparticles or coated Fe nanoparticles (optionally including an active agent within / on the nanoparticles) enter the gastrointestinal tract, or buccal or sublingual administration can be employed, by which the Fe nanoparticles or coated Fe nanoparticles enter the bloodstream directly from the oral cavity.

[0180] Compositions suitable for oral administration include solid compositions such as tablets, capsules containing microparticles, liquids, powders, lozenges (including liquid-filled lozenges), chewables, multi- and nanoparticulates, gels, solid solutions, liposomes, films, ovules, sprays, and liquid compositions.

[0181] Liquid compositions for oral administration include suspensions, solutions, syrups and elixirs. Such oral compositions can be used as fillers in soft or hard capsules and may contain one or more suitable carriers and / or excipients, such as water, ethanol, polyethylene glycol, propylene glycol, chitosan polymers and chitosan derivatives (e.g., N-trimethylene chloride chitosan, chitosan esters, chitosan modified with hydrophilic groups (e.g., amino groups, carboxyl groups, sulfate groups, etc.), methylcellulose, suitable oils, one or more emulsifiers, and / or suspending agents. Liquid compositions for oral administration can also be prepared by reconstitution of solids (e.g., from pouches).

[0182] Optionally, the Fe nanoparticles or coated Fe nanoparticles are contained in a fast dissolving and / or fast disintegrating dosage form.

[0183] For tablet or capsule dosage forms, in addition to the Fe nanoparticles or coated Fe nanoparticles described herein, the tablets typically contain a disintegrant, a binder, a diluent, a surfactant, a lubricant, a glidant, an antioxidant, a colorant, a flavoring agent, a preservative or a taste-masking agent, or a combination thereof.

[0184] Examples of suitable disintegrants for forming tablets or capsule dosage forms containing Fe nanoparticles or coated Fe nanoparticles include, but are not limited to, sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Typically, the concentration of the disintegrant can range from about 1 wt% to about 25 wt%, about 5 wt% to about 20 wt% of the tablet or capsule dosage form containing Fe NPs or coated Fe NPs.

[0185] Binders are generally used to impart cohesiveness to tablet compositions containing Fe nanoparticles or coated Fe nanoparticles. Suitable binders for forming tablet or capsule formulations containing Fe nanoparticles or coated Fe nanoparticles include, but are not limited to, microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, chitosan polymers and chitosan derivatives (e.g., N-trimethylene chloride chitosan, chitosan esters, chitosan modified with hydrophilic groups (e.g., amino groups, carboxyl groups, sulfate groups, etc.), hydroxypropyl cellulose, and hydroxypropyl methylcellulose.

[0186] Suitable diluents for forming tablet or capsule compositions containing Fe nanoparticles or coated Fe nanoparticles include, but are not limited to, lactose (such as, for example, monohydrate, spray-dried monohydrate or anhydrous form), chitosan polymers and chitosan derivatives (e.g., N-trimethylene chloride chitosan, chitosan esters, chitosan modified with hydrophilic groups (e.g., amino groups, carboxyl groups, sulfate groups, etc.)), N-sulfonated derivatives of chitosan, quaternized derivatives of chitosan, carboxyalkylated chitosan, microcrystalline chitosan, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

[0187] Tablet or capsule compositions containing Fe nanoparticles or coated Fe nanoparticles may also contain surfactants such as sodium lauryl sulfate and polysorbate 80 in the coating, and glidants such as silicon dioxide and talc. When a surfactant is present, the surfactant concentration may range from about 0.2 wt% to 5 wt% of the tablet or capsule formulation.

[0188] The tablet or capsule composition containing Fe nanoparticles or coated Fe nanoparticles generally also contains a lubricant, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. The concentration of the lubricant can range from about 0.25wt% to 10wt%, about 0.5wt% to 3wt% of the tablet or capsule composition.

[0189] Other possible excipients included in the tablet or capsule formulation containing Fe nanoparticles or coated Fe nanoparticles include glidants (e.g., talc or colloidal anhydrous silicon dioxide at about 0.1 wt % to about 3 wt % of the tablet or capsule formulation), antioxidants, colorants, flavoring agents, preservatives, and taste masking agents. When a glidant is present, the glidant concentration ranges from about 0.2 wt % to 1 wt % of the tablet or capsule composition.

[0190] Exemplary tablet compositions contain up to about 80 wt % of the Fe nanoparticles or coated Fe nanoparticles described herein, about 10 wt % to about 90 wt % of a binder, about 0 wt % to about 85 wt % of a diluent, about 2 wt % to about 10 wt % of a disintegrant, and about 0.25 wt % to about 10 wt % of a lubricant.

[0191] Tablets or capsule mixtures (including Fe nanoparticles or coated Fe nanoparticles and one or more suitable excipients) can be compressed directly or by rollers to form tablets. Tablets or capsule mixtures or a portion of the mixture can alternatively be wet, dry, or melt granulated, melt coagulated or extruded before tableting. The final tablet or capsule composition can contain one or more layers and can be coated or uncoated; it can even be encapsulated in particles, such as polymer particles or liposome particles.

[0192] Solid formulations containing Fe nanoparticles or coated Fe nanoparticles for oral administration can be formulated for immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release formulations.

[0193] b. Parenteral Preparations

[0194] Optionally, the pharmaceutical composition containing a plurality of the disclosed Fe nanoparticles or coated Fe nanoparticles is in a form suitable for direct administration to the bloodstream, muscle or internal organs. Suitable routes for such parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, epidural, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular and subcutaneous delivery. Suitable methods for parenteral administration include needle (including microneedle) syringes, needle-free syringes and infusion techniques.

[0195] For example, the pharmaceutical formulation containing a plurality of Fe nanoparticles or coated Fe nanoparticles is in a form suitable for intramuscular administration, intravenous administration, intraperitoneal administration, or subcutaneous administration, or a combination thereof.

[0196] Parenteral formulations containing the Fe nanoparticles or coated Fe nanoparticles described herein are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (e.g., about pH 6.5 to about pH 8.0, about pH 6.5 to about pH 7.4, about pH 6.5 to about pH 7.0, about pH 7.0 to pH 8.0, or about pH 7.0 to about pH 7.4), however, for certain applications, they may be more suitably formulated as sterile aqueous solutions or in dry form for use in conjunction with a suitable vehicle (e.g., sterile, pyrogen-free water).

[0197] The liquid composition containing Fe nanoparticles or coated Fe nanoparticles for parenteral administration may be a solution, a suspension or an emulsion.

[0198] The liquid pharmaceutically acceptable carrier forming the parenteral composition containing Fe nanoparticles or coated Fe nanoparticles may include one or more physiologically compatible buffers, such as phosphate buffer. Those skilled in the art can easily determine the appropriate salt content and pH of the aqueous carrier for administration (e.g., about pH 6.5 to about pH 8.0, about pH 6.5 to about pH 7.4, about pH 6.5 to about pH 7.0, about pH 7.0 to pH 8.0, or about pH 7.0 to about pH 7.4).

[0199] Liquid compositions containing Fe nanoparticles or coated Fe nanoparticles for parenteral administration may include one or more suspending agents, such as cellulose derivatives, sodium alginate, polyvinyl pyrrolidone, tragacanth gum or lecithin. Liquid compositions may also include one or more preservatives, such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate.

[0200] Optionally, the liquid composition containing Fe nanoparticles or coated Fe nanoparticles contains one or more solvents that are low toxicity organic (i.e., non-aqueous) Class 3 residual solvents, such as ethanol, acetone, ethyl acetate, tetrahydrofuran, ether, and propanol, and combinations thereof. Any such solvents included in the liquid formulation should not react harmfully with one or more active agents present in the Fe nanoparticles or coated Fe nanoparticles in the liquid composition. Solvents such as freon, alcohol, ethylene glycol, polyethylene glycol, or fatty acids may also be included in the liquid composition containing Fe nanoparticles or coated Fe nanoparticles as needed to increase the volatility of the solution or suspension.

[0201] Liquid compositions containing Fe nanoparticles or coated Fe nanoparticles for parenteral administration may also contain a small amount of polymers, surfactants, or other pharmaceutically acceptable excipients known to those skilled in the art. In this context, "a small amount" refers to an amount small enough to avoid adverse effects on the uptake of Fe nanoparticles or coated Fe nanoparticles by target cells (e.g., pituitary gonadotropins).

[0202] The preparation of parenteral compositions containing Fe nanoparticles or coated Fe nanoparticles is typically performed under sterile conditions, such as by lyophilization, which can be achieved using standard pharmaceutical techniques known to those skilled in the art.

[0203] Compositions for parenteral administration containing Fe nanoparticles or coated Fe nanoparticles can be formulated to provide immediate and / or modified release of the active agent. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release formulations.

[0204] c. Amount of Fe NPs or coated Fe NPs

[0205] The pharmaceutical composition generally contains an effective amount of Fe nanoparticles or coated Fe nanoparticles and one or more pharmaceutically acceptable carriers and / or excipients. As used herein, the term "effective amount" refers to any amount of Fe nanoparticles or coated Fe nanoparticles sufficient to achieve the desired therapeutic, preventive and / or diagnostic effect on a biological sample or in a subject to be administered. Depending on the condition to be treated and / or the route of administration, the effective amount of the Fe nanoparticles or coated Fe nanoparticles can be between 0.01 and 1000 mg per kilogram of subject body weight per day, between 0.1 and 500 mg, such as between 1 and 250 mg, such as about 5, 10, 20, 50, 100, 150, 200 or 250 mg per kilogram of subject body weight per day, which can be administered as a single daily dose, divided into more than one or more daily doses. The amount of Fe nanoparticles or coated Fe nanoparticles administered, the route of administration, and further treatment regimen can be determined by the treating clinician or detection technology according to factors such as the age, sex and general condition of the subject, the nature and severity of the disease / symptom to be prevented, treated or diagnosed, and / or the sample tested.

[0206] In some forms, the total amount of Fe nanoparticles or coated Fe nanoparticles in the pharmaceutical composition can be in the range of about 1 μM to about 1 mM, about 10 μM to about 500 μM, about 10 μM to about 200 μM, or about 25 μM to about 100 μM. The term "total concentration of Fe nanoparticles or coated Fe nanoparticles in the pharmaceutical composition" refers to the sum of the weight of the Fe nanoparticles or coated Fe nanoparticles in the composition relative to the weight of the composition.

[0207] In some forms, the pharmaceutical composition is in unit dosage form and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or any other suitable single-dose or multi-dose holder or container (which may be suitably labeled); optionally with one or more leaflets containing product information and / or instructions for use. Typically, such unit doses may contain between 1 and 1000 mg, and typically between 5 and 500 mg, of the disclosed Fe nanoparticles or coated Fe nanoparticles, for example about 10, 25, 50, 100, 200, 300 or 400 mg per unit dose.

[0208] III. How to use

[0209] The complex and the particles formed therefrom are suitable for use as photothermal transducers. Specifically, the FeNPs and coated FeNPs formed by the complex have excellent photothermal properties and can target tumors through the EPR effect. For example, the FeNPs and coated FeNPs disclosed herein have a perceptible near-infrared (NIR) absorbance and a high photothermal conversion efficiency of at least 30% (e.g., about 60%, measured using an 808 nm laser irradiated at 1.0 W / cm for about 20 min, e.g., 22 min). Such photothermal conversion efficiency is significantly higher than that of commercial gold nanorods (21.0%), Cu2-xSe (22%) and Cu9S5 (25.7%) (Wang, S., et al., Advanced Materials, 2016, 28(38), 8379-8387; Hessel, CM, et al., Nano Letters, 2011, 11(6), 2560-2566; and Tian, ​​Q., et al., ACS Nano, 2011, 5(12), 9761-9771). In addition or alternatively, the disclosed Fe NPs and coated Fe NPs have excellent photothermal stability under near-infrared (e.g., 808 nm) laser irradiation (e.g., the photothermal conversion efficiency decreases by less than 10% in at least 4 cycles of laser irradiation-cooling, wherein each laser irradiation lasts at least 5 min). In addition, the disclosed Fe nanoparticles generally have an average diameter of less than 200 nm, allowing them to target tumors through the EPR effect.

