Poly(sarcosine) polymer excipients

Abstract

The present disclosure relates to the field of polymer chemistry, and more specifically to poly(sarcosine) polymers and uses thereof. The present disclosure also relates to compositions comprising proteins and poly(sarcosine) polymers and uses thereof.

Description

[Technical field]

[0001] Claiming priority This application claims priority to U.S. Provisional Application No. 63 / 263,900, filed November 11, 2021, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to the field of polymer chemistry, and more specifically to poly(sarcosine) polymers and uses thereof. The present disclosure also relates to compositions comprising proteins and poly(sarcosine) polymers and uses thereof. [Background technology]

[0003] Biological drug products (biologics) are generally large complex molecules produced via biotechnology techniques in living systems (such as microorganisms, plant cells, or animal cells). Biologics are often more difficult to purify and characterize than small molecule drugs. Despite these challenges, technological advances have led to the emergence of biologics as an important category of pharmaceuticals. Biologics are now used for the diagnosis, prevention, and treatment of diseases and medical conditions that previously relied on small molecules. Currently, the majority of approved and developmental biologics are protein-based (protein biologics), with monoclonal antibodies (mAbs) representing the largest subcategory. Proteins are inherently fragile molecules, especially when compared to small molecules. Conditions such as temperature, pH, ionic strength, light, mechanical stress, and interfacial stress can all cause physical or chemical damage. This can alter the structure of the protein, leading to denaturation and aggregation, and ultimately loss of protein solubility. This can be a problem throughout the lifespan of protein biologics. During manufacturing, proteins face stressful conditions, for example, during chromatography, mixing, filtration, pumping, filling, and lyophilization. After manufacturing, conditions during shipping, storage, clinical handling, and administration can also have a negative impact on protein biopharmaceuticals. Protein aggregation and denaturation can increase the cost and complexity of manufacturing and create obstacles for drug development. For the final drug product, protein aggregation and denaturation can reduce storage condition flexibility and shelf life, hinder administration, and lead to inaccurate dosing.

[0004] Importantly, protein aggregation has been linked to increased adverse immune responses to biological proteins. Specifically, protein biologics can trigger the formation of anti-drug antibodies (ADAs) that can have neutralizing activity. Such is the case for the tumor necrosis factor (TNF) blockers Remicade (infliximab) and Humira (adalimumab), whose ADAs have been shown to be 90% and 97% neutralizing, respectively (see van Schie, KA, et al. Ann. Rheum. Dis. 2015, 74, 311). The development of ADAs can lead to the formation of immune complexes that reduce serum levels of protein biologics. Other immunologically related adverse clinical events can manifest as anaphylaxis, cytokine release syndrome, infusion reactions, reduced drug efficiency, and cross-reactive neutralization of endogenous proteins that mediate critical functions (see Moussa, EM, et al. J. Pharm. Sci. 2016, 105, 417). Protein biologics may aggregate during manufacture, shipping, storage, or preparation for administration prior to administration. Such pre-administration protein aggregation correlates with an increased risk for the formation of ADA (see Kijanka, G., et al. J. Pharm. Sci. 2018, 107, 2847).

[0005] Protein biopharmaceuticals are therefore formulated with excipients, typically surfactants, that are included to reduce protein aggregation and denaturation. Surfactant excipients are generally amphipathic compounds that function to reduce the interfacial tension between two phases (such as an air-water interface). Solution proteins are absorbed into such interfaces and initiate conformational changes that can lead to denaturation and aggregation. This interfacial stress for solution proteins can arise from liquid-gas interfaces (such as headspace and air bubbles in containers). Liquid-oil interfacial stress between proteins in solution can arise from the use of lubricating oils (e.g. silicone oils) with the rubber plungers of pre-filled syringes and rubber vial stoppers used in primary packaging. Liquid-solid interfaces for proteins in solution are perhaps the most common, and these include interfaces with vial or container walls, packing materials used in chromatography, filtration membranes, mixing equipment, tubing used in manufacturing, and infusion sets, to name a few. Surfactants can outcompete proteins at such interfaces, preventing protein interaction and absorption, thus reducing protein denaturation and aggregation. Protection by surfactant excipients can be beneficial for protein biopharmaceuticals formulated as solutions, whether liquid or frozen, and in lyophilized forms.

[0006] Polysorbates (PS) are the most widespread surface active excipients utilized in the formulation of protein biopharmaceuticals to prevent denaturation and aggregation. Polysorbates are non-ionic surfactants composed of polyethoxylated sorbitan functionalized with fatty acid esters, monolaurate for polysorbate 20 (PS20) and monooleate for polysorbate 80 (PS80). Despite their widespread use, polysorbates have well-studied problems. Polysorbates are inherently unstable compounds, especially under the conditions in which they are used in protein formulations (i.e., aqueous solutions for manufacture and storage). Polysorbates undergo an autoxidation process with ethylene oxide subunits and fatty acid esters to produce reactive hydroperoxides and alkylperoxides that oxidize proteins (see Ha, E., et al. J. Pharm. Sci. 2002, 91, 2252; Kerwin, BAJ Pharm. Sci. 2008, 97, 2924). Through another process, polysorbates degrade into reactive aldehyde species (e.g., formaldehyde and acetaldehyde), which also react with proteins (see Erlandsson, B. Polym. Degrad. Stab. 2002, 78, 571). In addition to the autolytic pathway, proteins (especially mAbs) themselves have been observed to catalyze the cleavage of polysorbates to produce fatty acids, polyethylene glycols (PEGs), and PEGylated sorbitans (see Labrenz, SR Pharm. Biotechnol. 2014, 103, 2268). Regardless of the degradation pathway, polysorbate degradants can react with proteins, causing denaturation and aggregation, and related downstream problems. Of particular concern is the polysorbate degradation pathway that produces free PEG. Immunological studies have implied that PEG and PEG-containing materials are associated with undesirable immunogenic responses. This problem is particularly pronounced for parenteral administration, the most common method for the delivery of protein biologics (see Garay, R. et al., Expert Opin. Drug Delivery, 2012, 1319; Yang, Q. et al., Anal. Chem. 2016, 88(23), 11804; Wenande, E. et al., Clin. Exp. Allergy, 2016, 46(7), 907; Webster, R. Drug Metab. Dispos, 2007, 35(1), 9). Additionally, PEG-containing pharmaceutical products can produce infusion-related reactions and anaphylaxis (see Browne, EK et al. J. Pediatr Oncolo. Nurs. 2018, 35(2), 103; Wylon, K., et al., J. Allergy Clin. Immunol. 2016, 12(1), 1.). It would therefore be desirable to develop excipients that prevent protein denaturation and aggregation without utilizing PEG, which would have broad application in the manufacturing, shipping, storage, and administration of proteins, particularly protein biopharmaceuticals. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] van Schie,KA,et al.Ann.Rheum.Dis.2015,74,311 [Non-Patent Document 2] Moussa,EM,et al.J.Pharm.Sci.2016,105,417 [Non-Patent Document 3] Kijanka,G.,et al.J.Pharm.Sci.2018,107,2847 [Non-Patent Document 4] Ha,E.,et al.J.Pharm.Sci.2002,91,2252

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Summary of the Invention

[0008] The present disclosure relates to polymers comprising hydrophilic poly(sarcosine) chains and hydrophobic aliphatic groups, and compositions thereof, and related methods of making and using. In some embodiments, such polymers are synthesized by polymerizing sarcosine N-carboxyanhydride with hydrophobic aliphatic amines or by treating poly(sarcosine) polymers with fatty acid halides, together with other methods described herein and / or known to those skilled in the art. As described herein, it has been unexpectedly discovered that certain polymers and / or compositions of the present disclosure are useful for stabilizing proteins through prevention of aggregate formation and denaturation. Also provided herein are compositions comprising such polymers and proteins for use as described herein. Further description of exemplary embodiments of the present disclosure are provided in the figures, detailed description, examples, and claims herein. [Brief description of the drawings]

[0009] [Figure 1] Temperature ramp study of IgG (1 mg / mL, PBS, pH 7) with varying poly(sarcosine) length hexadecyl polymers (each at 1 mg / mL). [Diagram 2] Temperature ramp study of IgG (1 mg / mL, PBS, pH 7) with varying poly(sarcosine) length oleyl polymers (each at 1 mg / mL). [Diagram 3] Temperature ramp study of IgG (1 mg / mL, PBS, pH 7) with poly(sarcosine) 30 polymers of varying carbohydrate length (each at 1 mg / mL). [Figure 4] Temperature ramp studies of IgG (1 mg / mL, PBS, pH 7) with selected PEG and poly(sarcosine) polymers (each at 1 mg / mL). [Diagram 5] Temperature ramp studies of IgG (20 mg / mL, PBS, pH 7) with selected PEG and poly(sarcosine) polymers (each at 20 mg / mL). [Figure 6]Temperature hold studies of IgG (20 mg / mL, PBS, pH 7) at 50° C. with selected PEG and poly(sarcosine) polymers (each at 1 mg / mL). [Figure 7] Temperature ramp studies of BSA (20 mg / mL, PBS, pH 7) with selected PEG and poly(sarcosine) polymers (each at 20 mg / mL). [Figure 8] Temperature ramp studies of BSA (20 mg / mL, PBS, pH 7) with selected PEG and poly(sarcosine) polymers (at 1 mg / mL and 20 mg / mL, respectively). [Figure 9] Shaking stability assay at 37° C. of selected PEG and poly(sarcosine) polymers with a 200:1 IgG to polymer ratio (w / w). [Figure 10] Shaking stability assay at 37° C. of selected PEG and poly(sarcosine) polymers with an abatacept to polymer ratio (w / w) of 20:1. [Figure 11] Temperature ramp studies of IgG (1 mg / mL, PBS, pH 7) with selected PEG and poly(sarcosine) polymers (each at 1 mg / mL). [Figure 12] Temperature ramp studies of cetuximab (2 mg / mL) with selected PEG and poly(sarcosine) polymers (each at 2 mg / mL). [Figure 13] Temperature ramp studies of bevacizumab (5 mg / mL) with selected PEG and poly(sarcosine) polymers (each at 5 mg / mL). [Figure 14] Temperature ramp studies of infliximab (1 mg / mL) with selected PEG and poly(sarcosine) polymers (each at 1 mg / mL). [Figure 15] Temperature ramp studies of rituximab (1 mg / mL) with selected PEG and poly(sarcosine) polymers (each at 1 mg / mL). [Figure 16] Percentage increase in cetuximab particle size after lyophilization using selected polymers. [Figure 17]Percentage increase in bevacizumab particle size after lyophilization using selected polymers. [Figure 18] Percentage increase in infliximab particle size after lyophilization using selected polymers. [Figure 19] Percentage increase in Rituximab particle size after lyophilization using selected polymers. [Figure 20] Images after lyophilization of cetuximab (0.5 mg / mL) with selected polymers (each at 1 mg / mL). [Figure 21] Images after lyophilization of bevacizumab (0.5 mg / mL) with selected polymers (each at 1 mg / mL). [Figure 22] Images after lyophilization of infliximab (0.5 mg / mL) with selected polymers (each at 1 mg / mL). [Figure 23] Images after lyophilization of rituximab (0.5 mg / mL) with selected polymers (each at 1 mg / mL). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] 1. General Description: As described herein, the present disclosure features polymers that include hydrophilic poly(sarcosine) chains and hydrophobic aliphatic groups. Such polymers can be synthesized, among other methods, by initiating the polymerization of sarcosine N-carboxyanhydride with a hydrophobic aliphatic amine or by reacting a poly(sarcosine) polymer with a fatty acid halide.

[0011] The polymers of the present disclosure behave as surfactants and thus can reduce the interfacial tension between two phases (e.g., liquid-gas and liquid-solid). Without wishing to be bound by any particular theory, it is believed that the polymers of the present disclosure can outcompete the protein for absorption to the interface between two phases, thus reducing the possibility for protein adsorption that can lead to aggregation and denaturation. This property is crucial for pharmaceutical bioproteins that encounter such interfacial stresses during manufacture, storage, and administration. In one embodiment, a protein formulation as a composition comprising the protein and a polymer of the present disclosure (e.g., any polymer of formula (I)-(Vb) or a salt thereof) exhibits improved stability and / or lower aggregation in solution compared to a protein formulation in the absence of the polymer of the present disclosure (e.g., any polymer of formula (I)-(Vb) or a salt thereof).

[0012] In some embodiments, the polymers of the present disclosure contain water-soluble hydrophilic poly(sarcosine) chains and water-insoluble hydrophobic aliphatic moieties (such as hydrocarbon chains). The amide backbone of the poly(sarcosine) chains can adopt both cis and trans conformations, while the hydrophobic hydrocarbon chains can oscillate between coil conformations (e.g., folded and unfolded). Without wishing to be bound by any particular theory, it is believed that these two properties taken together provide the polymers of the present disclosure with the ability to adopt the lowest possible energy state at the interfacial surface, thus preventing adsorption by proteins.

[0013] As described herein, the present disclosure further relates to compositions comprising poly(sarcosine) polymers and proteins. Such compositions may reduce protein aggregation and denaturation.

[0014] 2.Definition: Below are definitions of various terms used herein to describe the present disclosure, and are further illustrated by the embodiments, subembodiments, and species disclosed herein. These definitions apply to the terms as they are used throughout the specification, unless otherwise indicated in specific instances, either individually or as part of a larger group.

[0015] For purposes of this disclosure, chemical elements are defined as those elements listed in the Periodic Table of the Elements (CRC Handbook of Chemistry and Physics, 100 th In addition, the general principles of organic chemistry are identified in Sorrell, T. Organic Chemistry, 2 nd Ed., Sausalito, University Science Books, 2005; and Smith, MBMarch's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7 th Ed., New York, J. John Wiley & Sons, 2001, the entire contents of which are incorporated herein by reference.

[0016] The term "about," when referring to measurable values ​​(such as amounts, temporal durations, and the like), refers to a variation from the stated value of ±20%, or in some instances ±10%, or in some instances ±5%, in some instances ±2%, or in some instances ±1%, or in some instances ±0.1%, where such variations are appropriate for the practice of the present disclosure.

[0017] "CBP-1", "Oleyl-NH-poly(Sar 15 ), "Oleylamine-Sar 15 " "Oleyl-Sar15" "CH 3 (CH 2 ) 7 CH=CH(CH 2 ) 7 CH 2 NH-Poly(sarcosine)15 and a polymer having the structure: [ka] It is understood that all refer to the same compound and may be used interchangeably.

[0018] "CBP-2", "Oleyl-NH-poly(Sar 30 ), "Oleylamine-Sar 30 ", "Oleyl-Sar30", "CH 3 (CH 2 ) 7 CH=CH(CH 2 ) 7 CH 2 NH-Poly(sarcosine) 30 and a polymer having the structure: [ka] It is understood that all refer to the same compound and may be used interchangeably.

[0019] "CBP-3", "Dodecyl-NH-poly(Sar 20 ), "Dodecylamine-Sar 20 ", "Dodecyl-Sar20", "CH 3 (CH 2 ) 10 CH 2 NH-Poly(sarcosine) 20 and a polymer having the structure: [ka] It is understood that all refer to the same compound and may be used interchangeably.

[0020] "CBP-4", "Tetradecyl-NH-poly(Sar 15 ), "Tetradecylamine-Sar 15 ", "Tetradecyl-Sar15", "CH 3 (CH 2 ) 12 CH2 NH-Poly(sarcosine) 15 and a polymer having the structure: [ka] It is understood that all refer to the same compound and may be used interchangeably.

[0021] "CBP-5," "Tetradecyl-NH-poly(Sar 20 ), "Tetradecylamine-Sar 20 ", "Tetradecyl-Sar20", "CH 3 (CH 2 ) 12 CH 2 NH-Poly(sarcosine) 20 and a polymer having the structure: [ka] It is understood that all refer to the same compound and may be used interchangeably.

[0022] "CBP-6", "Hexadecyl-NH-poly(Sar 30 ), "Hexadecylamine-Sar 30 ", "Hexadecyl-Sar30", "CH 3 (CH 2 ) 14 CH 2 NH-Poly(sarcosine) 30 and a polymer having the structure: [ka] It is understood that all refer to the same compound and may be used interchangeably.

[0023] "CBP-7", "Octadecyl-NH-poly(Sar 30 ), "Octadecylamine-Sar 30 ", "Octadecyl-Sar30" "CH 3 (CH 2 ) 16 CH2 NH-Poly(sarcosine) 30 and a polymer having the structure: [ka] It is understood that all refer to the same compound and may be used interchangeably.

[0024] "CBP-8", "Didecyl-N-poly(Sar 30 ), "Didecylamine-Sar 30 ", "Didecyl-Sar30", "(CH 3 (CH 2 ) 8 CH 2 ) 2 -N-Poly(sarcosine) 30 and a polymer having the structure: [ka] It is understood that all refer to the same compound and may be used interchangeably.

