Medical uses of functionalized polymers.

Abstract

The present disclosure relates to a functionalized polymer for use in treating a disease associated with heavy metal-induced toxicity or heavy metal-induced carcinogenesis in a subject in need thereof, wherein the functionalized polymer is soluble in aqueous solution and has a mass average molecular weight of 30 kDa to 5000 kDa, and a portion of the monomer units are functionalized with chelating moieties, and wherein a therapeutically effective amount of the functionalized polymer is orally administered to the subject.

Description

[Technical Field]

[0001] The present invention relates to medical uses of functionalized polymers. In particular, the present invention relates to a functionalized polymer for use in treating a disease associated with heavy metal-induced toxicity or carcinogenesis in a subject in need thereof, the functionalized polymer being soluble in aqueous solution and having a mass average molecular weight of 30 kDa to 5000 kDa, a portion of the monomer units being functionalized with chelating moieties, and a therapeutically effective amount of the functionalized polymer being orally administered to the subject. [Background technology]

[0002] Heavy metals are widespread in our environment as a result of human industrialization of our world (waste disposal, factory pollution, nuclear reactions, etc.), and humans are inevitably exposed to them through contaminated air, water, and food (animals, crops, etc.). Trace levels of lead and cadmium are present in human blood worldwide, and dietary intake is directly linked to many serious conditions, including cancer and chronic kidney disease (CKD) (Satarug, S.; Vesey, DA; Gobe, GC Health Risk Assessment of Dietary Cadmium Intake: Do Current Guidelines Indicate How Much Is Safe? Environ Health Perspect 2017, 125 (3), pp. 284-288; Satarug, S.; C. Gobe, G.; A. Vesey, D.; Phelps, KR Cadmium and Lead Exposure, Nephrotoxicity, and Mortality. Toxics 2020, 8 (4), 86; European Food Safety Authority. Cadmium Dietary Exposure in the European Population. EFSA Journal No. 2012;10(1):2551; Boon, PE; Pustjens, AM; te Biesebeek, JD; Brust, GMH; Castenmiller, JJM Dietary Intake and Risk Assessment of Elements for 1- and 2-Year-Old Children in the Netherlands. Food and Chemical Toxicology 2022, 161, 112810).

[0003] High blood levels of heavy metals, particularly lead and cadmium, are most prevalent in people with high exposure levels due to work-related exposure in mines and factories. However, even small exposures can cause significant blood levels over time. When these heavy metals are introduced into the body, many are eliminated through natural elimination pathways, but a small proportion are absorbed into the bloodstream and accumulate in organs (liver, kidneys, and bones) over the long term. This long-term exposure, particularly among children, has been confirmed in various regions due to contaminated food and water. Also of concern is the vicious cycle of heavy metals present in aging populations or in subjects with certain pathologies, such as chronic kidney disease (CKD). In these populations, the efficiency of natural elimination pathways is reduced, leading to the accumulation of large amounts of heavy metals in these systems and increased toxicity.

[0004] These metals, along with other heavy metals, have been associated with a wide range of pathologies, including but not limited to neurodegeneration and neurodegenerative diseases such as Parkinson's disease, cardiovascular disease, renal failure and chronic kidney disease (CKD), male reproductive dysfunction, miscarriage, and childhood growth retardation (Reuben, A. Childhood Lead Exposure and Adult Neurodegenerative Disease. JAD 2018, 64 (1), pp. 17-42; Kumar, A.; Kumar, A.; MMs, C.-P.; Chaturvedi, A.K.; Shabnam, A.A.; Subrahmanyam, G.; Mondal, R.; Gupta, D.K.; Malyan, S.K.; Kumar, S.S.; A. Khan, S.; Yadav, K.K. Lead Toxicity: Health Hazards, Influence on Food Chain, and Sustainable Remediation Approaches. International Journal of Environmental Research and Public Health 2020, 17 (7), pp. 2179; Leggett, R.W. An Age-Specific Kinetic Model of Lead Metabolism in Humans. Environ Health Perspect 1993, 101 (7), pp. 598-616; Rossi, E. Low Level Environmental Lead Exposure - A Continuing Challenge. Clin Biochem Rev 2008, 29 (2), pp. 63-70).