[0210] In some forms, the disclosed Fe NPs, coated NPs, or pharmaceutical compositions containing Fe NPs or coated NPs can be used to treat cancer. Preferably, the cancer is a solid cancer (also referred to herein as a "tumor"). "Treatment" or "treating" refers to the medical management of a patient with the goal of curing, improving, stabilizing, or preventing a disease, pathological condition, or disorder, such as cancer. The term includes active treatment, i.e., treatment specifically directed to improving a disease, pathological condition, or disorder (e.g., cancer); and also includes etiological treatment, i.e., treatment directed to eliminating the cause of the relevant disease, pathological condition, or disorder (e.g., cancer). In addition, the term also includes palliative treatment, i.e., treatment designed to relieve symptoms rather than cure a disease, pathological condition, or disorder (e.g., cancer); preventive treatment, i.e., treatment intended to minimize or partially or completely inhibit the development of a relevant disease, pathological condition, or disorder (e.g., cancer); and supportive treatment, i.e., treatment used to supplement another specific therapy directed to improving a relevant disease, pathological condition, or disorder (e.g., cancer).

[0211] In some forms, a method of treating cancer (e.g., a solid cancer) using a pharmaceutical composition containing Fe NPs or coated NPs comprises: (i) administering the pharmaceutical composition to a subject in need thereof; and (ii) applying laser irradiation to the subject or a target area of ​​the subject.

[0212] Administration in step (i) may be performed using any suitable technique, such as oral administration, intramuscular administration, intravenous administration, intraperitoneal administration or subcutaneous administration, or a combination thereof.

[0213] Typically, in step (ii), the wavelength of the laser irradiation is at least 670 nm, in the range of 670 nm to 1500 nm, 670 nm to 1200 nm, 670 nm to 1000 nm, 700 nm to 1500 nm, 700 nm to 1200 nm, or 700 nm to 1000 nm, such as about 800 nm, such as 808 nm. The laser irradiation may be operated at any suitable laser power density, such as a laser power density in the range of about 0.01 W / cm 2 To about 10W / cm 2 , about 0.05W / cm 2 To about 10W / cm 2 , about 0.1W / cm 2 To about 10W / cm 2 , about 0.1W / cm 2 To about 5W / cm 2 , about 0.01W / cm 2 About 1W / cm 2 , about 0.01W / cm 2 To about 0.5W / cm 2 , about 0.05W / cm 2 About 1W / cm 2 , about 0.05W / cm 2 To about 0.5W / cm 2 , about 0.1W / cm 2 To about 1W / cm 2 , about 0.1W / cm 2 To about 0.5W / cm 2 , about 0.01W / cm 2 To about 0.3W / cm 2 , about 0.05W / cm 2 To about 0.3W / cm 2 , or about 0.1W / cm 2 To about 0.3W / cm 2 , for example about 1W / cm 2 , about 0.5W / cm 2 or about 0.3W / cm 2In some forms, the laser irradiation is operated at a laser power density such that mild PTT is obtained. In these forms, the laser power density under the operating laser irradiation is, for example, less than 0.3 W / cm 2 , for example about 0.01 W / cm 2 To about 0.3W / cm 2 , about 0.05W / cm 2 To about 0.3W / cm 2 , or about 0.1W / cm 2 To about 0.3W / cm 2 , for example about 0.3W / cm 2 .

[0214] In step (ii), laser irradiation is maintained for a period of time sufficient to achieve the desired therapeutic effect (e.g., tumor volume and / or tumor weight reduction). Typically, laser irradiation is maintained for a period of time ranging from about 1 min to about 1 hour, from about 5 min to about 1 hour, from about 1 min to about 30 min, from about 5 min to about 30 min, from about 1 min to about 20 min, from about 5 min to about 20 min, from about 1 min to about 15 min, or from about 5 min to about 15 min (e.g., about 6 min).

[0215] Step (i) (administering the pharmaceutical composition) or step (ii) (applying laser irradiation), or steps (i) and (ii) of the disclosed method can occur one or more times. For example, the administering step is performed one or more times, and after all the administering steps, one laser irradiation is applied to the subject or the target area of ​​the subject. For example, the administering step is performed one or more times, and after all the administering steps, two or more laser irradiations are applied to the subject or the target area of ​​the subject. For example, the administering is performed once, and one or more laser irradiations are applied to the subject. For example, the administering step is performed once, and then two or more laser irradiations are applied to the subject or the target area of ​​the subject. For example, the administering step is performed one or more times, and after all the administering steps, laser irradiation is applied to the subject or the target area of ​​the subject, which can be performed one or more times. For example, the administering step is performed once, and then one laser irradiation is applied to the subject or the target area of ​​the subject, followed by another administering step and a subsequent laser irradiation step to repeat the cycle.

[0216] When the application step or the laser irradiation step is performed more than once, or the application and laser irradiation cycle is performed more than once, each step or cycle may be performed regularly every 5 minutes, every 10 minutes, every 20 minutes, every 30 minutes, every hour, every 2 hours, every day, every two days, every three days, every week, every two weeks, every month, etc.; or irregularly at time intervals of 5 minutes, 10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, etc. For example, the application step is performed once, and the laser irradiation step is performed twice or more, on the 1st day, 3rd day, 5th day, etc. after the administration of the pharmaceutical composition or all the administrations of the pharmaceutical composition (when step (i) is performed more than once). For example, the application step is performed once, and the laser irradiation step is performed twice, on the 1st day and 3rd day after the administration of the pharmaceutical composition or all the administrations of the pharmaceutical composition (when step (i) is performed more than once). For example, a first cycle of administration and laser irradiation is performed on day 1, a second cycle of administration and laser irradiation is performed on day 3, and a third cycle of administration and laser irradiation is performed on day 5. The specific number of treatments and the time intervals for treatment can be determined by the treating clinician or the detection technology according to factors such as the age, sex and general condition of the subject, the nature and severity of the disease / symptom to be prevented, treated or diagnosed, and / or the sample detected.

[0217] Step (ii) (application of laser irradiation) may be performed immediately after step (i) (administration of the pharmaceutical composition) (e.g., within 2 hours, within 1 hour, or within 30 minutes), or at a later time after step (i), such as 24 hours, 48 ​​hours, 72 hours, 5 days, 7 days, 2 weeks, 1 month, and / or 3 months after administration of the pharmaceutical composition or all administrations of the pharmaceutical composition (when step (i) is performed more than once). For example, laser irradiation is applied to the subject or the target area of ​​the subject on the 1st, 2nd, 3rd, 4th, and / or 5th day after administration of the pharmaceutical composition or all administrations of the pharmaceutical composition (when step (i) is performed more than once). For example, laser irradiation is applied to the subject or the target area of ​​the subject on the 1st and 3rd days after administration of the pharmaceutical composition or all administrations of the pharmaceutical composition (when step (i) is performed more than once).

[0218] Typically, after the administration step or all administration steps, an effective amount of Fe NPs or coated Fe NPs in a pharmaceutical formulation is administered to a subject, such that after the application of laser radiation in step (ii), cancer cells are killed and / or the growth or proliferation of cancer cells is reduced or prevented, and thereby one or more symptoms associated with cancer are improved in the subject, such as reduction in tumor volume and / or tumor weight. Optionally, the cancer treatment effect occurs without any significant side effects, such as normal cell death.

[0219] For example, after the administering step or all the administering steps, the dose of the metal supramolecular particles administered to the subject is about 0.1 μg to about 100 μg, about 0.5 μg to about 50 μg, about 1 μg to about 100 μg, about 1 μg to about 50 μg, about 1 μg to about 25 μg, about 1 μg to about 10 μg, about 1 μg to about 5 μg, about 4 μg to about 10 μg, or about 1 μg to about 4 μg per gram of the subject. After step (ii) or all steps (ii) (if step (ii) occurs more than once), the tumor volume is reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to the tumor volume before administration of the pharmaceutical composition; and / or the tumor weight is reduced by at least 50%, at least 60%, at least 70%, or at least 80% compared to the tumor weight before administration of the pharmaceutical composition, optionally compared to a control administered with only a pharmaceutically acceptable excipient, without any cytotoxicity to normal cells, as indicated by standard hematological markers and / or blood biochemical parameters.

[0220] Cancer treatment effects, such as tumor volume and / or tumor weight reduction, can occur immediately after treatment, or within a few days after treatment. For example, the reduction in tumor volume and / or weight occurs within about 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks or 1 month after step (ii) or the entire step (ii).

[0221] In some forms, the disclosed method may further include administering an active agent to the subject before administering a pharmaceutical composition containing Fe nanoparticles or coated Fe nanoparticles in step (i), simultaneously with step (i), after step (i) and before applying laser radiation in step (ii), or after step (ii), or a combination thereof. The active agent can be any agent that contributes to the photothermal therapeutic effect of the Fe nanoparticles or coated Fe nanoparticles. In some forms, the active agent can be an anticancer agent, such as any of those described above. In some forms, the active agent can be an immunotherapeutic agent, such as an immunomodulator for target molecules on immune cells (e.g., an activator of CD4 and / or CD8) and an immunomodulator for tumor antigen release and an immunostimulatory molecule activated by ablated tumor cells (e.g., oligodeoxynucleotides containing cytosine-guanine (CpG) motifs, imiquimod (R837), anti-PD-L1 antibodies (aPD-L1), CpG, anti-CTL A4 Ab, anti-PD-L1 Ab, adoptive T cell therapy, etc.). Additional exemplary immunomodulators that can be used in combination with PTT are described in Nam et al., Nature Reviews Materials 4.6 (2019): 398-414.

[0222] In some forms, the disclosed method may further include a step of forming a pharmaceutical composition containing Fe NPs or coated Fe NPs before or in step (i). In some forms, the pharmaceutical composition is formed by adding one or more iron (II) complexes disclosed herein to an aqueous solvent to form a pharmaceutical composition containing Fe NPs. In some forms, the pharmaceutical composition is formed by (a) dissolving one or more iron (II) complexes disclosed herein in a first solvent (e.g., an organic solvent (e.g., DMSO)) to form an iron (II) complex solution, (b) adding the iron (II) complex solution to an aqueous solvent to form Fe NPs, and optionally (c) collecting the Fe NPs and optionally washing the Fe NPs. The formed Fe NPs can then be added to a carrier to form a pharmaceutical composition containing Fe NPs. When coated Fe NPs are used in a pharmaceutical composition, an additional coating step is performed after the Fe NPs are formed in an aqueous solvent. For example, after the Fe NPs formed in the aqueous solvent are collected and washed, the Fe NPs and the coating agent are added to a suitable solvent, optionally under ultrasonic treatment, at room temperature for a suitable period of time to form coated Fe NPs. Specific exemplary conditions for forming Fe NPs and coated Fe NPs are described in the following examples.

[0223] The disclosed Fe(II) complexes, metallosupramolecular particles and methods may be further understood by reference to the following enumerated paragraphs.

[0224] 1. An iron (II) complex having the following structure:

[0225]

[0226] in:

[0227] (i) X1, X4, X5, X6, X7 and X9 are independently carbon or nitrogen, and X is an anion;

[0228] (ii) Each ----- does not exist or is a single bond, each Absent or double bond;

[0229] (iii) R1, R'1, R2, R'2, R3 and R'3, when present, are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted alkylaryl;

[0230] (iv) R4, R'4, R5, R'5, R6, R'6, R7, R'7, R8, R'8, R9 and R'9 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cyclic, substituted or unsubstituted heterocyclic, halide, amino, amide, thiol, hydroxy, cyano, nitro, carbonyl, or alkoxy;

[0231] (v) R"4, R"'4, R"5, R"6, R"7, R"'7, R"8, R"'8, R"9 and R"'9, when present, are independently hydrogen, halide, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cyclic, or substituted or unsubstituted heterocyclic; and

[0232] (vi) when substituents are present, they are independently unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted heteropolyaryl, unsubstituted alkylaryl, unsubstituted cyclic, unsubstituted heterocyclic, halide, amino, amide, thiol, hydroxy, cyano, nitro, carbonyl, or alkoxy.

[0233] 2. The iron (II) complex of paragraph 1, which has the following structure:

[0234]

[0235] in:

[0236] (i) X1, X4, X5, X6, X7 and X9 are independently carbon or nitrogen, and X is an anion;

[0237] (ii) Each ----- does not exist or is a single bond, each Absent or double bond;

[0238] (iii) R1, R'1, R2, R'2, R3 and R'3, when present, are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl;

[0239] (iv) R4, R'4, R"4, R"'4, R5, R'5, R"5, R6, R'6, R"6, R7, R'7, R"7, R"'7, R8, R'8, R"8, R9, R'9, R"9 and R"'9 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, or halide; and

[0240] (v) when substituents are present, they are independently unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted heteropolyaryl, unsubstituted alkylaryl, unsubstituted cyclic, unsubstituted heterocyclic, halide, amino, amide, thiol, hydroxy, cyano, nitro, carbonyl, or alkoxy.