[0025] "CBP-9", Didodecyl-N-poly(Sar 30 ), "Didodecylamine-Sar 30 ", "Didodecyl-Sar30", "(CH 3 (CH 2 ) 10 CH 2 ) 2 -N-Poly(sarcosine) 30 and a polymer having the structure: [ka] It is understood that all refer to the same compound and may be used interchangeably.

[0026] "CBP-10", ("Oleyl-NH-poly(Sar 10 ), "Oleylamine-Sar 10 ", "Oleyl-Sar10", "CH 3 (CH 2 )7 CH=CH(CH 2 ) 7 CH 2 NH-Poly(sarcosine) 10 and a polymer having the structure: [ka] It is understood that all refer to the same compound and may be used interchangeably.

[0027] "CBP-11", "Tetradecyl-NH-poly(Sar 23 ), "Tetradecylamine-Sar 23 ", "Tetradecyl-Sar23", "CH 3 (CH 2 ) 12 CH 2 NH-Poly(sarcosine) 23 and a polymer having the structure: [ka] It is understood that all refer to the same compound and may be used interchangeably.

[0028] As used herein, the monomer repeat units described above are numbers that represent the average number of monomer units that make up a polymer chain. For example, (A) 10A polymer represented by corresponds to a polymer consisting of 10 "A" monomer units linked together. One skilled in the art will recognize that the number 10, in this case, would represent a distribution with the average number being 10. The breadth of this distribution is represented by the polydispersity index (PDI). A PDI of 1.0 represents a polymer (e.g., a protein) in which each chain length is exactly the same. A PDI of 2.0 represents a polymer with a Gaussian distribution of chain lengths. Polymers of the present disclosure typically possess a PDI of less than 1.10. In some embodiments, the polymers of the present disclosure have a PDI of about 1.01, about 1.02, about 1.03, about 1.04, about 1.05, about 1.06, about 1.07, about 1.08, about 1.09, about 1.10, about 1.11, about 1.12, about 1.13, about 1.14, about 1.15, about 1.16, about 1.17, about 1.18, about 1.19, or about 1.2.

[0029] As used herein, the phrase "living polymer chain end" refers to a terminus resulting from a polymerization reaction that retains the ability to further react with additional monomer or polymerization terminating material.

[0030] As used herein, the term "termination" refers to the addition of a terminal group to the end of a polymer chain by reacting a living polymer with an appropriate compound. Alternatively, the term "termination" can refer to the addition of a terminal group to the amine or hydroxyl end of a polymer chain, or derivatives thereof.

[0031] As used herein, the terms "polymerization terminating substance", "terminating agent" and "terminating agent" are used interchangeably and may refer to a compound that reacts with a living polymer chain end to give a polymer with a terminal group, or alternatively, may refer to a compound that reacts with an amine or hydroxyl end of a polymer chain or derivatives thereof to give a polymer with a terminal group. Exemplary polymerization terminating substances include anhydrides, sulfonyl halides, and acid halides, including, but not limited to, fatty acid halides, linoleoyl chloride, lauroyl chloride, myristoyl chloride, palmitoyl chloride, steroyl chloride, and oleyl chloride. Further exemplary terminating agents include acid chloride derivatives of elaidic acid and ricinoelic acid.

[0032] The term "leaving group" or "LG" refers to a molecule or atom that leaves with a pair of electrons during heterolytic bond cleavage. Exemplary leaving groups include halides and carboxylates.

[0033] As used herein, the term "polymerization initiator" or "initiator" refers to a compound that reacts with a desired monomer, or whose anionic or free base form reacts with a desired monomer, in a manner that results in polymerization of that monomer. Exemplary polymerization initiators include primary amines, secondary amines, and their corresponding salts, including but not limited to neopentylamine, benzylamine, 4-methoxybenzylamine, N-butylamine, hexylamine, heptylamine, octylamine, decylamine, dodecylamine, tetradecylamine, hexadecylamine, octadecylamine, oleylamine, nonadecylamine, eicosylamine, dihexylamine, dioctylamine, didecylamine, didodecylamine, dioctadecylamine, and dioleylamine.

[0034] The term "aliphatic" or "aliphatic group", as used herein, refers to a hydrocarbon moiety that may be linear (i.e., unbranched), branched, or cyclic (including fused, bridged, and spiro-fused polycyclic), may be fully saturated or may contain one or more units of unsaturation, but is not aromatic. Unless otherwise specified, an aliphatic group contains 1-30 carbon atoms. In some embodiments, an aliphatic group contains 1-20 carbon atoms. In some embodiments, an aliphatic group contains 8-20 carbon atoms. In other embodiments, an aliphatic group contains 12-20 carbon atoms. In still other embodiments, an aliphatic group contains 14-20 carbon atoms, and in still other embodiments, an aliphatic group contains 16-20 carbon atoms. The number of carbon atoms present in an aliphatic group may also be defined prior to the recitation of the aliphatic group. For example, the term (C8-C20)aliphatic refers to an aliphatic group, as defined herein, containing 8-20 carbon atoms. The present disclosure is specifically intended to encompass each and every individual subcombination of such range members. In particular, the term (C1-C6)aliphatic is intended to encompass C1 aliphatic (e.g., methyl), C2 aliphatic (e.g., ethyl, ethylene, or ethylyne), C3 aliphatic, C4 aliphatic, C5 aliphatic, and C6 aliphatic. Aliphatic groups include, but are not limited to, straight or branched chain alkyl, alkenyl, and alkynyl groups, as well as hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl. Exemplary aliphatic groups include, but are not limited to, C24 aliphatic groups (e.g., didodecyl), C20 aliphatic groups (e.g., dodecyl), C18 aliphatic groups (e.g., oleyl, octadecyl), C16 aliphatic groups (e.g., hexadecyl, dioctyl), C14 aliphatic groups (e.g., tetradecyl), C12 aliphatic groups (e.g., dodecyl, dihexyl), and C10 aliphatic groups (e.g., decyl).

[0035] The term "hydrophobic aliphatic group" or "hydrophobic aliphatic" as used herein refers to a moiety having an overall hydrophobic character and containing six or more carbon atoms. The hydrophobic aliphatic group may be characterized by properties including, but not limited to, a static water contact angle θ>90°. The number of carbon atoms present in the hydrophobic aliphatic group may also be defined prior to the recitation of said hydrophobic aliphatic group. For example, the term (C6-C20) hydrophobic aliphatic group refers to an aliphatic group, as defined herein, containing 6 to 20 carbon atoms. Exemplary hydrophobic aliphatic groups include oleyl (i.e., CH 3 (CH 2 ) 7 CH=CH(CH 2 ) 7 CH 2 -), tetradecyl (i.e. CH 3 (CH 2 ) 12 CH 2 -), hexadecyl (i.e. CH 3 (CH 2 ) 14 CH 2 -), octadecyl (i.e. CH 3 (CH 2 ) 16 CH 2 -), dodecyl (i.e. (CH 3 (CH 2 ) 8 CH 2 ) 2 -), and didodecyl (i.e. (CH 3 (CH 2 ) 10 CH 2 ) 2 -), but are not limited to these.

[0036] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. It also includes any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, including =N- in 3,4-dihydro-2H-pyrrolyl, -NH- in pyrrolidinyl, or =N(R†)- in N-substituted pyrrolidinyl.

[0037] The term "aryl," used alone or as part of a larger moiety, such as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, at least one ring in the system is aromatic, and each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring."

[0038] As described herein, compounds of the present disclosure may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally", means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. In some embodiments, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in a given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at all positions. In some embodiments, an "optionally substituted" group refers to a group having 0-5 substituents independently selected from a specified group. In some embodiments, an "optionally substituted" group refers to a group having 0-3 substituents independently selected from a specified group. In some embodiments, an "optionally substituted" group refers to a group having 0-1 substituents independently selected from a specified group. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable" as used herein refers to compounds that are substantially unaltered when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0039] The monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH 2 ) 0-4 R 〇 ;-(CH 2 ) 0-4 OR 〇 ;-O-(CH 2 ) 0-4 C(O)OR 〇 ;-(CH 2 ) 0-4 CH(OR 〇 ) 2 ;-(CH 2 ) 0-4 S.R. 〇 ;-(CH 2 ) 0-4 Ph(R 〇 may be substituted by);-(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph(R 〇 -CH=CHPh(R 〇 may be substituted by );-NO 2 ;-CN;-N 3 ;-(CH 2 ) 0-4 N(R 〇 )2;-(CH 2 ) 0-4 N(R 〇 )C(O)R 〇 ;-N(R 〇 )C(S)R 〇 ;-(CH 2 ) 0-4 N(R 〇 )C(O)NR 〇 2 ;-N(R 〇 )C(S)NR 〇 2 ;-(CH 2 ) 04 N(R 〇 )C(O)OR 〇 ;-N(R 〇 )N(R 〇 )C(O)R 〇 ;-N(R 〇 )N(R 〇 )C(O)NR 〇 2 ;-N(R〇 )N(R 〇 )C(O)OR 〇 ;-(CH 2 ) 0-4 C(O)R 〇 ;-C(S)R 〇 ;-(CH 2 ) 0-4 C(O)OR 〇 ;-(CH 2 ) 0-4 C(O)SR 〇 ;-(CH 2 ) 0-4 C(O)OSiR 〇 3 ;-(CH 2 ) 0-4 OC(O)R 〇 ;-OC(O)(CH 2 ) 0-4 SR-、SC(S)SR 〇 ;-(CH 2 ) 0-4 SC(O)R 〇 ;-(CH 2 ) 0-4 C(O)NR 〇 2 ;-C(S)NR 〇 2 ;-C(S)SR 〇 ;-SC(S)SR 〇 、-(CH 2 ) 0-4 OC(O)NR 〇 2 ;-C(O)N(OR 〇 )R 〇 ;-C(O)C(O)R 〇 ;-C(O)CH 2 C(O)R 〇 ;-C(NOR 〇 )R 〇 ;-(CH 2 ) 0-4 SSR 〇 ;-(CH 2 ) 0-4 S(O) 2 R 〇 ;-(CH 2 ) 0-4 S(O) 2 OR 〇 ;-(CH 2 ) 0-4OS(O) 2 R 〇 ;-S(O) 2 NR 〇 2 ;-(CH 2 ) 0-4 S(O)R 〇 ;-N(R 〇 )S(O) 2 NR 〇 2 ;-N(R 〇 )S(O) 2 R 〇 ;-N(OR 〇 )R 〇 ;-C(NH)NR 〇 2 ;-P(O) 2 R 〇 ;-P(O)R 〇 2 ;-OP(O)R 〇 2 ;-OP(O)(OR 〇 ) 2 ;SiR 〇 3 ;-(C 1-20 (R 〇 ) 2 ; or -(C 1-20 (R) 〇 ) 2 where each R 〇 may be substituted as defined below and independently represents hydrogen, C 1-20 Aliphatic, -CH 2 Ph, O(CH 2 ) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definition, two independently occurring R 〇 together with the atom(s) between them form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur (which may be substituted as defined below).

[0040] R 〇 (or two independently occurring R 〇 The monovalent substituents on the ring formed by (with the atoms between them) are independently halogen, -(CH 2 ) 0-2 R ● , -(Halo R ● ), -(CH 2 ) 0-2 OH, -(CH 2 ) 0-2 OR ● , -(CH 2 ) 0-2 CH(OR ● ) 2 ;-O(HaloR ● ), -CN, -N 3 , -(CH 2 ) 0-2 C(O)R ● , -(CH 2 ) 0-2 C(O)OH, -(CH 2 ) 0-2 C(O)OR ● , -(CH 2 ) 0-2 S.R. ● , -(CH 2 ) 0-2 SH, -(CH 2 ) 0-2 NH 2 , -(CH 2 ) 0-2 NHR ● , -(CH 2 ) 0-2 NR ● 2 , -NO 2 , -SiR ● 3 , -OSiR ● 3 , -C(O)SR ● , -(C 1-4 (straight or branched chain alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by halo, substituted only with one or more halogens, and independently, C 1-4Aliphatic, -CH 2 Ph, O(CH 2 ) 0-1 R is selected from Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 〇 Such divalent substituents on a saturated carbon atom of include ═O and ═S.

[0041] Divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =O, =S, =NNR * 2 , =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O) 2 R * , =NR * , =NOR * , -O(C(R * 2 )) 2-3 O-, or -S(C(R * 2 )) 2-3 S- is listed, and each R * is hydrogen, C 1-20 A divalent substituent attached to the adjacent substitutable carbon of an "optionally substituted" group is selected from the following: -O(CR * 2 ) 2-3 O- is listed, and each R * is hydrogen, C 1-20 is selected from an aliphatic (which may be substituted as defined below) or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0042] R * Suitable substituents on the aliphatic group include halogen, -R ●, -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2 , -NHR ● , -NR ● 2, or -NO 2 In the formula, each R ● is unsubstituted or, if preceded by halo, substituted only with one or more halogens, and independently, C 1-20 Aliphatic, -CH 2 Ph, O(CH 2 ) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0043] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include R † , N.R. † 2 , C(O)R † ,C(O)OR † , C(O)C(O)R † , C(O)CH 2 C(O)R † , S(O) 2 R † , S(O) 2 NR † 2 , C(S)NR † 2 , C(NH)NR † 2 , or N(R † )S(O) 2 R † wherein R † are each independently hydrogen, C which may be substituted as defined below 1-6 aliphatic, unsubstituted OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definition, two independently occurring R †together with the atom(s) between them form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0044] R † Suitable substituents on the aliphatic groups are independently halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2 , -NHR ● , -NR ● 2, or -NO 2 where each R ● is unsubstituted or, if preceded by halo, substituted only with one or more halogens, and independently, C 1-20 Aliphatic, -CH 2 Ph, O(CH 2 ) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0045] In some embodiments, an "optionally substituted aliphatic" group refers to an aliphatic group, as defined above, that is substituted with 0-40 substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, oxo, phenyl, azide, or alkyne, wherein the phenyl is selected from the group consisting of halogen, -CH 3 , -CF 2 H, -CF 2 , -OCH 3 For example, an "optionally substituted aliphatic" group is a group selected from CH 2 C 6 H 5 It may refer to a methyl group substituted with a group (i.e., a benzyl group).

[0046] Protected hydroxyl groups are well known in the art and are described in Wuts, PGM Protecting Groups in Organic Synthesis, 5 thEd., New York, John Wiley & Sons, 2014 (the entirety of which is incorporated herein by reference). Examples of suitable protected hydroxyl groups further include, but are not limited to, esters, carbonates, sulfonates, allyl ethers, ethers, silyl ethers, alkyl ethers, aryl alkyl ethers, and alkoxy alkyl ethers. Examples of suitable esters include formates, acetates, proprionates, pentanoates, crotonates, and benzoates. Specific examples of suitable esters include formate, benzoylformate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetate), crotonate, 4-methoxy-crotonate, benzoate, p-benylbenzoate, 2,4,6-trimethylbenzoate. Examples of carbonates include 9-fluorenylmethylcarbonate, ethylcarbonate, 2,2,2-trichloroethylcarbonate, 2-(trimethylsilyl)ethylcarbonate, 2-(phenylsulfonyl)ethylcarbonate, vinylcarbonate, allylcarbonate, and p-nitrobenzylcarbonate. Examples of silyl ethers include trimethylsilyl ether, triethylsilyl ether, t-butyldimethylsilyl ether, t-butyldiphenylsilyl ether, triisopropylsilyl ether, and other trialkylsilyl ethers. Examples of alkyl ethers include methyl ether, benzyl ether, p-methoxybenzyl ether, 3,4-dimethoxybenzyl ether, trityl ether, t-butyl ether, and allyl ether, or derivatives thereof.Alkoxyalkyl ethers include acetals such as methoxymethyl ether, methylthiomethyl ether, (2-methoxyethoxy)methyl ether, benzyloxymethyl ether, β-(trimethylsilyl)ethoxymethyl ether, and tetrahydropyran-2-yl ether. Examples of arylalkyl ethers include benzyl ether, p-methoxybenzyl (MPM) ether, 3,4-dimethoxybenzyl ether, O-nitrobenzyl ether, p-nitrobenzyl ether, p-halobenzyl ether, 2,6-dichlorobenzyl ether, p-cyanobenzyl ether, 2-picolyl ether, and 4-picolyl ether.

