WO2025199201A1 - Ionic polymers for solute capture and methods of making and use thereof - Google Patents

Abstract

The present invention relates to a polymer comprising a repeat unit, a divalent linker, and a negatively charged functional group, as well as a method of synthesizing a polymer using ring¬ opening metathesis polymerization (ROMP) and a method of removing at least one solute from a solution.

Description

TITLE OF THE INVENTION

IONIC POLYMERS FOR SOLUTE CAPTURE AND METHODS OF MAKING AND USE THEREOF

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional Patent Application No. 63/710,812, filed October 23, 2024, and U.S. Provisional Patent Application No. 63/567,177, filed March 19, 2024, the disclosures of which are each incorporated by reference herein in their entirety.

BACKGROUND OF THE INVENTION

There is presently a growing global concern of removing detrimental heavy metal ions from water, such as Cd²⁺, Pb²⁺, and Ni²⁺, even when present in trace concentrations. Existing technologies are not broadly effective for wide ranges of metal cations and lack adaptability, versatility, and precise control.

Rare earth elements (REEs) have become indispensable, serving as essential components in applications including semiconductors, lasers, catalysts, and aerospace components (Charalampides, G. et al., 2015, Proc. Econ. Financ., 24, 126; Mancheri, N. A. et al., 2012, China Rep., 48, 449; Kolodynska, D. et al., 2019, Applications of Ion Exchange Materials in the Environment, 161; Balaram, V., 2019, Geoscience Frontiers, 10, 1285). As technology continues to advance, maintaining a steady supply of these essential materials is critical for driving the growth of high-tech industries and fostering the development of cutting-edge innovations (Liu, S.-L. et al., 2023, Ore Geology Reviews, 157, 105428). However, the methods for selectively separating and purifying REEs have not kept pace with this rising demand (Goodenough, K. M. et al., 2018, Nat. Resour. Res., 27, 201). The extraction and separation of REEs pose significant challenges due to: (1) the large abundance of interfering ions, (2) the low concentrations of REEs in natural sources, and (3) their highly similar chemical properties, which complicate their separation (Taggart, R. K. et al., 2016, Environmental Science and Technology, 50, 5919; Takahashi, Y. et al., 2011, Chem. Geol., 288, 178; Hu, Q. H. et al., 2024, Nat. Commun., 15, ARTN 1558). These challenges underscore the need for more efficient and targeted approaches to REE separation. Current techniques often struggle to balance selectivity and efficiency, leading to suboptimal recovery rates (Traore, M. et al., 2023, J. Rare Earth, 41, 182). Thus, there is a pressing need for innovative strategies that can overcome these hurdles, enabling the sustainable extraction and purification of REEs to meet the growing demands of modern technology (Brown, R. M. et al., 2023, Energ. Rev., 41, 182).

Among the rare earth elements, middle rare earth elements (MREEs), including Samarium (Sm) and Europium (Eu) (Gergoric, M. et al., 2017, Renew. Sust. Energ. Rev., 173, ARTN 113099), present a particularly high level of difficulty in separation due to their intermediate position within the REE spectrum of ionic radii. Traditional size-dependent separation methods have significant limitations when it comes to effectively isolating these elements (Johnson, K. R. et al., 2023, JACS Au, 3, 584), and there is a dearth of size-based separation mechanisms for MREEs. As such, there is a growing need to identify materials that can achieve more precise, size-specific separation of MREEs. Indeed, overcoming this challenge is essential for improving the efficiency and selectivity of REE extraction processes, particularly in applications where MREEs play a critical role (Hossain, M. K. et al., 2022, ACS Appl. Electron. Ma., 4, 3327).

Thus, there is a need in the art for compositions and methods for making and use of well-defined polymer systems for ion capture and removal. The present invention satisfies this unmet need.

SUMMARY OF THE INVENTION

The present invention is drawn to, in part, a polymer comprising a structure represented by Formula (I):

Formula (I) wherein:

A represents a repeat unit selected from the group consisting of C5-C7 alkyl, C5-C7 heteroalkyl, C5-C?aryl, C5-C7 heteroaryl, or C5-C7 cycloalkyl; n represents an integer from 5- 500; L represents a divalent organic linker; and Z represents a negatively charged functional group.

In one embodiment, ring A is represented by one of the following structures: wherein the wave line represents connection to the polymer backbone; X represents 0, S, NR¹, or CR²R³; R¹, R², and R³ each independently represent a substituent selected from the group consisting of hydrogen, halide, hydroxy, C1-C30 alkyl, C1-C30 alkyl halide, C1-C30 alkoxy, and any combination thereof; and each structure is independently optionally further substituted.

In one embodiment, the polymer comprises a structure represented by Formula (la):

Formula (la) wherein each occurrence of R^z is independently a substituent selected from the group consisting of hydrogen, halide, hydroxy, C1-C30 alkyl, C1-C30 alkyl halide, C1-C30 alkoxy, carbonyl, ester, amine, and any combination thereof, wherein at least one R^z is a negatively charged; p is an integer from 1 to 10; and m is an integer from 1 to 9.

In one embodiment, L is represented by one of the following structures:

wherein the wavy line represents a bond to ring A; * represents a bond to Z; and R’ represents a substituent selected from the group consisting of hydrogen, halide, hydroxy, C1-C30 alkyl, C1-C30 alkyl halide, C1-C30 alkoxy, and any combination thereof. In one embodiment, L comprises a C1-C30 alkyl which is optionally further substituted.

In one embodiment, Z is selected from the group consisting of a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, any stereochemical isomer thereof, and any combination thereof. In one embodiment, Z comprises a sugar selected from the group consisting of glucuronic acid, gluconic acid, glucaric acid, and glutamic acid, and any ionic form thereof; or Z comprises an anionic derivative of galactose, glucose, mannose, allose, altrose, gulose, idose, talose, psicose, fructose, sorbose, or tagatose. In one embodiment, the polymer is a copolymer comprising a repeat unit of at least two monomers, wherein at least one monomer comprises glucuronic acid. In one embodiment, the polymer has a zeta potential of about -60 mV to about 0 mV.

The present invention is further drawn to a composition comprising the polymer, and a method of synthesizing a polymer using ring-opening metathesis polymerization (ROMP), comprising the steps of: providing a monomer; polymerizing the monomer using a ROMP catalyst; and isolating the polymer; wherein the monomer is represented by Formula (II):

Formula (II) wherein: R represents a substituent on ring A selected from the group consisting of hydrogen, halide, hydroxy, C1-C30 alkyl, C1-C30 alkyl halide, C1-C30 alkoxy, and any combination thereof; L represents a divalent organic linker; and Z represents a negatively charged functional group.

In one embodiment, the degree of polymerization is about 5 to about 500.

In one embodiment, ring A is represented by one of the following structures: wherein: X represents 0, S, NR¹, or CR²R³; R¹, R², and R³ each independently represent a substituent selected from the group consisting of hydrogen, halide, hydroxy, C1-C30 alkyl, Ci- C30 alkyl halide, C1-C30 alkoxy, and any combination thereof; and each structure is independently optionally further substituted.

The present invention is further drawn to, in part, a method of removing at least one solute from a solution comprising the steps of: providing a polymer; and contacting the polymer with at least one solute; wherein the polymer comprises a structure represented by Formula (I):

Formula (I) wherein: A represents a repeat unit selected from the group consisting of C5-C7 alkyl, C5-C7 heteroalkyl, C5-C? aryl, C5-C7 heteroaryl, or C5-C7 cycloalkyl; n represents an integer from 5-500; L represents a divalent organic linker; and Z represents a negatively charged functional group.

In one embodiment, the at least one solute is selected from the group consisting of monovalent cations, divalent cations, trivalent cations, monovalent anions, divalent anions, trivalent anions, and combinations thereof In one embodiment, the at least one solute is a metal ion. In one embodiment, the at least one solute is selected from the group consisting of manganese, magnesium, nickel, zinc, copper, cadmium, iron, lead, barium, any ionic state thereof, and any combination thereof. In one embodiment, the at least one solute is a rare earth element selected from the group consisting of lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, lutetium, scandium, and yttrium.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description of embodiments of the invention will be better understood when read in conjunction with the appended drawings. It should be understood that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

Fig. 1 depicts representative schemes displaying stability of glucuronic acid in basic and acidic conditions.

Fig. 2 depicts representative target compounds.

Fig. 3 depicts the target polymers comprising glucose (C4-Glu), glucuronic acid (C4- GlcA), and the copolymer (C4-Glu + GlcA (1 : 1)) with gel-permeation chromatography (GPC) measurements. Fig. 4 depicts polymerization kinetics of C4-Glu and C4-GlcA polymerization.

Fig. 5 depicts proton nuclear magnetic resonance f'H-NMR) of the deprotection of C4- GlcA polymers.

Fig. 6 depicts a representative diagram of binding tests using colorimetric dyes.

Fig. 7 depicts sensitivity testing of the synthesized target polymers and hyaluronic acid (HA) control.

Fig. 8 depicts surface charge density measurements of experimental polymers.

Fig. 9 depicts transmission electron microscopy (TEM) images of GlcA particles before and after aggregation upon binding.

Fig. 10 depicts quantification of binding using inductively coupled plasma mass spectrometry (ICP-MS).

Fig. 11 depicts reversibility experiments of C4-GlcA polymers upon Cd²⁺ binding.

Fig. 12 comprises Fig. 12A through Fig. 12C. Fig. 12A depicts structures of glycopolymers explored herein. Fig. 12B depicts size exclusion chromatograph with multi-angle light scattering (SEC-MALS) analysis of glycopolymers. Fig. 12C depicts Zeta potential of glycopolymers. All samples were analyzed at pH = 7.0. Error bars represent the standard deviation of the mean of triplicate samples. Statistical analysis was performed using an ordinary one-way ANOVA, where “****” represents a P value of <0.0001.

Fig. 13 depicts 'H-NMR spectra of pGlcA-40 before and after deprotection of the methyl ester group.

Fig. 14 depicts ^-NMR spectra of pGlcA-80 before and after deprotection of the methyl group.

Fig. 15 comprises Fig. 15A and Fig. 15B. Fig. 15A depicts the selectivity profile of pGlcA-40 for a ternary mixture containing equal parts Mg²⁺ (green bars), Cd²⁺ (blue bars), and Ce³⁺ (purple bars). Left bar in each set represents the starting concentration of metal, while right bar shows the concentration of metal remaining in solution after incubation with pGlcA-40 and filtration. Fig. 15B depicts the ability of each glycopolymer to remove Ce³⁺ (left bar of each set), Sm³⁺ (middle bar of each set), and Ho³⁺ (right bar of each set) from individual solutions of each REE. Starting concentration of all REEs prior to glycopolymer addition was 100 pM.

Fig. 16 comprises Fig. 16A and Fig. 16B. Fig. 16A depicts glycopolymer REE selectivity, based on a 1 : 1 : 1 ternary mixture of Ce³⁺, Sm³⁺, and Ho³⁺, using the residual amount of Ce³⁺ as a reference. Fig. 16B depicts a selectivity profile of pGlcA-40 for MREEs over heavier and lighter REEs, generated using a series of 1 : 1 : 1 ternary mixtures containing Ce³⁺/X³⁺/Ho³⁺, where “X” represents Nd, Eu, or Gd.

Fig. 17 comprises Fig. 17A through Fig. 17C. Fig. 17A depicts REE selectivity of pGlcA-40, based on a 1 :1 binary mixture of Ce³⁺ and Sm³⁺. Fig. 17B depicts REE selectivity of pGlcA-40, based on a 10: 1 binary mixture of Ce³⁺ and Sm³⁺. Fig. 17C depicts REE enrichment following multiple filtrations with pGlcA-40.

DETAILED DESCRIPTION

The present invention provides compositions comprising an ionic polymer and methods for the synthesis of an ionic polymer. In one embodiment, the invention provides a polymer comprising a repeat unit, a divalent linking group, and a negatively charged functional group. In one embodiment, the invention provides a method of synthesizing the polymer. In one embodiment, the invention provides a method of use of the polymer.

Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used herein, each of the following terms has the meaning associated with it in this section.

The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

“About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

As used herein, the term “organic” includes polymeric materials as well as small molecule organic materials. “Small molecule” refers to any organic material that is not a polymer, and “small molecules” may actually be quite large. Small molecules may include repeat units in some circumstances. For example, using a long chain alkyl group as a substituent does not remove a molecule from the “small molecule” class. Small molecules may also be incorporated into polymers, for example as a pendent group on a polymer backbone or as a part of the backbone. Small molecules may also serve as the core moiety of a dendrimer, which consists of a series of chemical shells built on the core moiety.

As used herein, the term “alkyl,” by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (z.e. Ci-6 means one to six carbon atoms) and including straight, branched chain, or cyclic substituent groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl.

As used herein, the term “substituted alkyl” means alkyl as defined above, substituted by one, two or three substituents selected from the group consisting of halogen, -OH, alkoxy, -NH2, amino, azido, -N(CH3)2, -C(=O)OH, trifluoromethyl, -C=N, -C(=O)O(Ci-C4)alkyl, -C(=0)NH2, -SO2NH2, -C(=NH)NH2, and -NO2. Examples of substituted alkyls include, but are not limited to, 2,2-difluoropropyl, 2-carboxy cyclopentyl and 3 -chloropropyl.

As used herein, the term “olefin” encompasses compounds having a C=C bond.

The term "olefin-based polymer," as used herein, refers to a polymer that contains at least a majority weight percent, based on the weight of the polymer, polymerized olefin (for example, ethylene or propylene), and, optionally, one or more additional comonomers.

As used herein, the term “heteroalkyl” by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of 0, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quatemized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include -O-CH2-CH2-CH3, -CH2-CH2-CH2-OH, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, and -CH₂CH₂-S(=O)-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3, or -CH2-CH2-S-S-CH3. As used herein, the term “alkoxy” employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1 -propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.

As used herein, the term “halo” or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

As used herein, the term “cycloalkyl” refers to a mono cyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In one embodiment, the cycloalkyl group is saturated or partially unsaturated. In another embodiment, the cycloalkyl group is fused with an aromatic ring. Cycloalkyl groups include groups having from 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moi eties:

Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Dicyclic cycloalkyls include, but are not limited to, tetrahydronaphthyl, indanyl, and tetrahydropentalene. Polycyclic cycloalkyls include adamantine and norbornane. The term cycloalkyl includes “unsaturated nonaromatic carbocyclyl” or “nonaromatic unsaturated carbocyclyl” groups, both of which refer to a nonaromatic carbocycle as defined herein, which contains at least one carbon double bond or one carbon triple bond.

As used herein, the term “heterocycloalkyl” or “heterocyclyl” or “heterocyclic” refers to a cyclic group containing one to four ring heteroatoms each selected from 0, S, and N. In one embodiment, each heterocycloalkyl group has from 4 to 10 atoms in its ring system, with the proviso that the ring of said group does not contain two adjacent 0 atoms. In another embodiment, the heterocycloalkyl group is fused with an aromatic ring. In one embodiment, the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quatemized. The heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure. A heterocycle may be aromatic or non-aromatic in nature. In one embodiment, the heterocycle is a heteroaryl.