[0241] 3. The iron (II) complex of paragraph 1 or 2, wherein:

[0242] (i) X1, X5 and X6 are carbon, and X4, X7 and X9 are nitrogen; or

[0243] (ii) X1, X9, X5 and X6 are carbon, and X4 and X7 are nitrogen; or

[0244] (iii) X4, X7 and X5 are carbon, and X1, X9 and X6 are nitrogen.

[0245] 4. The iron (II) complex according to any one of paragraphs 1 to 3, wherein:

[0246] (i) R1, R'1, R2, R'2, R3 and R'3, when present, are independently hydrogen, unsubstituted alkyl or unsubstituted aryl;

[0247] (ii) R4, R'4, R5, R'5, R6, R'6, R7, R'7, R8, R'8, R9 and R'9 are independently hydrogen, unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, or halide; and

[0248] (iii) R"4, R"'4, R"5, R"6, R"7, R"'7, R"8, R"'8, R"9 and R"'9, when present, are independently hydrogen, unsubstituted heteroaryl, or halide.

[0249] 5. The iron (II) complex of any one of paragraphs 1 to 4, which has the following structure:

[0250]

[0251]

[0252]

[0253] 6. The iron (II) complex of any of paragraphs 1-5, which has absorption at a wavelength of at least 650 nm, for example ranging from 600 nm to about 850 nm or from about 700 nm to about 850 nm, and / or a lifetime of at least 1 ps.

[0254] 7. Metal supramolecular particles comprising the iron (II) complex according to any one of paragraphs 1 to 6.

[0255] 8. The metal supramolecular particle of paragraph 7, further comprising a coating agent, wherein the coating agent is covalently or non-covalently attached to the surface of the metal supramolecular particle, and optionally wherein the coating agent is bovine serum albumin, polyalkylene or a copolymer thereof (e.g., F-127, DSPE-PEG (2000)) or a polysaccharide (e.g., hyaluronic acid), or a combination thereof.

[0256] 9. The metal supramolecular particle of paragraph 7 or 8, further comprising a targeting moiety.

[0257] 10. The metal supramolecular particle of any one of paragraphs 7-9, having an average morphological diameter in the range of about 50 nm to about 150 nm or about 80 nm to about 100 nm, as measured using transmission electron microscopy; and / or having an average hydrodynamic diameter in the range of about 60 nm to about 200 nm, for example about 90 nm, as measured using dynamic light scattering.

[0258] 11. The metal supramolecular particle of any one of paragraphs 7-10, having a photothermal conversion efficiency of at least 30%, at least 40%, at least 50% or at least 60% measured using 808 nm laser irradiation at 1.0 W / cm for about 20 min.

[0259] 12. The metal supramolecular particle of any one of paragraphs 7 to 11, which has a photothermal stability of at least four laser irradiation-cooling cycles, each laser irradiation lasting at least 5 min.

[0260] 13. A pharmaceutical composition comprising the metal supramolecular particles according to any one of paragraphs 7 to 12, and optionally one or more pharmaceutically acceptable excipients.

[0261] 14. The pharmaceutical composition of paragraph 13, wherein the amount of the metal supramolecular particles ranges from about 1 μM to about 1 mM, from about 10 μM to about 500 μM, from about 10 μM to about 200 μM, or from about 25 μM to about 100 μM.

[0262] 15. A method for treating cancer using the pharmaceutical composition of paragraph 13 or 14, comprising:

[0263] (i) administering the pharmaceutical composition to a subject in need thereof; and

[0264] (ii) applying laser irradiation to the subject or a target area of ​​the subject,

[0265] wherein step (i), step (ii), or steps (i) and (ii) occur one or more times.

[0266] 16. The method of paragraph 15, wherein in step (ii), the wavelength of the laser irradiation is at least 670 nm, in the range of 670 nm to 1500 nm, 670 nm to 1200 nm, 670 nm to 1000 nm, 700 nm to 1500 nm, 700 nm to 1200 nm, or 700 nm to 1000 nm, such as about 800 nm; and the laser power density range is 0.01 W / cm 2 To about 10W / cm 2 , about 0.05W / cm 2 To about 10W / cm 2 , about 0.1W / cm 2 To about 10W / cm 2 , about 0.1W / cm 2 To about 5W / cm 2 , about 0.01W / cm 2 About 1W / cm 2 , about 0.01W / cm 2 To about 0.5W / cm 2 , about 0.05W / cm 2 About 1W / cm 2 , about 0.05W / cm 2 To about 0.5W / cm 2 , about 0.1W / cm 2 About 1W / cm 2 , about 0.1W / cm 2 To about 0.5W / cm 2 , about 0.01W / cm 2 To about 0.3W / cm 2 , about 0.05W / cm 2 To about 0.3W / cm 2 , or about 0.1W / cm 2 To about 0.3W / cm 2 , for example about 1W / cm 2 , about 0.5W / cm 2 or about 0.3W / cm 2 and / or maintained for a time period ranging from about 1 min to about 1 hour, from about 5 min to about 1 hour, from about 1 min to about 30 min, from about 5 min to about 30 min, from about 1 min to about 20 min, from about 5 min to about 20 min, from about 1 min to about 15 min, or from about 5 min to about 15 min.

[0267] 17. The method of paragraph 15 or 16, wherein the pharmaceutical composition is administered orally, intramuscularly, intravenously, intraperitoneally, or subcutaneously, or a combination thereof.

[0268] 18. The method of any of paragraphs 15-17, further comprising administering an active agent, optionally wherein the active agent is an anti-cancer agent.

[0269] 19. The method of any one of paragraphs 15-18, wherein in step (i), the dose of the administered metal supramolecular particles is about 0.1 μg to about 100 μg, about 0.5 μg to about 50 μg, about 1 μg to about 100 μg, about 1 μg to about 50 μg, about 1 μg to about 25 μg, about 1 μg to about 10 μg, about 1 μg to about 5 μg, about 4 μg to about 10 μg, or about 1 μg to about 4 μg per gram of subject.

[0270] 20. The method of any one of paragraphs 15-19, wherein after step (ii) or all steps (ii) (if step (ii) occurs more than once), the tumor volume is reduced by at least 10%, at least 20%, at least 30%, at least 40% or at least 50% compared to the tumor volume before administration of the pharmaceutical composition; and / or the tumor weight is reduced by at least 50%, at least 60%, at least 70% or at least 80% compared to the tumor weight before administration of the pharmaceutical composition, optionally compared to a control administered with only a pharmaceutically acceptable excipient, without any cytotoxicity to normal cells, as indicated by standard hematological markers and / or blood biochemical parameters.

[0271] 21. An iron (II) complex having the following structure:

[0272]

[0273] wherein (i) X1 and X9 are independently carbon or nitrogen; (ii) Y1, Y2, Y3 and Y4 are independently phosphorus, halogen, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; (iii) R8, R'8, R"8, R"'8, R9, R'9, R"9, R 18 (when present) and R 19 (when present) is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, or halide; (iv) when substituents are present, the substituents are independently unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted heteropolyaryl, unsubstituted alkylaryl, unsubstituted ring (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl), unsubstituted heterocycle, halide, amino, amide, thiol, hydroxy, cyano, nitro, carbonyl, or alkoxy.

[0274] 22. The iron (II) complex of paragraph 21, which has the following structure:

[0275]

[0276] wherein (i) X1 and X9 are independently carbon or nitrogen; (ii) Y1, Y2, Y3 and Y4 are independently phosphorus or halogen; (iii) R8, R'8, R"8, R"'8, R9, R'9, R"9, R 18 (when present) and R 19 (iv) when present, the substituents are independently unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted heteropolyaryl, unsubstituted alkylaryl, unsubstituted ring (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl), unsubstituted heterocycle, halide, amino, amide, thiol, hydroxy, cyano, nitro, carbonyl, or alkoxy.

[0277] 23. The iron (II) complex of paragraph 22, wherein:

[0278] X1 is nitrogen, and X9 is carbon;

[0279] Y1, Y2, Y3 and Y4 are independently trialkylphosphine (eg trimethylphosphine) or halogen; or

[0280] R8, R'8, R"8, R"'8, R9, R'9 and R"9 are independently hydrogen or unsubstituted alkyl; or

[0281] R"8 and R"9 are independently hydrogen; or

[0282] R 18 and R 19 , when present, is independently hydrogen or unsubstituted alkyl; or

[0283] Its combination.

[0284] 24. The iron (II) complex of paragraph 21, which has the following structure:

[0285]

[0286] wherein (i) X1, X4, X7 and X9 are independently carbon or nitrogen; (ii) Y1 is phosphorus, halogen, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; (iii) R4, R'4, R"4, R"'4, R6, R'6, R"6, R"'6, R7, R'7, R"7, R8, R'8, R"8, R"'8, R9, R'9, R"9, R 18 (when present) and R 19(iv) when present, the substituents are independently unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted heteropolyaryl, unsubstituted alkylaryl, unsubstituted ring (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl), unsubstituted heterocycle, halide, amino, amide, thiol, hydroxy, cyano, nitro, carbonyl, or alkoxy.

[0287] 25. The iron (II) complex of paragraph 24, which has the following structure:

[0288]

[0289] wherein (i) X1, X4, X7 and X9 are independently carbon or nitrogen; (ii) Y1 is phosphorus or a halogen; (iii) R4, R'4, R"4, R"'4, R6, R'6, R"6, R"'6, R7, R'7, R"7, R8, R'8, R"8, R"'8, R9, R'9 and R"9 are independently hydrogen, substituted or unsubstituted alkyl, or a halide; and (iv) when substituents are present, the substituents are independently unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted heteropolyaryl, unsubstituted alkylaryl, unsubstituted ring (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl), unsubstituted heterocycle, halide, amino, amide, thiol, hydroxyl, cyano, nitro, carbonyl, or alkoxy.

[0290] 26. The iron (II) complex of paragraph 24 or 25, wherein:

[0291] X1, X4 and X9 are nitrogen and X7 is carbon;

[0292] Y1 is halogen (eg fluorine, chlorine or bromine); or

[0293] R4, R'4, R"4, R"'4, R6, R'6, R"6, R"'6, R7, R'7, R"7, R8, R'8, R"8, R"'8, R9, R'9 and R"9 are independently hydrogen or unsubstituted alkyl;

[0294] R"8 and R"9 are independently hydrogen; or

[0295] R 18 and R 19 , when present, is independently hydrogen or unsubstituted alkyl; or

[0296] Its combination.

[0297] The invention will be further understood with reference to the following non-limiting examples.

[0298] 27. The iron (II) complex of any one of paragraphs 21-26, which has the following structure:

[0299] Example

[0300] Example 1. Synthesis and Spectroscopic Studies of Exemplary Cyclometallated Fe(II) Complexes

[0301] A series of air-stable monocyclometallated tri(bidentate)[Fe II (ppy)(N^N)2] + and [Fe II (BQ)(N^N)2] + (ppy = 2-(pyridin-2-yl)benzene-1-anion, BQ = benzo[h]quinoline-10-anion) complexes. The electronic absorption and electrochemical properties of these complexes were studied and compared with the benchmark [Fe II (bpy)3] 2+ The complexes were compared, revealing the strong σ-donor effect of the cyclometalated donor. Three dicyclometalated tri(bidentate)Fe complexes and one [Fe II (ppy)(tpy)Cl] complex (tpy = 2,2':6',2"-terpyridine).

[0302] With [Fe(bpy)3] 2+ In contrast, for the exemplary iron(II) complex, a significant red shift of ∼170-180 nm and stronger absorption in the visible region were observed. Electrochemical studies showed that E 1 / 2 (Fe III / II ) with a sharp cathodic shift of ∼0.95 V (e.g., complex CO) or ∼1.05 V (e.g., complex R), and relative to [Fe(bpy)3] 2+ The UV-vis and CV results demonstrate the great σ-donating ability of the cyclometallated ligands in the Fe(II) complex, and the donor effect is stronger in the tri(bident) than in the di(tridentate) form. The fs-TA measurements reveal the 3 The lifetime of the MLCT excited state is 2.59 ps, which indicates that the cyclometallated structure plays an important role in enhancing the Fe(II) complex. 3 The complex R is a useful precursor for the synthesis of cyclometallated Fe derivatives, where Cl can be replaced by a range of substituents for catalytic or photochemical studies. In addition, complex R exhibits low energy absorption, λ max =998,805nm, and extends to 1100nm.