[0047] Protected amines are well known in the art and are described in Wuts, PGM Greene's Protective Groups in Organic Synthesis, 5 thEd., New Jersey, J. John Wiley & Sons, 2014. Mono-protected amines further include, but are not limited to, aralkylamines, carbamates, allylamines, amides, and the like. Examples of mono-protected amino moieties include t-butyloxycarbonylamino (-NHBOC), ethyloxycarbonylamino, methyloxycarbonylamino, trichloroethyloxycarbonylamino, allyloxycarbonylamino (-NHAlloc), benzyloxocarbonylamino (-NHCBZ), allylamino, benzylamino (-NHBn), fluorenylmethylcarbonyl (-NHFmoc), formamide, acetamide, chloroacetamide, dichloroacetamide, trichloroacetamide, phenylacetamide, trifluoroacetamide, benzamide, t-butyldiphenylsilyl, and the like. Di-protected amines include amines substituted with two substituents independently selected from those described above as mono-protected amines, and further include cyclic imides, such as phthalimide, maleimide, succinimide, and the like. Di-protected amines also include pyrrole and the like, 2,2,5,5-tetramethyl-[1,2,5]azadisilolidine and the like, and azides.

[0048] Protected aldehydes are well known in the art and include those described in detail in Wuts (2014). Protected aldehydes further include, but are not limited to, acyclic acetals, cyclic acetals, hydrazones, imines, and the like. Examples of such groups include dimethyl acetal, diethyl acetal, diisopropyl acetal, dibenzyl acetal, bis(2-nitrobenzyl) acetal, 1,3-dioxane, 1,3-dioxolane, semicarbazones, and derivatives thereof.

[0049] Protected carboxylic acids are well known in the art and include those described in detail in Wuts (2014). Protected carboxylic acids include optionally substituted C 1-20 Further included are, but are not limited to, aliphatic esters, optionally substituted aryl esters, silyl esters, activated esters, amides, hydrazides, and the like. Examples of such ester groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, and phenyl esters, each of which is optionally substituted. Additional protected carboxylic acids include oxazolines and orthoesters.

[0050] Protected thiols are well known in the art and include those described in detail in Wuts (2014). Protected thiols further include, but are not limited to, disulfides, thioethers, silyl thioethers, thioesters, thiocarbonates, and thiocarbamates, and the like. Examples of such groups include, but are not limited to, alkyl thioethers, benzyl and substituted benzyl thioethers, triphenylmethyl thioethers, and trichloroethoxycarbonyl thioesters, to name a few.

[0051] Unless otherwise stated, structures depicted herein are meant to encompass all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations of each asymmetric center, the Z and E double bond isomers, and the Z and E conformational isomers. Thus, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds, are within the scope of the disclosure. Unless otherwise stated, all tautomers of the compounds of the disclosure are within the scope of the disclosure. Additionally, unless otherwise stated, structures depicted herein are meant to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure except for the replacement of carbon with a C-enriched carbon are within the scope of this disclosure. Such compounds are useful as analytical tools or probes in biological assays, for example, as in neutron scattering experiments.

[0052] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety that is capable of being detected (e.g., primary labels and secondary labels). A "detectable moiety" or "label" is the radical of a compound that is detectable.

[0053] "Primary" labels include radioisotope-containing moieties, e.g. 32 P, 33 P, 35 S, or 14 C-containing moieties), mass tags, and fluorescent labels are signal generating reporter groups that can be detected without further modification.

[0054] "Secondary" labels include moieties (such as biotin or protein antigens) that require the presence of a second compound to generate a detectable signal. For example, in the case of a biotin label, the second compound may include a streptavidin-enzyme conjugate. In the case of an antigen label, the second compound may include an antibody-enzyme conjugate. Additionally, certain fluorescent groups can act as secondary labels by transferring energy to another compound or group in the process of non-radioactive fluorescence resonance energy transfer (FRET), causing the second compound or group to generate a signal that is then detected.

[0055] The terms "fluorescent label," "fluorescent group," "fluorescent compound," "fluorescent dye," and "fluorophore," as used herein, refer to a compound or moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent compounds include Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Cyanine Dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, Dialkylaminocoumarin, 4',5'-Dichloro-2',7'-Dimethoxy-Fluorescein, DM-NERF, Eosin, Erythrosine, Fluorescein, FAM, Hydroxycoumarin, IRDye (IRD40, IRD700, IRD800), JOE, Lissamine, Rhodamine B, Marina Blue, Methoxycoumarin, Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-tetra-bromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, and Texas Red-X.

[0056] The term "substrate" as used herein refers to any material or macromolecular complex to which a polymer can be added. Examples of commonly used substrates include, but are not limited to, glass surfaces, silica surfaces, plastic surfaces, metal surfaces, surfaces containing metal or chemical coatings, membranes (e.g., nylon, polysulfone, silica), microbeads (e.g., latex, polystyrene, or other polymers), porous polymer matrices (e.g., polyacrylamide gels, polysaccharides, polymethacrylates), macromolecular complexes (e.g., proteins, polysaccharides).

[0057] Unless otherwise indicated, a radioisotope-containing moiety is an optionally substituted hydrocarbon group that contains at least one radioisotope. Unless otherwise indicated, a radioisotope-containing moiety contains 1-40 carbon atoms and one radioisotope. In certain embodiments, a radioisotope-containing moiety contains 10-20 carbon atoms and one radioisotope.

[0058] The term "isotopic enrichment" or "isotopically enriched" refers to the alteration of the relative abundances of isotopes, thereby producing a form of an element that is enriched in one particular isotope and depleted in others. For example, C 14 The compounds are said to be isotopically enriched.

[0059] The term "as received" when referring to the use of solvents, reagents, resins, or other components used in a chemical reaction or isolation refers to their use in the condition provided by the manufacturer, without additional isolation and / or purification.

[0060] As used herein, the term "protein" or "polypeptide" refers to a polymer of one or more amino acids connected through peptide bonds. Proteins generally contain more than 20 such amino acids. The term encompasses a single polypeptide chain or multiple polypeptide chains complexed together or covalently linked together (e.g., via disulfide bonds).

[0061] As used herein, the terms "drug," "therapeutic agent," "pharmaceutical," "medicine," and their derivatives are used interchangeably and refer to a substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease.

[0062] As used herein, the terms "protein biologic," "protein drug," "protein therapeutic," and derivatives thereof, are used interchangeably and refer to one or more poly(amino acid) chains (e.g., one or more proteins) intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease. Exemplary protein biologics include monoclonal antibodies, polyclonal antibodies, immunoglobins, fusion proteins, anticoagulants, blood factors, bone morphogenetic proteins, engineered protein scaffolds, enzymes, growth factors, hormones, interferons, interleukins, thrombolytics, insulin, glycosylated proteins, antigens, antigen subunits, and combinations thereof.

[0063] As used herein, the term "pH adjusting agent" refers to any pharma- ceutically acceptable composition, compound, or agent suitable for adjusting the pH of the compositions described herein without negatively affecting any of its properties. Suitable pH adjusting agents may include any pharma- ceutically acceptable acid or base. Suitable pH adjusting agents may include hydrochloric acid, sulfuric acid, citric acid, acetic acid, formic acid, phosphoric acid, tartric acid, trolamine, sodium hydroxide, and potassium hydroxide.

[0064] As used herein, the term "preservative" refers to any known pharma- ceutically acceptable preservative that functions by inhibiting bacteria, fungi, yeasts, molds, other microorganisms, and / or by inhibiting oxidation. Suitable preservatives include, but are not limited to, antimicrobial agents and / or antioxidants. In some embodiments, suitable preservatives are preservatives known in the art for stabilization of certain vaccines. In some embodiments, suitable preservatives are preservatives known in the art for stabilization of certain protein biopharmaceutical compositions. Suitable antimicrobial agents may include, but are not limited to, benzoates, benzyl alcohol, sodium benzoate, sorbates, propionates, nitrites. Suitable antioxidants may include, but are not limited to, vitamin C, butylated hydroxytoluene (BHT), sulfites, and vitamin E.

[0065] As used herein, "unit dosage form" or "unit dose form" refers to a physically discrete unit of preparation suitable for the subject to be treated. However, it will be understood that the total daily usage of the composition of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific active agent used; the specific composition used; the age, weight, general health, sex, and diet of the subject; the administration time and excretion rate of the specific active agent used; the duration of treatment, drugs, and / or additional therapies used in conjunction with or simultaneously with the specific compound(s) used, and the like factors well known in the medical field.

[0066] As used herein, a "drug product" refers to a therapeutic agent and one or more "excipients" selected from, but not limited to, isotonicity agents, cryoprotectants, stabilizers, anti-adhesive substances, binding substances, coatings, pigments, disintegration substances, flavoring substances, fluidizing substances, lubricating substances, preservative substances, adsorbents, sweetening substances, vehicles, surfactants, and poly(sarcosine) polymers. As will be appreciated by those skilled in the art, the amount of each excipient will depend on the therapeutic agent, the route of administration, the desired biological endpoint, the target cells, or tissues.

[0067] As used herein, "cryoprotectant" or "cryoprotectant" refers to a compound that prevents freezing or prevents freezing-related damage or denaturation to other compounds, including, but not limited to, sugars, monosaccharides, disaccharides, polyhydric alcohols, amino acids, polyvinylpyrrolidine, polyethylene glycol, mannitol, sorbitol, sucrose, glucose, raffinose, sucralose, lactose, trehalose, dextran, and dextrose.

[0068] As used herein, a "surfactant" is a compound (including but not limited to, an amphiphilic compound) capable of reducing the interfacial tension between two phases (e.g., an air-liquid interface). In certain embodiments, the surfactant is an amphiphilic polymer comprising a hydrophilic poly(sarcosine) chain and a hydrophobic aliphatic chain.

[0069] As used herein, "therapeutically effective amount" refers to an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount sufficient to treat, diagnose, slow the progression of, and / or delay the onset of a disease, disorder, and / or condition when administered as part of a dosing regimen to a subject suffering from or susceptible to the disease, disorder, and / or condition. As will be recognized by those skilled in the art, the effective amount of a substance can vary depending on factors such as the desired biological endpoint, the substance delivered, the target cell, or tissue. For example, an effective amount of a compound in a formulation for treating a disease, disorder, and / or condition is an amount that alleviates, relieves, relieves, inhibits, slows the progression of, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms or features of the disease, disorder, and / or condition. In some embodiments, a "therapeutically effective amount" is at least the minimal amount of a compound, or a composition containing a compound, sufficient to treat one or more symptoms of a disease or disorder.

[0070] The term "subject" as used herein means a mammal, and includes human and animal subjects, such as domestic animals (e.g., horses, dogs, cats, etc.). In one embodiment, the subject is a human.

[0071] As used herein, the terms "treatment", "treat" and "treating" refer to partially or completely alleviating, inhibiting, delaying the onset of, slowing the progression of, ameliorating, and / or alleviating a disease or disorder, or one or more symptoms of a disease or disorder, as described herein. In some embodiments, treatment may be administered after one or more symptoms have occurred. In some embodiments, the term "treating" encompasses preventing, slowing, or halting the progression of a disease or disorder. In some embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account the history of symptoms and / or taking into account genetic or other susceptibility factors). Treatment may be continued after symptoms have been cured to, for example, prevent or delay their recurrence. Thus, in some embodiments, the term "treating" encompasses preventing relapse or recurrence of a disease or disorder.

[0072] The term "parenteral" or "parenterally" as used herein includes techniques for subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion. Preferably, the composition is administered intraperitoneally or intravenously. Sterile injectable forms of the compositions of the present disclosure may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents (e.g., as solutions in 1,3-butanediol). Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution.

[0073] The term "in solution," when referring to a protein, refers to a liquid medium in which the protein is continuously distributed to form a homogenous mixture.

[0074] 3. Description of Exemplary Embodiments 3.1 Polymers In some aspects, the present disclosure relates to a polymer comprising a hydrophilic poly(sarcosine) chain and a hydrophobic aliphatic group. In certain embodiments, the present disclosure relates to a polymer of formula I: [ka] or a salt thereof [wherein R 1a is an optionally substituted (C1-C20) aliphatic group; R 1b is H or an optionally substituted (C1-C20) aliphatic group; R 2 is H or an optionally substituted (C1-C20) aliphatic group; x is between 5 and 250. to provide.

[0075] In certain embodiments, the present disclosure provides a polymer of formula I: [ka] [In the formula, R 1a is an optionally substituted (C1-C20) aliphatic group; R 1b is H or an optionally substituted (C1-C20) aliphatic group; R 2 is H or an optionally substituted (C1-C20) aliphatic group; x is between 5 and 250. to provide.

[0076] In some embodiments, the present disclosure provides 1a is an aliphatic group having an overall hydrophobic character and containing one or more carbon atoms. In some embodiments, the present disclosure relates to a polymer of formula I, 1bis an aliphatic group having an overall hydrophobic character and containing one or more carbon atoms. In some embodiments, the present disclosure relates to a polymer of formula I, 2 is an aliphatic group having an overall hydrophobic character and containing one or more carbon atoms.

[0077] In some embodiments, R 1a is an aliphatic group that includes an alkenyl group (e.g., (C2-C20) alkenyl). In some embodiments, R 1b is an aliphatic group that includes an alkenyl group (e.g., (C2-C20) alkenyl). In some embodiments, R 1a is H and R 1b is an aliphatic group that includes an alkenyl group (e.g., (C2-C20) alkenyl). In some embodiments, R 1b is an aliphatic group that contains an alkenyl group (e.g., (C2-C20) alkenyl), and R 1a is H. In any and all embodiments, the alkenyl group contains a double bond which may have a cis or trans geometric configuration. In any and all embodiments, the alkenyl group includes all Z and E double bond isomers and all Z and E conformational isomers.

[0078] As described above, the present disclosure relates to polymers characterized in that the hydrophilic chain comprises a polymer of N-methylglycine (i.e., poly(sarcosine)). The present disclosure further contemplates other N-alkylglycines that can be used to generate water-soluble chains (see Robinson, J Wet al. Macromolecules 2013, 46(3), 580). In some embodiments, the present disclosure encompasses polymers in which the hydrophilic chain is poly(N-methylglycine), poly(N-ethylglycine), poly(N-{n-propyl})glycine, poly(N-isopropyl)glycine, or poly(N-allyl)glycine. In some aspects, the present disclosure also encompasses mixtures of two or more N-alkylglycines (such as a mixture of N-methylglycine and N-ethylglycine) used to construct the water-soluble chain.

[0079] As also described above, in some embodiments, R in the polymer of Formula I 1a , R 1b , and R 2 is optionally and independently substituted. For example, in some embodiments, such optional and independent substitutions contemplated by the present disclosure include, but are not limited to, optionally substituted benzyl groups, optionally substituted hydrocarbons, optionally substituted silyl groups, poly(amino acid) polymers, poly(ethylene glycol) polymers, poly(N-isopropylacrylamide) polymers, poly(acrylamide) polymers, poly(2-oxazoline) polymers, poly(ethyleneimine), poly(acrylic acid) polymers, poly(methacrylate) polymers, poly(vinyl alcohol) polymers, poly(vinylpyrrolidone) polymers, and their corresponding amine salts. In some embodiments, each R 1a , R 1b , and R 2 is optionally and independently substituted with (C1-C20) alkyl, (C2-C20) alkenyl, (C2-C20) alkynyl, halogen, hydroxy, cyano, or oxo. 1ais optionally and independently substituted with (C1-C20) alkyl, (C2-C20) alkenyl, (C2-C20) alkynyl, halogen, hydroxy, cyano, or oxo. 1b is optionally and independently substituted with (C1-C20) alkyl, (C2-C20) alkenyl, (C2-C20) alkynyl, halogen, hydroxy, cyano, or oxo. 2 is optionally and independently substituted with (C1-C20) alkyl, (C2-C20) alkenyl, (C2-C20) alkynyl, halogen, hydroxy, cyano, or oxo.

[0080] In some embodiments, R 1a The aliphatic group is selected from (C1-C20) alkyl, (C2-C20) alkenyl, (C2-C20) alkynyl, or (C3-C20) cycloalkyl, wherein the (C1-C20) alkyl, (C2-C20) alkenyl, (2-20) alkynyl, or (C3-C20) cycloalkyl is substituted with 0-20 halogen, hydroxy, cyano, nitro, oxo, or phenyl, and the phenyl is substituted with halogen, -CH 3 , -CF 2 H, -CF 3 , -OCH 3 or -OH.

[0081] In some embodiments, R 1a An aliphatic group is as defined and described above and has at least one point of unsaturation. In some such embodiments, R 2 is H.

[0082] In some embodiments, R 1bThe aliphatic group is selected from a (C1-C20) alkyl, a (C2-C20) alkene, a (C2-C20) alkyne, or a (C3-C20) cycloalkyl, wherein the (C1-C20) alkyl, the (C2-C20) alkenyl, the (C2-C20) alkynyl, or the (C3-C20) cycloalkyl is substituted with 0 to 20 halogen, hydroxy, cyano, nitro, oxo, or phenyl groups, and the phenyl is substituted with halogen, -CH 3 , -CF 2 H, -CF 3 , -OCH 3 or -OH.