An example of a 3-membered heterocycloalkyl group includes, and is not limited to, aziridine. Examples of 4-membered heterocycloalkyl groups include, and are not limited to, azetidine and a beta lactam. Examples of 5-membered heterocycloalkyl groups include, and are not limited to, pyrrolidine, oxazolidine and thiazolidinedione. Examples of 6-membered heterocycloalkyl groups include, and are not limited to, piperidine, morpholine and piperazine.

Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, pyrazolidine, imidazoline, dioxolane, sulfolane, 2, 3 -dihydrofuran, 2, 5 -dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran,

2.3 -dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine,

1.3-dioxepane, 4,7-dihydro-l,3-dioxepin, and hexamethyleneoxide.

As used herein, the term “aromatic” refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e. having (4n + 2) delocalized 7i (pi) electrons, where n is an integer.

As used herein, the term “aryl,” employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings), wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples of aryl groups include phenyl, anthracyl, and naphthyl.

As used herein, the term “aryl-(Ci-C3)alkyl” means a functional group wherein a one- to three-carbon alkylene chain is attached to an aryl group, e.g., -CH2CH2- phenyl, -CTE-phenyl (benzyl), aryl-CH - and aryl-CH(CH3)-. The term “substituted aryl-(Ci-C3)alkyl” means an aryl-(Ci-C3)alkyl functional group in which the aryl group is substituted. Similarly, the term “heteroaryl-(Ci-C3)alkyl” means a functional group wherein a one to three carbon alkylene chain is attached to a heteroaryl group, e.g., -CFhCFE-pyridyl. The term “substituted heteroaryl-(Ci-C3)alkyl” means a heteroaryl-(Ci-C3)alkyl functional group in which the heteroaryl group is substituted.

As used herein, the term “heteroaryl” or “heteroaromatic” refers to aryl groups which contain at least one heteroatom selected from N, 0, Si, P, and S; wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen atom(s) may be optionally quaternized. Heteroaryl groups may be substituted or unsubstituted. A heteroaryl group may be attached to the remainder of the molecule through a heteroatom. A polycyclic heteroaryl may include one or more rings that are partially saturated. Examples include tetrahydroquinoline,

2.3-dihydrobenzofuryl, 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4- imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2- benzimidazolyl, 5-indolyl, 1 -isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3- quinolyl, and 6-quinolyl.

Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2, 3 -dihydrofuran, 2, 5 -dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran,

2.3 -dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine,

1.3-dioxepane, 4,7-dihydro-l,3-dioxepin and hexamethyleneoxide.

Examples of heteroaryl groups also include pyridyl, pyrazinyl, pyrimidinyl (particularly 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl (particularly 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (particularly 3- and 5-pyrazolyl), isothiazolyl, 1,2,3-triazolyl,

1.2.4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,

1.3.4-thiadiazolyl and 1,3,4-oxadiazolyl.

Examples of polycyclic heterocycles and heteroaryls include indolyl (particularly 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (particularly 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (particularly 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (particularly 3-, 4-, 5-, 6- and 7-benzofuryl),

2.3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (particularly 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (particularly 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl (particularly 2-benzimidazolyl), benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl.

As used herein, the term “substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group. The term “substituted” further refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. In one embodiment, the substituents vary in number between one and four. In another embodiment, the substituents vary in number between one and three. In yet another embodiment, the substituents vary in number between one and two.

As used herein, the term “optionally substituted” means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.

In one embodiment, the substituents are independently selected from the group consisting of oxo, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, alkyl (including straight chain, branched and/or unsaturated alkyl), substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, fluoro alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, fluoroalkoxy, -S-alkyl, S(=O)2alkyl, S(=0)2N[H, alkyl, or aryl], - C(=O)NH[substituted or unsubstituted alkyl, or substituted or unsubstituted phenyl], - C(=O)N[H or substituted or unsubstituted alkyl or aryl]?, -OC(=O)N[substituted or unsubstituted alkyl]2, -NHC(=O)NH[substituted or unsubstituted alkyl, or substituted or unsubstituted phenyl], -NHC(=O)alkyl, -Nfsubstituted or unsubstituted alkyl]C(=O)[substituted or unsubstituted alkyl], -NHC(=O) [substituted or unsubstituted alkyl], -C(OH)[substituted or unsubstituted alkyl]?, and -C(NH2)[substituted or unsubstituted alkyl]?. In another embodiment, by way of example, an optional substituent is selected from oxo, fluorine, chlorine, bromine, iodine, -CN, -NH?, -OH, -NH(CH₃), -N(CH₃)₂, -CH3, -CH2CH3, -CH(CH₃)?, -CF₃, -CH₂CF₃, - OCH3, -OCH2CH3, -OCH(CH₃)2, -OCF3, - OCH2CF3, -S(=O)₂-CH3, -C(=O)NH?, -C(=O)- NHCH3, -NHC(=O)NHCH₃, -C(=O)CH₃, -ON(O)?, and -C(=O)OH. In yet one embodiment, the substituents are independently selected from the group consisting of C1-6 alkyl, -OH, C1-6 alkoxy, halo, amino, acetamido, oxo and nitro. As used herein, where a substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic.

As used herein, the term “protected,” as used herein, refers to the presence of a “protecting group” or moiety that prevents reaction of the chemically reactive functional group under certain reaction conditions. The protecting group will vary depending on the type of chemically reactive group being protected. By way of example only, (i) if the chemically reactive group is an amine or a hydrazide, the protecting group may be selected from tert- butyloxycarbonyl (t-Boc) and 9-fluorenylmethoxycarbonyl (Fmoc); (ii) if the chemically reactive group is a thiol, the protecting group may be orthopyridyldisulfide; and (iii) if the chemically reactive group is a carboxylic acid, such as butanoic or propionic acid, or a hydroxyl group, the protecting group may be benzyl or an alkyl group such as methyl, ethyl, or tert-butyl. Additionally, protecting groups include, but are not limited to, photolabile groups, such as Nvoc and MeNvoc, and other protecting groups known in the art. Other protecting groups are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999.

The term “derivative” refers to a small molecule that differs in structure from the reference molecule but retains the essential properties of the reference molecule. A derivative may change its interaction with certain other molecules relative to the reference molecule. A derivative molecule may also include a salt, an adduct, tautomer, isomer, or other variant of the reference molecule.

The term “tautomers” are constitutional isomers of organic compounds that readily interconvert by a chemical process (tautomerization).

The term “isomers” or “stereoisomers” refer to compounds, which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

As used herein, the term “polymer” refers to a molecule composed of repeating structural units typically connected by covalent chemical bonds. The term “polymer” is also meant to include the terms copolymer and oligomers.

As used herein, the term “polymerization” refers to at least one reaction that consumes at least one functional group in a monomeric molecule (or monomer), oligomeric molecule (or oligomer) or polymeric molecule (or polymer), to create at least one chemical linkage between at least two distinct molecules (e.g., intermolecular bond), at least one chemical linkage within the same molecule (e.g., intramolecular bond), or any combination thereof. A polymerization reaction may consume between about 0% and about 100% of the at least one functional group available in the system. In one embodiment, polymerization of at least one functional group results in about 100% consumption of the at least one functional group. In another embodiment, polymerization of at least one functional group results in less than about 100% consumption of the at least one functional group.

As used herein, the term “polymer segment” means and includes a grouping of multiple monomer units of a single type (i.e., a homopolymer segment) or multiple types (i.e., a copolymer segment) of constitutional units into a continuous region of a polymer block that are of a length that is insufficient for microphase separation to inherently occur with other segments in the same block type.

As used herein, the term “block copolymer” means and includes a polymer composed of chains where each chain contains two or more polymer blocks as defined above and at least two of the blocks are of sufficient segregation strength (e.g., N>10) for those blocks to phase separate. A wide variety of block polymers are contemplated herein including diblock copolymers (i.e., polymers including two polymer blocks), triblock copolymers (i.e., polymers including three polymer blocks), multiblock copolymers (i.e., polymers including more than three polymer blocks), and combinations thereof.

As used herein, a “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate.

As used herein, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.

As used herein with respect to the compositions of the invention, “biologically active” means that the compositions elicit a biological response in a mammal that can be monitored and characterized in comparison with an untreated mammal.

As used herein, the term “treating” means ameliorating the effects of, or delaying, halting or reversing the progress of a disease or disorder. The word encompasses reducing the severity of a symptom of a disease or disorder and/or the frequency of a symptom of a disease or disorder.

As used herein, the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease. Disease and disorder are used interchangeably herein.

As used herein, the term “medical intervention” means a set of one or more medical procedures or treatments that are required for ameliorating the effects of, delaying, halting or reversing a disease or disorder of a subject. A medical intervention may involve surgical procedures or not, depending on the disease or disorder in question. A medical intervention may be wholly or partially performed by a medical specialist, or may be wholly or partially performed by the subject himself or herself, if capable, under the supervision of a medical specialist or according to literature or protocols provided by the medical specialist.

As used herein, the terms “effective amount” or “therapeutically effective amount” or “pharmaceutically effective amount” of a composition are used interchangeably to refer to the amount of the composition that is sufficient to provide a beneficial effect to the subject to which the composition is administered. The term to “treat,” as used herein, means reducing the frequency with which symptoms are experienced by a patient or subject or administering a composition to reduce the severity with which symptoms are experienced. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

By the term “specifically bind” or “specifically binds,” as used herein, is meant that a first molecule (e.g., an antibody) preferentially binds to a second molecule (e.g., a particular antigenic epitope), but does not necessarily bind only to that second molecule.

As used herein, a “prophylactic” or “preventive” treatment is a treatment administered to a subject who does not exhibit signs of a disease or disorder or exhibits only early signs of the disease or disorder for the purpose of decreasing the risk of developing pathology associated with the disease or disorder. As used herein, a “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology of a disease or disorder for the purpose of diminishing or eliminating those signs.

As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

As used herein, a “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a compound(s) of the present invention within or to the subject such that it can perform its intended function. Typically, such compounds are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound, and are physiologically acceptable to the subject. Supplementary active compounds can also be incorporated into the compositions. As used herein, the language “pharmaceutically acceptable salt” refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof.

As used herein, the term “subject” refers to a human or another mammal (e.g., primate, dog, cat, goat, horse, pig, mouse, rat, rabbit, and the like) that can have a disease, disorder, or condition; or be at risk for developing a disease, disorder, or condition; but may or may not have a disease, disorder, or condition or be at risk for developing a disease, disorder, or condition. In many embodiments of the present invention, the subject is a human being. In such embodiments, the subject is often referred to as an “individual” or a “patient.” The terms “individual” and “patient” do not denote a particular age.

As used here, “biocompatible” refers to any material, which, when implanted in a mammal, does not provoke an adverse response in the mammal. A biocompatible material, when introduced into an individual, is not toxic or injurious to that individual, nor does it induce immunological rejection of the material in the mammal.

The term “biodegradable” includes polymers, compositions and formulations, such as those described herein, that are intended to degrade during use. Biodegradable polymers typically differ from non-biodegradable polymers in that the former may be degraded during use. In one embodiment, such use involves in vivo use, such as in vivo therapy. In another embodiment, such use involves in vitro use. In general, biodegradation involves the degradation of a biodegradable polymer into its component subunits, or digestion, e.g., by a biochemical process, of the polymer into smaller, non-polymeric subunits. Two types of biodegradation may generally be identified. For example, biodegradation may involve cleavage of bonds (whether covalent or otherwise) in the polymer backbone. In such biodegradation, monomers and oligomers typically result, and even more typically, such biodegradation occurs by cleavage of a bond connecting one or more of subunits of a polymer. Further, biodegradation may involve cleavage of a bond (whether covalent or otherwise) internal to side chain or that connects a side chain to the polymer backbone. For example, a therapeutic agent or other chemical moiety attached as a side chain to the polymer backbone may be released by biodegradation. In one embodiment, at least one type of biodegradation may occur during use of a polymer. As used herein, the term “biodegradation” encompasses all known types of biodegradation. As used herein, the terms “biocompatible polymer” and “biocompatibility” when used in relation to polymers are recognized in the art. For example, biocompatible polymers include polymers that are generally neither toxic to the host, nor degrade (if the polymer degrades) at a rate that produces monomeric or oligomeric subunits or other byproducts at toxic concentrations in the host. In one embodiment, biodegradation generally involves degradation of the polymer in a host, e.g., into its monomeric subunits, which may be known to be effectively non-toxic. Intermediate oligomeric products resulting from such degradation may have different toxicological properties, however, or biodegradation may involve oxidation or other biochemical reactions that generate molecules other than monomeric subunits of the polymer. Consequently, in one embodiment, toxicology of a biodegradable polymer intended for in vivo use, such as implantation or injection into a patient, may be determined after one or more toxicity analyses. It is not necessary that any subject composition have a purity of 100% to be deemed biocompatible; indeed, it is only necessary that the subject compositions be biocompatible as set forth above. Hence, a subject composition may comprise polymers comprising 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75% or even less of biocompatible polymers, e.g., including polymers and other materials and excipients described herein, and still be biocompatible.

The term “cancer” as used herein is defined as disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers include but are not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, renal cancer, liver cancer, brain cancer, head and neck cancers, lymphoma, leukemia, lung cancer and the like.

As used herein, the phrase “a tumor site” refers to any site or region within a subject which a tumor has formed, may be expected to form, or was previously located. In certain embodiments, the tumor site is in need of anti-tumor activity.

Several references to integers and R, R¹, R², R³, R⁴, R⁵, R⁶, etc. are made in chemical structures and moieties disclosed and described herein. Any description of integers and R, R¹, R², R³, R⁴, R⁵, R⁶, etc. in the specification is applicable to any structure or moiety reciting integers and R, R¹, R², R³, R⁴, R⁵, R⁶, etc. respectively. Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

Compositions

The present invention is drawn to, in part, a polymer comprising a structure represented by Formula (I):

Formula (I) wherein:

A represents a repeat unit selected from the group consisting of C5-C7 alkyl, C5-C7 heteroalkyl, Cs-Cvaryl, C5-C7 heteroaryl, C5-C7 cycloalkyl, and combinations thereof; n represents an integer from 5-500; L represents a divalent organic linker; and Z represents a negatively charged functional group.

In one embodiment, ring A comprises a cycloalkyl. In one embodiment, ring A comprises a heterocycloalkyl. In one embodiment, ring A comprises an aryl. In one embodiment, ring A comprises at least one olefin. In one embodiment, ring A is further substituted. In one embodiment, the polymer is represented by Formula (I).

In one embodiment, ring A comprises a norbornene. In one embodiment, ring A comprises an olefin that is more reactive than norbomene. In one embodiment, ring A is in an endo-configuration. In one embodiment, ring A is in an exo-configuration. In one embodiment, ring A is a racemate.