[0303] Materials and methods

[0304] Synthesis of Exemplary Mononuclear Complexes

[0305] Figure 1. Synthesis of monocyclometallated tri(bidentate) Fe(II) complexes CG and HK

[0306]

[0307]

[0308] The reaction of Fe(PMe3)4 with Hg-(ppy)-Cl or Hg-(BG)-Cl in benzene yielded dark brown-red substance A or dark purple-red substance B within half an hour (Scheme 1). Both A and B were sensitive to air in solution and were not separated. A and B reacted with bidentate diamine ligands to give complex CK. 31 In the P NMR spectrum, A was observed to have a triplet at 22.6 ppm and a doublet at 14.7 ppm (J = 56.8 Hz), with a ratio of ~1:2, and B was observed to have a triplet at 26.0 ppm and a doublet at 14.4 ppm (J = 56.9 Hz) (data not shown). Therefore, it is speculated that complexes A and F are Fe-(C^N) ppy / BQ -(PMe3)3-Cl. ESI-MS measurements support this designation (data not shown). In the presence of KPF6, a mixture of the benzene filtrate of the Fe-(C^N)-(PMe3)3-Cl compound and the N^N ligand is refluxed to give a light-colored solution with a dark precipitate within 2-6 hours. After evaporation of the solvent, the dark solid is washed with benzene or ether and column purified over neutral alumina to give the complex in a relatively pure form in a yield of 60-82%, wherein E is obtained as two stereoisomers in a ratio of 1:1.1. bpy complexes C and H are dark green in color; bpy complex J and phen complexes D, E, I, G and K are dark blue; and complex F is dark brown.

[0309] Scheme 2. Synthesis of monocyclometallated tri(bidentate) Fe(II) complex O

[0310]

[0311] Using Fe(PMe3)4 and 2,2'-(2,5-dichloro-1,4-phenylidene)bipyridine as precursors, the mononuclear complex O generated by a single oxidative addition process was isolated as the major product (Scheme 2), with the second Cl atom on the 2,2'-(2,5-dichloro-1,4-phenylidene)bipyridine ligand precursor remaining intact as revealed by HR ESI-MS.

[0312] Scheme 3. Synthesis of monocyclometallated tri(bidentate) Fe(II) complexes P, Q, S

[0313]

[0314] The dark purple bicyclometallated bis(trimethylphosphine)Fe(II) complex P can be obtained in low yields varying from 5-15% by reacting Fe(PMe3)4 with an excess of 2-(perfluorophenyl)pyridine (Scheme 3). P is air sensitive and is not usually obtained in pure form. Single crystals of P for X-ray diffraction can be obtained by placing pentane in a benzene solution. The synthesis of S by replacing two PMe3 with bpy leads to a mixture of products as shown by NMR, which may be a mixture of diastereoisomers (Scheme 3). Purification by alumina column followed by recrystallization of the majority (benzene / pentane) gives dark single crystals suitable for X-ray diffraction. The mononuclear complex Q is obtained by replacing the PMe3 ligand of P with a bridged 2,5-di(pyridin-2-yl)pyrazine (2,5-dpp) (Scheme 3). Complex Q is purified over a neutral alumina column. Complex Q is purple in solution and is air stable.

[0315] Scheme 4. Synthesis of monocyclometallated Fe(II) complex R

[0316]

[0317] By replacing three phosphines with tpy ligands, complex A was used as a precursor for the synthesis of [Fe(II)-ppy-tpy-Cl] complex R (Scheme 4). Complex A is a synthetic intermediate for a series of cyclometallated polypyridyl Fe complexes. Complex R is brownish yellow in DCM and is slightly air sensitive in both the solid and solution states.

[0318] result

[0319] NMR spectroscopy and X-ray structure

[0320] Complex CR 1 H NMR spectra showed signals in the typical diamagnetic region, indicating that all complexes were in a low-spin state. 1 The H NMR spectrum shows an upfield-shifted aromatic proton signal that is slightly broadened at 5.80 ppm, indicating that the signal is caused by a shielding effect in the related cyclometallated Fe(II) complex and can be attributed to the ortho-H atom of the cyclometallated donor. 1 The H NMR spectrum (due to the asymmetry of the 5-Me-phen ligand) showed multiple aromatic signals, with one broad signal discernible at 5.93 ppm and four methyl signals in the range of 2.88-2.78 ppm.

[0321] P in benzene-d6 31 The P NMR spectrum shows multiple peaks at 19.64 ppm, while the PMe3 proton 1 In the H NMR spectrum, multiple peak resonances were also observed at 0.56 ppm. Four proton signals were observed in the aromatic region, and an obvious proton signal was observed at 5.87 ppm in the high-field region.

[0322] In complex Q(CD2Cl2) 1 In the H NMR spectrum, the signal appeared in the range of 8.92-6.81 ppm. The mononuclear molecular formula was confirmed by HRESI-MS (m / z measured and calculated value 742.0815). 1 The H NMR spectrum showed a high-field doublet at 5.29 ppm ( 2 J HH =7.7Hz), and exhibits a low-field doublet at 10.53ppm ( 2 J HH =5.6 Hz). This signal pattern indicates that the molecule adopts a cyclometallated C trans-connected to the Cl atom and N ppy The signal at 5.29 ppm is attributed to the CH adjacent to the cyclometalated C atom, while the signal at 10.53 ppm is attributed to the N ppy The CH adjacent to the atom.

[0323] Single crystals of complex C suitable for X-ray diffraction were obtained by slow vapor diffusion of Et2O into its CH3CN solution. Complex C adopts a slightly distorted octahedral geometry ( Figures 1A-1E ), the Fe-C bond length is This is comparable to the reported values ​​for cyclometallated Fe(II) complexes. Complex P adopts a slightly distorted octahedral coordination, with the two PMe3 in cis position relative to each other ( Figure 1C ). The two perfluorophenyl carbanion donors occupy the two axial positions in a trans manner, and the two Fe-C bond lengths are 2.012(2) and It is located in the typical Fe-C Ar The long side of the bond length range reflects the mutually destabilizing trans effects. The two Fe-N bonds are 2.002(2) and Two Ph 5F The non-coplanar arrangement of the -Py ligands supports an upfield shift of the pyridine signal, where screening effects are usually present.

[0324] Unlike the structure of the precursor complex P, complex S exhibits a structural arrangement in which the two carbanion donors are cis to each other and trans to the bpy-N donor ( Figure 1E ). The Fe-C bond length of complex S is The bond length of Fe-N in complex S is significantly shorter than that in complex P. bpy The bond length is It is also relatively short. py The length of the key is

[0325] Single crystals of Q were obtained by storing an Et2O solution layered with pentane at 0°C for one week. The trans-arrangement of the two Fe-C bonds in the X-ray structure of complex A remains unchanged in the X-ray structure of complex Q ( Figure 1D ), the bond length is 2.021(2) and It is also comparable to the bond length of complex A. C^N The bond lengths are 1.993(2) and It is slightly shorter than the bond length of complex A. The two Fe-N 2,5-dpp The bond length is 1.900(1) and This indicates that the π reverse donor interaction between the Fe center and the bipyridine moiety is stronger than that between the Fe center and the pyridine C^N The π reverse donor interaction is strong.

[0326] UV-vis absorption and electrochemistry

[0327] Figure 2 The UV-vis absorption spectra and data of the five Fe-ppy complexes in CH3CN are shown in Table 1. Complex C has a λ of 690, 602 and 418 nm in the visible region. max There are three broad absorption bands at 300 nm, and the ligand center absorption is at 300 nm. 2+ In comparison, the lowest energy band is red-shifted by 170 nm, while the 418 nm band is shifted by ∼70 nm. These bands are even more red-shifted in diPh-bpy complex F, with λ shifts of 730, 622, and 482 nm. max The phen complexes D, E and G also show broad and strong low-energy absorption. The three phen complexes D, B and G have higher energy absorptions at 412, 414 and 421 nm, respectively (ε = 2360, 2390 and 2990 L mol -1 cm -1 ) is significantly lower than the intensity of the two bpy complexes C and F (ε = 8500 and 10140 L mol at 418 and 482 nm, respectively). -1 cm -1 ).

[0328] Table 1: [Fe(bpy)3] 2+and spectral data of an exemplary cyclometalated tribidentate Fe(II) complex in MeCN.

[0329]

[0330]

[0331] *Y. Liu, et al., Chem. Eur. J. 2015, 21, 3628-3639

[0332] The UV-vis absorption patterns of the four Fe-BQ complexes are similar to that of the Fe-ppy complex ( Figure 3 The two lowest energy bands of the Fe-BQ complex are slightly blue-shifted compared to the two lowest energy bands of the Fe-ppy complex. A slight blue shift is also observed for the higher energy bands at 409-468 nm for complexes I, J, and K, respectively, compared to the corresponding higher energy bands of Fe-ppy complexes D, F, and G, while a small red shift is observed for complex H compared to complex C. The absorption of the phen complexes at these wavelengths is much weaker than that of the bpy derivatives, which is consistent with the observations for the Fe-ppy analogs.

[0333] Complex O shows an absorption curve similar to that of complex C ( Figure 4A ). The main band of complex O is slightly blue-shifted compared to complex C, with the maximum shift of the lowest energy band being 17 nm. Complex Q shows four bands in the visible range, with a wide band of the lowest energy at 744 nm ( Figure 4B ). The complex R is in the range of λ in the visible and near IR range. mas = 998, 805, 689, 476nm show four absorption bands, low energy absorption extends to 1100nm ( Figure 4C The monocyclometallated tri(bidentate)Fe(II) complex CO shows full-color absorption with two low-energy bands spanning 500–800 nm, as well as with [Fe(bpy)3] 2+ The shape and relative intensity of the three absorption bands of complex C are similar to those of [Ru(ppy)(bpy)2] + The two broad absorptions at 690 and 602 nm are therefore assigned to the Fe→bpy MLCT transitions. +, the broad band at 418 nm can be assigned to the Fe→ppy MLCT transition. These assignments should apply to the absorption of the other complexes DO. It is noteworthy that in phen-derived complexes, such as D and G, the absorption at ∼420 nm is much weaker relative to the lower band, which is consistent with the case of cyclometalated Ru-phen analogs. Complex S exhibits full-color absorption in MeCN, λ max =710, 597 and 432 nm, and the low energy absorption extends to 850 nm. The lowest energy band in 2Me-THF shows a significant red shift, λ max =750nm.

[0334] The electrochemistry of the mononuclear complex in 0.1 M TBAP CH3CN solution was studied by cyclic voltammetry (“CV”). The voltammograms and CV data are presented in Figure 5 and as shown in Table 2. Figure 5 As shown, there are three reversible redox waves, which are attributed to the oxidation of Fe(II) to Fe(III) and the reduction of two ligands. 1 / 2 (Fe III / II )(i.e. -0.28V relative to E(Fc + / 0 ))Compared to the benchmark [Fe II -(bpy)3] 2+ E of the complex (Y. Liu, et al., Chem. Eur. J. 2015, 21, 3628-3639) 1 / 2 (Fe III / II ) is 0.96 V more toward the cathode. This potential shift is more dramatic than the potential shift between Ru analogs (PG Bomben, et al., Inorg. Chem. 2009, 48, 9631-9643), indicating a significant donor effect of the cyclometallated ligand on the Fe(II) center. The two reduction potentials of complex C are higher than [Fe(bpy)3] 2+ The two reduction potentials of Fe III / II The shift of is smaller, indicating a more obvious HOMO-relative to LUMO-energy level increase effect. This is consistent with the fact that complex C has a higher energy level than [Fe(bpy)3] 2+ This is consistent with the sharply red-shifted absorption.

[0335] The other four Fe-ppy complexes show redox waves at nearly the same potential as complex C. The two ligand reduction potentials of complexes F and G are shifted toward the anode by ∼0.1 and 0.15 V, respectively, which is expected due to the π-delocalized phenyl substituents. Surprisingly, the two ligand reduction peaks of complex D are pseudo-reversible under the same conditions with a waveform scan rate dependence.