[0083] In some embodiments, R 1b An aliphatic group is as defined and described above and has at least one point of unsaturation. In some such embodiments, R 2 is H.

[0084] In some embodiments, R 1a is an aliphatic group selected from (C1-C20) alkyl and (C2-C20) alkenyl; R 1b is H and R 2 is H. In some embodiments, R 1a is selected from the aliphatic groups (C1-C20) alkyl and (C2-C20) alkenyl; R 1b is selected from the aliphatic groups (C1-C20) alkyl and (C2-C20) alkenyl; R 2 is H. In some embodiments, R 1a is selected from the aliphatic groups (C1-C20) alkyl and (C2-C20) alkenyl; R 1b is selected from the aliphatic groups (C1-C20) alkyl and (C2-C20) alkenyl; R 2 is selected from the aliphatic groups (C1-C20) alkyl and (C2-C20) alkenyl.

[0085] In some embodiments, the present disclosure provides a polymer of formula I1a , R 1b , and R 2

[0043] In certain embodiments, R is a substituted amine, which may add a functional group that would not otherwise be present, including, but not limited to, a detectable moiety, a fluorescent label, or a substrate. One of skill in the art will recognize that isotopically enriched material may be a useful probe in biological assays, such as quantitative whole body autoradiography (QWBA) assays, which are useful for determining the distribution of a composition in an animal. In certain embodiments, R is a substituted amine, which may add a functional group that would not otherwise be present, including, but not limited to, a detectable moiety, a fluorescent label, or a substrate. 1a , R 1b , or R 2 is isotopically enriched. In some embodiments, R 1a teeth, 14 In some embodiments, R 2 teeth, 14 Contains C isotopically enriched hydrocarbons.

[0086] In certain embodiments, the present disclosure provides a polymer of formula II: [ka] or a salt thereof [wherein R is an optionally substituted (C12-C20) hydrophobic aliphatic group; x is 5 to 50. to provide.

[0087] In certain embodiments, the present disclosure provides a polymer of formula II: [ka] [In the formula, R is an optionally substituted (C12-C20) hydrophobic aliphatic group; x is 5 to 50. to provide.

[0088] In some such embodiments, R is CH 3 -(CH 2 ) y-, where y is 11 to 19.

[0089] In some such embodiments, R is CH 3 (CH 2 ) 7 CH=CH(CH 2 ) 7 CH 2 -It is.

[0090] In some such embodiments, x is 15. In some such embodiments, x is 30.

[0091] In certain embodiments, the present disclosure provides a polymer of formula III: [ka] or a salt thereof [wherein R 1a is an optionally substituted (C6-C20) hydrophobic aliphatic group; R 1b is an optionally substituted (C6-C20) hydrophobic aliphatic group; and x is 5 to 50. to provide.

[0092] In certain embodiments, the present disclosure provides a polymer of formula III: [ka] [In the formula, R 1a is an optionally substituted (C6-C12) hydrophobic aliphatic group; R 1b is an optionally substituted (C6-C12) hydrophobic aliphatic group; and x is 5 to 50. to provide.

[0093] In some such embodiments, R 1a is CH 3 -(CH 2 ) y - and R 1b is CH 3 -(CH 2 )z -, y is 5 to 19, and z is 5 to 19. In some such embodiments, R 1a is CH 3 -(CH 2 ) y - and R 1b is CH 3 -(CH 2 ) z -, y is 5 to 11, and z is 5 to 11.

[0094] In certain embodiments, the present disclosure provides a polymer of formula IV: [ka] or a salt thereof [wherein R 1a is an optionally substituted (C1-C6) aliphatic group; R 1b is H or an optionally substituted (C1-C6) aliphatic group; R 2 is an optionally substituted (C11-19) hydrophobic aliphatic group; and x is 5 to 50. to provide.

[0095] In certain embodiments, the present disclosure provides a polymer of formula IV: [ka] [In the formula, R 1a is an optionally substituted (C1-C6) aliphatic group; R 1b is H or an optionally substituted (C1-C6) aliphatic group; R 2 is an optionally substituted (C11-19) hydrophobic aliphatic group; and x is 5 to 50. to provide.

[0096] In some such embodiments, R 2 is -(CH 2 ) y -CH3 In the formula, y is 10 to 18.

[0097] In some such embodiments, R 2 is -(CH 2 ) 7 CH=CH(CH 2 ) 7 CH 3 It is.

[0098] In some embodiments, the present disclosure provides a polymer selected from formula (Va) or (Vb): [ka] or a salt thereof, wherein x is 2 to 250. to provide.

[0099] In some embodiments, the present disclosure provides a polymer of the following structure: [ka] or a salt thereof, wherein x is 5 to 90. to provide.

[0100] In some embodiments, the present disclosure provides a polymer of the following structure: [ka] [In the formula, x is 5 to 90.] to provide.

[0101] For any of formulas (Va) and (Vb), in some such embodiments, x is between 5 to 80, 5 to 75, 5 to 70, 5 to 65, 5 to 60, 5 to 55, 5 to 50, 5 to 45, 5 to 40, 5 to 35, 5 to 30, 5 to 25, 5 to 20, 5 to 15, and 5 to 10. In some such embodiments, x is between 10 to 90, 10 to 85, 10 to 80, 10 to 75, 10 to 70, 10 to 65, 10 to 60, 10 to 55, 10 to 50, 10 to 45, 10 to 40, 10 to 35, 10 to 30, 10 to 25, 10 to 20, and 10 to 15. In some such embodiments, x is between 20-90, 20-75, 20-60, 20-50, 20-35, 25-90, 25-75, 25-50, 30-90, 30-60, 35-90, 35-80, 35-70, 35-60, 35-50, 40-90, 45-70, 50-90, and 50-75.

[0102] In some such embodiments, x is greater than 10. In some such embodiments, x is greater than 20. In some such embodiments, x is greater than 30. In some such embodiments, x is greater than 40. In some such embodiments, x is greater than 50. In some such embodiments, x is greater than 60. In some such embodiments, x is greater than 70. In some such embodiments, x is greater than 80. In some such embodiments, x is greater than 90. In some such embodiments, x is greater than 100. In some such embodiments, x is less than 100. In some such embodiments, x is less than 90. In some such embodiments, x is less than 80. In some such embodiments, x is less than 70. In some such embodiments, x is less than 60. In some such embodiments, x is less than 50. In some such embodiments, x is less than 40. In some such embodiments, x is less than 30. In some such embodiments, x is less than 20. In some such embodiments, x is less than 10.

[0103] In some such embodiments, x is 5. In some such embodiments, x is 10. In some such embodiments, x is 15. In some such embodiments, x is 20. In some such embodiments, x is 25. In some such embodiments, x is 30. In some such embodiments, x is 35. In some such embodiments, x is 40. In some such embodiments, x is 45. In some such embodiments, x is 50. In some such embodiments, x is 55. In some such embodiments, x is 60. In some such embodiments, x is 65. In some such embodiments, x is 70. In some such embodiments, x is 75. In some such embodiments, x is 80. In some such embodiments, x is 85. In some such embodiments, x is 90.

[0104] In some embodiments, the present disclosure provides for use in accordance with the present invention, a polymer of any of the following structures: [ka] [ka] to provide.

[0105] In some embodiments, the present disclosure provides a polymer of the following structure: [ka] to provide.

[0106] In some embodiments, the present disclosure provides a polymer of the following structure: [ka] to provide.

[0107] In some embodiments, the present disclosure provides a polymer of the following structure: [ka] to provide.

[0108] In some embodiments, the present disclosure provides a polymer of the following structure: [ka] to provide.

[0109] In some embodiments, the present disclosure provides a polymer of the following structure: [ka] to provide.

[0110] In some embodiments, the present disclosure provides a polymer of the following structure: [ka] to provide.

[0111] In some embodiments, the present disclosure provides a polymer of the following structure: [ka] to provide.

[0112] 3.2 Polymer synthesis In certain embodiments, the present disclosure provides methods for preparing polymers of formula II. One embodiment of a general method for preparing said polymers is illustrated in Scheme 1 and involves initiating the polymerization of sarcosine NCA (formula VI) with a suitable amine-containing initiator (formula V) to provide a polymer of formula II.

[0113] Scheme 1 [ka] One of skill in the art will recognize that numerous amines of formula V can serve as initiators for the polymerization of sarcosine NCA. Initiators of formula V contemplated by the present disclosure include optionally substituted (C12-C20) hydrophobic aliphatic amines and their corresponding amine salts derived from anions including, but not limited to, halides, organic acids (e.g., acetate, trifluoroacetate), and tetrafluoroborate.

[0114] In some embodiments, the starting material of formula V is an alkylamine of formula Va: [ka] [In the formula, x=11~19] It is.

[0115] In some embodiments, the starting material of formula V is oleylamine (i.e., CH 3 (CH 2 ) 7 CH=CH(CH 2 ) 7 CH 2 -NH 2 ).

[0116] In certain embodiments, the present disclosure provides a method for preparing a polymer of formula III. One embodiment of a general method for preparing the polymer is illustrated in Scheme 2 and includes initiating the polymerization of a sarcosine NCA of formula VI with a suitable secondary amine-containing starting material of formula VII to provide a polymer of formula III, wherein R 1a , R 1b and x are each defined and described herein.

[0117] Scheme 2 [ka] One of skill in the art will recognize that numerous secondary amines of formula VII can serve as starting materials for the polymerization of the sarcosine NCA depicted in Scheme 2. Starting materials of formula VII contemplated by the present disclosure include those having R 1a is an optionally substituted (C6-C20) hydrophobic aliphatic group, R 2a is an optionally substituted (C6-C20) hydrophobic aliphatic group. In some embodiments, the starting material of formula VII is an amine salt derived from an anion, including, but not limited to, a halide, an organic acid (e.g., acetic acid, trifluoroacetic acid), and a tetrafluoroborate.

[0118] In some embodiments, the starting material of formula VII is an alkyl secondary amine of structural formula VIIa: [ka] [In the formula, x=5~19;y=5~19] In some embodiments, x=6-12; y=6-12.

[0119] In certain embodiments, the present disclosure provides a method for preparing a polymer of formula IV. One embodiment of a general method for preparing the polymer is illustrated in Scheme 3 and includes the following steps: (1) initiating the polymerization of a sarcosine NCA of formula VI with a suitable amine-containing initiator of formula VII, and (2) adding a terminator represented by formula VIII to provide a polymer of formula IV, where R 1a , R 1b , R 2 Each of , LG, and x is defined and described herein.

[0120] Scheme 3 [ka] One of skill in the art will recognize that numerous amines of formula VII can serve as starting materials for the polymerization of the sarcosine NCA depicted in Scheme 3. Starting materials of formula VII contemplated by the present disclosure include those having R 1a is an optionally substituted (C-C) aliphatic group, and R 2a is H or an optionally substituted (C1-C6) aliphatic group. In some embodiments, the starting material of formula VII is an amine salt derived from an anion, including, but not limited to, a halide, an organic acid (e.g., acetic acid, trifluoroacetic acid), and a tetrafluoroborate.

[0121] In some embodiments, the starting material of formula VII is neopentylamine, N-butylamine, or benzylamine.

[0122] Those skilled in the art will recognize that numerous terminating agents in addition to those of formula VIII are capable of reacting with the final amine of the compound represented by formula III and its corresponding anion. Terminating agents contemplated by the present disclosure include anhydrides, sulfonyl halides, other acylating agents, and other groups that contain a leaving group (LG) susceptible to nucleophilic displacement.

[0123] In some embodiments, the terminator is an acyl chloride of Formula VIIIa, represented by the following structure: [ka] wherein x is an optionally substituted (C12-C20) hydrophobic aliphatic group. It is.

[0124] In some embodiments, the terminator of formula VIII is oleyl chloride (i.e., CH 3 (CH 2 ) 7 CH=CH(CH 2 ) 7 CO-Cl).

[0125] Those skilled in the art will recognize that the treatment of the compound of formula III with a terminating agent can be performed in a process described as a "one-pot" synthesis without isolation of the compound of formula III upon completion of polymerization with sarcosine NCA of formula VI. Alternatively, the treatment with the end group can be performed after isolation of the compound of formula III from the reaction mixture in a "multi-step" process. In certain embodiments, the compound of formula IV is prepared in a one-pot process. In certain embodiments, the compound of formula IV is prepared in a multi-step process.

[0126] In certain embodiments, the sarcosine NCA is added to a solution of a polymerization initiator.In certain embodiments, the polymerization initiator is added to a solution of the sarcosine NCA.

[0127] In certain embodiments, the sarcosine NCA is added as a solid.

[0128] In certain embodiments, sarcosine NCA is added as a solution. In certain embodiments, sarcosine NCA is added as a solution in N,N-dimethylacetamide (DMAc). In certain embodiments, sarcosine NCA is added as a solution in N,N-dimethylformamide (DMF).

[0129] In certain embodiments, the process depicted in Scheme 1, Scheme 2, or Scheme 3 is carried out in a single solvent. In certain embodiments, the solvent will be capable of solubilizing the starting materials, the living polymer chains, and the final polymer such that all materials remain in solution for the duration of the process. In some embodiments, a suitable solvent comprises an amide-containing solvent. In certain embodiments, the solvent is or comprises N,N-dimethylformamide (DMF). In certain embodiments, the solvent is or comprises N,N-dimethylacetamide (DMAc).

[0130] One of ordinary skill in the art will recognize that numerous amines are suitable for initiating the polymerization reaction with sarcosine NCA in the processes depicted in Scheme 1, Scheme 2, or Scheme 3. Initiating materials contemplated by the present disclosure include, but are not limited to, optionally substituted benzylamines, optionally substituted hydrocarbylamines, optionally substituted silylamines, poly(amino acid) polymers, poly(ethylene glycol) polymers, poly(N-isopropylacrylamide) polymers, poly(acrylamide) polymers, poly(2-oxazoline) polymers, poly(ethyleneimine), poly(acrylic acid) polymers, poly(methacrylate) polymers, poly(vinyl alcohol) polymers, poly(vinylpyrrolidone) polymers, and their corresponding amine salts.

[0131] In some embodiments, the present disclosure relates to methods of preparing compounds of formula I, II, III, or IV using reagents, solvents, resins, and other components that are used as received in chemical reactions or isolation. In some embodiments, the compounds are prepared without measures taken to exclude air and / or moisture (e.g., Schlenk technique). Those skilled in the art will recognize the advantages of NCA polymerization reactions under these conditions, as they reduce the cost and increase the robustness of such processes.

[0132] The present disclosure also relates to isolating the polymer of formula I, formula II, formula III, or formula IV from the reaction mixture using an anti-solvent. In some embodiments, the isolation is performed using a single anti-solvent. In some embodiments, the ratio of reaction mixture to anti-solvent is such that the total amount used is minimized. Those skilled in the art will recognize the advantage of using a minimum amount of anti-solvent, as it reduces the cost and complexity of preparation and increases scale. Such reaction mixture to anti-solvent ratios contemplated by the present disclosure include, but are not limited to, 1:0.25, 1:0.5, 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:10.

[0133] The present disclosure also relates to the use of a single reaction solvent and a single anti-solvent.Those skilled in the art will recognize the advantage of using only two solvents in total for the preparation of compounds of formula I, formula II, formula III, or formula IV, because it minimizes costs, especially on a commercial scale under Good Manufacturing Practice (GMP) guidelines, since the minimum number of solvents that need to be procured and quantified during release testing.In certain embodiments, the anti-solvent is selected from the list including, but not limited to, ketone-containing solvents, hydroxyl-containing solvents, ester-containing solvents, ether-containing solvents, hydrocarbon solvents, aromatic solvents, and aqueous solvents.

[0134] Anti-solvents contemplated in this disclosure include, but are not limited to, methyl ethyl ketone, acetone, butanone, ethanol, methanol, isopropanol, butanol, tert-butanol, methyl acetate, butyl acetate, diethyl ether, dioxane, tetrahydrofuran, hexane, heptane, toluene, water, and aqueous buffer solutions. In some embodiments, the anti-solvent is tert-butyl methyl ether. In some embodiments, the anti-solvent is ethyl acetate.

[0135] The present disclosure also relates to subjecting the polymer of Formula I, Formula II, Formula III, or Formula IV to a freeze-drying process. In some embodiments, freeze-drying is performed from an aqueous solution. In certain embodiments, freeze-drying is performed from an aqueous solution containing tert-butanol.