As used herein, the terms “endo-” and “exo-” define isomerism of organic compounds comprising a substituent in a bridged ring system. The prefix “endo” or a compound or moiety in an “endo-configuration” is defined to have the highest priority substituent closest, or “syn” to the longest bridge, whereas “exo” or a compound or moiety in an “exo-configuration” is defined to have the highest priority substituent close, or “anti” to the longest bridge.

In one embodiment, ring A is represented by one of the following structures: wherein X represents 0, S, NR¹, or CR²R³; wherein R¹, R², and R³ each independently represent a substituent selected from the group consisting of hydrogen, halide, hydroxy, C1-C30 alkyl, C1-C30 alkyl halide, C1-C30 alkoxy, and any combination thereof; and wherein each structure is independently optionally further substituted.

In one embodiment, the polymer backbone is hydrogenated. In one embodiment, the polymer backbone is rigid. In one embodiment, the polymer backbone is partially saturated. In one embodiment, the polymer backbone is saturated. In one embodiment, the polymer backbone is flexible. In one embodiment, the polymer backbone comprises one or more pendant hydroxyl groups. In one embodiment, the polymer backbone is functionalizable. In one embodiment, the polymer backbone has an end group comprising a compound selected from the group consisting of a fluorophore, a terminal alkene, a benzyl group, an amino group, a therapeutic small molecule, and combinations thereof.

In one embodiment, L selected from the group consisting of alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof. In one embodiment, L comprises a repeat unit selected from the group consisting of - (CH₂)_n-, -(CH2)n-C(O)N(R)-(CH₂)m-, -(CH₂)n-N(R)C(O)-(CH₂)_m-, -(CH₂)p-(OCH₂CH₂)_q-, and combinations thereof, wherein n, m, p, and q are each independently 0 or a positive integer.

In one embodiment, the linker comprises an amino acid. In one embodiment, the linker comprises a glycol. In one embodiment, the linker is capable of hydrogen-bonding. In one embodiment, R’ is hydrogen. In one embodiment, R’ is an alkoxy group. In one embodiment, R’ participates in hydrogen bonding. In one embodiment, R’ participates in intramolecular hydrogen bonding. In one embodiment, R’ participates in intermolecular hydrogen bonding. In one embodiment, the linker comprises a C1-C30 alkyl. In one embodiment, the linker promotes solubility in aqueous solution. In one embodiment, the linker is aliphatic.

In one embodiment, L is represented by one of the following structures: wherein the wavy line represents a bond to ring A; * represents a bond to Z; and R’ represents a substituent selected from the group consisting of hydrogen, halide, hydroxy, C1-C30 alkyl, C1-C30 alkyl halide, C1-C30 alkoxy, and any combination thereof. In one embodiment, L comprises a C1-C30 alkyl which is optionally further substituted.

In one embodiment, Z is anionic. In one embodiment, Z has a charge of -1. In one embodiment, Z has a charge of -2. In one embodiment, Z has a counterion. Exemplary counterions may include, but are not limited to, charged metals, weak acids, conjugate acids, weak bases, conjugate bases, and quaternary salts.

In one embodiment, Z is selected from the group consisting of charged derivatives of: a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, any stereochemical isomer thereof, and any combination thereof. Exemplary Z groups include charged derivatives of carbohydrates including, but are not limited to, monosaccharides including trioses (such as: ketotriose (dihydroxyacetone); aldotriose (glyceraldehyde)); tetroses which include: ketotetrose (such as: erythrulose) and aldotetroses (such as:erythrose, threose); pentoses which include: ketopentose (such as:ribulose, xylulose) aldopentose (such as:ribose, arabinose, xylose, lyxose), deoxy sugar (such as: deoxyribose); hexoses which include: ketohexose (such as:psicose, fructose, sorbose, tagatose), aldohexose (such as: allose, altrose, glucose, mannose, gulose, idose, galactose, talose), deoxy sugar (such as: fucose, fuculose, rhamnose); heptose (such as: sedoheptulose); octose; nonose (such as: neuraminic acid); disaccharides which include: sucrose; lactose; maltose; trehalose; turanose; cellobiose; kojiboise; nigerose; isomaltose; and palatinose; tri saccharides which include: melezitose; and maltotriose; oligosaccharides that include: corn syrups and maltodextrin; and polysaccharides that include: glucan (such as dextrin, dextran, beta-glucan), glycogen, mannan, galactan, and starch (such as those from corn, wheat, tapioca, rice, and potato, including amylose and amylopectin. The starches can be natural or modified or gelatinized); or combinations thereof. Carbohydrates also include source of sweeteners such as honey, maple syrup, glucose (dextrose), corn syrup, com syrup solids, high fructose corn syrups, crystalline fructose, juice concentrates, dextrose polymers, malt syrup, rice syrup solids, sorghum syrup, refiner syrup, crystalline fructose, brown or invert sugars, molasses, or other grain/nut syrups consisting of rice syrup, agave syrup, palm syrup, and crystalline juice. In one embodiment, Z comprises a sugar selected from the group consisting of glucuronic acid, gluconic acid, glucaric acid, and glutamic acid, and any ionic form thereof; or Z comprises an anionic derivative of galactose, glucose, mannose, allose, altrose, gulose, idose, talose, psicose, fructose, sorbose, or tagatose. In one embodiment, Z comprises glucuronic acid. In one embodiment, Z comprises glucose. In one embodiment, Z comprises mannose. In one embodiment, Z is stereochemically pure. In one embodiment, Z is a racemate. In one embodiment, Z is enantioenriched. In one embodiment, Z is derived from commercially available sources. In one embodiment, Z is extracted from food.

In one embodiment, the polymer comprises a structure represented by Formula (la):

Formula (la) wherein each occurrence of R^z is independently a substituent selected from the group consisting of hydrogen, halide, hydroxy, C1-C30 alkyl, C1-C30 alkyl halide, C1-C30 alkoxy, carbonyl, ester, amine, and any combination thereof, wherein at least one R^z is a negatively charged; p is an integer from 1 to 10; and m is an integer from 1 to 9. In one embodiment, at least one occurrence of R^z is a hydroxy. In one embodiment, at least one occurrence of R^z is a C1-C30 alkoxy. In one embodiment, at least one occurrence of R^z is a carboxylate.

In one embodiment, the polymer comprises a structure represented by Formula (lb):

Formula (lb).

In one embodiment, the polymer is a copolymer comprising a repeat unit of at least two monomers, wherein at least one monomer comprises glucuronic acid. In one embodiment, the polymer is a block copolymer. Other exemplary copolymers which may describe the present invention include, but are not limited to, random copolymers, statistical copolymers, alternating copolymers, stereoblock copolymers, gradient copolymers, graft copolymers, star copolymers, and combinations thereof. In one embodiment, the polymer comprises a monomer which does not comprise a Z group. In one embodiment, the polymer comprises a monomer which comprises a hydroxyl capped linker. In one embodiment, the polymer comprises a monomer which comprises a linker bonded to a protecting group. In one embodiment, Z is acetylated. In one embodiment, Z comprises an alkyl ester. In one embodiment, Z comprises a group which is readily deprotected. In one embodiment, Z comprises an acidic proton.

In one embodiment, the polymer forms higher order assemblies. In one embodiment, the polymer forms secondary structures. In one embodiment, the polymer comprises exposed hydrophilic pockets. In one embodiment, the polymer comprises exposed hydrophobic pockets. In one embodiment, the polymer forms nanoassemblies. In one embodiment, the polymer participates in intramolecular hydrogen bonding. In one embodiment, the polymer participates in intermolecular hydrogen bonding.

In one embodiment, the polymer readily binds a solute. Exemplary solutes include, but are not limited to, cations, dications, anions, metal ions, neutral contaminants, and ionic contaminants. In one embodiment, the polymer readily forms micelles. In one embodiment, the polymer readily forms micelles with hydrophobic dyes. In one embodiment, the polymer is biocompatible. In one embodiment, the polymer is a biomimetic. In one embodiment, the polymer has a negative zeta potential. In one embodiment, the polymer has a zeta potential less than 0 mV. In one embodiment, the polymer has a zeta potential of about -60 mV to about 0 mV. In one embodiment, the polymer has a zeta potential of about -50 mV to about 0 mV. In one embodiment, the polymer has a zeta potential of about - 40 mV to about 0 mV. In one embodiment, the polymer has a zeta potential of about -30 mV to about 0 mV. In one embodiment, the polymer has a zeta potential of about -20 mV to about 0 mV. In one embodiment, the polymer has a zeta potential of about -10 mV to about 0 mV. In one embodiment, the polymer has a maximum zeta potential of about 0 mV.

In one embodiment, the degree of polymerization is about 5 to about 500. In one embodiment, the degree of polymerization is about 10 to about 500. In one embodiment, the degree of polymerization is about 20 to about 500. In one embodiment, the degree of polymerization is about 30 to about 500. In one embodiment, the degree of polymerization is about 40 to about 500. In one embodiment, the degree of polymerization is about 50 to about 500. In one embodiment, the degree of polymerization is about 60 to about 500. In one embodiment, the degree of polymerization is about 70 to about 500. In one embodiment, the degree of polymerization is about 80 to about 500. In one embodiment, the degree of polymerization is about 90 to about 500. In one embodiment, the degree of polymerization is about 100 to about 500. In one embodiment, the degree of polymerization is about 10 to about 400. In one embodiment, the degree of polymerization is about 20 to about 400. In one embodiment, the degree of polymerization is about 30 to about 400. In one embodiment, the degree of polymerization is about 40 to about 400. In one embodiment, the degree of polymerization is about 50 to about 400. In one embodiment, the degree of polymerization is about 60 to about 400. In one embodiment, the degree of polymerization is about 70 to about 400. In one embodiment, the degree of polymerization is about 80 to about 400. In one embodiment, the degree of polymerization is about 90 to about 400. In one embodiment, the degree of polymerization is about 100 to about 400. In one embodiment, the degree of polymerization is about 10 to about 300. In one embodiment, the degree of polymerization is about 20 to about 300. In one embodiment, the degree of polymerization is about 30 to about 300. In one embodiment, the degree of polymerization is about 40 to about 300. In one embodiment, the degree of polymerization is about 50 to about 300. In one embodiment, the degree of polymerization is about 60 to about 300. In one embodiment, the degree of polymerization is about 70 to about 300. In one embodiment, the degree of polymerization is about 80 to about 300. In one embodiment, the degree of polymerization is about 90 to about 300. In one embodiment, the degree of polymerization is about 100 to about 300. In one embodiment, the degree of polymerization is about 50 to about 250. In one embodiment, the degree of polymerization is about 60 to about 250. In one embodiment, the degree of polymerization is about 70 to about 250. In one embodiment, the degree of polymerization is about 80 to about 250. In one embodiment, the degree of polymerization is about 90 to about 250. In one embodiment, the degree of polymerization is about 100 to about 250.

In one embodiment, the polymer has a molecular weight of about 10 kg/mol to about 50 kg/mol. In one embodiment, the polymer has a molecular weight of about 15 kg/mol to about 50 kg/mol. In one embodiment, the polymer has a molecular weight of about 15 kg/mol to about 45 kg/mol. In one embodiment, the polymer has a molecular weight of about 15 kg/mol to about 40 kg/mol. In one embodiment, the polymer has a molecular weight of about 15 kg/mol to about 35 kg/mol. In one embodiment, the polymer has a molecular weight of about 15 kg/mol to about 30 kg/mol. In one embodiment, the polymer has a molecular weight of about 15 kg/mol to about 25 kg/mol. In one embodiment, the polymer has a molecular weight of about 15 kg/mol to about 20 kg/mol. In one embodiment, the polymer has a molecular weight of about 20 kg/mol to about 50 kg/mol. In one embodiment, the polymer has a molecular weight of about 30 kg/mol to about 50 kg/mol. In one embodiment, the polymer has a molecular weight of about 40 kg/mol to about 50 kg/mol.

In one embodiment, the polymer is monodisperse. In one embodiment, the polymer has a dispersity of less than 1.5. In one embodiment, the polymer has a dispersity of about 1.0. In one embodiment, the polymer is multi disperse.

In one embodiment, the polymer has a grafting density of about 5% to about 100%. In one embodiment, the polymer has a grafting density of about 10% to about 100%. In one embodiment, the polymer has a grafting density of about 15% to about 100%. In one embodiment, the polymer has a graft density of about 20% to about 100%. In one embodiment, the polymer has a grafting density of about 30% to about 100%. In one embodiment, the polymer has a graft density of about 40% to about 100%. In one embodiment, the polymer has a grafting density of about 50% to about 100%. In one embodiment, the polymer has a graft density of about 60% to about 100%. In one embodiment, the polymer has a grafting density of about 70% to about 100%. In one embodiment, the polymer has a graft density of about 80% to about 100%. In one embodiment, the polymer has a grafting density of about 90% to about 100%. In one embodiment, the polymer has a grafting density of about 10% to about 90%. In one embodiment, the polymer has a graft density of about 20% to about 90%. In one embodiment, the polymer has a grafting density of about 30% to about 90%. In one embodiment, the polymer has a graft density of about 40% to about 90%. In one embodiment, the polymer has a grafting density of about 50% to about 90%. In one embodiment, the polymer has a graft density of about 60% to about 90%. In one embodiment, the polymer has a grafting density of about 70% to about 90%. In one embodiment, the polymer has a graft density of about 80% to about 90%.

In one embodiment, the polymer is readily dissolved in a biorelevant medium. In one embodiment, the polymer readily forms a suspension in a biorelevant medium.

The present invention is further drawn to, in part, compositions and formulations comprising the polymer. In one embodiment, the composition is a biodegradable composition. In one embodiment, the composition is a medical biodegradable composition.

In various aspects, the composition comprises: one or more polymers of the present invention and one or more stabilizers. In other aspects, the composition comprises: one or more nanoparticles of the present invention and one or more stabilizers. In various embodiments, the stabilizer to nanoparticle weight ratio is less than 50%. In one embodiment, the stabilizer comprises a biocompatible polymer. Examples of stabilizers include, but are not limited to, biocompatible polymer, a biodegradable polymer, a multifunctional linker, starch, modified starch, and starch derivatives, gums, including but not limited to polymers, polypeptides, albumin, amino acids, thiols, amines, carboxylic acid and combinations or derivatives thereof, citric acid, xanthan gum, alginic acid, other alginates, benitoniite, veegum, agar, guar, locust bean gum, gum arabic, quince psyllium, flax seed, okra gum, arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin, etc., cross-linked polyvinylpyrrolidone, ion-exchange resins, potassium polymethacrylate, carrageenan (and derivatives), gum karaya and biosynthetic gum, polycarbonates (linear polyesters of carbonic acid); microporous materials (bisphenol, a microporous polyvinylchloride), micro-porous polyamides, microporous modacrylic copolymers, microporous styrene-acrylic and its copolymers); porous polysulfones, halogenated poly(vinylidene), polychloroethers, acetal polymers, polyesters prepared by esterification of a dicarboxylic acid or anhydride with an alkylene polyol, poly(alkylenesulfides), phenolics, polyesters, asymmetric porous polymers, cross-linked olefin polymers, hydrophilic microporous homopolymers, copolymers or interpolymers having a reduced bulk density, and other similar materials, poly(urethane), cross-linked chain-extended poly(urethane), poly(imides), poly(benzimidazoles), collodion, regenerated proteins, semi-solid cross-linked polyvinylpyrrolidone), monomeric, dimeric, oligomeric or long-chain, copolymers, block polymers, block co-polymers, polymers, PEG, dextran, modified dextran, polyvinylalcohol, and polyvinylpyrollidone.