[0336] A series of Fe-BQ complexes exhibit similar redox waves at comparable potentials, except that E 1 / 2 (Fe III / II ) and E pa (Ox.I) are slightly more negative than the Fe-ppy analogs by ~20-40 mV and ~70-150 mV, respectively. An irreversible oxidation wave was observed at E = 1.41-1.52 (ppy complex) and 1.34-1.37 V (BQ complex) Figure 5 ), which may be related to the Fe(III)-to-Fe(IV) oxidation, reminiscent of the oxidation wave of di(tridentate) monocyclometalated Fe(II) complexes (Z. Tang, et al., Organometallics 2020, 39, 2791-2802). The voltammogram of complex O is similar to that of complex C, except that E 1 / 2 (Fe III / II ) than the latter E 1 / 2 (Fe III / II )Anode offset ~ 0.08V( Figure 6 ), which indicates that the HOMO of complex O is lowered to be comparable to that of complex C, which is consistent with the observed absorption band shift ( Figure 2 and 4A , Table 1). The voltammogram of complex Q shows two reversible redox pairs. 1 / 2 = -0.37 and -2.06 V relative to Fc + / Fc has a relatively large ΔE p The former is attributed to Fe III / II The relatively negative value of redox reaction may be a direct result of the bicyclometallated structure.

[0337] Table 2. CV data of cyclometalated tribidentate Fe(II) complexes in MeCN.

[0338]

[0339] *Pseudo-reversible

[0340] Electrochemical studies of the three complexes showed that E 1 / 2 (Fe III / II ) (i.e. at ~0.28V) and [Fe(bpy)3] 2+ E 1 / 2 (Fe III / II ) is shifted by ∼0.95 V compared to the cathode, which is even higher than the single ring metallized bi(tridentate) [Fe(ppy)(bpy)2] + E 1 / 2 (Fe III / II) is more negative ~ 0.17 V (Z. Tang, et al., Organometallics 2020, 39, 2791-2802; J. Steube, et al., Chem. Eur. J. 2019, 25, 11826-11830). 2+ In comparison, the ligand reduction potential of complex C is only negatively shifted by ∼0.25 V, and the ligand reduction potential of complex C is only negatively shifted by ∼0.25 V compared to [Fe(ppy)(bpy)2] + These results indicate that the HOMO of the cyclometallated complex is unstable and the HOMO-LUMO gap is smaller than that of [Fe(bpy)3] 2+ narrower, which is consistent with the red-shift in visible light absorption compared to the latter. These results also suggest that the cyclometallated unit has a strong σ-donating ability.

[0341] Femtosecond transient absorption spectroscopy

[0342] The excited state dynamics of complexes C, F, and K were investigated using fs-TA measurements in CH3CN at 293 K. For bpy complexes C and F, bleaching of the ground state absorption (GSA) was observed only at 420-470 and >600 nm in the spectral range 450–850 nm ~350 fs after excitation when excited at 266 and 455 nm, respectively (F is Fig. 7A , C is Fig. 8A ). For complex C at 420nm ( Figure 8B ) and complex F at 470nm ( Figure 7B ) showed that the time constants of complex C were 2 and 15 ps, while those of complex F were 1.5 and 12.1 ps. For complex K, absorption features were observed at 353 and 380 nm in the early stage when excited at 690 nm at 293 K ( Figure 8C The spectral evolution is dominated by bleaching of GSA in the >500 nm region. The kinetic fit at 595 nm gave three time constants of 0.19, 2.0, and 20.3 ps ( Fig.8D ).

[0343] For complex C, excited at 266 nm, the main features in the TA spectrum after 775 fs are ground state bleaching at wavelengths of ∼420 and 600 nm ( Fig. 8A ). This excited state absorption (ESA) feature decays to a large extent as GSA recovers. Fitting the dynamics at 420 nm ( Figure 8B ) yields two time components of 2 ps and 15 ps, each of which may be associated with a triplet excited state, since the singlet excited state is expected to have a much shorter lifetime, and for the cyclometallic structure, 5The singlet excited state of MC is expected to be higher in energy.

[0344] For complex G, a significant ESA at 515 nm was observed immediately after excitation at 400 nm within 154 fs, which decayed within a few picoseconds and the GSA recovered ( Fig.9A and 9B ). The kinetic fitting of the 500nm feature yielded two time constants of 0.15 and 2.59ps ( Fig. 9C ). The former should be related to the singlet-to-triplet intersystem crossing, while the latter may be related to the triplet excited state.

[0345] Apart from a possible artifact at λ ∼ 340 nm, there are no absorption features in the fs-TA spectrum of complex C, thus precluding a more detailed assignment of triplet excited states ( Fig. 8A and 10 ). For complex G, the longer 2.59-ps temporal component can be attributed to the triplet excited state. The ESA at 500 nm associated with this excited state is highly similar to the absorption at 495 nm in the reduction differential spectrum ( Figures 9A-9B and Fig.11 ), which indicates that the excited state has 3 MLCT characteristics. The 2.59-ps lifetime is longer than that of typical Fe(bpy)3] 2+ The lifetime of the complex is one order of magnitude longer, which may be attributed to the strong field effect and low-lying π*(diPh-phen) of the cyclometalated donor.

[0346] Spectroelectrochemistry

[0347] UV-vis spectroelectrochemical (SEC) studies were performed on complexes C and G in MeCN. After one-electron oxidation, the MLCT bands of the complexes disappeared, consistent with the depletion of the Fe(II) center. After one-electron reduction, broad new absorptions ( Fig.10 and 11 ). For complex C, at λ max There are three main absorptions at 787, 535 (506) and 357 nm ( Fig.10 ). These features may be attributed to the absorption of the bpy ligand radical anion. An increase in the intensity of these absorptions was observed after further single electron reduction, indicating the generation of a second bpy ligand radical anion. Qualitatively similar SEC spectral changes were observed for complex G with phen ligands, where three major bands were noted after single electron reduction, with the mid-energy band appearing at 495 nm ( Fig.11 ).

[0348] Example 2. Self-assembly of exemplary cyclometallated Fe(II) complexes as photosensitizers for effective photothermal therapy

[0349] Exemplary cyclometallated polypyridyl Fe(II) complexes are demonstrated as photothermal transducers (PTAs). This type of complex has high structural robustness due to Fe-L bond enhancement (where enhanced metal-to-ligand π-back-donation may play a role) and good visible-to-NIR absorptivity due to the narrowed energy gap caused by higher metal-based HOMO. In addition, the cyclometallated Fe(II) photosensitizer combines the advantages of the flexibility of metal supramolecular self-assembly and strong near-infrared (NIR) absorptivity, with a high photothermal conversion efficiency of 60.6% (commercial gold nanorods: 21.0%, Cu2-xSe: 22% and Cu9S5: 25.7%) and excellent photothermal stability under 808 nm laser irradiation. The data show that the supramolecular photosensitizers formed using the cyclometallated polypyridyl Fe(II) complexes disclosed herein (also referred to herein as "metallic supramolecular particles," "Fe nanoparticles," or "Fe NPs") have excellent tumor-targeted photothermal efficacy and good biosafety in vitro and in vivo.

[0350] The exemplary benzo[h]quinolin-10-ylbis(bromophenanthroline) Fe(II) complex (Fe(II)-BQ-Bphen2) exhibits NIR absorbance and can self-assemble into metal supramolecular particles (i.e., Fe NPs) in aqueous systems via non-covalent interactions ( Fig. 12A , left and middle). To enhance the tumor accumulation and biocompatibility of metal supramolecular particles in vivo, bovine serum albumin (BSA) was used to coat Fe NPs to form Fe(II)-BQ-Bphen2@BSA nanoparticles (also referred to herein as “Fe NP@BSA,” “Fe-BB nanoparticles,” “Fe-BB NPs,” or “BSA-coated Fe NPs”)) ( Fig. 12A , middle and right). The data indicate that the particles act as efficient PTT agents. In terms of anticancer efficacy, 4T1 tumor-bearing balb / c mice were treated with Fe-BB NPs to explore the in vivo PTT efficacy.

[0351] Materials and methods

[0352] Preparation of Fe NPs and coated Fe NPs

[0353] To produce Fe NPs of Fe complex, 2 mg of Fe complex was dissolved in 0.5 mL of DMSO. Then, the solution was added dropwise to 10 mL of deionized water, and the mixture was stirred at room temperature for 4 h. Subsequently, the resulting product was collected and washed three times using an Amico tube (10 kDa).

[0354] To produce Fe NPs coated with BSA, the prepared Fe nanoparticles and BSA (w:w = 1:0.5) were added to 15 mL of phosphate buffer (Na2HPO4-NaH2PO4, pH = 8.0) and continued under ultrasound at room temperature for 4 hours. Finally, the product was conventionally centrifuged (13,000 rpm, 10 min) and washed three times with distilled water. The collected material was stored in a dark environment for further use.

[0355] Fe NPs and Fe-BB NPs were characterized using TEM, dynamic light scattering, zeta potential, FTIR, and XRD.

[0356] Cell culture

[0357] Human NCI-H460 lung cancer cells and mouse 4T1 breast cancer cells were purchased from the American Type Culture Collection (ATCC). MycoSET Mycoplasma Real-Time PCR Detection Kit (Life Technologies, Foster City, CA, USA) was used to routinely detect whether cells were contaminated with mycoplasma. NCI-H460 cells and 4T1 cells were cultured in an incubator at 37°C in an atmosphere of 5% CO2 and 90% relative humidity in Roswell Park Memorial Institute-1640 (RPMI-1640) with 10% (v: v) fetal bovine serum (FBS), 100U mL-1 penicillin and 100μg mL-1 streptomycin. A549 cells were cultured in a Dulbecco's modified Eagle medium (DMEM) supplemented with 10% (v: v) FBS, 100U mL-1 penicillin and 100μg mL-1 streptomycin in the same incubator as NCI-H460 cells. These cells were digested and subcultured using 0.25% trypsin.

[0358] In vitro photocytotoxicity of Fe NP@BSA

[0359] NCI-H460 cells or 4T1 cells were plated in 96-well plates (8×10 3 After 24 h of incubation, the medium was replaced with fresh medium containing Fe nanoparticles at a final concentration of 0-100 μg / mL. After overnight incubation, each well of half of the cell plate was illuminated by 808 nm laser (0.5 W / cm 2 or 1W / cm 2) for 10 min as the PTT group, and the remaining wells were placed in the dark as the control group. After incubation for another 24 h, 10 μL CCK-8 (WST-8) was added to each well and incubated for another 1 h. Cell viability was determined as absorbance at 450 nm using a Thermo Scientific VarioskanTM Lux multi-mode microplate reader.

[0360] Cellular ROS measurement

[0361] NCI H460 cells or 4T1 cells were seeded in 96-well plates (8×10 3 cells / well) and incubated for 24 h. The cells were divided into 6 groups: control (with / without laser) and Fe NP@BSA (25 μg / mL or 50 μg / mL) (with / without laser). After incubation for 6 h, 808 nm laser (1 W / cm 2 ) irradiate the PTT group of the plate for 10 min / well. Finally, add 10uL ROS probe-H2DCFDA to each well (finally 5μM / well), and detect the fluorescence of the plate by a microplate reader (Ex 490nm, Em 525nm) after incubating the plate for 60min.

[0362] Immunofluorescence staining for DNA damage.

[0363] 2×10 4 Cells were seeded on glass coverslips. After 24 h of incubation, the cells were treated with vehicle or Fe NP@BSA (50 μg / mL) for 4 h in an incubator and then illuminated with 808 nm laser (1 W / cm 2 ) for 10 min. For γH2AX staining, cells were fixed in 4% paraformaldehyde / PBS for 15 min at room temperature, permeabilized with 0.3% Triton X-100 / PBS on ice for 15 min, and then blocked in 0.2% BSA / PBS for 1 h at room temperature. Finally, cells were stained with γH2AX (Cell Signaling, #2577L, 1:100 dilution, at 4°C for 2 h) and immunostained with secondary antibody (Invitrogen, Alexa Fluor 568 dye, 1:200 dilution, 2h, RT). For DNA staining, cells were stained with DAPI (1:400 dilution, 15min at 4°C). Coverslips were then visualized and recorded by Micro Confocal High-Content Imaging (ZEISS).

[0364] Apoptosis studies by flow cytometry

[0365] 4T1 cells were seeded in 6-well plates (3 × 10 5 The cells were treated with 25, 50, or 100 μg / mL FeNP@BSA or PBS for 4 h and then illuminated with an 808 nm laser (1 W / cm 2 ) for 10 min as light treatment or placed in the dark as a control. Then, cells are collected in a 1.5 mL tube. According to the manufacturer's scheme, Annexin V-FITC / PI assay kit is used at room temperature to measure apoptosis by flow cytometry for 15 min. Flow cytometry is used to measure the fluorescence of cells. The result is represented by the percentage of normal cells and apoptotic cells at different stages.