[0005] At the cellular level, these metals use their strong affinity for sulfur, nitrogen, and oxygen to bind to and inhibit a wide range of enzymes, proteins, and cell signaling pathways, while increasing the concentration of reactive oxygen species (ROS) (Chen, P.; Bornhorst, J.; Diana Neely, M.; Avila, D.S. Mechanisms and Disease Pathogenesis Underlying Metal-Induced Oxidative Stress. Oxidative Medicine and Cellular Longevity 2018, 2018, pp. 1-3; Ercal, N.; Gurer-Orhan, H.; Aykin-Burns, N. Toxic Metals and Oxidative Stress Part 1: Mechanisms Involved in Metal Induce Oxidative Damage. Current Topics in Medicinal Chemistry. 1st Edition 2001, pp. 529-539; Flora, S.J.S.; Mittal, M.; Mehta, A. Heavy Metal Induced Oxidative Stress & Its Possible Reversal by Chelation Therapy. INDIAN J MED RES 2008, 24).On a global scale, these metals are highly nephrotoxic as they are directly associated with a decrease in glomerular filtration rate (GFR) and show large organ accumulation after absorption into the bloodstream (Reyes, JL; Molina-Jijon, E.; Rodriguez-Munoz, R.; Bautista-Garcia, P.; Debray-Garcia, Y.; Namorado, M. del C. Tight Junction Proteins and Oxidative Stress in Heavy Metals-Induced Nephrotoxicity. BioMed Research International 2013, 2013, pp. 1-14; Johri, N.; Jacquillet, G.; Unwin, R. Heavy Metal Poisoning: The Effects of Cadmium on the Kidney. Biometals: an international journal on the role of metal ions in biology, biochemistry, and medicine 2010, 23, pp. 783-792; Lentini, P.; Zanoli, L.; Granata, A.; Signorelli, SS; Castellino, P.; Dellaquila, R. Kidney and Heavy Metals - The Role of Environmental Exposure. Molecular Medicine Reports 2017, 15 (5), pp. 3413-3419). Accumulation in bone may reintroduce these metals into the bloodstream during osteoporosis and similar pathologies associated with aging anatomy.

[0006] Current therapies for acute heavy metal poisoning (>200 μg / L) include the administration of chelating moieties, also called chelators, such as EDTA and DMSA. However, such therapies are ineffective in lowering blood levels (<100 μg / L). Trace levels of lead (<50 μg / L) and cadmium (<1 μg / L) are associated with insidious symptoms in humans, but these levels are considered "tolerable" and do not require treatment strategies defined by the WHO and CDC. The only treatment strategy suggested for this population is distance from the source of exposure (ABLES - Reference Blood Lead Levels (BLLs) for Adults in the US | NIOSH | CDC. https: / / www.cdc.gov / niosh / topics / ables / ReferenceBloodLevelsforAdults.html (accessed 2022-05-23); Center for Disease Control (CDC). Blood Lead Reference Value | Lead | CDC. https: / / www.cdc.gov / nceh / lead / data / blood-lead-reference-value.htm (accessed 2022-05-19); World Health Organization; Regional Office for Europe; Joint WHO / Convention Task Force on the Health Aspects of Air Pollution. Health Risks of Heavy Metals from Long-Range Transboundary Air Pollution; World Health Organization Regional Office Europe: Copenhagen, 2007).

[0007] Therefore, it is extremely difficult to distance yourself from the source of exposure when it comes from food and water.

[0008] WO2019 / 122790 discloses a medical device containing a chelating moiety for extracting metals that can be introduced into the body to maintain metal homeostasis for therapeutic purposes.

[0009] WO2022 / 023677 describes statistical polysaccharides having a mass average molecular weight of 100 kDa to 1000 kDa and their use in a dialysis process for capturing at least one metal, an MRI imaging process, a brachytherapy process, or a process for marking food to prevent counterfeiting. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] WO2019 / 122790 [Patent Document 2] WO2022 / 023677 [Non-patent literature]

[0011] [Non-Patent Document 1] Satarug, S.; Vesey, DA; Gobe, GC Health Risk Assessment of Dietary Cadmium Intake: Do Current Guidelines Indicate How Much Is Safe? Environ Health Perspect 2017, 125 (3), pp. 284-288 [Non-patent document 2] Satarug, S.; C. Gobe, G.; A. Vesey, D.; Phelps, KR Cadmium and Lead Exposure, Nephrotoxicity, and Mortality. Toxics 2020, 8 (4), 86 [Non-patent document 3] European Food Safety Authority. Cadmium Dietary Exposure in the European Population. EFSA Journal No. 2012;10(1):2551 [Non-patent document 4] Boon, PE; Pustjens, AM; te Biesebeek, JD; Brust, GMH; Castenmiller, JJM Dietary Intake and Risk Assessment of Elements for 1- and 2-Year-Old Children in the Netherlands. Food and Chemical Toxicology 2022, 161, 112810 [Non-patent document 5] Reuben, A. Childhood Lead Exposure and Adult Neurodegenerative Disease. JAD 2018, 64 (1), pp. 17-42 [Non-patent document 6] Kumar, A.; Kumar, A.; MMs, C.-P.; Chaturvedi, AK; Shabnam, AA; Subrahmanyam, G.; Mondal, R.; 2020, 17 (7), 2179 [Non-Patent Document 7] Leggett, RW An Age-Specific Kinetic Model of Lead Metabolism in Humans. Environ Health Perspect 1993, 101 (7), pp. 598~616

Non-patent document 8

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[0012] Therefore, the challenge remains to design safe and effective treatments that meet this clinical need to treat diseases associated with heavy metal-induced toxicity or carcinogenesis in subjects in need thereof. [Means for solving the problem]

[0013] A first aspect of the present disclosure relates to a functionalized polymer for use in treating a disease associated with heavy metal-induced toxicity or heavy metal-induced carcinogenesis in a subject in need thereof, wherein the functionalized polymer is soluble in aqueous solution and has a mass average molecular weight of 30 kDa to 5000 kDa, and a portion of the monomer units are functionalized with chelating moieties, and wherein a therapeutically effective amount of the functionalized polymer is orally administered to the subject.