The compositions are formulated in a pharmaceutically acceptable excipient, such as wetting agents, buffers, disintegrants, binders, fillers, flavoring agents and liquid carrier media such as sterile water, water/ethanol etc. The compositions should be suitable for administration either by topical administration or injection or inhalation or catheterization or instillation or transdermal introduction into any of the various body cavities including the alimentary canal, the vagina, the rectum, the bladder, the ureter, the urethra, the mouth, etc. For oral administration, the pH of the composition is preferably in the acid range (e.g., 2 to 7) and buffers or pH adjusting agents may be used. The contrast media may be formulated in conventional pharmaceutical administration forms, such as tablets, capsules, powders, solutions, dispersion, syrups, suppositories etc.

The compounds, nanoparticles, or compositions of the invention can be formulated and administered to a subject, as now described. The invention encompasses the preparation and use of pharmaceutical compositions comprising the compound, nanoparticle, and/or compositions of the invention useful for the delivery of a therapeutic agent to a cell. The invention also encompasses the preparation and use of pharmaceutical compositions comprising the compound, nanoparticle, and/or compositions of the invention useful for the treatment of a disease or disorder.

Such a pharmaceutical composition may consist of the active ingredient alone, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise the active ingredient and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these. The active ingredient may be present in the pharmaceutical composition in the form of a physiologically acceptable ester or salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art. The pharmaceutical compositions useful for practicing the invention may be administered to deliver a dose of between about 0.01 ng/kg/day and 500 mg/kg/day.

In various embodiments, the pharmaceutical compositions useful in the methods of the invention may be administered, by way of example, systemically, parenterally, or topically, such as, in oral formulations, inhaled formulations, including solid or aerosol, and by topical or other similar formulations. In addition to the appropriate therapeutic composition, such pharmaceutical compositions may contain pharmaceutically acceptable carriers and other ingredients known to enhance and facilitate drug administration. Other possible formulations, such as nanoparticles, liposomes, resealed erythrocytes, and immunologically based systems may also be used to administer an appropriate modulator thereof, according to the methods of the invention.

Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals, patients, and subjects of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals and patients is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation.

Pharmaceutical compositions that are useful in the methods of the invention may be prepared, packaged, or sold in formulations suitable for oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, intravenous, ophthalmic, intrathecal and other known routes of administration. Other contemplated formulations include projected nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient, and immunologically-based formulations.

A pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a “unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w/w) active ingredient.

In addition to the active ingredient, a pharmaceutical composition of the invention may further comprise one or more additional pharmaceutically active agents.

Controlled- or sustained-release formulations of a pharmaceutical composition of the invention may be made using conventional technology.

A formulation of a pharmaceutical composition of the invention suitable for oral administration may be prepared, packaged, or sold in the form of a discrete solid dose unit including, but not limited to, a tablet, a hard or soft capsule, a cachet, a troche, or a lozenge, each containing a predetermined amount of the active ingredient. Other formulations suitable for oral administration include, but are not limited to, a powdered or granular formulation, an aqueous or oily suspension, an aqueous or oily solution, or an emulsion.

A tablet comprising the active ingredient may, for example, be made by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free- flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface active agent, and a dispersing agent. Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents. Known dispersing agents include, but are not limited to, potato starch and sodium starch glycolate. Known surface active agents include, but are not limited to, sodium lauryl sulphate. Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate. Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid. Known binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Known lubricating agents include, but are not limited to, magnesium stearate, stearic acid, silica, and talc.

Tablets may be non-coated or they may be coated using known methods to achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient. By way of example, a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets. Further by way of example, tablets may be coated using methods described in U.S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874 to form osmotically-controlled release tablets. Tablets may further comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide pharmaceutically elegant and palatable preparation.

Hard capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such hard capsules comprise the active ingredient, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.

Soft gelatin capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such soft capsules comprise the active ingredient, which may be mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

Liquid formulations of a pharmaceutical composition of the invention which are suitable for oral administration may be prepared, packaged, and sold either in liquid form or in the form of a dry product intended for reconstitution with water or another suitable vehicle prior to use.

Liquid suspensions may be prepared using conventional methods to achieve suspension of the active ingredient in an aqueous or oily vehicle. Aqueous vehicles include, for example, water and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Liquid suspensions may further comprise one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents. Oily suspensions may further comprise a thickening agent.

Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, and hydroxypropylmethylcellulose. Known dispersing or wetting agents include, but are not limited to, naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with a fatty acid, with a long chain aliphatic alcohol, with a partial ester derived from a fatty acid and a hexitol, or with a partial ester derived from a fatty acid and a hexitol anhydride (e.g. polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifying agents include, but are not limited to, lecithin and acacia. Known preservatives include, but are not limited to, methyl, ethyl, or n-propyl-para-hydroxybenzoates, ascorbic acid, and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin. Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.

Liquid solutions of the active ingredient in aqueous or oily solvents may be prepared in substantially the same manner as liquid suspensions, the primary difference being that the active ingredient is dissolved, rather than suspended in the solvent. Liquid solutions of the pharmaceutical composition of the invention may comprise each of the components described with regard to liquid suspensions, it being understood that suspending agents will not necessarily aid dissolution of the active ingredient in the solvent. Aqueous solvents include, for example, water and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.

Powdered and granular formulations of a pharmaceutical preparation of the invention may be prepared using known methods. Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations.

A pharmaceutical composition of the invention may also be prepared, packaged, or sold in the form of oil-in-water emulsion or a water-in-oil emulsion. The oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these. Such compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. These emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents.

Methods for impregnating or coating a material with a chemical composition are known in the art, and include, but are not limited to methods of depositing or binding a chemical composition onto a surface, methods of incorporating a chemical composition into the structure of a material during the synthesis of the material (i.e., such as with a physiologically degradable material), and methods of absorbing an aqueous or oily solution or suspension into an absorbent material, with or without subsequent drying.

As used herein, “parenteral administration” of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, cutaneous, subcutaneous, intraperitoneal, intravenous, intramuscular, intraci sternal injection, and kidney dialytic infusion techniques.

Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi -dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (i.e., powder or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

The pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1,3-butane diol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides. Other parentally-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer systems. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.

Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes, and solutions or suspensions. Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, and preferably from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant may be directed to disperse the powder or using a self-propelling solvent/powder-dispensing container such as a device comprising the active ingredient dissolved or suspended in a low-boiling propellant in a sealed container. Preferably, such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. More preferably, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions preferably include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid nonionic or solid anionic surfactant or a solid diluent (preferably having a particle size of the same order as particles comprising the active ingredient).

Pharmaceutical compositions of the invention formulated for pulmonary delivery may also provide the active ingredient in the form of droplets of a solution or suspension. Such formulations may be prepared, packaged, or sold as aqueous or dilute alcoholic solutions or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration preferably have an average diameter in the range from about 0.1 to about 200 nanometers.

The formulations described herein as being useful for pulmonary delivery are also useful for intranasal delivery of a pharmaceutical composition of the invention.

Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers.

Such a formulation is administered in the manner in which snuff is taken i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nares. Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may further comprise one or more of the additional ingredients described herein.

A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for buccal administration. Such formulations may, for example, be in the form of tablets or lozenges made using conventional methods, and may, for example, contain 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations suitable for buccal administration may comprise a powder or an aerosolized or atomized solution or suspension comprising the active ingredient. Such powdered, aerosolized, or aerosolized formulations, when dispersed, preferably have an average particle or droplet size in the range from about 0.1 nanomaters to about 2000 micrometers, and may further comprise one or more of the additional ingredients described herein.

A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution or suspension of the active ingredient in an aqueous or oily liquid carrier. Such drops may further comprise buffering agents, salts, or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form or in a liposomal preparation.

As used herein, “additional ingredients” include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials. Other “additional ingredients” which may be included in the pharmaceutical compositions of the invention are known in the art and described, for example in Genaro, ed., 1985, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. Typically dosages of the compound of the invention which may be administered to an animal or patient, preferably a human, range in amount from about 0.01 mg to about 100 g per kilogram of body weight of the animal or patient. While the precise dosage administered will vary depending upon any number of factors, including, but not limited to, the type of animal and type of disease state being treated, the age of the animal or patient and the route of administration. Preferably, the dosage of the compound will vary from about 0.01 mg to about 500 mg per kilogram of body weight of the animal or patient. The compound can be administered to an animal or patient as frequently as several times daily, or it can be administered less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every several months or even once a year or less. The frequency of the dose will be readily apparent to the skilled artisan and will depend upon any number of factors, such as, but not limited to, the type and severity of the disease being treated, the type and age of the animal, patient, etc.

Administration of the compounds of the present invention or the compositions thereof may be continuous or intermittent, depending, for example, upon the recipient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners. The administration of the agents of the invention may be essentially continuous over a preselected period of time or may be in a series of spaced doses. Both local and systemic administration is contemplated. The amount administered will vary depending on various factors including, but not limited to, the composition chosen, the particular disease, the weight, the physical condition, and the age of the mammal, and whether prevention or treatment is to be achieved. Such factors can be readily determined by the clinician employing animal models or other test systems which are well known to the art.

One or more suitable unit dosage forms having the therapeutic agent(s) of the invention, which, as discussed below, may optionally be formulated for sustained release, can be administered by a variety of routes including parenteral, including by intravenous and intramuscular routes, as well as by direct injection into the diseased tissue. For example, the therapeutic agent may be directly injected into the muscle. The formulations may, where appropriate, be conveniently presented in discrete unit dosage forms and may be prepared by any of the methods well known to pharmacy. Such methods may include the step of bringing into association the therapeutic agent with liquid carriers, solid matrices, semi-solid carriers, finely divided solid carriers or combinations thereof, and then, if necessary, introducing or shaping the product into the desired delivery system.

When the therapeutic agents of the invention are prepared for administration, they are preferably combined with a pharmaceutically acceptable carrier, diluent or excipient to form a pharmaceutical formulation, or unit dosage form. The total active ingredients in such formulations include from 0.1 to 99.9% by weight of the formulation. A “pharmaceutically acceptable” is a carrier, diluent, excipient, and/or salt that is compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof. The active ingredient for administration may be present as a powder or as granules; as a solution, a suspension or an emulsion.

Pharmaceutical formulations containing the therapeutic agents of the invention can be prepared by procedures known in the art using well known and readily available ingredients. The therapeutic agents of the invention can also be formulated as solutions appropriate for parenteral administration, for instance by intramuscular, subcutaneous or intravenous routes.

The pharmaceutical formulations of the therapeutic agents of the invention can also take the form of an aqueous or anhydrous solution or dispersion, or alternatively the form of an emulsion or suspension.

Thus, the therapeutic agent may be formulated for parenteral administration (e g., by injection, for example, bolus injection or continuous infusion) and may be presented in unit dose form in ampules, pre-filled syringes, small volume infusion containers or in multi-dose containers with an added preservative. The active ingredients may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredients may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

It will be appreciated that the unit content of active ingredient or ingredients contained in an individual aerosol dose of each dosage form need not in itself constitute an effective amount for treating the particular indication or disease since the necessary effective amount can be reached by administration of a plurality of dosage units. Moreover, the effective amount may be achieved using less than the dose in the dosage form, either individually, or in a series of administrations.

The pharmaceutical formulations of the present invention may include, as optional ingredients, pharmaceutically acceptable carriers, diluents, solubilizing or emulsifying agents, and salts of the type that are well-known in the art. Specific non-limiting examples of the carriers and/or diluents that are useful in the pharmaceutical formulations of the present invention include water and physiologically acceptable buffered saline solutions, such as phosphate buffered saline solutions pH 7.0-8.0.

In general, water, suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration contain the active ingredient, suitable stabilizing agents and, if necessary, buffer substances. Antioxidizing agents such as sodium bisulfate, sodium sulfite or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium Ethylenediaminetetraacetic acid (EDTA). In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, a standard reference text in this field.

The active ingredients of the invention may be formulated to be suspended in a pharmaceutically acceptable composition suitable for use in mammals and in particular, in humans. Such formulations include the use of adjuvants such as muramyl dipeptide derivatives (MDP) or analogs that are described in U.S. Patent Nos. 4,082,735; 4,082,736; 4,101,536; 4,185,089; 4,235,771; and 4,406,890. Other adjuvants, which are useful, include alum (Pierce Chemical Co.), lipid A, trehalose dimycolate and dimethyldioctadecylammonium bromide (DDA), Freund’s adjuvant, and IL-12. Other components may include a polyoxypropylenepolyoxyethylene block polymer (Pluronic®), a non-ionic surfactant, and a metabolizable oil such as squalene (U.S. Patent No. 4,606,918).

Additionally, standard pharmaceutical methods can be employed to control the duration of action. These are well known in the art and include control release preparations and can include appropriate macromolecules, for example polymers, polyesters, polyamino acids, polyvinyl, pyrolidone, ethylenevinylacetate, methyl cellulose, carboxymethyl cellulose or protamine sulfate. The concentration of macromolecules as well as the methods of incorporation can be adjusted in order to control release. Additionally, the agent can be incorporated into particles of polymeric materials such as polyesters, polyamino acids, hydrogels, poly(lactic acid) or ethylenevinylacetate copolymers. In addition to being incorporated, these agents can also be used to trap the compound in microcapsules.

Accordingly, the composition of the present invention may be delivered via various routes and to various sites in a mammal body to achieve a particular effect (see, e.g., Rosenfeld et al., 1991; Rosenfeld et al., 1991a; Jaffe et al., supra; Berkner, supra). One skilled in the art will recognize that although more than one route can be used for administration, a particular route can provide a more immediate and more effective reaction than another route. In one embodiment, the composition described above is administered to the subject by subretinal injection. In other embodiments, the composition is administered by intravitreal injection. Other forms of administration that may be useful in the methods described herein include, but are not limited to, direct delivery to a desired organ (e.g., the eye), oral, inhalation, intranasal, intratracheal, intravenous, intramuscular, subcutaneous, intradermal, and other parental routes of administration. Additionally, routes of administration may be combined, if desired. In another embodiments, route of administration is subretinal injection or intravitreal injection.