[0366] Photothermal effect of nanoparticles

[0367] The photothermal heating curves were obtained by measuring the power density at different power densities (0.2, 0.5, 1.0 W / cm 2 ) or using sample solutions of different concentrations to monitor the temperature change of sample solutions in 1.5mL Eppendorf tubes under the irradiation of 808nm laser. The laser is provided by a fiber-coupled continuous semiconductor diode laser, and the temperature is recorded by a fixedly mounted thermal imaging camera (FLIR A300 series). The photothermal conversion efficiency (η) of Fe NP@BSA is calculated using the method of Roper, et al., The Journal of Physical Chemistry C, 2007, 111 (9), 3636-3641.

[0368] Specifically, according to Roper's method, the photothermal conversion efficiency (η) of Fe NPs was calculated using the following formula:

[0369]

[0370] Where h(mW / (m 2 ·℃)) is the heat transfer coefficient, S(m 2 ) is the surface area of ​​the container, Tmax is the equilibrium temperature, and Tsurr is the ambient temperature of the surrounding environment. Fig. 13C , Tmax-Tsurr is 51.3℃. Dis (mW) represents the heat from the light absorbed by the cuvette sample wall and was measured as 8.80 mW using a quartz cuvette cell containing an aqueous sample without Fe NPs. I is the incident laser power (1 W), and A808 is the absorbance of supra-CND at 808 nm (0.579).

[0371] To obtain hS, the maximum system temperature Tmax is used to introduce θ

[0372]

[0373] And the sampling system time constant τs

[0374]

[0375] According to the following expression

[0376] t=-t s ln(θ) (4)

[0377] τs was determined to be 473.13 s, from which hS was deduced to be 9.91 mW / °C (substituting m=1 g and C=4.2 J / g·K in formula (3)).

[0378] Finally, the photothermal conversion efficiency (η) of Fe NPs was calculated to be 60.6% according to formula (1).

[0379] Photothermal imaging (PTI)

[0380] Female BALB / c mice (~20 g, purchased from Charles River Laboratories (Wilmington, MA)) were injected into the hind limbs of each mouse with 1×10 7 4T1 cells were used to establish a 4T1 tumor-bearing mouse model. When the average tumor volume reached about 100 mm 3 Two experienced researchers randomly divided the mice into three groups (n=3 in each group). Tumor-bearing mice were injected with 100 μL PBS (Group 1) or 10 mg / kg Fe NP@BSA (Group 2) via the tail vein. One hour after injection, the cells were irradiated with 0.5 W / cm 2 The mice were irradiated with 808 nm laser for 6 min. During irradiation, the temperature changes in the tumor site were monitored using an infrared thermal imaging camera (FLIR A300 series). Group 1 served as the control group. The Animal Research Administration Committee of the University of Hong Kong approved the protocols for all animal experiments.

[0381] In vivo tumor therapy studies

[0382] Female BALB / c mice were purchased from Charles River Laboratories (Wilmington, MA). Mice were maintained in accordance with the requirements of the Laboratory Animal Unit (LAU) of the University of Hong Kong (HKU), and animal experiments were performed in accordance with the guidelines approved by the HKU Teaching and Research Living Animal Use Committee. To establish the mouse tumor model, 1×10 7 4T1 cells were injected subcutaneously into the flank of each mouse. When the tumor size reached approximately 60-100 mm 3(designated as day 0). Two experienced researchers randomly divided the mice into four groups (n=5 for 4T1 tumors), which were injected (administered intravenously via the tail vein) with 100 μL PBS without 808 nm laser irradiation and with 808 nm laser irradiation (as blank control, group 1 and group 2), 10 mg / kg Fe nanoparticles (as thermal therapy control, group 3), or 10 mg / kg Fe nanoparticles with 808 nm laser irradiation (as thermal therapy group, group 4) on days 1, 3, and 5. Groups 2 and 4 were treated with 808 nm laser at 0.5 W / cm 2 The tumor site was treated for 6 min. The body weight and tumor size of each mouse were recorded every other day.

[0383] The body weight and tumor size of each mouse were recorded three times a week, and the tumor volume (V) was calculated by the following formula:

[0384] V=ab 2 ×0.5

[0385] a and b are the longest and shortest diameters of the tumor, respectively. After 16 days of treatment, the mice were humanely sacrificed and all tumors were collected for further analysis.

[0386] Liver / renal function and hematologic toxicity analyses.

[0387] Two experienced researchers randomly divided BALB / c mice into 3 groups (n=4 in each group), which were intravenously injected with 100 μL PBS (as control, group 1), 100 μL 10 mg / kg Fe nanoparticles (group 2), or 100 μL 20 mg / kg Fe nanoparticles (group 3). After 16 days, blood was collected from each mouse and analyzed using a blood cell analyzer (BC-31s, Mindray) and a detection kit (Beyotime Biotechnology).

[0388] result

[0389] Synthesis and characterization of Fe-BB NPs

[0390] Transmission electron microscopy (TEM) showed that the morphological sizes of the Fe(II)-BQ-Bphen2 complex and Fe-BB NPs were approximately 80 nm and 100 nm, respectively. Fig.12E Due to the introduction of BSA, an organic layer was observed on the surface of the nanoparticles by TEM images (data not shown). The hydrodynamic diameter of the Fe(II)-BQ-Bphen2 complex nanoparticles was determined to be about 90 nm ( Fig. 12C). After coating with BSA, the hydrodynamic size of the nanoparticles increased from 90 nm (Fe NP) to 110 nm (Fe-BB NP). The hydrodynamic size and polydispersity index (PDI) of the nanoparticles showed negligible changes over 7 days (data not shown). In addition, the zeta potential charge of the nanoparticles decreased from +40 mV (Fe NP) to -10 mV (Fe-BB NP) and eventually stabilized, confirming the successful coating with BSA ( Fig.12D ). These results indicate that the preparation of Fe NPs and Fe-BB NPs was successful.

[0391] In addition, the stability of Fe-BB NPs was examined and compared with that of Fe NPs. In vitro, Fe NPs precipitated in PBS due to the positive surface charge of Fe NPs, which resulted in anionic interactions with PBS ( Fig.12F and 12G ). In contrast, the coated Fe NPs were more stable in PBS ( Fig.12H and 12I ).

[0392] Photothermal effects in vitro and in vivo

[0393] The UV-Vis-NIR absorption spectrum of Fe(II)-BQ-Bphen2 complex@BSA nanodrug is shown in Fig. 12B In the figure, it shows absorption in the NIR wavelength range. The photothermal temperature increase of 100 μg / mL Fe(II)-BQ-Bphen2 complex@BSA was measured using a thermal imaging camera under 808 nm laser irradiation with different power densities. Fig.13A As shown in Figure 2, the temperature of the Fe-BB NP solution increases with increasing laser power density, with a maximum temperature increase of 51.8 °C at 1.0 W / cm. In contrast, even at the highest power density (1.0 W / cm 2 ), deionized water only had a slight temperature rise (2.5°C). 2 At a moderate power density of 1.5 Å, the temperature of the Fe-BB NP solution still increased by ∼26°C. The photothermal conversion efficiency (η) of Fe-BB NP nanoparticles at 808 nm was calculated to be 60.6% based on the maximum steady-state temperature. The η value of Fe NPs is higher than that of currently reported photothermal agents, such as Au nanorods (21%), Cu2-xSe (22%), and Cu9S5 (25.7%), indicating that Fe NPs have a high ability to convert NIR irradiation into heat.

[0394] The temperature of the Fe-BB NP solution increased with the increase of solution concentration, and even at a low concentration (12.5 μg / mL), the temperature increased by 18.5 °C ( Fig. 13B ). These results demonstrate the excellent and dose-dependent photothermal effect of Fe-BB NPs. The photothermal stability of Fe-BB NPs was also evaluated ( Fig. 13C When the laser was turned on and off four times repeatedly, the maximum temperature increase did not change significantly, proving that the Fe-BB nanoparticles have good photothermal stability ( Fig.13D ).

[0395] Fig.13E Figure 2 shows the photothermal curve of mouse tumors during 808 nm laser irradiation for 6 min 1 h after intravenous injection of Fe(II)-BQ-Bphen2 complex nanoparticles (10 mg / kg) via the tail vein. Fig.13E As shown, the PBS control group showed 2 After 808 nm laser irradiation for 6 min, the temperature at the tumor site increased by about 3.7 °C, while the Fe NP@BSA treatment group showed a temperature increase of about 13.8 °C, demonstrating that the coated Fe NPs were effectively accumulated at the tumor site via a passive targeting manner (i.e., the EPR effect) and had a significant photothermal effect on thermal therapy of cancer.

[0396] Furthermore, these in vivo experiments showed that 808 nm laser irradiation (0.5 W / cm 2 , 6 min), mice treated with uncoated FeNPs showed a weaker photothermal effect, indicating that few Fe nanoparticles accumulated at the tumor site ( Fig.13E and 13F In contrast, Fe NPs coated with BSA exhibited a strong photothermal effect at the tumor site, indicating that an appreciable amount of coated Fe NPs accumulated at the tumor site ( Fig.13E and 13F ).

[0397] These results demonstrate the excellent photothermal performance of Fe-BB NPs both in vitro and in vivo.

[0398] Extracorporeal photothermal efficacy

[0399] Fe-BB NPs were further investigated for cancer therapy. The cytotoxicity of Fe-BB NPs against cancer cells (NCI H460 and 4T1 cells) under 808 nm laser irradiation was investigated using MTT assay. Figures 14A-14B). In the absence of 808 nm laser irradiation, Fe-BB NPs did not cause a significant decrease in cell viability. Even at a high concentration of 200 μg / mL, the maximum viability of 4T1 and NCIH460 cells decreased by no more than 10%, indicating that the cytotoxicity of Fe-BB NPs was low. Under 808 nm laser irradiation, Fe-BB NPs showed concentration- and laser power density-dependent cytotoxicity to cancer cells. Figures 14C-14D As shown, microscopic counting of dead and whole cells using propidium iodide and Hoechst staining supported the dose-dependent cytotoxicity of Fe-BB NPs against cancer cells under NIR and the biosafety of Fe-BB NPs in the dark. To investigate the localization of Fe-BB NPs in cells, Fe(II)-BQ-Bphen2 complex was co-assembled with Dir fluorescent dye to form Fe nanoparticles. After coating with BSA, Fe-BB nanoparticles were incubated with NCI H460 cells. Confocal laser scanning microscopy (CLSM) images of NCI H460 cells after co-incubation with Dir-labeled Fe NPs showed that Fe-BB nanoparticles entered lysosomes within 2 h of incubation (data not shown).

[0400] To directly observe the photothermal treatment effect of Fe-BB NPs, NCI H460 cells treated with Fe-BB NPs were co-stained with Calcein-AM / PI to distinguish live and dead cells (data not shown). For cells incubated with culture medium alone, there was no obvious cell death in the illuminated area, which was similar to the dark area, indicating that laser irradiation alone had no special killing effect on cancer cells. After treatment with Fe-BB NPs, laser irradiation of cells resulted in a significant increase in the number of dead cells, which was due to the killing effect of excessive heat on cancer cells.

[0401] Hypothermia can cause mitochondrial damage and induce ROS in cells. To measure the level of ROS in cells, the DCFH-DA probe was used to verify the production of ROS in cells. Fig.14EAs shown, in the dark and under laser irradiation, cells treated with the vehicle produced the least ROS. When treated with Fe-BB NP, cells produced significantly more ROS under laser irradiation. In addition, under laser irradiation, as the concentration of Fe-BB nanoparticles increased, cellular ROS increased. In order to observe the level of cellular DNA damage, γH2AX was stained using immunofluorescence in NCI-H460 cells. As shown in CLSM imaging of NCI H460 cells using γ-H2AX and DAPI staining (data not shown), cells treated with PBS showed negligible DNA damage with or without laser irradiation. Cells treated with Fe-BB nanoparticles in the dark produced observable amounts of DNA damage. However, when treated with Fe-BB nanoparticles under laser irradiation, the level of DNA damage was the most significant, which supports the cytotoxicity results described above.

[0402] The mechanism of cell death was investigated using flow cytometry based on the Annexin V-FITC / propidium iodide (PI) assay. Fig.14F As shown, Fe-BB nanoparticles induced negligible apoptosis and cell death in the dark, which was similar to that of PBS-treated cells. However, after laser irradiation, Fe-BB nanoparticles induced a significant increase in the incidence of early-stage and late-stage apoptosis in 4T1 cells. When the concentration of Fe-BB nanoparticles increased, the apoptosis rate increased significantly from 10.6% (25 μg / mL) to 75.08% (50 μg / mL) and 79.82% (100 μg / mL), respectively, confirming the role of ROS in the photocytotoxicity of Fe-BB nanoparticles.