[0136] The present disclosure also relates to subjecting the polymer of Formula I, Formula II, Formula III, or Formula IV to a spray drying process. In some embodiments, spray drying is performed from an aqueous solution. In certain embodiments, freeze drying is performed from an aqueous solution containing tert-butanol. In certain embodiments, freeze drying is performed from methanol.

[0137] 3.3 Polymer and protein composition In certain embodiments, the present disclosure relates to compositions comprising proteins of formula I, formula II, formula III, or formula IV and polymers. Without wishing to be bound by any particular theory, it is believed that the polymers of the present disclosure outcompete proteins for absorption into the interface between two phases, thus reducing the possibility of protein adsorption that can lead to aggregation and denaturation. This property is crucial for the formulation of pharmaceutical biological proteins, which encounter significant interfacial stresses during production, storage, and administration.

[0138] In some embodiments, the present disclosure provides: (i) A polymer of Formula I: [ka] or a salt thereof [wherein R 1a is an optionally substituted (C1-C20) aliphatic group; R 1b is H or an optionally substituted (C1-C20) aliphatic group; R 2 is H or an optionally substituted (C1-C20) aliphatic group; x is 5 to 250; and (ii) Protein A composition comprising:

[0139] In some embodiments, the present disclosure provides: (i) A polymer of Formula I: [ka] [In the formula, R 1a is an optionally substituted (C1-C20) aliphatic group; R 1b is H or an optionally substituted (C1-C20) aliphatic group; R 2 is H or an optionally substituted (C1-C20) aliphatic group; x is 5 to 250; and (ii) Protein A composition comprising:

[0140] In some embodiments, the composition comprises: (i) A polymer of formula II: [ka] or a salt thereof [wherein R is an optionally substituted (C12-C20) hydrophobic aliphatic group; x is 5 to 50; and (ii) Protein Includes.

[0141] In some embodiments, the composition comprises: (i) A polymer of formula II: [ka] or a salt thereof [wherein R is an optionally substituted (C12-C20) hydrophobic aliphatic group; x is 5 to 50; and (ii) Protein Includes.

[0142] In some embodiments, the composition comprises: (i) A polymer of formula II: [ka] [In the formula, R is an optionally substituted (C12-C20) hydrophobic aliphatic group; x is 5 to 50; and (ii) Protein Includes.

[0143] In some such embodiments, R is CH 3 -(CH 2 ) y- and y is 11 to 19.

[0144] In some such embodiments, R is CH 3 (CH 2 ) 7 CH=CH(CH 2 ) 7 CH 2 -It is.

[0145] In some embodiments, the composition comprises: (i) a polymer of Formula III: [ka] or a salt thereof [wherein R 1a is an optionally substituted (C6-C20) hydrophobic aliphatic group; R 1b is an optionally substituted (C6-C20) hydrophobic aliphatic group; x is 5 to 50; and (ii) Protein Includes.

[0146] In some embodiments, the composition comprises: (i) a polymer of Formula III: [ka] [In the formula, R 1a is an optionally substituted (C6-C12) hydrophobic aliphatic group; R 1b is an optionally substituted (C6-C12) hydrophobic aliphatic group; x is 5 to 50; and (ii) Protein Includes.

[0147] In some such embodiments, the polymer has formula III, R 1a is CH 3 -(CH 2 ) y - and; R1b is CH 3 -(CH 2 ) z - and; y is 5 to 19; z is 5 to 19. It is.

[0148] In some such embodiments, the polymer has formula III, R 1a is CH 3 -(CH 2 ) y - and; R 1b is CH 3 -(CH 2 ) z - and; y is between 5 and 11; z is 5 to 11. It is.

[0149] In some embodiments, the composition comprises: (i) A polymer of formula IV: [ka] or a salt thereof [wherein R 1a is an optionally substituted (C1-C6) aliphatic group; R 1b is H or an optionally substituted (C1-C6) aliphatic group; R 2 is an optionally substituted (C11-19) hydrophobic aliphatic group; x is 5 to 50; and (ii) Protein Includes.

[0150] In some embodiments, the composition comprises: (i) A polymer of formula IV: [ka] [In the formula, R 1ais an optionally substituted (C1-C6) aliphatic group; R 1b is H or an optionally substituted (C1-C6) aliphatic group; R 2 is an optionally substituted (C11-19) hydrophobic aliphatic group; x is 5 to 50; and (ii) Protein Includes.

[0151] In some such embodiments, R 2 is -(CH 2 ) y -CH 3 and y is 10 to 18.

[0152] In some such embodiments, R 2 is R 2 and -(CH 2 ) 7 CH=CH(CH 2 ) 7 CH 3 It is.

[0153] In some embodiments, the composition is any of those described above and herein, and further comprises one or more of water, a preservative, and a pH adjusting substance.

[0154] In some embodiments, the composition is any of those described above and herein, and the protein is a biologic. Exemplary such proteins are described above and herein and known to those skilled in the art of biology.

[0155] In some embodiments, the composition comprises: (i) a polymer selected from formula (Va) or (Vb): [ka] or a salt thereof, wherein x is 2 to 250; and (ii) Protein Includes.

[0156] In some embodiments, the composition comprises: (i) a polymer of the structure: [ka] or a salt thereof, wherein x is 2 to 250; and (ii) Protein Includes.

[0157] In some embodiments, the composition comprises: (i) a polymer of: [ka] [wherein x is 5 to 90]; and (ii) Protein Includes.

[0158] In some such embodiments, x is between 5 to 80, 5 to 75, 5 to 70, 5 to 65, 5 to 60, 5 to 55, 5 to 50, 5 to 45, 5 to 40, 5 to 35, 5 to 30, 5 to 25, 5 to 20, 5 to 15, and 5 to 10. In some such embodiments, x is between 10 to 90, 10 to 85, 10 to 80, 10 to 75, 10 to 70, 10 to 65, 10 to 60, 10 to 55, 10 to 50, 10 to 45, 10 to 40, 10 to 35, 10 to 30, 10 to 25, 10 to 20, and 10 to 15. In some such embodiments, x is between 20-90, 20-75, 20-60, 20-50, 20-35, 25-90, 25-75, 25-50, 30-90, 30-60, 35-90, 35-80, 35-70, 35-60, 35-50, 40-90, 45-70, 50-90, and 50-75.

[0159] In some such embodiments, x is greater than 10. In some such embodiments, x is greater than 20. In some such embodiments, x is greater than 30. In some such embodiments, x is greater than 40. In some such embodiments, x is greater than 50. In some such embodiments, x is greater than 60. In some such embodiments, x is greater than 70. In some such embodiments, x is greater than 80. In some such embodiments, x is greater than 90. In some such embodiments, x is greater than 100. In some such embodiments, x is less than 100. In some such embodiments, x is less than 90. In some such embodiments, x is less than 80. In some such embodiments, x is less than 70. In some such embodiments, x is less than 60. In some such embodiments, x is less than 50. In some such embodiments, x is less than 40. In some such embodiments, x is less than 30. In some such embodiments, x is less than 20. In some such embodiments, x is less than 10.

[0160] In some such embodiments, x is 5. In some such embodiments, x is 10. In some such embodiments, x is 15. In some such embodiments, x is 20. In some such embodiments, x is 25. In some such embodiments, x is 30. In some such embodiments, x is 35. In some such embodiments, x is 40. In some such embodiments, x is 45. In some such embodiments, x is 50. In some such embodiments, x is 55. In some such embodiments, x is 60. In some such embodiments, x is 65. In some such embodiments, x is 70. In some such embodiments, x is 75. In some such embodiments, x is 80. In some such embodiments, x is 85. In some such embodiments, x is 90.

[0161] In some embodiments, the composition is any of those described above and herein, wherein the polymer has the following structure: [ka] It is.

[0162] In some embodiments, the composition comprises a polymer of the following structure: [ka] Includes.

[0163] In some embodiments, the composition is any of those described above and herein, wherein the polymer has the following structure: [ka] It is.

[0164] In some embodiments, the composition is any of those described above and herein, wherein the polymer has the following structure: [ka] It is.

[0165] In some embodiments, the composition is any of those described above and herein, wherein the polymer has the following structure: [ka] It is.

[0166] In some embodiments, the composition is any of those described above and herein, wherein the polymer has the following structure: [ka] It is.

[0167] In some embodiments, the composition is any of those described above and herein, wherein the polymer has the following structure: [ka] It is.

[0168] In some embodiments, the composition is any of those described above and herein, wherein the polymer has the following structure: [ka] It is.

[0169] In some embodiments, the composition is any of those described above and herein, wherein the polymer has the following structure: [ka] It is.

[0170] In some embodiments, the composition is any of those described above and herein, wherein the polymer has the following structure: [ka] It is.

[0171] In some embodiments, the composition is any of those described above and herein, wherein the polymer has the following structure: [ka] It is.

[0172] In some embodiments, the composition is any of those described above and herein, wherein the polymer has the following structure: [ka] It is.

[0173] In some embodiments, the composition is any of those described above and herein, wherein the polymer has the following structure: [ka] It is.

[0174] In some embodiments, the composition is any of those described above and herein, wherein the polymer has the following structure: [ka] It is.

[0175] In some embodiments, the composition is any of those described above and herein, wherein the polymer has the following structure: [ka] It is.

[0176] In some embodiments, the composition is any of those described above and herein, wherein the polymer has the following structure: [ka] It is.

[0177] In some embodiments, the composition is any of those described above and herein, and the polymer is of Formula I, where R 1a is optionally replaced by C 12 is an aliphatic group, R 1b is H or optionally substituted C 12 is an aliphatic group, R 2 is H and x is 23. In some embodiments, the composition is any of those described above and herein, wherein the polymer is of Formula I, where R 1a is C 12 is an aliphatic group, R 1b is H and R 2 is H and x is 23. In some embodiments, the composition is any of those described above and herein, wherein the polymer is of Formula I, where R 1a is -(CH 2 ) 11 CH 3 and R 1b is H and R 2 is H and x is 23.

[0178] In certain embodiments, the present disclosure provides a composition comprising a protein and a polymer of Formula I, Formula II, Formula III, Formula IV, Formula (Va), or Formula (Vb), where the protein is pharma- ceutical active (i.e., a biopharmaceutical protein). Such compositions may further comprise one or more excipients as defined herein. In certain embodiments, the present disclosure provides a composition comprising a protein and a polymer of Formula I, Formula II, Formula III, or Formula IV, where the protein is pharma- ceutical active (i.e., a biopharmaceutical protein). Such compositions may further comprise one or more excipients as defined herein.

[0179] In certain embodiments, the compositions of the present disclosure can be provided as a drug product useful for treating patients in need of treatment.The compositions of the present disclosure can provide a therapeutically effective amount of a protein biologic suitable for treating a subject in need of treatment.In some embodiments, the subject is a human.

[0180] In certain embodiments, the disclosure provides compositions comprising one or more proteins and a polymer of Formula I, Formula II, Formula III, Formula IV, Formula (Va), or Formula (Vb), wherein the weight ratio of protein to polymer is about 0.01:1 to about 500:1. In certain embodiments, the disclosure provides compositions comprising one or more proteins and a polymer of Formula I, Formula II, Formula III, or Formula IV, wherein the weight ratio of protein to polymer is about 0.01:1 to about 500:1. In some embodiments of the disclosure, the weight ratio of protein to polymer is about 10:1 to about 250:1. In some embodiments, the weight ratio of protein to polymer is about 1:0.1 to about 1:1. In some embodiments, the weight ratio of protein to polymer is about 1:0.1, about 1:0.2, about 1:0.3, about 1:0.4, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about 1:0.9, about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, or about 1.5:1. In some embodiments, the weight ratio of protein to polymer is about 1.5:1, about 2:1, about 2.5:1, about 3:1, about 3.5:1, about 4:1, about 4.5:1, about 5:1, about 5.5:1, about 6:1, about 6.5:1, about 7:1, about 7.5:1, about 8:1, about 8.5:1, about 9:1, about 9.5:1, or about 10:1.

[0181] Certain embodiments of the present disclosure are provided as pharmaceutically acceptable compositions. Such compositions include, but are not limited to, pills, tablets, capsules, suppositories, creams, aerosols, syrups, films, skin patches, vaginal rings, and eye drops. In some embodiments, the pharmaceutically acceptable compositions are lyophilized powders. In some embodiments, the pharmaceutically acceptable compositions are aqueous solutions or suspensions.

[0182] Certain embodiments of the present disclosure are provided as pharma- ceutically acceptable compositions packaged in a pre-filled syringe, an autoinjector, a pen injector, or a needle-free system.

[0183] The present disclosure also provides compositions that are administered to a patient in need of the composition. Routes of administration include, but are not limited to, parenteral, oral, sublingual, buccal, rectal, vaginal, ocular, auricular, nasal, inhalation, aerosol, dermal, topical, systemic, or transdermal. In some embodiments, the compositions of the present disclosure are formulated as part of an implant or device, or are formulated for sustained or extended release. In some embodiments, the route of administration is intravenous. In some embodiments, the route of administration is via a central venous catheter. In some embodiments, the route of administration is via a peripheral venous catheter. In some embodiments, the route of administration is subcutaneous.

[0184] In certain embodiments of the present disclosure, the compositions are formulated for oral administration in the form of, for example, capsules, cachets, pills, tablets, lozenges (using flavored bases, usually sucrose and acacia or tragacanth), powder, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a troche (using an inert base such as gelatin and glycerin or sucrose and acacia), and the like.

[0185] In some embodiments, in solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, and the like), the compositions of the present disclosure are combined with one or more pharma- ceutically acceptable carriers (such as sodium citrate or dicalcium phosphate), and / or the following: (1) filler or bulking substances (such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid); (2) binding substances (such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and / or gum acacia); (3) humectants (such as glycerol). (4) disintegrating agents (such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate); (5) solution retarding agents (such as paraffin); (6) absorption enhancers (such as quaternary ammonium compounds); (7) wetting agents (such as cetyl alcohol and glycerol monostearate); (8) adsorbing materials (such as kaolin and bentonite clay); (9) lubricating materials (such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof); and (10) coloring agents. In some embodiments, the solid dosage form is a capsule, tablet, or pill, and the pharmaceutical composition includes one or more buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, and polyethylene glycols and the like.

[0186] In some embodiments, the drug product of the present disclosure is formulated as a liquid dosage form for oral administration. Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In some embodiments, the liquid dosage form comprises an inert diluent (such as water or other solvents), solubilizers, and emulsifiers (such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyline glycol, oils (such as cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranyl alcohol, polyethylene glycol, and fatty acid esters or sorbitan, and mixtures thereof) commonly used in the art. In some embodiments, oral compositions contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

[0187] In certain embodiments, the compositions of the present disclosure are formulated for parenteral administration. For example, in some embodiments, the compositions of the present disclosure are formulated for parenteral administration by including one or more pharma- ceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders (which in some embodiments are reconstituted into sterile injectable solutions or dispersions immediately before use). In some embodiments, the compositions for parenteral administration contain antioxidants, buffers, bacteriostatic substances, and / or solutes that make the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents. Examples of aqueous and non-aqueous vehicles suitable for use in the pharmaceutical compositions of the present disclosure include water, Ringer's solution, isotonic saline, ethanol, polyols (such as 1,3-butanediol, glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). In some embodiments, compositions of the present disclosure are intended for parenteral administration and include a vehicle selected from water, 1,3-butanediol, Ringer's solution, or isotonic sodium chloride solution.

[0188] In some embodiments, the compositions of the present disclosure are formulated for sustained release, controlled release, and / or extended release. The term "extended release" is widely recognized in the art of pharmaceutical science and is used herein to refer to the controlled release of an active compound or agent from a dosage form to an environment over (through or during) an extended period of time (e.g., one hour or more). In some embodiments, an extended release dosage form will release a drug at a substantially constant rate over an extended period of time or will release a substantially constant amount of drug incrementally over an extended period of time. The term "extended release" as used herein encompasses the terms "controlled release", "prolonged release", "sustained release", "delayed release", or "slow release" as these terms are used in pharmaceutical science. In some embodiments, an extended release dosage is administered in the form of a patch or pump.

[0189] 3.4 Specific examples The present disclosure provides a polymer having the following structure: [ka] [ka] [ka] [ka] [ka] [ka] Let us further assume that:

[0190] The present disclosure contemplates compositions comprising a protein and a selected polymer of Formula IX-Formula XXXIV. EXAMPLES

[0191] In order that this disclosure may be more fully understood, the following examples are set forth, it being understood that these examples are for illustrative purposes only and are not to be construed as limiting the disclosure in any manner.