The active ingredients of the present invention can be provided in unit dosage form wherein each dosage unit, e.g., a teaspoonful, tablet, solution, or suppository, contains a predetermined amount of the composition, alone or in appropriate combination with other active agents. The term “unit dosage form” as used herein refers to physically discrete units suitable as unitary dosages for human and mammal subjects, each unit containing a predetermined quantity of the compositions of the present invention, alone or in combination with other active agents, calculated in an amount sufficient to produce the desired effect, in association with a pharmaceutically acceptable diluent, carrier, or vehicle, where appropriate. The specifications for the unit dosage forms of the present invention depend on the particular effect to be achieved and the particular pharmacodynamics associated with the composition in the particular host.

These methods described herein are by no means all-inclusive, and further methods to suit the specific application will be apparent to the ordinary skilled artisan. Moreover, the effective amount of the compositions can be further approximated through analogy to compounds known to exert the desired effect. It will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure.

Methods of Making

The present invention is further drawn to, in part, a method of synthesizing a polymer using ring-opening metathesis polymerization (ROMP), comprising the steps of: providing a monomer; polymerizing the monomer using a ROMP catalyst; and isolating the polymer; wherein the monomer is represented by Formula (II):

Formula (II) wherein: R represents a substituent on ring A selected from the group consisting of hydrogen, halide, hydroxy, C1-C30 alkyl, C1-C30 alkyl halide, C1-C30 alkoxy, and any combination thereof; L represents a divalent organic linker, and Z represents a negatively charged functional group.

In one embodiment, polymerization is performed with a target degree of polymerization. In one embodiment, the degree of polymerization is about 5 to about 500. In one embodiment, the degree of polymerization is about 10 to about 500. In one embodiment, the degree of polymerization is about 20 to about 500. In one embodiment, the degree of polymerization is about 30 to about 500. In one embodiment, the degree of polymerization is about 40 to about 500. In one embodiment, the degree of polymerization is about 50 to about 500. In one embodiment, the degree of polymerization is about 60 to about 500. In one embodiment, the degree of polymerization is about 70 to about 500. In one embodiment, the degree of polymerization is about 80 to about 500. In one embodiment, the degree of polymerization is about 90 to about 500. In one embodiment, the degree of polymerization is about 100 to about 500. In one embodiment, the degree of polymerization is about 10 to about 400. In one embodiment, the degree of polymerization is about 20 to about 400. In one embodiment, the degree of polymerization is about 30 to about 400. In one embodiment, the degree of polymerization is about 40 to about 400. In one embodiment, the degree of polymerization is about 50 to about 400. In one embodiment, the degree of polymerization is about 60 to about 400. In one embodiment, the degree of polymerization is about 70 to about 400. In one embodiment, the degree of polymerization is about 80 to about 400. In one embodiment, the degree of polymerization is about 90 to about 400. In one embodiment, the degree of polymerization is about 100 to about 400. In one embodiment, the degree of polymerization is about 10 to about 300. In one embodiment, the degree of polymerization is about 20 to about 300. In one embodiment, the degree of polymerization is about 30 to about 300. In one embodiment, the degree of polymerization is about 40 to about 300. In one embodiment, the degree of polymerization is about 50 to about 300. In one embodiment, the degree of polymerization is about 60 to about 300. In one embodiment, the degree of polymerization is about 70 to about 300. In one embodiment, the degree of polymerization is about 80 to about 300. In one embodiment, the degree of polymerization is about 90 to about 300. In one embodiment, the degree of polymerization is about 100 to about 300. In one embodiment, the degree of polymerization is about 50 to about 250. In one embodiment, the degree of polymerization is about 60 to about 250. In one embodiment, the degree of polymerization is about 70 to about 250. In one embodiment, the degree of polymerization is about 80 to about 250. In one embodiment, the degree of polymerization is about 90 to about 250. In one embodiment, the degree of polymerization is about 100 to about 250.

In one embodiment, the polymerization is performed at about 25 °C to about 100°C. In one embodiment, the polymerization is performed at about 25 °C to about 90°C. In one embodiment, the polymerization is performed at about 25 °C to about 80°C. In one embodiment, the polymerization is performed at about 35°C to about 80°C. In one embodiment, the polymerization is performed at about 45°C to about 80°C. In one embodiment, the polymerization is performed at about 55°C to about 80°C. In one embodiment, the polymerization is performed at about 60°C to about 80°C. In one embodiment, the polymerization is performed at about 60°C to about 90°C. In one embodiment, the polymerization is performed at about 60°C to about 100°C.

In one embodiment, the ROMP catalyst comprises a transition metal. In one embodiment, the ROMP catalyst comprises a metal selected from the group consisting of titanium, molybedenum, tungsten, tantalum, rhenium, ruthenium, any oxidation state thereof, and any combination thereof. In one embodiment, the ROMP catalyst comprises a carbene. In one embodiment, the ROMP catalyst comprises a halide. In one embodiment, the ROMP catalyst comprises a phosphine ligand. In one embodiment, the ROMP catalyst is selected from the group consisting of first-generation Grubbs catalyst (Grubbs I), second-generation Grubbs catalyst (Grubbs II), and third-generation Grubbs catalyst (Grubbs III). In one embodiment, the ROMP catalyst is air stable. In one embodiment, the ROMP catalyst is stable to moisture.

In one embodiment, the step of polymerizing the monomer using a ROMP catalyst is performed in a glove box. In one embodiment, the step of polymerizing the monomer is done in an air-free environment. In one embodiment, the step of polymerizing the monomer is done open to air. In one embodiment, the step of polymerizing the monomer further comprises the step of adding the monomer and ROMP catalyst with at least one solvent to a solution. In one embodiment, the solvent is organic. Exemplary organic solvents include, but are not limited to, acetic acid, acetone, acetonitrile, alkanes (e.g., hexanes, heptane), amyl acetate, butanol, butyl acetate, chlorobenzene, chloroform, cumene, cyclohexane, 1,2-di chloroethene, dichloromethane, diethyl ether, dimethoxyethane, dimethylacetamide, dimethylformamide, dimethyl sulfoxide, 1,4-di oxane, ethanol, 2-ethoxy ethanol, ethyl acetate, ethyl nitrate, ethyleneglycol, formic acid, hydrazine, isopropanol, methanol, methyl acetate, 2-methyl-l- butanol, 2-methyl-l -propanol, methylbutyl ketone, methylcyclohexane, methylethyl ketone, methylpyrrolidone, methyl tert-butyl ether, nitromethane, propanol, propyl acetate, sulfolane, sarcosine, tetrahydrofuran, tetralin, toluene, 1,1,2-tricholoroethane, tri ethylamine, urea, xylene, and any combination thereof. In one embodiment, the step of polymerizing the monomer is automated. In one embodiment, the step of polymerizing the monomer is performed on a stir plate. In one embodiment, the step of polymerizing the monomer is performed on a hot plate. In one embodiment, the step of polymerizing the monomer is performed using a heating block.

In one embodiment, the polymerization step is monitored by percent conversion. In one embodiment, “percent conversion” is defined as the percentage of monomer converted to polymer. In one embodiment, the polymerization reaches full conversion of monomer to polymer after 1 minute. In one embodiment, the polymerization reaches full conversion after about 1 minute to about 5 minutes. In one embodiment, the polymerization reaches full conversion after about 5 minutes to about 10 minutes. In one embodiment, the polymerization reaches full conversion after about 10 minutes to about 30 minutes. In one embodiment, the polymerization reaches full conversion after about 30 minutes to about 60 minutes. In one embodiment, the polymerization reaches full conversion after about 60 minutes.

In one embodiment, the polymerization is performed using two or more monomers comprising different / groups. In one embodiment, the polymerization step is performed using a monomer which does not comprise Z. In one embodiment, the polymerization step is performed using at least one monomer which is negatively charged. In one embodiment, the polymerization step is performed on two or more monomers with a ROMP catalyst to produce a random copolymer. In one embodiment, the polymerization step is performed to produce a statistical copolymer. In one embodiment, the polymerization step is performed on two or more monomers to produce a block copolymer. In one embodiment, the polymerization step is performed on two or more monomers to produce an alternating copolymer. In one embodiment, the polymerization step is performed to produce a stereoblock copolymer. In one embodiment, the polymerization step is performed to produce a gradient copolymer.

In one embodiment, a method of polymerization alternative to ROMP is used to produce a copolymer of the polymer. Exemplary methods of polymerization include, but are not limited to, atom transfer free radical polymerization (ATRP), reversible addition fragmentation chain transfer (RAFT) polymerization, anionic polymerization, cationic polymerization, living polymerization, chain shuttling polymerization, free radical polymerization, and nitroxide mediated radical polymerization (NMP).

In one embodiment, the polymer is isolated by evaporating solvent. In one embodiment, the polymer is isolated by filtration. In one embodiment, the polymer is isolated by precipitation. In one embodiment, the polymer is isolated using drying. In one embodiment, the polymer is isolated using dialysis.

Methods of Use

The present invention is further drawn to, in part, polymers and/or compositions which can be used to remove solutes from a solution. In one embodiment, the polymer is used to bind solutes in a solution. In one embodiment, the polymer is used to bind ions in a solution. In one embodiment, the polymer is used to remove solutes from a solution.

In one embodiment, the present invention provides a method of removing at least one solute from a solution comprising the steps of: providing a polymer; and contacting the polymer with at least one solute; wherein the polymer comprises a structure represented by Formula (I) as defined elsewhere herein.

Thus, in various embodiments, the present invention provides a method of removing solutes from a solution using a composition comprising a polymer of the present invention. In one embodiment, the compound or composition forms an insoluble precipitate upon binding the solute. In one embodiment, the compound or composition when bound to the solute can be filtered out of solution. In one embodiment, the degree of binding of the compound or composition to the solute is dependent on pH. In one embodiment, the compound or composition forms an aggregate upon solute binding. In one embodiment, the compound or composition has a high affinity for binding ions. Exemplary ions include, but are not limited to, metal ions, metal cations, metal dications, metal anions, metal dianions, heavy metals, and precious metals. In one embodiment, the at least one solute is a metal ion. In one embodiment, the at least one solute is selected from the group consisting of monovalent cations, divalent cations, trivalent cations, monovalent anions, divalent anions, trivalent anions, and combinations thereof. In one embodiment, the at least one solute is selected from the group consisting of manganese, magnesium, nickel, zinc, copper, cadmium, iron, lead, barium, any ionic state thereof, and any combination thereof. In one embodiment, the at least one solute is an element selected from the lanthanide series of the periodic table. In one embodiment, the at least one solute is an ion of an element selected from the lanthanide series of the periodic table. In one embodiment, the at least one solute is a rare earth element selected from the group consisting of lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, lutetium, scandium, yttrium, any ionic state thereof, and any combination thereof.

In one embodiment, the method is uniquely suited for the removal of rare earth elements over other metal ions. In other words, the method provides unexpectedly high levels of removal of rare earth elements in solutions comprising solutes other than said rare earth elements. In one embodiment, the method is uniquely suited for the removal of dications, including, but not limited to, Mg²⁺ and Cd²⁺. In one embodiment, the method is uniquely suited for the removal of trications, including, but not limited to, Ce³⁺, Sm³⁺, and Ho³⁺.

In one embodiment, the solution is aqueous. In one embodiment, the solution is water. In one embodiment, the solution is drinking water. In one embodiment, the solution comprises a biological fluid. Exemplary biological fluids include, but are not limited to, saliva, whole blood, plasma, serum, lymph, synovial fluid, peritoneal fluid, pleural fluid, urine, sputum, semen, vaginal lavage, bone marrow, cerebrospinal cord fluid and tears. In one embodiment, the solution comprises contaminated water. In one embodiment, the solution comprises contaminated soil. In one embodiment, the solution comprises industrial waste. In one embodiment, the solution comprises a food product. In one embodiment, the solution comprises electronic waste.

In one embodiment, the compound or composition releases a bound solute upon addition of an acid. In one embodiment, the solution is acidic. In one embodiment, the solution is basic.

In one embodiment, the polymer solution comprises about 0.01 mg/mL to about 1.00 mg/mL of the polymer. In one embodiment, the polymer solution comprises about 0.10 mg/mL to about 1.00 mg/mL of the polymer. In one embodiment, the polymer solution comprises about 0.20 mg/mL to about 1.00 mg/mL of the polymer. In one embodiment, the polymer solution comprises about 0.30 mg/mL to about 1.00 mg/mL of the polymer. In one embodiment, the polymer solution comprises about 0.40 mg/mL to about 1.00 mg/mL of the polymer. In one embodiment, the polymer solution comprises about 0.50 mg/mL to about 1.00 mg/mL of the polymer. In one embodiment, the polymer solution comprises about 0.60 mg/mL to about 1.00 mg/mL of the polymer. In one embodiment, the polymer solution comprises about 0.70 mg/mL to about 1.00 mg/mL of the polymer. In one embodiment, the polymer solution comprises about 0.80 mg/mL to about 1.00 mg/mL of the polymer. In one embodiment, the polymer solution comprises about 0.90 mg/mL to about 1.00 mg/mL of the polymer.

In one embodiment, the compound or composition is bound to a pharmaceutical composition. In one embodiment, the compound or composition readily releases the pharmaceutical composition. In one embodiment, the compound or composition binds ions in high concentrations of calcium and magnesium ions. In one embodiment, the present invention is drawn to a sensor comprising the compound or composition.

In one embodiment, the compound or composition binds to a protein which participates in the progression of a disease. In one embodiment, the compound or composition binds to a protein which binds carbohydrates. In one embodiment, the composition binds to a target which is involved in the progression of cancer. In one embodiment, the composition binds to a lectin. The term “lectin” as used herein refers to a carbohydrate-binding protein. Any therapeutic agent or any combination of therapeutic agents disclosed herein may be administered to a subject to treat a disease or disorder. The therapeutic agents herein can be formulated in any number of ways, often according to various known formulations in the art or as disclosed or referenced herein.

In certain embodiments, the method of treating a disease or disorder comprises a “triggered” functionality. In other words, the system may remain inert in the body until specifically triggered. In some embodiments, the polymer is used advantageously in therapeutic applications such as to first target the polymer to a specified location, and then trigger them into an activated state. Sometimes referred to as a “dual targeted delivery system,” this feature may minimize the side effects of systemic therapeutic agents. For example, in some embodiments, upon delivering the polymer to a specific cell, a reagent, such as water, proton, acid, or protonated water, may be applied to the cell thereby causing the release of a therapeutic agent from the polymer. In some embodiments, this may provide a clinician the ability to control and visualize drug therapy noninvasively.

In some embodiments, the size (e.g., average diameter of a polymer assembly) of the compound or composition of the present invention allows for passive diffusion into cells. In some embodiments, where the compound or composition is on a smaller scale, the small size (e.g., average diameter of a polymer assembly) allows the compound or compositions to travel almost anywhere in the body where therapy may need to be performed. For example, in some embodiments, the method comprises compounds that act as a hydrolysis triggered therapeutic agent delivery and therapeutic agent release systems.