[0403] In vivo photothermal therapy

[0404] The photothermal effect of Fe-BB-NPs was then investigated for tumor therapy in mice according to the procedures described in the Methods section above. Mice treated with intravenous injection of Fe-BB NPs were sacrificed ( Fig.15A ). 4T1 tumor-bearing mice were randomly divided into four groups (PBS, Fe-BB NPs with or without laser irradiation) to study the anticancer effect of Fe-BB NPs using photothermal treatment. After PTT treatment, tumor growth was not affected in the control group, while tumor growth was significantly inhibited in the Fe-BB NP-treated group under laser irradiation ( Figures 15B-15C These results are consistent with the in vitro results ( Figures 14A-14F ). The therapeutic effect of Fe-BB NPs was further confirmed by measuring the weight and size of the tumors extracted in all groups 16 days after treatment, with the PTT group showing the best therapeutic outcome ( Figures 15B-15CAt the end of treatment, the tumors of mice in all groups were dissected and then stained with hematoxylin and eosin (H&E) (data not shown). In the control group, there were a large number of stromal-compacted cells with intact nuclei and cytoplasm, indicating that the tumor cells were in good condition.

[0405] In order to destroy tumors, photothermal therapy needs to be heated to high temperatures, but high temperatures can also damage normal tissues around the tumor, and it is difficult to completely kill the tumor if mild temperatures are used. One solution is to activate the immune response through mild PTT or combined PTT.

[0406] 4T1 tumor-bearing mice with low immune response and insufficient immunogenicity were used to further verify that mild PTT could convert tumors from "cold" to "hot". 4T1 tumor-bearing BALB / c mice were randomly divided into groups and when the tumor volume reached about 50mm 3 Each mouse was treated with a single intratumoral injection of PBS or Fe nanoparticles. The dose of Fe nanoparticles was 10 mg / kg. Mice treated with PBS or Fe nanoparticles were irradiated with 808 nm laser near-infrared irradiation (0.3 W / cm 2 , 6min) to achieve a mild PTT.

[0407] In addition, the study found that while performing mild PTT, Fe nanoparticles can activate the immune response in the body, thereby achieving anti-tumor immunity. The combination of mild PTT and activated anti-tumor immunity showed effective inhibition of tumor growth ( Fig.17A ), no changes in the weight of the mice were observed ( Fig. 17B ). To verify the enhanced anti-tumor immune response induced by mild PTT combined with activated anti-tumor immunity, the response of immune cells in tumors and lymph nodes was measured 15 days after mice were treated (n=6). It is well known that dendritic cells (DCs) play a role in initiating and regulating innate and adaptive immunity. Therefore, it was investigated whether mild PTT could activate DC maturation in tumors. The percentage of mature DCs (CD80+CD86+) in the mild PTT group was significantly higher than that in the PBS group ( Fig. 17C and 17D ). These results suggest that mild PTT can induce immune stimulation. At the same time, the individual numbers of CD8+T cells and CD4+ helper T cells in primary tumors were analyzed. Both CD8+T cells and CD4+T cells are T lymphocytes and are important in the immune response to anti-tumor therapy. The numbers of CD8+T cells and CD4+T in the mild PTT group were higher than those in the PBS group ( Fig.17E and 17F), indicating that cytotoxic T cells efficiently infiltrated into 4T1 tumors.

[0408] In vivo toxicity

[0409] The in vivo toxicology of Fe-BB nanoparticles was systematically studied. Female Balb / c mice (4-6 weeks old) were randomly divided into 4 groups and treated with different conditions: (1) control group without laser irradiation, (2) control group with laser irradiation for 6 min (3) Fe-BB nanoparticle treatment by direct intravenous injection without laser irradiation and (4) Fe-BB nanoparticle treatment by direct intravenous injection after 808 nm laser irradiation for 6 min. The injection dose of Fe-BB nanoparticles was 10 mg / kg. Hematology, blood biochemistry and histology were performed 16 days after injection.

[0410] Standard hematological markers including white blood cells, red blood cells, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets, and hematocrit ( Figures 16A-16J ). The difference between the control group and the Fe-BB nanoparticles treated group (10 mg / kg or 20 mg / kg) was not statistically significant. Therefore, the Fe-BB nanoparticles treated group looked normal. These results indicate that Fe-BB nanoparticles do not cause significant infection and inflammation in the treated mice.

[0411] Blood biochemistry analysis was performed, and various parameters including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), blood urea nitrogen (BUN), and creatinine (CREA) were examined ( Figure 16K-16O ). No statistically significant differences were observed at the end time point in the Fe-BB nanoparticle-treated group compared to the control group. These results indicate that Fe-BB nanoparticle treatment did not affect the blood chemistry of mice. Since alanine aminotransferase, aspartate aminotransferase, and creatinine are closely related to liver and kidney function in mice, the results indicate that Fe-BB nanoparticles do not produce significant liver and kidney toxicity in mice.

[0412] The corresponding histological changes of organs were examined by immunohistochemistry using hematoxylin and eosin staining of the collected and sectioned major organs (including liver, spleen, kidney, heart and lung) (data not shown). No obvious organ damage was observed during the entire treatment period in all groups, indicating that there were no obvious histological differences.

[0413] References:

[0414] OSWenger,J.Am.Chem.Soc.2018,140,13522-13533;

[0415] J.K.McCusker,Science 2019,363,484.

[0416] C. and K.Heinze,Chemi.Soc.Rev.2020,49,1057-1070.

[0417] O.S.Wenger,Chem.Eur.J.2019,25,6043-6052;

[0418] J.Chen and W.R.Browne,Coord.Chem.Rev.2018,374,15-35.

[0419] J.Wu,et al.,Inorganics 2020,8.

[0420] J.D.Braun,et al.,Nature Chem.2019,11,1144-1150.

[0421] T.Jiang,et al.,Proc.Natl.Acad.Sci.U.S.A.2020,117,20430.

[0422] P.Dierks,et al.,Inorg.Chem.2020.

[0423] B.C.Paulus,et al.,Nature 2020,582,214-218.

[0424] Y.Liu,et al.,Acc.Chem.Res.2016,49,1477-1485.

[0425] L.Lindh,et al.,Catalysts 2020,10.

[0426] P.Chábera,et al.,J.Phys.Chem.Lett.2018,9,459-463.

[0427] M.Albrecht,Chem.Rev.2010,110,576-623.

[0428] Z.Tang,et al.,Organometallics 2020,39,2791-2802.

[0429] J.Steube,et al.,Chem.Eur.J.2019,25,11826-11830.

[0430] P.Aguirre-Etcheverry and D.O'Hare,Chem.Rev.2010,110,4839-4864.

[0431] S.Campagna,et al.,inPhotochemistry and Photophysics of CoordinationCompounds I(Eds.:V.Balzani,S.Campagna),Springer Berlin Heidelberg,Berlin,Heidelberg,2007,pp.117-214.

[0432] Y.-W.Zhong,et al.,Coord.Chem.Rev.2016,312,22-40.

[0433] Y.Shi,et al.,Organometallics 2009,28,2206-2210.

[0434] L.-Z.Sui,et al.,Inorg.Chem.2012,51,1590-1598.

[0435] PGBomben,et al.,Inorg.Chem.2009,48,9631-9643.

[0436] ECConstable and JMHolmes,J.Organomet.Chem.1986,301,203-208.

[0437] Z.Zuo,et al.,Dalton Trans.2014,43,11716-11722.

[0438] L.Wang,et al.,Eur.J.Inorg.Chem.2016,2016,5205-5214.

[0439] Y.Liu,et al.,Chem.–Eur.J.2015,21,3628-3639.

[0440] I.M.Dixon,et al.,Dalton Trans.2015,44,13498-13503.

[0441] A.M.Brown,et al.,Dalton Trans.2014,43,17635-17646.

[0442] C.Consani,et al.,Angew.Chem.Inter.Ed.2009,48,7184-7187.

[0443] J.E.Monat and J.K.McCusker,J.Am.Chem.Soc.2000,122,4092-4097.

[0444] P.S.Braterman,et al.,Inorg.Chem.1992,31,555-559.

[0445] T.Bessho,et al.,J.Am.Chem.Soc.2009,131,5930-5934.

[0446] C.Kreitner and K.Heinze,Dalton Trans.2016,45,13631-13647.

[0447] M.L.Muro-Small,et al.,Eur.J.Inorg.Chem.2012,2012,4004-4011.

[0448] Z.Ji,et al.,J.Phys.Chem.C 2012,116,16854-16863.

[0449] Q.Sun,et al.,Coord.Chem.Rev.2015,282-283,87-99.

[0450] A.D.Ryabov,et al.,Inorg.Chem.2001,40,6529-6532.

[0451] S.Finck,et al.,J.Organomet.Chem.2014,760,248-259.

[0452] P.Reveco,et al.,Inorg.Chem.1986,25,1842-1845.

[0453] JASolís-Ruiz,et al.,Journal of Inorganic Biochemistry 2020,208,111080.

[0454] T.Hofbeck and H.Yersin,Inorg.Chem.2010,49,9290-9299;

[0455] S.Tschierlei,et al.,Phys.Chem.Chem.Phys.2016,18,10682-10687.

[0456] R.Bevernaegie,et al.,Phys.Chem.Chem.Phys.2018,20,27256-27260.

[0457] A.Cannizzo,et al.,Coord.Chem.Rev.2010,254,2677-2686.

[0458] Li,X.,et al.,Nat Rev Clin Oncol 2020,17(11),657-674.

[0459] Yao,Y.,et al.,J Am Chem Soc 2022,144(16),7346-7356.

[0460] Shao,J.,et al.,Nat Commun 2016,7,12967.

[0461] Liu,Y.,et al.,Nat Commun 2020,11(1),1724.

[0462] Hu,K.,et al.,Nat Commun 2020,11(1),2778.

[0463] Ali,MRK,et al.,The Journal of Physical Chemistry C 2019,123(25),15375-15393.

[0464] Liu,Y.,et al.,Chem Soc Rev 2019,48(7),2053-2108.

[0465] <Electronic structure in the transition metal block and itsimplications forlight harvesting.pdf>

[0466] Wenger,O.S.,Chemistry 2019,25(24),6043-6052.

[0467] Ng,K.K.,et al.,Chem Rev 2015,115(19),11012-42.

[0468] Wang,Y.,et al.,ACS Applied Polymer Materials 2020,2(10),4258-4272.

[0469] Tang,Z.,et al.,Organometallics 2020,39(15),2791-2802.

[0470] Steube,J.,et al.,Chemistry 2019,25(51),11826-11830.

[0471] Dixon,I.M.,et al.,Dalton Trans 2015,44(30),13498-503.

[0472] Aggarwal,P.,et al.,Adv Drug Deliv Rev 2009,61(6),428-37.

[0473] Fleischer,C.C.,et al.,Acc Chem Res 2014,47(8),2651-9.

[0474] Xia,B.,et al.,ACS Appl Mater Interfaces 2013,5(22),11718-24.

[0475] <Hydrophilic Cu9S5 nanocrystals:a photothermal agent with a 25.7%heat conversion efficiency for photothermal ablation of cancer cells invivo.pdf>.

[0476] Hessel,C.M.,et al.,Nano Lett 2011,11(6),2560-6.

[0477] Lei,P.,et al.,Advanced Functional Materials 2017,27(35).

[0478] Aggarwal,P.,et al.,Advanced Drug Delivery Reviews 2009,61(6),428-437.

[0479] Fleischer,C.and Payne,C.,Accounts of Chemical Research 2014,47(8),2651-2659.

[0480] Elsadek,B.and Kratz,F.,Journal of Controlled Release 2012,157(1):4-28.

[0481] Blanco,E.,et al.,Nature Biotechnology 2015,33(9),941-951.

[0482] Xu,G.,et al.,Nature Communications,2022,13(1),3064.

[0483] Karges,J.,et al.,European Journal of Inorganic Chemistry,2020,34,3242-3248.

[0484] Yu,W.,et al.,Advanced Functional Materials,2020,30(49),2002239.

[0485] Meng,J.,et al.,Science Advances,2020,6(20),eaba1362.

[0486] Xi,D.,et al.,Advanced Materials,2022,34(6),2106797.

[0487] Yang,Zhe,et al.,Nature Reviews Clinical Oncology 20.2(2023):116-134.

[0488] Nam,Jutaek,et al.,Nature Reviews Materials 4.6(2019):398-414.

[0489] Huang,Liping,et al.,Nature communications 10.1(2019):4871.