[0192] The following abbreviations are used: bovine serum albumin (BSA); sourced from bovine unless otherwise stated, immunoglobin G (IgG); Fourier transform infrared spectroscopy (FT-IR); attenuated total reflectance (ATR); nuclear magnetic resonance (NMR); gel permeation chromatography (GPC); dynamic light scattering (DLS); revolutions per minute (RPM); UV-Vis (ultraviolet-visible); high performance liquid chromatography (HPLC); N,N-dimethylformamide (DMF); N,N-dimethylacetamide (DMAc); methyl tert-butyl ether (MTBE); dimethyl sulfoxide (DMSO); polyethersulfone (PES); polydispersity index (PDI); sarcosine N-carboxyanhydride (Sar NCA); polysorbate 20 (PS20); polysorbate 80 (PS80); poloxamer 188 (PO188); phosphate buffered saline (PBS); polyethylene glycol (PEG).

[0193] In the examples, unless otherwise stated, abbreviated names for certain compositions are used. For example, "Octadecyl-NH-poly(Sar 15 "Octadecyl-Sar15" is an abbreviation for an octadecyl hydrocarbon chain covalently attached via an amide bond to a poly(sarcosine) chain with 15 repeat units terminating in hydrogen, and has the following structure: [ka] As shown in the figure.

[0194] In another example, "dihexyl-N-poly(Sar 15"Dihexyl-Sar15" is an abbreviation for two hexyl hydrocarbon chains covalently attached via amide bonds to a poly(sarcosine) chain with 15 repeat units terminating in hydrogen, and has the following structure: [ka] As shown in the figure.

[0195] In another example, “N-butyl-NH-poly(Sar 30 "Butyl-Sar30-lauroyl" and "Butyl-Sar30-lauroyl" are shorthand for an N-butyl hydrocarbon chain covalently attached via an amide bond to a poly(sarcosine) chain with 30 repeating units terminating in an amide bond to a saturated hydrocarbon with a lauroyl hydrocarbon chain, having the following structure: [ka] As shown in the figure.

[0196] 1.Analysis method The following analytical methods were used to characterize the compounds of the present disclosure.

[0197] (IR) Spectroscopy: All samples were analyzed using a PerkinElmer Spectrum 100 FT-IR Spectrometer equipped with a Universal ATR Sampling Accessory (Diamond / ZnSe). When IR was used to monitor the reaction, approximately 100 μL aliquots were taken and measured directly. Solid samples were measured without further manipulation.

[0198] NMR spectroscopy: All samples were analyzed on a 400 MHz spectrometer with the following parameters: 45° pulse, 2 s acquisition time, 5 s recycle delay, 16–32 transients.

[0199] GPC analysis: Samples were analyzed using a Shimadzu LC-20AD pump connected in series to a 2xPSS GRAM analytical 100A, 8x300mm, 10μm column; a 1xPSS GRAM analytical 1000A, 8x300mm, 10μm column; a Wyatt TREOS II Light Scattering Detector, and a Wyatt Optilab T-rEX refractive index detector. Analytes were eluted using a mobile phase of DMF supplemented with LiBr (50mM) at a flow rate of 1.0 mL. The column temperature was maintained at 45°C. A run time of 45 minutes was typically used.

[0200] HPLC analysis: Samples were analyzed using a Shimadzu LC-20AT pump connected to a Shimadzu SPD-20A UV-Vis detector. The column used was a Waters Ultrahydrogel DP 120 Å, 6 μm, 7.8 mm×300 mm. Analytes were eluted using a mobile phase of 80:20 (v / v) methanol:water supplemented with 0.1% (v / v) trifluoroacetic acid at a flow rate of 1.0 mL. Samples were prepared at 1 mg / mL in the mobile phase and the detector wavelengths were set at 220 nm and 225 nm. Typically, a run time of 15 minutes was used.

[0201] General procedure for shaking stability assay: The following is a general procedure for this assay, with modifications to protein, concentration, amount, time, and temperature indicated where applicable. Stock solutions of 40 mg / mL protein (e.g., IgG or BSA) and 2 mg / mL of each polymer excipient were prepared in phosphate buffer (25 mM sodium phosphate buffer, 150 mM NaCl, pH 5.0) and then filtered through a syringe-driven 0.22 μm PES filter. For each stability assay, the applicable amounts of protein, polymer excipient, and phosphate buffer were combined to a final volume of 1.5 mL unless otherwise noted. For example, for an assay with a protein concentration of 20 mg / mL and a polymer excipient concentration of 0.1 mg / mL, 750 μL of 40 mg / mL protein stock, 75 μL of 2 mg / mL polymer excipient stock, and 675 μL of phosphate buffer were combined. Stability assay solutions were prepared in 2 mL clear serum vials (USP type 1 borosilicate glass, 15 x 32 mm, 13 mm crimp) and capped with stoppers (bromobutyl rubber stoppers, 13 mm). The vials were placed in an orbital shaker set at 37°C and 120 RPM. At each time point, 150 μL aliquots were transferred to a 96-well plate (Greiner Bio-One, Sensoplate microplate, glass bottom, black). Data were collected on a dynamic light scattering (DLS) instrument (Wyatt Technology, DynaPro Plate Reader III) using the following parameters: 1 second acquisition time, 5 acquisitions, 25°C. Data were processed by DYNAMICS (Wyatt Technology, v8.0).

[0202] General procedure for temperature ramp studies: The following is a general procedure for this assay, with modifications to protein, concentration, amount, time, and temperature indicated where applicable. Stock solutions of 2 mg / mL protein (e.g., IgG or BSA) and 2 mg / mL of each polymer excipient were prepared in phosphate buffer (25 mM sodium phosphate buffer, 150 mM NaCl, pH 7.0) and then filtered through a syringe-driven 0.22 μm PES filter. For each temperature ramp assay, the applicable amounts of protein, polymer excipient, and phosphate buffer were combined in a scintillation vial to a final volume of 0.8 mL unless otherwise noted. For example, for an assay with a protein concentration of 1 mg / mL and a polymer excipient concentration of 1 mg / mL, 400 μL of 2 mg / mL protein stock and 400 μL of 2 mg / mL polymer excipient stock were combined. An aliquot (35 μL) of each sample was transferred to a 384-well plate (Aurora, round 384 IQ-LV, black, cycloolefin polymer, 188 micron clear film bottom, ultraflat) and then sealed with clear sealing tape. Data were collected with a DLS instrument (Wyatt Technology, DynaPro Plate Reader III) using the following parameters: 1 second acquisition time, 5 acquisitions, temperature ramp from 25°C to 80°C at a rate of 0.05°C / min. Data were processed with DYNAMICS (Wyatt Technology, v8.0).

[0203] General procedure for temperature maintenance studies: The following is a general procedure for this assay, with modifications to protein, concentration, amount, time, and temperature indicated where applicable. Stock solutions of 40 mg / mL protein (e.g., IgG or BSA) and 2 mg / mL of each polymer excipient were prepared in phosphate buffer (25 mM sodium phosphate buffer, 150 mM NaCl, pH 7.0) and then filtered through a syringe-driven 0.22 μm PES filter. For each temperature maintenance assay, the applicable amounts of protein, polymer excipient, and phosphate buffer were combined in a scintillation vial to a final volume of 0.8 mL unless otherwise noted. For example, for an assay with a protein concentration of 20 mg / mL and a polymer excipient concentration of 1 mg / mL, 400 μL of 40 mg / mL protein stock and 400 μL of 2 mg / mL polymer excipient stock were combined. An aliquot (35 μL) of each sample was transferred to a 384-well plate (Aurora, round 384 IQ-LV, black, cycloolefin polymer, 188 micron clear film bottom, ultraflat) and then sealed with clear sealing tape. Data were collected with a DLS instrument (Wyatt Technology, DynaPro Plate Reader III) using the following parameters: 1 second acquisition time, 5 acquisitions, and a temperature hold of 50° C. for 92 hours. Data were processed by DYNAMICS (Wyatt Technology, v8.0).

[0204] General Procedure for Lyophilization Studies: The following is a general procedure for this assay, with modifications to protein, concentration, amount, time, and temperature indicated where applicable. Stock solutions of protein (e.g., IgG, abatacept, cetuximab, etc.) at 0.5 mg / mL and each polymer excipient ranging from 0.1 to 2.0 mg / mL were prepared in phosphate buffer (25 mM sodium phosphate buffer, pH 7.0). For each lyophilization study, the applicable amounts of protein, polymer excipient, and phosphate buffer were combined in an Eppendorf tube to a final volume of 1.0 mL unless otherwise noted. For example, for an assay with a protein concentration of 0.5 mg / mL and a polymer excipient concentration of 0.5 mg / mL, 100 μL of 5 mg / mL protein stock, 250 μL of 2 mg / mL polymer excipient stock, and 650 μL of phosphate buffer were combined. Each aliquot was then filtered through a syringe-driven 0.22 μm PES filter. An aliquot (35 μL) of each sample was transferred to a 384-well plate (Aurora, round 384 IQ-LV, black, cycloolefin polymer, 188 micron clear film bottom, ultraflat). Data was collected with a DLS instrument (Wyatt Technology, DynaPro Plate Reader III) using the following parameters: 1 second acquisition time, 5 acquisitions, and 25°C temperature maintenance. Data was processed by DYNAMICS (Wyatt Technology, v8.0). For each solution, 0.2 mL was then placed into a 2 mL serum vial and lyophilized (freeze at -30°C for 2 hours; vacuum at 180-250 mTorr; primary drying at 25°C for 4 hours; secondary drying at 40°C for 36 hours). Lyophilates were reconstituted with 0.2 mL of filtered deionized water. An aliquot (35 μL) of each sample was transferred to a 384-well plate and the particle size after lyophilization was measured as previously described in this paragraph. Images of each well were captured by the DYNAMICS software.

[0205] 2. Polymer synthesis examples Example 1: Neopentyl-NH-poly(Sar 15 Preparation of A 25 mL round bottom flask was charged with neopentylamine (90 mg, 1.032 mmol, 1 equiv.) and N,N-dimethylacetamide (DMAc) (10 mL). The reaction flask was then placed in a jacketed reaction beaker equipped with a circulating isopropanol / water bath with the temperature set at 15 °C. The solution was stirred and allowed to equilibrate for approximately 10 minutes, after which sarcosine N-carboxyanhydride (Sar NCA) (1.78 g, 15.5 mmol, 15 equiv.) was added. IR spectroscopy was used to obtain a 1:1 peak at approximately 1850 and 1778 cm. -1 The reaction progress was monitored via the disappearance of the carbonyl stretch at 100° C. After stirring overnight, the reaction mixture was transferred to a beaker and DMAc (2 mL) was used to rinse the reaction flask. With vigorous stirring from an overhead stirrer, methyl tert-butyl ether (MTBE) (120 mL, ca. 10 vol) was added slowly over 10-15 s. After stirring for 1-2 min, the precipitation was stopped and the material was allowed to settle and then collected via vacuum filtration in a medium porosity fritted glass funnel. The semi-dry material was briefly slurried on the frit with additional MTBE (60 mL, 5 vol). The product was dried in a vacuum oven at ca. 50° C. for 2 days to give 1.07 g (89.9%) of the title compound as a white dense powder. GPC (DMF, 50 mM LiBr) Mn = 1,129 Daltons, Mp = 1,158 Daltons, PDI = 1.02; Purity (HPLC) = 92.4%.

[0206] Example 2: Neopentyl-NH-poly(Sar 30 Preparation of Following the general procedure of Example 1, the following equivalents and amounts of reagents were used: neopentylamine (45 mg, 1 eq.), sarcosine NCA (1.78 g, 30 eq.), DMAc (10 mL). This afforded the title compound (1.09 g, 95.1%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=1,972 Daltons, Mp=2,038 Daltons, PDI=1.02; Purity (HPLC)=95.3%.

[0207] Example 3: Neopentyl-NH-poly(Sar 60 Preparation of Following the general procedure of Example 1, the following equivalents and amounts of reagents were used: neopentylamine (40 mg, 1 eq.), sarcosine NCA (3.17 g, 60 eq.), DMAc (12 mL). This afforded the title compound (1.89 g, 94.6%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=3,627 Daltons, Mp=3,668 Daltons, PDI=1.01; Purity (HPLC)=92.6%.

[0208] Example 4: Neopentyl-NH-poly(Sar 120 Preparation of Following the general procedure of Example 1, the following equivalents and amounts of reagents were used: neopentylamine (20 mg, 1 eq.), sarcosine NCA (3.17 g, 120 eq.), DMAc (12 mL). This afforded the title compound (1.84 g, 93.1%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=5,847 Daltons, Mp=6,017 Daltons, PDI=1.02; Purity (HPLC)=96.8%.

[0209] Example 5: Neopentyl-NH-poly(Sar 175 Preparation of Following the general procedure of Example 1, the following equivalents and amounts of reagents were used: neopentylamine (4 mg, 1 eq.), sarcosine NCA (924 mg, 175 eq.), DMAc (2 mL). GPC (DMF, 50 mM LiBr) Mn=6,546 Daltons, Mp=7,104 Daltons, PDI=1.04.

[0210] Example 6: Neopentyl-NH-poly(Sar 240 Preparation of Following the general procedure of Example 1, the following equivalents and amounts of reagents were used: neopentylamine (10 mg, 1 eq.), sarcosine NCA (3.17 g, 240 eq.), DMAc (12 mL). This afforded the title compound (0.680 g, 34.6%) as a dense off-white solid. GPC (DMF, 50 mM LiBr) Mn=7,842 Daltons, Mp=8,481 Daltons, PDI=1.06; Purity (HPLC)=91.1%.

[0211] Example 7: Neopentyl-NH-poly(Sar 480 Preparation of Following the general procedure of Example 1, the following equivalents and amounts of reagents were used: neopentylamine (5 mg, 1 eq.), sarcosine NCA (3.17 g, 480 eq.), DMAc (12 mL). This afforded the title compound (1.90 g, 96.8%) as a dense off-white solid. GPC (DMF, 50 mM LiBr) Mn=8,036 Daltons, Mp=9,742 Daltons, PDI=1.11; Purity (HPLC)=94.4%.

[0212] Example 8: 4-Methoxybenzyl-NH-poly(Sar 15 Preparation of A 25 mL round bottom flask was charged with 4-methoxybenzylamine (140 mg, 1.02 mmol, 1 equiv.) and N,N-dimethylacetamide (DMAc) (12 mL). The reaction flask was then placed in a jacketed reaction beaker equipped with a circulating isopropanol / water bath with the temperature set at 15 °C. The solution was stirred and allowed to equilibrate for approximately 10 minutes, after which sarcosine N-carboxyanhydride (Sar NCA) (1.76 g, 15.3 mmol, 15 equiv.) was added. IR spectroscopy was used to obtain a 1:1 peak at approximately 1850 and 1778 cm. -1Reaction progress was monitored via disappearance of the carbonyl stretch at 37°C. After stirring overnight, the reaction mixture was transferred to a beaker and DMAc (5 mL) was used to rinse the reaction flask. With vigorous stirring from an overhead stirrer, methyl tert-butyl ether (MTBE) (120 mL, approximately 7 volumes) was added gradually over 10-15 seconds. After stirring for 1-2 minutes, the precipitation was allowed to settle, and then collected via vacuum filtration in a medium porosity fritted glass funnel. The semi-dry material was briefly slurried on the frit with additional MTBE (50 mL). The product was dried in a vacuum oven at approximately 50°C for 2 days to give 1.21 g (98.6%) of the title compound as a dense white powder. GPC (DMF, 50 mM LiBr) Mn = 1,261 Daltons, Mp = 1,341 Daltons, PDI = 1.02; purity (HPLC) = 94.7%.

[0213] Example 9: 4-Methoxybenzyl-NH-poly(Sar 30 Preparation of Following the general procedure of Example 8, the following equivalents and amounts of reagents were used: 4-methoxybenzylamine (70 mg, 1 eq.), sarcosine NCA (1.76 g, 30 eq.), DMAc (12 mL). This afforded the title compound (1.03 g, 89.0%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=2,212 Daltons, Mp=2,278 Daltons, PDI=1.01; Purity (HPLC)=97.4%.

[0214] Example 10: Octyl-NH-Poly(Sar 15 Preparation of A 25 mL round bottom flask was charged with octylamine (130 mg, 1.01 mmol, 1 equiv.) and N,N-dimethylacetamide (DMAc) (12 mL). The reaction flask was then placed in a jacketed reaction beaker equipped with a circulating isopropanol / water bath with the temperature set at 15 °C. The solution was stirred and allowed to equilibrate for approximately 10 minutes, after which sarcosine N-carboxyanhydride (Sar NCA) (1.74 g, 15.2 mmol, 15 equiv.) was added. IR spectroscopy was used to obtain a peak at approximately 1850 and 1778 cm. -1 The reaction progress was monitored via the disappearance of the carbonyl stretch at 37 °C. After stirring overnight, the reaction mixture was transferred to a beaker and DMAc (5 mL) was used to rinse the reaction flask. With vigorous stirring from an overhead stirrer, methyl tert-butyl ether (MTBE) (120 mL, approximately 7 volumes) was added gradually over 15-20 seconds. After stirring for 1-2 minutes, the precipitation was allowed to settle, and then collected via vacuum filtration in a medium porosity fritted glass funnel. The semi-dry material was briefly slurried on the frit with additional MTBE (50 mL). The material was dried in a vacuum oven at approximately 50 °C for 2 days. This gave 993 mg (82.8%) of the title compound as a dense white powder. GPC (DMF, 50 mM LiBr) Mn = 1,048 Daltons, Mp = 1,149 Daltons, PDI = 1.03; purity (HPLC) = 98.2%.