In various embodiments, the method further comprises allowing the compound or composition to accumulate in a region of the biological tissue, wherein the targeting domain facilitated accumulation of the compound, nanoparticle, or composition in the region. In one embodiment, the compound or composition localizes around the exterior of the nucleus.

In various aspects, the compound or composition of the present invention can be used alone or in combination with a therapeutic agent to deliver a therapeutic agent payload to a target cell. Often, the therapeutic agent may be released based on the degradation of, e.g., a controlled release biodegradable matrix and/or polymer.

The preferred dosage of the compound or nanoparticle will vary according to a number of factors, such as the administration route, the age, weight and species of the subject, but in general containing in the order of from 1 pmol/kg to 1 mmol/kg body weight of the compound or nanoparticle.

Administration may be topical, parenteral (e.g., intravenously, intraarterially, intramuscularly, interstitially, subcutaneously, transdermally, or intrasternally), or into an externally voiding body cavity (e.g., the gastrointestinal tract, rectum, bladder, uterus, vagina, nose, ears or lungs), peritoneally, orally, intradermal, ocular, in an animate human or nonhuman (e.g., mammalian, reptilian or avian) body.

In certain embodiments, the compound or composition herein is used in conjunction with an anti-cancer agent known in the art. Exemplary anti-cancer agents include, but are not limited to, immunotherapy agents, immunomodulatory agents, antineoplastic agents, chemotherapeutic agents, radioimmunotherapy agents, and monoclonal antibodies.

In some embodiments, the anti-cancer agent may be a prodrug form of an anti-cancer agent. As used herein, the term “prodrug form” and its derivatives is used to refer to a drug that has been chemically modified to add and/or remove one or more substituents in such a manner that, upon introduction of the prodrug form into a subject, such a modification may be reversed by naturally occurring processes, thus reproducing the drug. The use of a prodrug form of an anti-cancer agent in the compositions, among other things, may increase the concentration of the anti-cancer agent in the compositions of the present disclosure. In certain embodiments, an anticancer agent may be chemically modified with an alkyl or acyl group or some form of lipid. The selection of such a chemical modification, including the substituent(s) to add and/or remove to create the prodrug, may depend upon a number of factors including, but not limited to, the particular drug and the desired properties of the prodrug. One of ordinary skill in the art, with the benefit of this disclosure, will recognize suitable chemical modifications.

EMBODIMENTS

1. A polymer comprising a structure represented by Formula (I): Formula (I) wherein:

A represents a repeat unit selected from the group consisting of C5-C7 alkyl, C5-C7 heteroalkyl, Cs-Cvaryl, C5-C7 heteroaryl, or C5-C7 cycloalkyl; n represents an integer from 5-500;

L represents a divalent organic linker; and

Z represents a negatively charged functional group.

2. The polymer of embodiment 1, wherein ring A is represented by one of the following structures: wherein the wave line represents connection to the polymer backbone;

X represents 0, S, NR¹, or CR²R³;

R¹, R², and R³ each independently represent a substituent selected from the group consisting of hydrogen, halide, hydroxy, C1-C30 alkyl, C1-C30 alkyl halide, C1-C30 alkoxy, and any combination thereof; and each structure is independently optionally further substituted.

3. The polymer of embodiment 1 or 2, wherein the polymer comprises a structure represented by Formula (la): Formula (la) wherein each occurrence of R^z is independently a substituent selected from the group consisting of hydrogen, halide, hydroxy, C1-C30 alkyl, C1-C30 alkyl halide, C1-C30 alkoxy, carbonyl, ester, amine, and any combination thereof, wherein at least one R^z is a negatively charged; p is an integer from 1 to 10; and m is an integer from 1 to 9.

4. The polymer of any one of embodiments 1-3, wherein L is represented by one of the following structures: wherein the wavy line represents a bond to ring A; * represents a bond to Z; and

R’ represents a substituent selected from the group consisting of hydrogen, halide, hydroxy, C1-C30 alkyl, C1-C30 alkyl halide, C1-C30 alkoxy, and any combination thereof.

5. The polymer of any one of embodiments 1-4, wherein L comprises a C1-C30 alkyl which is optionally further substituted.

6. The polymer of any one of embodiments 1-5, wherein Z is selected from the group consisting of a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, any stereochemical isomer thereof, and any combination thereof.

7. The polymer of any one of embodiments 1-6, wherein Z comprises a sugar selected from the group consisting of glucuronic acid, gluconic acid, glucaric acid, and glutamic acid, and any ionic form thereof; or

Z comprises an anionic derivative of galactose, glucose, mannose, allose, altrose, gulose, idose, talose, psicose, fructose, sorbose, or tagatose.

8. The polymer of any one of embodiments 1-7, wherein the polymer is a copolymer comprising a repeat unit of at least two monomers, wherein at least one monomer comprises glucuronic acid.

9. The polymer of any one of embodiments 1-8, wherein the polymer has a zeta potential of about -60 mV to about 0 mV.

10. A composition comprising the polymer of any one of embodiments 1-9.

11. A method of synthesizing a polymer using ring-opening metathesis polymerization (ROMP), comprising the steps of: providing a monomer; polymerizing the monomer using a ROMP catalyst; and isolating the polymer; wherein the monomer is represented by Formula (II):

Formula (II) wherein:

R represents a substituent on ring A selected from the group consisting of hydrogen, halide, hydroxy, C1-C30 alkyl, C1-C30 alkyl halide, C1-C30 alkoxy, and any combination thereof;

L represents a divalent organic linker; and

Z represents a negatively charged functional group.

12. The method of embodiment 11, wherein the degree of polymerization is about 5 to about 500.

13. The method of embodiment 11 or 12, wherein ring A is represented by one of the following structures: wherein:

X represents 0, S, NR¹, or CR²R³;

R¹, R², and R³ each independently represent a substituent selected from the group consisting of hydrogen, halide, hydroxy, C1-C30 alkyl, C1-C30 alkyl halide, C1-C30 alkoxy, and any combination thereof; and each structure is independently optionally further substituted.

14. A method of removing at least one solute from a solution comprising the steps of: providing a polymer; and contacting the polymer with at least one solute; wherein the polymer comprises a structure represented by Formula (I):

Formula (I) wherein:

A represents a repeat unit selected from the group consisting of C5-C7 alkyl, C5- C7 heteroalkyl, Cs-Cvaryl, C5-C7 heteroaryl, or C5-C7 cycloalkyl; n represents an integer from 5-500;

L represents a divalent organic linker; and

Z represents a negatively charged functional group.

15. The method of embodiment 14, wherein the solution is aqueous.

16. The method of embodiment 14 or 15, wherein the polymer solution comprises about 0.01 mg/mL to about 1.00 mg/mL of the polymer.

17. The method of any one of embodiments 14-16, wherein the at least one solute is selected from the group consisting of monovalent cations, divalent cations, trivalent cations, monovalent anions, divalent anions, trivalent anions, and combinations thereof.

18. The method of any one of embodiments 14-17, wherein the at least one solute is a metal ion.

19. The method of any one of embodiments 14-18, wherein the at least one solute is selected from the group consisting of manganese, magnesium, nickel, zinc, copper, cadmium, iron, lead, barium, any ionic state thereof, and any combination thereof.

20. The method of any one of embodiments 14-20, wherein the at least one solute is a rare earth element selected from the group consisting of lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, lutetium, scandium, and yttrium.

EXPERIMENTAL EXAMPLES

The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods. The following working examples therefore are not to be construed as limiting in any way the remainder of the disclosure.

Example 1 : Sensitive Dication Trap Using Uronic Acid Polymer

The present invention is drawn to, in part, a novel polymer that efficiently captures a wide range of metal cations by utilizing negatively charged glucuronic acid as sidechains on a polymer synthesized using ring opening metathesis polymerization (ROMP) (Bao et al., 2024, Carbohydrate Polymers, 331, 121841). The present approach involves a specialized 'graft- through' polymerization method, which maximizes the density of grafted carbohydrates on the polymer backbone and generates a hydrophobic poly(norbomene) backbone to facilitate polymer aggregation upon metal binding. The synthesized polymer exhibits a ~3-fold higher affinity for Cd²⁺ ions relative to a negatively charged, naturally occurring polysaccharide (hyaluronic acid). A standout feature of the polymer is that it forms an insoluble precipitate when in contact with these cations, which allows the clean water to simply be filtered out. Moreover, the adsorption and desorption of divalent cations can be controlled through simple pH adjustments, making this a robust, recyclable, purification material.

The present invention stands out with its unique features of the polymer itself: firstly, the use of negatively charged glucuronic acid in the polymer significantly enhances its efficiency in capturing a wide range of metal cations, a notable deviation from existing technologies that may not be as broadly effective. Secondly, the specialized 'graft-through' polymerization method maximizes the grafting density of the uronic acids, which affords a higher affinity for metal ions, such as Cd²⁺, compared to natural polysaccharides like hyaluronic acid. Thirdly, the polymer system forms insoluble aggregates upon metal binding (rather than forming a hydrogel, as most saccharide systems do), which allows the material to be easily filtered off and does not result in loss of clean water to gelation (Peng et al., 2018, Nature Communications, 9, 187). Lastly, the polymer's innovative capability to control the adsorption and desorption of metal ions through simple pH adjustments presents a more adaptable and versatile approach than current technologies, which often lack such precise control.

The present invention effectively addresses several key problems: First, it provides a highly efficient solution for the removal of harmful heavy metal ions like Cd²⁺, Pb²⁺, and Ni²⁺ from water, even at trace levels, which is crucial for environmental protection and public health. Second, its unique capability to capture a broad spectrum of metal cations using negatively charged glucuronic acid represents an improvement over existing technologies that may be limited in scope. Finally, the polymer's pH-responsive adsorption and desorption properties offer a versatile and controllable approach to metal ion removal, enabling easier recovery and reuse of the polymer, and thereby making the process more sustainable and cost-effective.

The present invention possesses several advantages over current technologies, including, but not limited to, broader range of metal ion capture, enhanced metal binding affinity, aggregation, not gelation, and pH responsive control. Utilizing negatively charged glucuronic acid, the polymer is capable of efficiently binding a wide variety of metal cations, surpassing the specificity limitations of many existing materials. The 'graft-through' polymerization technique maximizes the grafting density of carbohydrates, resulting in a polymer that demonstrates at least a 3 -fold higher affinity for binding specific ions like Cd²⁺ compared to natural polysaccharides like hyaluronic acid. Many polysaccharide systems developed for cation removal generate hydrogels upon metal binding. This removes the cation from solution, but also traps water in the matrix. As such, some amount of clean water is lost, and separation is difficult. Conversely, the present materials form insoluble aggregates upon metal binding, which are easily filtered away from the clean water. Lastly, the polymer's ability to control adsorption and desorption of metal ions via simple pH adjustments is a significant improvement, offering more versatility and adaptability in various environmental conditions. The present invention involves a complex synthesis process wherein the specialized 'graft-through' polymerization method might be more complex and costly compared to simple ‘graft-to’ polymerization synthesis methods. This can be mitigated by optimizing the production process to make it more scalable and cost-effective. Further, possible stability and durability concerns may result from repeated use and exposure to various environmental conditions which could affect the polymer's stability and durability. Research into enhancing the polymer's resilience and longevity, possibly through material modifications or protective coatings, could help overcome this issue. The present invention is also pH dependent; the polymer's efficiency is pH-dependent for adsorption and desorption, which could be limiting in environments where pH control is challenging. Research into making the polymer's performance less pH-sensitive or finding efficient ways to manage pH in different settings could be beneficial. The expense of polymer generation via ring opening metathesis polymerization (ROMP), which relies on Ru- based catalysts, may prove costly for scale up. This can potentially be addressed by forming analogous polymers using acrylate-based monomers, which are amenable to radical polymerization techniques.

The present invention has diverse applications including, but not limited to, biomedical applications, chelation therapy, environmental remediation, sensor development, in the food industry, and in the battery and electronics industry. Given the ability of the present invention to selectively bind divalent cations in a pH-dependent manner, this polymer could be adapted for use in drug delivery systems, particularly for targeted delivery or controlled release of medication, leveraging its pH-responsive properties. As these materials are capable of trapping heavy metal cations, even in the presence of high concentrations of Ca²⁺ and Mg²⁺, they can be useful as therapeutics for heavy metal poisoning. Beyond water treatment, the polymer could be useful in broader environmental remediation efforts, such as cleaning up contaminated soils or aiding in the recovery of valuable metals from industrial waste. The polymer's specific binding characteristics could be harnessed to develop sensors for detecting trace amounts of heavy metals in various environments, which would be invaluable in monitoring and maintaining ecological and public health. In food processing and preservation, the polymer could be used to remove unwanted metal ions that affect the quality and safety of food products. The polymer's metal-binding properties might be applicable in the recycling or refining processes of the electronics industry, particularly in the recovery of precious metals from electronic waste. Example 2: Synthesis of Uronic Acid Polymer

The monomer utilized in the present invention was designed to have a backbone synthesized via graft-through ring-opening metathesis polymerization (ROMP) to maximize grafting density, a hydrophobic linker, and a binding site comprising a hydrophilic sugar. Synthesis of Glucuronic A cid Monomer (C4-GlcA)

Glucuronic acid was selected, in part, for its stability in basic and acidic conditions (Ranganathan et al., 2016, Critical Reviews in Food Science and Nutrition, 56, 2665; Fatouros et al., 2021, Journal of Agricultural and Food Chemistry, 69, 9376) (Fig. 1). Target compounds were selected to evaluate the effect of charged sugars, charge density, and backbone hydrophobicity (Fig. 2). C4-Glu was synthesized as a control to compare with C4-GlcA and a copolymer of 1: 1 glucose and glucuronic acid monomer (C4- Glu + GlcA) (Fig. 3, Fig. 4). Deprotection of the methyl of the glucuronic acid monomer was monitored using NMR (Fig. 5). Example 3: Binding Tests

The polymers designed herein were subject to sensitivity tests, specifically Cd²⁺ binding tests using a colorimetric dye with a polymer concentration of 0.1 mg/mL and a dye concentration of 100 pM wherein the dye used was 4-(2-pridylazo) resorcinol (PAR) (Fig. 6). Remaining Cd²⁺ concentration was assessed across all three materials and hyaluronic acid and showed that non-polar backbones increased binding with GlcA having the lowest slope in an absorbance vs Cd²⁺ concentration plot (Fig. 7). A measure of surface charge density showed that the GlcA polymer had a higher negative zeta potential when compared to natural hyaluronic acid (Fig. 8). Transmission electron microscopy (TEM) images of the materials show rapid aggregation of GlcA polymers after binding (Fig. 9).

Inductively coupled plasma mass spectrometry (ICP-MS) was used to quantify cation binding, specifically selectivity and detection limits (Fig. 10). Binding was found to be reversible upon variation of pH (Fig. 11).