[0490] Sagiv-Barfi,Idit,et al.,PNAS 112.9(2015):E966-E972.

[0491] Higgins,Jack P.,et al.,Cancer biology&therapy 8.15(2009):1440-1449.

[0492] Wen,Yi,and Joel H.Collier.Current opinion in immunology 35(2015):73-79.

[0493] Mahjub,Reza,et al.,Journal of Controlled Release 288(2018):239-263.

[0494] Krieg,Arthur M.Nature reviews Drug Discovery 5.6(2006):471-484.

[0495] Guo,Liangran,et al.ACS nano 8.6(2014):5670-5681.

[0496] Kasturi,S.P.et al.Nature 470,543-550(2011).

[0497] Le Mercier,Isabelle,et al.Cancer Research 73.15(2013):4629-4640.

[0498] Chen,Qian,et al.Nature Communications 7.1(2016):13193.

[0499] Huang,Liping,et al.Nature Communications 10.1(2019):4871.

[0500] Guo,L.et al.ACS Nano 8,5670-5681(2014).

[0501] Wang,Chao,et al.Advanced Materials 48(2014):8154-8162.

[0502] Liu,Yang,et al.Scientific Reports 7.1(2017):8606.

[0503] Bear,A.S.et al.PLOS ONE 8,e69073(2013).

[0504] Nam,Jutaek,et al.Nature Reviews Materials 4.6(2019):398-414.

[0505] Chen,W.R.,et al.Cancer Res.61,459-461(2001).

[0506] Toraya-Brown,S.et al.Nanomedicine 10,1273-1285(2014).

[0507] Shi,H.et al.J.Immunol.176,2134-2141(2006)。

Claims

1. An iron (II) complex having the following structure: in: (i) X1, X4, X5, X6, X7 and X9 are independently carbon or nitrogen, and X is an anion; (ii) Each ----- does not exist or is a single bond, each Absent or double bond; (iii) R1, R'1, R2, R'2, R3 and R'3, when present, are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted alkylaryl; (iv) R4, R'4, R5, R'5, R6, R'6, R7, R'7, R8, R'8, R9 and R'9 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cyclic, substituted or unsubstituted heterocyclic, halide, amino, amide, thiol, hydroxy, cyano, nitro, carbonyl, or alkoxy; (v) R"4, R"'4, R"5, R"6, R"7, R"'7, R"8, R"'8, R"9 and R"'9, when present, are independently hydrogen, halide, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cyclic, or substituted or unsubstituted heterocyclic; and (vi) when substituents are present, they are independently unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted heteropolyaryl, unsubstituted alkylaryl, unsubstituted ring, unsubstituted heterocycle, halide, amino, amide, thiol, hydroxy, cyano, nitro, carbonyl, or alkoxy.

2. The iron (II) complex of claim 1, having the following structure: in: (i) X1, X4, X5, X6, X7 and X9 are independently carbon or nitrogen, and X is an anion; (ii) Each ----- does not exist or is a single bond, each Absent or double bond; (iii) R1, R'1, R2, R'2, R3 and R'3, when present, are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; (iv) R4, R'4, R"4, R"'4, R5, R'5, R"5, R6, R'6, R"6, R7, R'7, R"7, R"'7, R8, R'8, R"8, R9, R'9, R"9 and R"'9 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, or halide; and (v) when substituents are present, they are independently unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted heteropolyaryl, unsubstituted alkylaryl, unsubstituted ring, unsubstituted heterocycle, halide, amino, amide, thiol, hydroxy, cyano, nitro, carbonyl, or alkoxy.

3. The iron (II) complex of claim 1, wherein: (i) X1, X5 and X6 are carbon, and X4, X7 and X9 are nitrogen; or (ii) X1, X9, X5 and X6 are carbon, and X4 and X7 are nitrogen; or (iii) X4, X7 and X5 are carbon, and X1, X9 and X6 are nitrogen.

4. The iron (II) complex of claim 1, wherein: (i) R1, R'1, R2, R'2, R3 and R'3, when present, are independently hydrogen, unsubstituted alkyl or unsubstituted aryl; (ii) R4, R'4, R5, R'5, R6, R'6, R7, R'7, R8, R'8, R9 and R'9 are independently hydrogen, unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, or halide; and (iii) R"4, R"'4, R"5, R"6, R"7, R"'7, R"8, R"'8, R"9 and R"'9, when present, are independently hydrogen, unsubstituted heteroaryl, or halide.

5. The iron (II) complex of claim 1, having the following structure:

6. The iron (II) complex of claim 1 having absorption at a wavelength of at least 600 nm, such as ranging from 600 nm to about 850 nm or from about 700 nm to about 850 nm, and / or having a lifetime of at least 1 ps.

7. Metal supramolecular particles comprising the iron (II) complex according to claim 1.

8. The metal supramolecular particle of claim 7, further comprising a coating agent, wherein the coating agent is covalently or non-covalently attached to the surface of the metal supramolecular particle, and optionally wherein the coating agent is bovine serum albumin, polyalkylene or a copolymer thereof (e.g., F-127, DSPE-PEG (2000)) or a polysaccharide (e.g., hyaluronic acid) or a combination thereof.

9. The metal supramolecular particle of claim 7, further comprising a targeting moiety.

10. The metal supramolecular particle of claim 7, having an average morphological diameter ranging from about 50 nm to about 150 nm or from about 80 nm to about 100 nm, as measured using transmission electron microscopy; and / or an average hydrodynamic diameter ranging from about 60 nm to about 200 nm, for example about 90 nm, as measured using dynamic light scattering.

11. The metal supramolecular particle of claim 7, having a photothermal conversion efficiency of at least 30%, at least 40%, at least 50% or at least 60% measured using 808 nm laser irradiation at 1.0 W / cm for about 20 min; and / or a photothermal stability for at least four laser irradiation-cooling cycles, each laser irradiation lasting at least 5 min.

12. A pharmaceutical composition comprising the metal supramolecular particles according to claim 7, and optionally one or more pharmaceutically acceptable excipients.

13. The pharmaceutical composition of claim 12, wherein the amount of the metal supramolecular particles ranges from about 1 μM to about 1 mM, from about 10 μM to about 500 μM, from about 10 μM to about 200 μM, or from about 25 μM to about 100 μM.

14. A method for treating cancer using the pharmaceutical composition of claim 12, comprising: (i) administering the pharmaceutical composition to a subject in need thereof; as well as (ii) applying laser irradiation to the subject or a target area of ​​the subject, wherein step (i), step (ii), or steps (i) and (ii) occur one or more times.

15. The method of claim 14, wherein in step (ii), the laser irradiation: (a) having a wavelength of at least 670 nm, ranging from 670 nm to 1500 nm, 670 nm to 1200 nm, 670 nm to 1000 nm, 700 nm to 1500 nm, 700 nm to 1200 nm, or 700 nm to 1000 nm, for example, about 800 nm; (b) having a laser power density in the range of about 0.1 W / cm to about 10 W / cm, about 0.1 W / cm to about 5 W / cm, about 0.1 W / cm to about 1 W / cm, about 0.1 W / cm to about 0.5 W / cm, or about 0.1 W / cm to about 0.3 W / cm, e.g., about 1 W / cm, about 0.5 W / cm, or about 0.3 W / cm; and / or (c) maintaining for a time period ranging from about 1 min to about 1 hour, about 5 min to about 1 hour, about 1 min to about 30 min, about 5 min to about 30 min, about 1 min to about 20 min, about 5 min to about 20 min, about 1 min to about 15 min, or about 5 min to about 15 min.

16. The method of claim 14, wherein the pharmaceutical composition is administered orally, intramuscularly, intravenously, intraperitoneally, or subcutaneously, or a combination thereof.

17. The method of claim 14, further comprising administering an active agent, optionally wherein the active agent is an anti-cancer agent.

18. The method of claim 14, wherein in step (i), the dose of the metal supramolecular particles administered is from about 0.1 μg to about 100 μg, from about 0.5 μg to about 50 μg, from about 1 μg to about 100 μg, from about 1 μg to about 50 μg, from about 1 μg to about 25 μg, from about 1 μg to about 10 μg, from about 1 μg to about 5 μg, from about 4 μg to about 10 μg, or from about 1 μg to about 4 μg per gram of subject.

19. The method of claim 14, wherein after step (ii) or all steps (ii) (if step (ii) occurs more than once), the tumor volume is reduced by at least 10%, at least 20%, at least 30%, at least 40% or at least 50% compared to the tumor volume before administration of the pharmaceutical composition; and / or the tumor weight is reduced by at least 50%, at least 60%, at least 70% or at least 80% compared to the tumor weight before administration of the pharmaceutical composition, optionally compared to a control administered with only the pharmaceutically acceptable excipient, without any cytotoxicity to normal cells, as indicated by standard hematological markers and / or blood biochemical parameters.

20. An iron (II) complex having the following structure: wherein (i) X1 and X9 are independently carbon or nitrogen; (ii) Y1, Y2, Y3 and Y4 are independently phosphorus, halogen, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; (iii) R8, R'8, R"8, R"'8, R9, R'9, R"9, R 18 (when present) and R 19 (when present) is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, or halide; and (iv) when substituents are present, the substituents are independently unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted heteropolyaryl, unsubstituted alkylaryl, unsubstituted ring (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl), unsubstituted heterocycle, halide, amino, amide, thiol, hydroxy, cyano, nitro, carbonyl, or alkoxy.

21. The iron (II) complex of claim 20, having the following structure: wherein (i) X1 and X9 are independently carbon or nitrogen; (ii) Y1, Y2, Y3 and Y4 are independently phosphorus or halogen; (iii) R8, R'8, R"8, R"'8, R9, R'9, R"9, R 18 (when present) and R 19 (when present) are independently hydrogen, substituted or unsubstituted alkyl, or halide; (iv) when substituents are present, they are independently unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted heteropolyaryl, unsubstituted alkylaryl, unsubstituted ring (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl), unsubstituted heterocycle, halide, amino, amide, thiol, hydroxy, cyano, nitro, carbonyl, or alkoxy.

22. The iron (II) complex of claim 21, wherein: X1 is nitrogen, and X9 is carbon; Y1, Y2, Y3 and Y4 are independently trialkylphosphine (eg trimethylphosphine) or halogen; or R8, R'8, R"8, R"'8, R9, R'9 and R"9 are independently hydrogen or unsubstituted alkyl; or R"8 and R"9 are independently hydrogen; or R 18 and R 19 , when present, is independently hydrogen or unsubstituted alkyl; or Its combination.

23. The iron (II) complex of claim 20, having the following structure: wherein (i) X1, X4, X7 and X9 are independently carbon or nitrogen; (ii) Y1 is phosphorus, halogen, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; (iii) R4, R'4, R"4, R"'4, R6, R'6, R"6, R"'6, R7, R'7, R"7, R8, R'8, R"8, R"'8, R9, R'9, R"9, R 18 (when present) and R 19 (when present) are independently hydrogen, substituted or unsubstituted alkyl, or halide; and (iv) when substituents are present, the substituents are independently unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted heteropolyaryl, unsubstituted alkylaryl, unsubstituted ring (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl), unsubstituted heterocycle, halide, amino, amide, thiol, hydroxy, cyano, nitro, carbonyl, or alkoxy.

24. The iron (II) complex of claim 23, having the following structure: wherein (i) X1, X4, X7 and X9 are independently carbon or nitrogen; (ii) Y1 is phosphorus or a halogen; (iii) R4, R'4, R"4, R"'4, R6, R'6, R"6, R"'6, R7, R'7, R"7, R8, R'8, R"8, R"'8, R9, R'9 and R"9 are independently hydrogen, substituted or unsubstituted alkyl, or a halide; and (iv) when substituents are present, the substituents are independently unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted heteropolyaryl, unsubstituted alkylaryl, unsubstituted ring (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl), unsubstituted heterocycle, halide, amino, amide, thiol, hydroxyl, cyano, nitro, carbonyl, or alkoxy.

25. The iron (II) complex of claim 23, wherein: X1, X4 and X9 are nitrogen and X7 is carbon; Y1 is halogen (eg fluorine, chlorine or bromine); or R4, R'4, R"4, R"'4, R6, R'6, R"6, R"'6, R7, R'7, R"7, R8, R'8, R"8, R"'8, R9, R'9 and R"9 are independently hydrogen or unsubstituted alkyl; or R"8 and R"9 are independently hydrogen; or R 18 and R 19 , when present, is independently hydrogen or unsubstituted alkyl; or Its combination.

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