[0215] Example 11: Octyl-NH-Poly(Sar 30 Preparation of Following the general procedure of Example 10, the following equivalents and amounts of reagents were used: octylamine (65 mg, 1 eq.), sarcosine NCA (1.74 g, 30 eq.), DMAc (12 mL). This afforded the title compound (1.02 g, 89.5%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=1,995 Daltons, Mp=2,041 Daltons, PDI=1.01; Purity (HPLC)=97.5%.

[0216] Example 12: Decyl-NH-Poly(Sar15 Preparation of A 25 mL round bottom flask was charged with decylamine (154 mg, 0.979 mmol, 1 equiv.) and N,N-dimethylacetamide (DMAc) (12 mL). The reaction flask was then placed in a jacketed reaction beaker equipped with a circulating isopropanol / water bath with the temperature set at 15 °C. The solution was stirred and allowed to equilibrate for approximately 10 minutes, after which sarcosine N-carboxyanhydride (Sar NCA) (1.69 g, 14.7 mmol, 15 equiv.) was added. IR spectroscopy was used to obtain a 1:1 peak at approximately 1850 and 1778 cm. -1 The reaction progress was monitored via the disappearance of the carbonyl stretch at 100° C. After stirring overnight, the reaction mixture was transferred to a beaker and DMAc (2×2.5 mL) was used to rinse the reaction flask. With vigorous stirring from an overhead stirrer, methyl tert-butyl ether (MTBE) (120 mL, approximately 7 volumes) was added slowly over 15-20 seconds. After stirring for 1-2 minutes, the precipitation was allowed to settle, after which it was collected via vacuum filtration in a medium porosity fritted glass funnel. The semi-dry material was briefly slurried on the frit with additional MTBE (50 mL). The material was dried in a vacuum oven at approximately 50° C. for 2 days. This gave 145 mg (12.1%) of the title compound as a dense white powder. GPC (DMF, 50 mM LiBr) Mn = 1,148 Daltons, Mp = 1,181 Daltons, PDI = 1.01; Purity (HPLC) = 98.5%.

[0217] Example 13: Decyl-NH-Poly(Sar 30 Preparation of Following the general procedure of Example 12, the following equivalents and amounts of reagents were used: decylamine (77 mg, 1 eq.), sarcosine NCA (1.69 g, 30 eq.), DMAc (12 mL). This afforded the title compound (800 mg, 71.4%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=1,895 Daltons, Mp=1,922 Daltons, PDI=1.01; Purity (HPLC)=97.6%.

[0218] Example 14: Dodecyl-NH-poly(Sar 15 Preparation of A 25 mL round bottom flask was charged with dodecylamine (180 mg, 0.971 mmol, 1 equiv.) and N,N-dimethylacetamide (DMAc) (12 mL). The reaction flask was then placed in a jacketed reaction beaker equipped with a circulating isopropanol / water bath with the temperature set at 25 °C. The solution was stirred and allowed to equilibrate for approximately 10 minutes, after which sarcosine N-carboxyanhydride (Sar NCA) (1.68 g, 14.6 mmol, 15 equiv.) was added. IR spectroscopy was used to obtain a peak at approximately 1850 and 1778 cm. -1 The reaction progress was monitored via the disappearance of the carbonyl stretch at 100° C. After stirring overnight, the reaction mixture was transferred to a beaker and DMAc (2×2.5 mL) was used to rinse the reaction flask. With vigorous stirring from an overhead stirrer, methyl tert-butyl ether (MTBE) (120 mL, approximately 7 volumes) was added slowly over 15-20 seconds. After stirring for 1-2 minutes, the precipitation was allowed to settle, and then collected via vacuum filtration in a medium porosity fritted glass funnel. The semi-dry material was briefly slurried on the frit with additional MTBE (50 mL). The material was dried in a vacuum oven at approximately 50° C. for 2 days. This gave 1.15 g (94.5%) of the title compound as a dense white powder. GPC (DMF, 50 mM LiBr) Mn = 1,178 Daltons, Mp = 1,251 Daltons, PDI = 1.02; Purity (HPLC) = 98.9%.

[0219] Example 15: Dodecyl-NH-poly(Sar 20 Preparation of The general procedure of Example 14 was followed using the following equivalents and amounts of reagents: dodecylamine (180 mg, 1 eq.), sarcosine NCA (2.24 g, 20 eq.), DMAc (15 mL). This afforded the title compound (1.34 g, 85.8%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=1,358 Daltons, Mp=1,411 Daltons, PDI=1.01; Purity (HPLC)=98.2%.

[0220] Example 16: Dodecyl-NH-poly(Sar 30 Preparation of Following the general procedure of Example 14, the following equivalents and amounts of reagents were used: dodecylamine (90 mg, 1 eq.), sarcosine NCA (1.68 g, 30 eq.), DMAc (12 mL). This afforded the title compound (1.02 g, 90.7%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=2,077 Daltons, Mp=2,132 Daltons, PDI=1.01; Purity (HPLC)=97.8%.

[0221] Example 17: Tetradecyl-NH-poly(Sar 15 Preparation of A 25 mL round bottom flask was charged with tetradecylamine (210 mg, 0.984 mmol, 1 equiv.) and N,N-dimethylacetamide (DMAc) (12 mL). The reaction flask was then placed in a jacketed reaction beaker equipped with a circulating isopropanol / water bath with the temperature set at 25 °C. The solution was stirred and allowed to equilibrate for approximately 10 minutes, after which sarcosine N-carboxyanhydride (Sar NCA) (1.70 g, 14.8 mmol, 15 equiv.) was added. IR spectroscopy was used to obtain a peak at approximately 1850 and 1778 cm. -1The reaction progress was monitored via the disappearance of the carbonyl stretch at 100° C. After stirring overnight, the reaction mixture was transferred to a beaker and DMAc (2×2.5 mL) was used to rinse the reaction flask. With vigorous stirring from an overhead stirrer, methyl tert-butyl ether (MTBE) (120 mL, approximately 7 volumes) was added slowly over 15-20 seconds. After stirring for 1-2 minutes, the precipitation was allowed to settle, after which it was collected via vacuum filtration in a medium porosity fritted glass funnel. The semi-dry material was briefly slurried on the frit with additional MTBE (50 mL). The material was dried in a vacuum oven at approximately 50° C. for 2 days. This gave 1.07 g (85.0%) of the title compound as a dense white powder. GPC (DMF, 50 mM LiBr) Mn = 1,187 Daltons, Mp = 1,225 Daltons, PDI = 1.01; Purity (HPLC) = 98.5%.

[0222] Example 18: Tetradecyl-NH-poly(Sar 20 Preparation of The general procedure of Example 17 was followed using the following equivalents and amounts of reagents: tetradecylamine (250 mg, 1 eq.), sarcosine NCA (2.70 g, 20 eq.), DMAc (15 mL). This afforded the title compound (1.81 g, 94.5%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=1,418 Daltons, Mp=1,475 Daltons, PDI=1.01; Purity (HPLC)=97.3%.

[0223] Example 19: Tetradecyl-NH-poly(Sar 30 Preparation of The general procedure of Example 17 was followed using the following equivalents and amounts of reagents: tetradecylamine (105 mg, 1 eq.), sarcosine NCA (1.70 g, 30 eq.), DMAc (12 mL). This afforded the title compound (1.09 g, 94.5%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=1,989 Daltons, Mp=2,025 Daltons, PDI=1.01; Purity (HPLC)=97.3%.

[0224] Example 20: Hexadecyl-NH-poly(Sar 15 Preparation of A 25 mL round bottom flask was charged with hexadecylamine (320 mg, 1.33 mmol, 1 equiv.) and N,N-dimethylacetamide (DMAc) (64 mL). The mixture was heated with a heat gun while swirling by hand and then immersed in a sonication water bath until a clear solution was obtained. The reaction flask was then placed in a jacketed reaction beaker equipped with a circulating isopropanol / water bath with the temperature set at 25° C. The solution was stirred and allowed to equilibrate for approximately 10 minutes, after which sarcosine N-carboxyanhydride (Sar NCA) (2.29 g, 19.9 mmol, 15 equiv.) was added. IR spectroscopy was used to obtain a chromatographically resolved chromatogram at approximately 1850 and 1778 cm. -1 The reaction progress was monitored via the disappearance of the carbonyl stretch at 100° C. After stirring overnight, the reaction mixture was transferred to a beaker and DMAc (4 mL) was used to rinse the reaction flask. Methyl tert-butyl ether (MTBE) (340 mL, 5 vol) was added slowly over 15-20 s with vigorous stirring from an overhead stirrer. After stirring for 3-5 min, the precipitation was stopped and the material was allowed to settle and then collected via vacuum filtration in a medium porosity fritted glass funnel. The semi-dry material was briefly slurried on the frit with additional MTBE (2×50 mL). The material was dried in a vacuum oven at approximately 50° C. for 2 days. The crude product was dissolved in methanol (25 mL) and then precipitated by adding MTBE (100 mL, 4 vol) with vigorous stirring. The product was collected via vacuum filtration in a medium porosity fritted glass funnel and then dried in a vacuum oven at approximately 50° C. for 2 days. This gave 224 mg (12.9%) of the title compound as a white dense powder. GPC (DMF, 50 mM LiBr) Mn = 1,247 Daltons, Mp = 1,322 Daltons, PDI = 1.01; Purity (HPLC) = 97.7%.

[0225] Example 21: Hexadecyl-NH-poly(Sar 30 Preparation of The general procedure of Example 20 was followed using the following equivalents and amounts of reagents: hexadecylamine (160 mg, 1 eq.), sarcosine NCA (2.29 g, 30 eq.), DMAc (47 mL). This afforded the title compound (0.767 g, 48.8%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=2,003 Daltons, Mp=2,080 Daltons, PDI=1.01; Purity (HPLC)=97.9%.

[0226] Example 22: Hexadecyl-NH-poly(Sar 60 Preparation of The general procedure of Example 20 was followed using the following equivalents and amounts of reagents: hexadecylamine (80 mg, 1 eq.), sarcosine NCA (2.29 g, 60 eq.), DMAc (20 mL). This afforded the title compound (1.39 g, 93.1%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=3,470 Daltons, Mp=3,534 Daltons, PDI=1.01; Purity (HPLC)=99.8%.

[0227] Example 23: Hexadecyl-NH-poly(Sar 120 Preparation of The general procedure of Example 20 was followed using the following equivalents and amounts of reagents: hexadecylamine (40 mg, 1 eq.), sarcosine NCA (2.29 g, 120 eq.), DMAc (16 mL). This afforded the title compound (1.35 g, 92.9%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=5,480 Daltons, Mp=5,572 Daltons, PDI=1.02; Purity (HPLC)=99.9%.

[0228] Example 24: Hexadecyl-NH-poly(Sar 240 Preparation of The general procedure of Example 20 was followed using the following equivalents and amounts of reagents: hexadecylamine (20 mg, 1 eq.), sarcosine NCA (2.29 g, 240 eq.), DMAc (16 mL). This afforded the title compound (1.34 g, 93.5%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=7,132 Daltons, Mp=7,898 Daltons, PDI=1.07; Purity (HPLC)=99.9%.

[0229] Example 25: Hexadecyl-NH-poly(Sar 480 Preparation of The general procedure of Example 20 was followed using the following equivalents and amounts of reagents: hexadecylamine (10 mg, 1 eq.), sarcosine NCA (2.29 g, 480 eq.), DMAc (16 mL). This afforded the title compound (1.24 g, 87.1%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=7,922 Daltons, Mp=9,265 Daltons, PDI=1.10; Purity (HPLC)=99.9%.

[0230] Example 26: Octadecyl-NH-poly(Sar 15 Preparation of A 25 mL round bottom flask was charged with octadecylamine (270 mg, 1.00 mmol, 1 equiv.) and N,N-dimethylacetamide (DMAc) (10 mL). The mixture was heated with a heat gun while swirling by hand and then immersed in a sonication water bath until a clear solution was obtained. The reaction flask was then placed in a jacketed reaction beaker equipped with a circulating isopropanol / water bath with the temperature set at 30° C. The solution was stirred and allowed to equilibrate for approximately 5 minutes after which sarcosine N-carboxyanhydride (Sar NCA) (1.73 g, 15.0 mmol, 15 equiv.) was added. IR spectroscopy was used to obtain a peak at approximately 1850 and 1778 cm. -1The reaction progress was monitored via the disappearance of the carbonyl stretch at 100° C. After stirring for 3 h, the reaction mixture was transferred to a beaker and DMAc (4 mL) was used to rinse the reaction flask. Methyl tert-butyl ether (MTBE) (340 mL, 5 vol) was added slowly over 15-20 s with vigorous stirring from an overhead stirrer. After stirring for 3-5 min, the precipitation was stopped and the material was allowed to settle and then collected via vacuum filtration in a medium porosity fritted glass funnel. The semi-dry material was briefly slurried on the frit with additional MTBE (2×50 mL). The material was dried in a vacuum oven at approximately 50° C. for 2 days. The crude product was dissolved in methanol (25 mL) and then precipitated by adding MTBE (100 mL, 4 vol) with vigorous stirring. The product was collected via vacuum filtration in a medium porosity fritted glass funnel and then dried in a vacuum oven at approximately 50° C. for 2 days. This gave 1.08 g (80.8%) of the title compound as a white dense powder. GPC (DMF, 50 mM LiBr) Mn = 1,197 Daltons, Mp = 1,216 Daltons, PDI = 1.01; Purity (HPLC) = 96.7%.

[0231] Example 27: Octadecyl-NH-poly(Sar 30 Preparation of Following the general procedure of Example 26, the following equivalents and amounts of reagents were used: octadecylamine (135 mg, 1 eq.), sarcosine NCA (1.73 g, 30 eq.), DMAc (10 mL). This gave 1.18 g (91.1%) of the title compound as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=1,911 Daltons, Mp=1,905 Daltons, PDI=1.01; Purity (HPLC)=95.7%.

[0232] Example 28: Oleyl-NH-poly(Sar 30 Preparation of A 100 mL round bottom flask was charged with oleylamine (436 mg, 1.63 mmol, 1 equiv.) and N,N-dimethylacetamide (DMAc) (40 mL). The mixture was heated with a heat gun while swirling by hand and then immersed in a sonication water bath until a clear, colorless solution was obtained. The reaction flask was then placed in a jacketed reaction beaker equipped with a circulating isopropanol / water bath with the temperature set at 15° C. The solution was stirred and allowed to equilibrate for approximately 10 minutes, after which sarcosine N-carboxyanhydride (Sar NCA) (5.63 g, 48.9 mmol, 30 equiv.) was added. IR spectroscopy was used to obtain a chromatographically resolved chromatogram at approximately 1850 and 1778 cm. -1 The reaction progress was monitored via the disappearance of the carbonyl stretch at 100° C. After stirring overnight, the reaction mixture was transferred to a beaker and DMAc (2×2.5 mL) was used to rinse the reaction flask. Methyl tert-butyl ether (MTBE) (225 mL, 5 vol) was added slowly over 30-60 s with vigorous stirring from an overhead stirrer. After stirring for 3-5 min, the stirring was stopped and the material was allowed to settle and then collected via vacuum filtration in a medium porosity fritted glass funnel. The semi-dry material was briefly slurried on the frit with additional MTBE (50 mL×2, 5 vol total). The product was dried in a vacuum oven at approximately 50° C. for 2 days to give 3.60 g (92.1%) of the title compound as a white dense powder. GPC (DMF, 50 mM LiBr) Mn = 2,034 Daltons, Mp = 2,055 Daltons, PDI = 1.01; Purity (HPLC) = 97.7%.

[0233] Example 29: Oleyl-NH-poly(Sar 10 Preparation of The general procedure of Example 28 was followed using the following equivalents and amounts of reagents: oleylamine (300 mg, 1 eq.), sarcosine NCA (1.29 g, 10 eq.). This gave the title compound (0.703 g, 64.1%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=930 Daltons, Mp=965 Daltons, PDI=1.01; Purity (HPLC)=93.5%.