Example 4: Selective Separation of Middle Rare Earth Elements

The selective separation of rare earth elements (REEs) remains a formidable challenge due to limitations of current methodologies, which struggle to achieve the separation efficiency required for their critical industrial applications. Middle REEs (MREEs), characterized by their intermediate ionic radii, are particularly challenging to separate without size-specific trapping mechanisms. The present example provides a novel approach that synergistically combines heavy metal sequestration with size-selective separation, utilizing negatively charged glycopolymers to achieve the targeted separation of MREEs. The binding affinities of these glycopolymers were systematically investigated for various REEs, focusing on the selective isolation of MREEs through a controlled variation of glycopolymer properties, including degree of polymerization (DP) and charge density. The findings revealed a distinctive U-shaped selectivity profile, with a marked preference for Samarium (Sm) and Europium (Eu) over other REEs such as Cerium (Ce) and Holmium (Ho). Moreover, enrichment experiments demonstrated the practical viability of the present methodology, achieving over 10% selectivity for Sm in a Ce/Sm mixture with a 10: 1 Ce/Sm ratio. A subsequent separation experiment using a 1 : 1 Ce/Sm mixture yielded a 15% enrichment after only five passes through a filter containing minimal amounts of glycopolymer, highlighting the promise of further refinement for enhanced separation efficiency. Overall, this selectivity underscores the potential for designing tailored separation processes optimized for specific MREEs using synthetic glycopolymers.

To address these challenges, the present invention provides materials that specifically and selectively bind these intermediate elements. Prior work recently reported the use of bioinspired synthetic glycopolymers bearing pendant glucuronate side chains to trap heavy metals from contaminated water (Jeon, S. et al., 2024, ACS Central Science, 10, 1782). Building on the properties discovered in this work, a goal of the present work was to determine if the sizedependent trapping capabilities of these polymers could be further developed for REE separation, with a focus on selectively binding MREEs. Specifically, a goal was to determine whether these polymers could overcome the limitations of existing methods, offering a more targeted approach to the challenging separation of MREEs.

Towards this end, a small suite of glycopolymers containing glucuronic acid was constructed using ring opening metathesis polymerization (ROMP), with systematic variations in the degree of polymerization (DP) and grafting charge density. To facilitate REE separation via precipitation, a system was designed based on a norbornenyl moiety linked to glucuronic acid via a hydrophobic alkyl chain. This method allows for easy recovery of the trapped REEs by acidifying the glucuronate, enabling the release of the bound ions. Owing to the ability of glucuronic acid to chelate the ruthenium in Grubbs’ 3^rd generation catalyst, a methyl-protected glucuronic acid monomer was prepared (Scheme 1). Scheme 1. Synthetic scheme for compounds mono-GlcA-Me, reagents and conditions, (a) NaOMe, dry MeOH, RT, 12 h. (b) BzCl, dry pyridine, RT, 12 h, 76% (2 steps), (c) HBr in AcOH, dry DCM, RT, 12 h, 74%. (d) C4-OH, AgOTf, dry DCM, RT, 12 h, 46% (a yield), (e) K2CO3, dry MeOH, RT, 4 h, 82%

Using this monomer, seven distinct polymers were synthesized (Fig. 12): four from glucuronic acid with varying degrees of polymerization (pGlcA-20 to 160), one from glucose (pGlc) to compare the REE separation ability based on the presence or absence of charge, and two copolymers of glucose with glucuronic acid at 25% and 50% ratios (pGlcA-50% and pGlcA-25%), respectively. This approach allowed for the exploration of the impact of carbohydrate charge density and degree of polymerization on REE separation. All polymers were characterized using size exclusion chromatography with multi-angle light scattering (SEC- MALS, Fig. 12B) to determine the degree of polymerization (DP) and dispersity (D). The measured DP closely aligned with the theoretical DP calculated from the initial monomer-to- initiator ratio ([M]0/[I]0) for each polymer and all dispersities (D) were below 1.20, indicating a controlled polymerization (Table 1). Following polymer analysis, the methyl group was removed from the pGlcA-Me series using lithium hydroxide in a mixture of water with tetrahydrofuran. This reaction yielded a fully deprotected polymer, as confirmed by ¹ H-NMR (Fig. 13, Fig. 14).

Table 1. Polymer characterization by SEC-MALS and NMR. pGlc 13110 13300 1.01 40 33 36 pGlcA-160 60230 63910 1.06 160 142 136 pGlcA-80 30030 30570 1.02 80 71 64 pGIcA-40 16710 17190 1.03 40 39 39 pGlcA-20 10380 10620 1.02 20 24 23 pGlcA-50% 14570 14790 1.02 40 35 33 52% pGlcA-25% 1.4540 14710 1.01 40 36 35 28%

The zeta potential of all polymers was evaluated to compare the effect of charge density on their colloidal stability and surface charge in neutral aqueous solution (Fig. 12C). As anticipated, pGlc had a nearly neutral zeta potential of -1.37 mV. Conversely, all charged polymers displayed significantly negative zeta potentials: -47.6 mV (pGlcA-160), -46.7 mV (pGlcA-80), -42.1 mV (pGlcA-40), -45.4 mV (pGlcA-20), -24.8 mV (pGlcA-50%) and -19.9 mV (pGlcA-25%), respectively. These results closely aligned with anticipated outcomes, in that the polymer with 50% and 25% charge density demonstrated a value approximately half and less than half that of the polymer with 100% charge density (pGlcA-20-160).

Before measuring the ability of the suite of polymers to bind REEs, their practical applicability was assessed by evaluating the ability of pGlcA-40 to bind Ce³⁺ in a ternary mixture containing Mg²⁺ as an abundant competing ion and Cd²⁺ as a competing heavy metal using inductively coupled plasma mass spectrometry (ICP-MS). The polymers exhibited remarkable selectivity for the REE over both competing ions (Fig. 15 A), which is especially noteworthy given previous findings of significant selectivity for heavy metals over benign divalent cations. This enhanced selectivity seems to be driven by size-dependent factors and the trivalent nature of the REE ions, highlighting the potential of this approach for REE-targeted applications.

Next, the binding capacity was investigated for various REEs of each glycopolymer. Holmium (Ho), Samarium (Sm), and Cerium (Ce) were selected as representative Heavy, Middle, and Light REEs, respectively. The binding capacity of the glycopolymers was evaluated for each REE at a fixed metal concentration of 100 pM, which exceeds the polymers’ saturation point. In these experiments, the polymers were incubated with REE³⁺ for 3 min, followed by spin-filtration to separate the polymer-bound ions from unbound REE³⁺. Then, the concentration of REEs remaining in solution was evaluated using ICP-MS (Fig. 15B). As expected, pGlc, which lacks charge, was unable to bind any REE. In contrast, all other glycopolymers exhibited the ability to bind REEs.

Notably, the degree of polymerization did significantly affect the overall REE binding capacity, with the exception of pGlcA-80, which exhibited a marginally reduced binding affinity for Sm³⁺ (p < 0.001, for all comparisons, one way ANOVA) and Ho³⁺ (p < 0.05 for all comparisons, one way ANOVA), relative to the other homopolymers. Additionally, all polymers exhibited a diminished binding capacity of Ce³⁺ as compared to Sm³⁺ and Ho³⁺. This is likely due to the larger ionic size of Ce³⁺, which occupies more surface area on the polymer per molecule and may hinder Ce³⁺ dimer formation (Fagnant Jr., D. P. et al., 2013, Inorg. Chem., 52, 549). Moreover, most polymers had a higher overall binding capacity for Ho³⁺ than for Sm³⁺. As expected, the REE binding ability of each polymer decreased as the charge density decreased. Specifically, while there was a modest reduction of about 5% in binding capacity between the 100% (pGlcA-40) and 50% charge densities, a sharp decline of over 30% was observed between the 50% and 25% charge densities (pGlcA-50% and pGlcA-25%, respectively).

To evaluate ion selectivity, the polymers were incubated in a 1 : 1 : 1 ternary solution containing Ce³⁺, Sm³⁺, and Ho³⁺. Given the observed reduced binding for Ce³⁺ compared to smaller REEs across all homopolymers, this comparison was standardized by using the residual amount of Ce³⁺ as a reference. Subsequently the relative amounts of Sm³⁺ and Ho³⁺ captured from the ternary mixture were assessed (Fig. 16A). Among the seven polymers tested, pGlcA- 80 and pGlcA-40 showed the most selective binding to Sm³⁺, exhibiting approximately a 15% selectivity over the other two REEs (Ce³⁺ and Ho³⁺). However, although the polymers with reduced charge density (pGlcA-50% and pGlcA-25%) demonstrated selectivity for Ho³⁺ and Sm³⁺ over Ce³⁺, there was diminished selectivity for Sm³⁺ over Ho³⁺, indicating that charge density may be a tunable handle to influence MREE selectivity.

Motivated by the fact that both pGlcA-80 and pGlcA-40 showed a distinct preference for Sm³⁺ over larger Ce³⁺ and smaller Ho³⁺, it was investigated whether this trend extended to other MREEs. To do so, a series of 1 : 1 : 1 ternary mixtures containing Ce³⁺/X³⁺/Ho³⁺ were generated, where “X” represents one of the following MREEs: Neodymium (Nd), Europium (Eu), or Gadolinium (Gd). pGlcA-40 was then incubated with each mixture and the same analyses was performed as with Sm³⁺ (Fig. 16B), revealing a distinct “U-shaped” selectivity pattern across the REEs positioned in the middle of the lanthanide series. This finding aligns with previous literature on the selective capture of REEs by carboxylate-rich bacterial cells (Takahashi, Y. et al., 2005, Chemical Geology, 219, 53). Overall, pGlcA-40 still had the strongest preference for Sm³⁺ over other REEs, but also exhibited -10% selectivity for Nd³ and -15% selectivity for Eu³⁺, with an attenuated propensity to bind Gd³⁺ over Ce³⁺ and Ho³⁺. This suggests that glycopolymer selectivity is influenced by specific ionic radii. Considering the very small differences in ion radii between these REEs (Table 2) (D’Angelo, P. et al., 2011, Inorg. Chem., 50, 4572), these results suggest a significant degree of MREE selectivity within this system. Table 2. Selectivity profile of pGlcA-40 for various MREEs. ionic radius * Selectivity over C e (%) using pGlcA-40

Nd 1.175 9.0

Sm 1.140 14.7

Eu 1.120 12.9

Gd 1.105 2.8

*from D’Angelo, P. et al., 2011, Inorg. Chem., 50, 4572

Considering these results, the practical applicability of separating Sm³⁺ from Ce³⁺ was investigated by adding pGlcA-40 to a 1 :1 binary mixture of both REEs and evaluating separation (Fig. 17A). In the binary mixture, pGlcA-40 demonstrated a 17% selectivity for Sm³⁺ over Ce³⁺. Furthermore, for continuous separation processes (Cole, K. P., 2018, Expert Rev. Clin. Phar., 11, 5), it is crucial to maintain selectivity across different concentrations. Therefore, the ability of pGlcA-40 to extract Sm³⁺ from a 10: 1 binary mixture of Ce³⁺ and Sm³⁺was also assessed. Despite the excess of Ce³⁺, pGlcA-40 still exhibited a significant selectivity for Sm³⁺, showing a 14% preference for the MREE, indicating its strong potential for Sm³⁺ separation, even in challenging conditions (Fig. 17B).

Finally, to evaluate the practical feasibility of separation, an experiment was conducted using a 1 : 1 binary mixture of Ce³⁺ and Sm³⁺ to determine whether consecutive filtration could achieve REE enrichment. For this experiment, the solution of REEs was passed over a filter containing 0.1 mg/mL pGlcA-40 to assess how much of each REE passed through the filter. This process was repeated 4 additional times, for a total of 5 filtration cycles (Fig. 17C). The graph represents the ion composition ratio of the remaining filtrate after each filtration, where solution enrichment of the larger REE was observed while retaining the MREE on the polymer. Based on previous findings which showed that trapped cations could be recovered from similar glycopolymers without loss of neither cation nor polymer, this process indicates that the cycle can be repeated for continuous use. Despite using a small amount of polymer, the purity was enhanced by nearly 30% from the initial 1 : 1 ratio, demonstrating the potential effectiveness of this method for separating challenging MREEs in future applications.

In summary, the present example has shown that bio-inspired synthetic glycopolymers bearing pendant glucuronate side chains can selectively differentiate between rare earth elements (REEs), particularly the challenging middle rare earth elements (MREEs) including Samarium (Sm) and Europium (Eu). By constructing a polymer library with varying degrees of polymerization (DP) and charge densities, it was observed that specific DPs (40 and 80) exhibited significant selectivity for MREEs. However, further research is needed to determine whether this selectivity is due to specific binding to particular sizes or if it results from the altered electronic effects caused by REE dimer formation via carboxylate interactions. This polymer was applied to binary mixtures of Ce³⁺ and Sm³⁺, which revealed significant selectivity for Sm³⁺, even in a Ce-rich environment. This highlights the system’s potential for selective REE separation. Consecutive filtration experiments further confirmed that these glycopolymers can generate REE-enriched solutions and enhance separation efficiency over multiple cycles and it can be anticipated that this trend would continue with additional cycles. Additionally, there is potential to further enhance the performance of this system through optimization of linker length, backbone composition, and inclusion of additional REE-chelating groups. These findings suggest that this glucuronate-based polymer approach offers a promising and efficient solution for REE separation, particularly for MREEs, with potential for application in various industrial settings where selective REE extraction is essential.

Materials

All reagents were of the highest commercial quality and used as received without further purification. Anhydrous di chloromethane (DCM) was obtained from distillation of HPLC grade dichloromethane. Cis-5-norbomene-exo-2,3-dicarboxylic anhydride was obtained from Oakwood chemical. 4-Amino-l -butanol, D-glucuronic acid lactone, penta-O-benzoyl-D- glucose, silver trifluoromethanesulfonate were obtained from Ambeed. Anhydrous toluene, tetrahydrofuran (THF), anhydrous N,N-dimethylformamide (DMF), anhydrous methanol, HBr in acetic acid, ethyl vinyl ether, samarium chloride hexahydrate, holmium chloride hexahydrate, cerium chloride heptahydrate, gadolinium chloride hexahydrate, europium chloride hexahydrate neodymium chloride hexahydrate and amicon ultra - 4 centrifugal filters ultracel - 3K were obtained from sigma-aldrich. Triethylamine, anhydrous pyridine and potassium carbonate were obtained from fisher scientific. Benzoyl chloride was obtained from Beantown chemical. Silica flash column chromatography was performed using silica gel (40-63 gm), which was supplied from Sorbtech. Aqueous solutions were freshly prepared with ultra-pure deionized water from a water purification system. Dialysis was performed with Snakeskin dialysis tubing, 3.5K MWCO. 16mm dry I.D. All chemicals not mentioned were obtained from Sigma-Aldrich.

General Methods, Instrumentation, and Measurements

Mono-GlcA-Me was prepared as per previously reported protocol (Jeon, S. et al., 2024, ACS Cent. Sci ., 10, 1782). Synthetic manipulations that required an inert atmosphere (where noted) were carried out under nitrogen using standard Schlenk techniques. NMR (' H, ¹³C) spectra were recorded on Varian 400 MHz, Bruker Prodigy 500 MHz and Bruker Advance Neo 400 MHz spectrometer. The 'H, and ¹³C chemical shifts were reported as 8 in units of parts per million (ppm), referenced to the residual solvent. Splitting patterns are denoted as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). High-resolution electrospray ionization (ESI) mass spectra were obtained at the mass spectrometry facility (the University of Texas at Austin). Zeta potential was measured by Dynamic Light Scattering Zetasizer Nano ZS. GPC data was measured by using TOSOH EcoSEC Elite HLC-8420GPC, ICP-MS data were obtained by sending samples to Quadrupole ICP-MS lab at the university of Texas at Austin.

Synthesis of compound C4-OH

Scheme 2. Synthetic scheme for compounds C4-OH, reagents and conditions, (a) 4-amino-l- butanol, dry toluene, reflux, 12 h, 91%.

Compound C4-OH To a stirred solution of cis-5-norbornene-exo-2,3-dicarboxylic anhydride (5 g, 30.46 mmol) in dry toluene (20 mL) at room temperature under a nitrogen atmosphere was added 4-amino-l -butanol (2.99 g, 33.51 mmol) followed by triethylamine (0.1 mL). After refluxing at 110 °C for 12 hours, the reaction solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel from 20: 1 hexanes:ethyl acetate to ethyl acetate as the mobile phase to afford C4-OH as a white solid (7.52 g, 91%). 'H-NMR (500 MHz, CDCh): 6 = 6.27 (s, 2H), 3.65 (q, J = 5.9 Hz, 2H), 3.50 (t, J = 7.2 Hz 2H), 3.25 (t, J = 1.9 Hz, 2H), 2.65 (d, J = 1.5 Hz, 2H), 1.60 (m, 4H), 1.49 (d, J = 9.9 Hz, 1H), 1.20 (d, J = 9.9 Hz, 1H). ¹³C-NMR (126 MHz, CDCh): 6 = 178.20, 137.82, 62.08, 47.80, 45.14, 42.73, 38.39, 29.81, 24.31. HR-MS (ESI): calcd. for C13H17NO3 [M+Na]⁺ 258.1101, found 258.1111.

Synthesis of compound mono-Glc

Scheme 3. Synthetic scheme for mono-Glc, reagents and conditions, (a) HBr/AcOH, dry DCM, 16 h, 73%. (b) C4-OH, AgOTf, dry DCM, 2 h, 67%. (c) K2CO3, MeOH/DCM (1 :2), 91%.

Compound 1. To a stirred solution of penta-O-benzoyl-D-glucose (5g, 7.14 mmol) in dry DCM (25mL), 15 mL of hydrobromic acid (33% wt. acetic acid) solution was added dropwise over 10 min. The reaction mixture was stirred for 16 h then slowly quenched with 25 mL of saturated sodium bicarbonate solution. Aqueous layer was removed, then the organic layer was washed 2 times with 50 mL sodium bicarbonate solution, dried over Na SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with 1 :5 ethyl acetate :hexanes as the mobile phase to afford 1 as a white solid (3.45g, 73%) . ^XH NMR (400 MHz, CDCh): 5 = 8.13 - 8.06 (m, 2H), 8.06 - 7.94 (m, 4H), 7.93 - 7.86 (m, 2H), 7.65 - 7.26 (m, 12H), 6.89 (d, J = 4.0 Hz, 1H), 6.29 (t, J = 9.8 Hz, 1H), 5.85 (t, J = 9.9 Hz, 1H), 5.35 (ddd, J = 10.0, 4.1, 1.1 Hz, 1H), 4.80 - 4.65 (m, 2H), 4.54 (dd, J = 12.5, 4.5 Hz, 1H). ¹³C NMR (101 MHz, CDCh): 5 = 166.05, 165.58, 165.32, 165.11, 133.82, 133.66, 133.37, 133.28, 130.10, 129.95, 129.84, 129.76, 129.47, 128.82, 128.58, 128.53, 128.51, 128.48, 128.40, 128.38, 86.88, 72.73, 71.49, 70.64, 68.01, 61.96. HR-MS (ESI): calcd. for C₃4H27BrO₉ [M+Na]⁺ = 681.0838, found 681.0729.

Compound 2. To a stirred solution of 1 (3.30g, 5.0 mmol) and C4-OH (2.25g, 10.0 mmol) in dry DCM (60 mL, containing 3 A molecular sieves) at -78 °C AgOTf (2.56g, 10.0 mmol) was added. After 16 hours the reaction at room temperature, the reaction mixture was filtered through celite The organic layer was washed three times with 50 mL brine solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with 1 : 10 ethyl acetate: hexanes as the mobile phase to afford 2 as a white solid (1.81g, 67%). ³H NMR (500 MHz, CDCh): 6 = 8.04 (dd, J = 8.3, 1.5 Hz, 2H), 7.99 - 7.95 (m, 2H), 7.94 - 7.90 (m, 2H), 7.87 - 7.82 (m, 2H), 7.59 - 7.29 (m, 12H), 6.27 (t, J = 1.8 Hz, 2H), 5.91 (t, J = 9.6 Hz, 1H), 5.69 (t, J = 9.7 Hz, 1H), 5.53 (dd, J = 9.7, 7.9 Hz, 1H), 4.86 (d, J = 7.9 Hz, 1H), 4.66 (dd, J = 12.2, 3.2 Hz, 1H), 4.52 (dd, J = 12.1, 5.2 Hz, 1H), 4.17 (dt, J = 9.9, 2.7 Hz, 1H), 3.95 (dd, J = 10.2, 5.3 Hz, 1H), 3.63 - 3.56 (m, 1H), 3.35 (t, J = 5.8 Hz, 2H), 3.22 (s, 2H), 2.60 (s, 2H), 1.59 - 1.48 (m, 4H), 1.45 (dt, J = 9.9, 1.6 Hz, 1H), 1.13 (d, J = 9.8 Hz, 1H). ¹³C NMR (126 MHz, CDCh): 6 = 177.93, 166.17, 165.84, 165.04, 137.81, 133.44, 133.24, 133.19, 133.13, 129.85, 129.80, 129.78, 129.77, 129.62, 129.31, 128.83, 128.81, 128.42, 128.40, 128.38, 128.31, 101.16, 72.93, 72.20, 71.86, 69.77, 69.29, 63.18, 60.43, 47.74, 45.11, 42.72, 38.01, 26.76, 24.27, 14.22. HR-MS (ESI): calcd. for C47H43NO12 [M+Na]⁺ = 836.2785, found 836.2667.

Compound mono-Glc. To a stirred solution of 2 (1.81g, 2.22 mmol) in 2: 1 DCMMeOH (20 mL) at room temperature 30 mg of K2CO3 (0.22 mmol) was added. After 12 hours the reaction mixture was eluted through a 2 inch silica plug using a 1:5 MeOH:DCM solution as the mobile phase. The collected solvent was concentrated under reduced vacuum then purified by column chromatography on silica gel with 1 :20 to 1 : 10 MeOH:DCM as the mobile phase. After concentration under reduced pressure, the purified material was redissolved in acetonitrile, frozen at -80 °C, and dried via lyophilization, yielding mono-Glc as a white solid (0.88g, 91%). 'H NMR (400 MHz, DMSO-d6): 5 = 6.31 (q, J = 1.5 Hz, 2H), 4.95 - 4.85 (m, 3H), 4.44 (t, J = 5.9 Hz, 1H), 4.09 (d, J = 7.7 Hz, 1H), 3.76 (dd, J = 10.1, 6.0 Hz, 1H), 3.66 (dd, J = 11.6, 6.0 Hz, 1H), 3.47 - 3.34 (m, 4H), 3.15 - 2.99 (m, 5H), 2.92 (td, J = 8.2, 4.7 Hz, 1H), 2.70 (s, 2H), 1.50 (q, J = 7.1 Hz, 4H), 1.42 - 1.35 (m, 1H), 1.13 (d, J = 9.7 Hz, 1H). ¹³C NMR (101 MHz, DMSO): 8 = 178.19, 138.11, 103.29, 77.30, 77.22, 73.89, 70.56, 68.41, 61.57, 47.72, 44.92, 42.87, 38.26, 27.27, 24.59. HR-MS (ESI): calcd. for C19H27NO8 [M+Na]⁺ = 420.1737, found 420.1619.

Synthesis of compound mono-GlcA-Me

Scheme 4. Synthetic scheme for compounds mono-GlcA-Me, reagents and conditions, (a) NaOMe, dry MeOH, RT, 12 h. (b) BzCl, dry pyridine, RT, 12 h, 76% (2 steps), (c) HBr in AcOH, dry DCM, RT, 12 h, 74%. (d) C4-OH, AgOTf, dry DCM, RT, 12 h, 46% (a yield), (e) K2CO3, dry MeOH, RT, 4 h, 82%

General Polymerization Procedure

Fq = CH₂OH

R₂ = COOMe Scheme 5. General polymerization procedure using the graft-through technique.

Grubbs 3rd generation catalyst (1 eq), as calculated, was added to a solution of each monomer (50 mg, 20-160 eq) in dry DMF (1 mL). After stirring for 1 hour, the reaction mixture was quenched using 20 equivalents of ethyl vinyl ether. The reaction mixture was then precipitated by adding excess ether and filtered to obtain each polymer. General methyl ester deprotection procedure

Scheme 6. General deprotection of methyl ester procedure.

Polymers, designated as pGlcA-(20-160), pGlcA-50% and pGlcA-25% were individually prepared for deprotection. Each polymer was initially dissolved in a solvent system comprising a 1 :2 ratio of tetrahydrofuran (THF) and water. Subsequently, lithium hydroxide (Li OH) was added to the solution, ensuring a stoichiometric ratio of 2 equivalents (eq) of Li OH per equivalent of the COOMe. This reaction mixture was then agitated continuously for 2 hours to facilitate the deprotection reaction. Following the completion of the reaction, the mixture was subjected to a desalting process. This was accomplished using Snakeskin dialysis tubing, characterized by a molecular weight cut-off (MWCO) of 3.5K. The success and progress of the deprotection process for each polymer were monitored using ¹ H-NMR spectroscopy.

The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

CLAIMS What is claimed is:

1. A polymer comprising a structure represented by Formula (I):

Formula (I) wherein:

A represents a repeat unit selected from the group consisting of C5-C7 alkyl, C5-C7 heteroalkyl, Cs-C7aryl, C5-C7 heteroaryl, or C5-C7 cycloalkyl; n represents an integer from 5-500;

L represents a divalent organic linker; and

Z represents a negatively charged functional group.

2. The polymer of claim 1, wherein ring A is represented by one of the following structures: wherein the wave line represents connection to the polymer backbone;

X represents O, S, NR¹, or CR²R³;

R¹, R², and R³ each independently represent a substituent selected from the group consisting of hydrogen, halide, hydroxy, C1-C30 alkyl, C1-C30 alkyl halide, C1-C30 alkoxy, and any combination thereof; and each structure is independently optionally further substituted.

3. The polymer of claim 1 , wherein the polymer comprises a structure represented by

Formula (la):

Formula (la) wherein each occurrence of R⁷ is independently a substituent selected from the group consisting of hydrogen, halide, hydroxy, C1-C30 alkyl, C1-C30 alkyl halide, C1-C30 alkoxy, carbonyl, ester, amine, and any combination thereof, wherein at least one R^z is a negatively charged; p is an integer from 1 to 10; and m is an integer from 1 to 9.

4. The polymer of claim 1, wherein L is represented by one of the following structures:

wherein the wavy line represents a bond to ring A;

* represents a bond to Z; and

R’ represents a substituent selected from the group consisting of hydrogen, halide, hydroxy, C1-C30 alkyl, C1-C30 alkyl halide, C1-C30 alkoxy, and any combination thereof.

5. The polymer of claim 1, wherein L comprises a C1-C30 alkyl which is optionally further substituted.

6. The polymer of claim 1, wherein Z is selected from the group consisting of a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, any stereochemical isomer thereof, and any combination thereof.

7. The polymer of claim 1, wherein Z comprises a sugar selected from the group consisting of glucuronic acid, gluconic acid, glucaric acid, and glutamic acid, and any ionic form thereof; or

Z comprises an anionic derivative of galactose, glucose, mannose, allose, altrose, gulose, idose, talose, psicose, fructose, sorbose, or tagatose.

8. The polymer of claim 1, wherein the polymer is a copolymer comprising a repeat unit of at least two monomers, wherein at least one monomer comprises glucuronic acid.

9. The polymer of claim 1, wherein the polymer has a zeta potential of about -60 mV to about 0 mV.

10. A composition comprising the polymer of claim 1.

11. A method of synthesizing a polymer using ring-opening metathesis polymerization

(ROMP), comprising the steps of: providing a monomer; polymerizing the monomer using a ROMP catalyst; and isolating the polymer; wherein the monomer is represented by Formula (II):

Formula (II) wherein:

R represents a substituent on ring A selected from the group consisting of hydrogen, halide, hydroxy, C1-C30 alkyl, C1-C30 alkyl halide, C1-C30 alkoxy, and any combination thereof;

L represents a divalent organic linker; and

Z represents a negatively charged functional group.

12. The method of claim 11, wherein the degree of polymerization is about 5 to about 500.

13. The method of claim 11, wherein ring A is represented by one of the following structures: wherein:

X represents O, S, NR¹, or CR²R³;

R¹, R², and R³ each independently represent a substituent selected from the group consisting of hydrogen, halide, hydroxy, C1-C30 alkyl, C1-C30 alkyl halide, C1-C30 alkoxy, and any combination thereof; and each structure is independently optionally further substituted.

14. A method of removing at least one solute from a solution comprising the steps of providing a polymer; and contacting the polymer with at least one solute; wherein the polymer comprises a structure represented by Formula (I):

Formula (I) wherein:

A represents a repeat unit selected from the group consisting of C5-C7 alkyl, C5-C7 heteroalkyl, C5-C?aryl, C5-C7 heteroaryl, or C5-C7 cycloalkyl; n represents an integer from 5-500;

L represents a divalent organic linker; and

Z represents a negatively charged functional group.

15. The method of claim 14, wherein the solution is aqueous.

16. The method of claim 14, wherein the polymer solution comprises about 0.01 mg/mL to about 1.00 mg/mL of the polymer.

17. The method of claim 14, wherein the at least one solute is selected from the group consisting of monovalent cations, divalent cations, trivalent cations, monovalent anions, divalent anions, trivalent anions, and combinations thereof.

18. The method of claim 14, wherein the at least one solute is a metal ion.

19. The method of claim 14, wherein the at least one solute is selected from the group consisting of manganese, magnesium, nickel, zinc, copper, cadmium, iron, lead, barium, any ionic state thereof, and any combination thereof.

20. The method of claim 14, wherein the at least one solute is a rare earth element selected from the group consisting of lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, lutetium, scandium, and yttrium.