[0234] Example 30: Oleyl-NH-poly(Sar 15 Preparation of The general procedure of Example 28 was followed using the following equivalents and amounts of reagents: oleylamine (200 mg, 1 eq.), sarcosine NCA (1.29 g, 15 eq.). This gave the title compound (0.850 g, 85.3%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=1,249 Daltons, Mp=1,272 Daltons, PDI=1.01; Purity (HPLC)=98.3%.

[0235] Example 31: Oleyl-NH-poly(Sar 20 Preparation of The general procedure of Example 28 was followed using the following equivalents and amounts of reagents: oleylamine (150 mg, 1 eq.), sarcosine NCA (1.29 g, 20 eq.). This gave the title compound (0.853 g, 90.0%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=1,485 Daltons, Mp=1,518 Daltons, PDI=1.01; Purity (HPLC)=98.4%.

[0236] Example 32: Oleyl-NH-poly(Sar 45 Preparation of The general procedure of Example 28 was followed using the following equivalents and amounts of reagents: oleylamine (66.6 mg, 1 eq.), sarcosine NCA (1.29 g, 45 eq.). This gave the title compound (0.850 g, 98.5%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=2,736 Daltons, Mp=2,766 Daltons, PDI=1.01; Purity (HPLC)=97.7%.

[0237] Example 33: Oleyl-NH-poly(Sar 60 Preparation of The general procedure of Example 28 was followed using the following equivalents and amounts of reagents: oleylamine (50 mg, 1 eq.), sarcosine NCA (1.29 g, 60 eq.). This gave the title compound (0.817 g, 96.4%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=3,637 Daltons, Mp=3,682 Daltons, PDI=1.02; Purity (HPLC)=98.0%.

[0238] Example 34: Oleyl-NH-poly(Sar 120 Preparation of The general procedure of Example 28 was followed using the following equivalents and amounts of reagents: oleylamine (25 mg, 1 eq.), sarcosine NCA (1.29 g, 120 eq.). This gave the title compound (0.817 g, 99.4%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=5,389 Daltons, Mp=5,684 Daltons, PDI=1.05; Purity (HPLC)=97.%.

[0239] Example 35: Dihexyl-N-poly(Sar 15 Preparation of A 25 mL round bottom flask was charged with dihexylamine (184 mg, 0.993 mmol, 1 equiv.) and N,N-dimethylacetamide (DMAc) (10 mL). The reaction flask was then placed in a jacketed reaction beaker equipped with a circulating isopropanol / water bath with the temperature set at 18 °C. The solution was stirred and allowed to equilibrate for approximately 5 minutes, after which sarcosine N-carboxyanhydride (Sar NCA) (1.71 g, 14.9 mmol, 15 equiv.) was added. IR spectroscopy was used to obtain a 1:1 peak at approximately 1850 and 1778 cm. -1The reaction progress was monitored via the disappearance of the carbonyl stretch at 100° C. After stirring overnight, the reaction mixture was transferred to a beaker and DMAc (2×2 mL) was used to rinse the reaction flask. With vigorous stirring from an overhead stirrer, methyl tert-butyl ether (MTBE) (100 mL, approximately 7 volumes) was added slowly over 5-10 seconds. After stirring for 1-2 minutes, the precipitation was allowed to settle, after which it was collected via vacuum filtration in a medium porosity fritted glass funnel. The semi-dry material was briefly slurried on the frit with additional MTBE (35 mL). The material was dried in a vacuum oven at approximately 50° C. for 2 days. This afforded 978 mg (78.8%) of the title compound as a dense white powder. GPC (DMF, 50 mM LiBr) Mn = 1,209 Daltons, Mp = 1,234 Daltons, PDI = 1.01; Purity (HPLC) = 98.6%.

[0240] Example 36: Dihexyl-N-poly(Sar 30 Preparation of The general procedure of Example 35 was followed using the following equivalents and amounts of reagents: dihexylamine (92 mg, 1 eq.), sarcosine NCA (1.71 g, 30 eq.), DMAc (10 mL). This afforded the title compound (890 mg, 77.4%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=1,861 Daltons, Mp=1,904 Daltons, PDI=1.01; Purity (HPLC)=96.8%.

[0241] Example 37: Dioctyl-N-poly(Sar 15 Preparation of A 25 mL round bottom flask was charged with dioctylamine (240 mg, 0.994 mmol, 1 equiv.) and N,N-dimethylacetamide (DMAc) (10 mL). The reaction flask was then placed in a jacketed reaction beaker equipped with a circulating isopropanol / water bath with the temperature set at 18 °C. The solution was stirred and allowed to equilibrate for approximately 5 minutes, after which sarcosine N-carboxyanhydride (Sar NCA) (1.71 g, 14.9 mmol, 15 equiv.) was added. IR spectroscopy was used to obtain a 1:1 peak at approximately 1850 and 1778 cm. -1 The reaction progress was monitored via the disappearance of the carbonyl stretch at 100° C. After stirring overnight, the reaction mixture was transferred to a beaker and DMAc (2×2 mL) was used to rinse the reaction flask. With vigorous stirring from an overhead stirrer, methyl tert-butyl ether (MTBE) (100 mL, approximately 7 volumes) was added slowly over 5-10 seconds. After stirring for 1-2 minutes, the precipitation was allowed to settle, after which it was collected via vacuum filtration in a medium porosity fritted glass funnel. The semi-dry material was briefly slurried on the frit with additional MTBE (35 mL). The material was dried in a vacuum oven at approximately 50° C. for 2 days. This gave 896 mg (69.0%) of the title compound as a dense white powder. GPC (DMF, 50 mM LiBr) Mn = 1,242 Daltons, Mp = 1,265 Daltons, PDI = 1.01; Purity (HPLC) = 98.0%.

[0242] Example 38: Dioctyl-N-poly(Sar 30 Preparation of The general procedure of Example 37 was followed using the following equivalents and amounts of reagents: dioctylamine (120 mg, 1 eq.), sarcosine NCA (1.71 g, 30 eq.), DMAc (10 mL). This afforded the title compound (860 mg, 72.9%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=1,879 Daltons, Mp=1,939 Daltons, PDI=1.01; Purity (HPLC)=98.3%.

[0243] Example 39: Didodecyl-N-poly(Sar30 Preparation of A 25 mL round bottom flask was charged with didodecylamine (150 mg, 0.424 mmol, 1 equiv.) and N,N-dimethylacetamide (DMAc) (10 mL). The reaction flask was then placed in a jacketed reaction beaker equipped with a circulating isopropanol / water bath with the temperature set at 40 °C. The solution was stirred and allowed to equilibrate for approximately 5 minutes, after which sarcosine N-carboxyanhydride (Sar NCA) (1.46 g, 12.7 mmol, 30 equiv.) was added. IR spectroscopy was used to obtain a peak at approximately 1850 and 1778 cm. -1 The reaction progress was monitored via the disappearance of the carbonyl stretch at 100° C. After stirring for 2 h, the reaction mixture was transferred to a beaker and DMAc (2×2 mL) was used to rinse the reaction flask. With vigorous stirring from an overhead stirrer, methyl tert-butyl ether (MTBE) (100 mL, approximately 7 volumes) was added slowly over 5-10 seconds. After stirring for 1-2 minutes, the precipitation was allowed to settle, and then collected via vacuum filtration in a medium porosity fritted glass funnel. The semi-dry material was briefly slurried on the frit with additional MTBE (35 mL). The material was dried in a vacuum oven at approximately 50° C. for 2 days. This gave 1.01 mg (95.8%) of the title compound as a dense white powder. GPC (DMF, 50 mM LiBr) Mn = 2,016 Daltons, Mp = 2,089 Daltons, PDI = 1.01; Purity (HPLC) = 95.8%.

[0244] Example 40: Didodecyl-N-poly(Sar 60 Preparation of The general procedure of Example 39 was followed using the following equivalents and amounts of reagents: didodecylamine (55 mg, 1 eq.), sarcosine NCA (1.07 g, 60 eq.), DMAc (10 mL). This afforded the title compound (706 mg, 98.3%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=3,273 Daltons, Mp=3,382 Daltons, PDI=1.02; Purity (HPLC)=98.1%.

[0245] Example 41: N-Butyl-NH-poly(Sar 30 Preparation of )-Lauroyl A 25 mL round bottom flask was charged with N-butylamine (30 mg, 0.410 mmol, 1 equiv.) and N,N-dimethylacetamide (DMAc) (5 mL). The reaction flask was then placed in a jacketed reaction beaker equipped with a circulating isopropanol / water bath with the temperature set at 15 °C. The solution was stirred and allowed to equilibrate for approximately 5 minutes, after which sarcosine N-carboxyanhydride (Sar NCA) (1.42 g, 12.3 mmol, 30 equiv.) was added. IR spectroscopy was used to obtain a peak at approximately 1850 and 1778 cm. -1 The reaction progress was monitored via the disappearance of the carbonyl stretch at 100° C. After stirring for 5 h, the Sar NCA was completely consumed and the temperature of the reaction was raised to 25° C. Triethylamine (572 μL, 4.10 mmol, 10 equiv.) was added to the reaction followed by lauroyl chloride (0.949 mL, 4.102 mmol, 10 equiv.). The reaction was stirred overnight and then filtered through a medium porosity fritted glass funnel and rinsed with DMAc (ca. 4 mL). The reaction mixture was transferred to a beaker and DMAc (2×1 mL) was used to rinse the filter flask. Methyl tert-butyl ether (MTBE) (80 mL, ca. 7 vol.) was added gradually over 5-10 s with vigorous stirring from an overhead stirrer. After stirring for 1-2 min, the stirring was stopped and the material was allowed to settle and then collected via vacuum filtration in a medium porosity fritted glass funnel. The semi-dry material was briefly slurried on the frit with additional MTBE (25 mL). The material was dried in a vacuum oven at about 50° C. for 2 days. This gave 708 mg (72.3%) of the title compound as a dense powder. GPC (DMF, 50 mM LiBr) Mn=2,009 Daltons, Mp=1,902 Daltons, PDI=1.05; Purity (HPLC)=99.1%.

[0246] Example 42: N-Butyl-NH-poly(Sar 30 Preparation of )-myristoyl A 25 mL round bottom flask was charged with N-butylamine (30 mg, 0.410 mmol, 1 equiv.) and N,N-dimethylacetamide (DMAc) (5 mL). The reaction flask was then placed in a jacketed reaction beaker equipped with a circulating isopropanol / water bath with the temperature set at 15 °C. The solution was stirred and allowed to equilibrate for approximately 5 minutes, after which sarcosine N-carboxyanhydride (Sar NCA) (1.42 g, 12.3 mmol, 30 equiv.) was added. IR spectroscopy was used to obtain a peak at approximately 1850 and 1778 cm. -1 The reaction progress was monitored via the disappearance of the carbonyl stretch at 100° C. After stirring for 5 h, the Sar NCA was completely consumed and the temperature of the reaction was raised to 25° C. Triethylamine (572 μL, 4.10 mmol, 10 equiv.) was added to the reaction followed by myristoyl chloride (1.115 mL, 4.102 mmol, 10 equiv.). The reaction was stirred overnight and then filtered through a medium porosity fritted glass funnel and rinsed with DMAc (ca. 4 mL). The reaction mixture was transferred to a beaker and DMAc (2×1 mL) was used to rinse the filter flask. Methyl tert-butyl ether (MTBE) (80 mL, ca. 7 vol.) was added gradually over 5-10 s with vigorous stirring from an overhead stirrer. After stirring for 1-2 min, the stirring was stopped and the material was allowed to settle and then collected via vacuum filtration in a medium porosity fritted glass funnel. The semi-dry material was briefly slurried on the frit with additional MTBE (25 mL). The material was dried in a vacuum oven at about 50° C. for 2 days. This gave 373 mg (37.6%) of the title compound as a dense powder. GPC (DMF, 50 mM LiBr) Mn=2,022 Daltons, Mp=1,906 Daltons, PDI=1.05; Purity (HPLC)=98.7%.

[0247] Example 43: N-Butyl-NH-poly(Sar 30 Preparation of )-palmitoyl A 25 mL round bottom flask was charged with N-butylamine (30 mg, 0.410 mmol, 1 equiv.) and N,N-dimethylacetamide (DMAc) (5 mL). The reaction flask was then placed in a jacketed reaction beaker equipped with a circulating isopropanol / water bath with the temperature set at 15 °C. The solution was stirred and allowed to equilibrate for approximately 5 minutes, after which sarcosine N-carboxyanhydride (Sar NCA) (1.42 g, 12.3 mmol, 30 equiv.) was added. IR spectroscopy was used to obtain a peak at approximately 1850 and 1778 cm. -1 The reaction progress was monitored via the disappearance of the carbonyl stretch at 100° C. After stirring for 5 h, the Sar NCA was completely consumed and the temperature of the reaction was raised to 25° C. Triethylamine (572 μL, 4.10 mmol, 10 equiv.) was added to the reaction followed by palmitoyl chloride (1.244 mL, 4.102 mmol, 10 equiv.). The reaction was stirred overnight and then filtered through a medium porosity fritted glass funnel and rinsed with DMAc (ca. 4 mL). The reaction mixture was transferred to a beaker and DMAc (2×1 mL) was used to rinse the filter flask. Methyl tert-butyl ether (MTBE) (80 mL, ca. 7 vol.) was added gradually over 5-10 s with vigorous stirring from an overhead stirrer. After stirring for 1-2 min, the stirring was stopped and the material was allowed to settle and then collected via vacuum filtration in a medium porosity fritted glass funnel. The semi-dry material was briefly slurried on the frit with additional MTBE (25 mL). The material was dried in a vacuum oven at about 50° C. for 2 days. This gave 373 mg (37.2%) of the title compound as a dense powder. GPC (DMF, 50 mM LiBr) Mn=2,101 Daltons, Mp=1,989 Daltons, PDI=1.05; Purity (HPLC)=98.5%.

[0248] Example 44: N-Butyl-NH-poly(Sar 30 Preparation of )-Oleoyl A 25 mL round bottom flask was charged with N-butylamine (30 mg, 0.410 mmol, 1 equiv.) and N,N-dimethylacetamide (DMAc) (5 mL). The reaction flask was then placed in a jacketed reaction beaker equipped with a circulating isopropanol / water bath with the temperature set at 15 °C. The solution was stirred and allowed to equilibrate for approximately 5 minutes, after which sarcosine N-carboxyanhydride (Sar NCA) (1.42 g, 12.3 mmol, 30 equiv.) was added. IR spectroscopy was used to obtain a peak at approximately 1850 and 1778 cm. -1 The reaction progress was monitored via the disappearance of the carbonyl stretch at 100° C. After stirring for 5 h, the Sar NCA was completely consumed and the temperature of the reaction was raised to 25° C. Triethylamine (572 μL, 4.10 mmol, 10 equiv.) was added to the reaction followed by oleoyl chloride (1.356 mL, 4.102 mmol, 10 equiv.). The reaction was stirred overnight and then filtered through a medium porosity fritted glass funnel and rinsed with DMAc (ca. 4 mL). The reaction mixture was transferred to a beaker and DMAc (2×1 mL) was used to rinse the filter flask. Methyl tert-butyl ether (MTBE) (80 mL, ca. 7 vol.) was added gradually over 5-10 s with vigorous stirring from an overhead stirrer. After stirring for 1-2 min, the stirring was stopped and the material was allowed to settle and then collected via vacuum filtration in a medium porosity fritted glass funnel. The semi-dry material was briefly slurried on the frit with additional MTBE (25 mL). The material was dried in a vacuum oven at about 50° C. for 2 days. This gave 792 mg (78.2%) of the title compound as a dense powder. GPC (DMF, 50 mM LiBr) Mn=2,340 Daltons, Mp=2,103 Daltons, PDI=1.11; Purity (HPLC)=98.6%.

[0249] Example 45: Tetradecyl-NH-poly(Sar 23 Preparation of The general procedure of Example 17 was followed using the following equivalents and amounts of reagents: tetradecylamine (407 mg, 1 eq.), sarcosine NCA (5.05 g, 23 eq.), DMAc (35 mL). This afforded the title compound (3.2 g, 90.8%) as a dense white solid. GPC (DMF, 50 mM LiBr) Mn=1,919 Daltons, Mp=2,010 Daltons, PDI=1.02.

Claims

1. The following structure: 【Chemistry 71】 or a salt thereof [wherein: R is CH ３ (CH ２ ) ７ CH=CH(CH ２ ) ７ CH ２ - and; x is 5 to 90. A polymer having

2. The following structure: 【Chemistry 72】 or a salt thereof, wherein x is 5 to 90. A polymer having

3. The following structure: 【Transformation 73】 wherein x is 5 to 90. A polymer having

4. The following structure: 【Chemistry 74】 wherein x is 5 to 50. A polymer having

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