[0014] A second aspect of the present disclosure relates to an oral formulation comprising a functionalized polymer as defined above and one or more pharmaceutically acceptable excipients, wherein the unit dose of said functionalized polymer is between 0.1 mg and 500 mg, preferably between 1 mg and 100 mg, more preferably between 2 mg and 10 mg, and even more preferably about 5 mg. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 shows qualitative biodistribution using fluorescence in kidney, liver, brain, spleen, heart, urine, lung, bone, skin, blood, muscle, stomach, intestine, and colon after 1, 2, 4, and 24 hours (Example 1). [Figure 2] FIG. 1 is a diagram of the mean percent of administered Gd in the gastrointestinal tract over 24 hours (Example 1). [Figure 3] FIG. 1 shows changes in body weight over 14 days following daily administration of MEX-CD1 in mice (Example 2). [Figure 4] Figure 2 shows hematology after 14 days of daily administration of MEX-CD1 to mice (Example 2). Hematological assays were performed after the mice were sacrificed. These results provide evidence of acute heavy metal intoxication in saline-treated mice. All relationships are not significant except as defined below: * p<0.05, ** p<0.01, *** p<0.001, **** p<0.0001. [Figure 5]

[0023] Figure 2 shows blood levels of lead and cadmium in mice after 14 days of daily administration of MEX-CD1 (Example 2). All mice were sacrificed 15 days after exposure. NS p>0.05, * p<0.05, ** p<0.01, *** p<0.001. [Figure 6] 1 is a graphical representation showing the chelating capacity of MEX-CD1 towards different concentrations of lead and cadmium (Example 4).Technique used: HPLC-MS. [Figure 6a] HPLC-MS chromatogram of detection of lead interacting with MEX-CD1 (Example 4). [Figure 6b]HPLC-MS chromatogram of detection of cadmium interacting with MEX-CD1 (Example 4). [Figure 7] FIG. 10: Direct evidence of lead chelation by MEX-CD1 using high performance liquid chromatography coupled with mass spectrometry (HPLC-MS) (Example 4). [Figure 8] 1 is a graphical representation showing the chelating capacity of MEX-CD1 towards lead (Example 4).Technique used: ICP-MS. [Figure 9] 1 is a graphical representation showing the chelating capacity of MEX-CD1 towards lead and cadmium (Example 4).Technique used: ICP-MS. DETAILED DESCRIPTION OF THE INVENTION

[0016] definition The following definitions are given for terms used in this specification.

[0017] The term "about" or "approximately" is used herein to mean that the subsequent value may vary by ±20%, preferably ±10%, more preferably ±5%, even more preferably ±2%, and even more preferably ±1%.

[0018] Unless otherwise defined, "%" herein has the meaning of weight percent (wt%), also known as weight-weight percent (w / w%).

[0019] As used herein, unless otherwise specified, the term "treat" or "treatment" means reversing, alleviating, inhibiting the progression of, or preventing or reducing the disorder or condition to which such term applies, or reversing, alleviating, inhibiting the progression of, or preventing one or more symptoms of, the disorder or condition to which such term applies. More preferably, in the context of the present invention, "treating" may include reducing heavy metals in the subject's blood or preventing an increase in certain heavy metals in the blood due to the transfer of heavy metals from water or nutritional supplementation into the blood circulation.

[0020] As used herein, the term "prevent" means at least significantly limiting the uptake of a particular heavy metal into the blood of a subject. For example, significantly limiting means at least reducing the uptake of the heavy metal by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or even 100% in a subject exposed to the heavy metal compared to a subject exposed to the heavy metal that is not treated with the functionalized polymer of the present disclosure.

[0021] As used herein, the terms "heavy metals," "heavy metal species," and "heavy metal ions" are used interchangeably to refer to atoms and cations of these metals that are toxic to humans. These toxic metals have no function in biological systems and pose a threat to the health and function of the system, even at trace levels. Such threats include enzyme and protein inhibition, cell membrane oxidation and signaling pathway degradation, DNA repair inhibition and promotion of DNA degradation, apoptosis, mutagenesis, etc., which can lead to cardiovascular disease, neurodegeneration and cognitive difficulties, kidney dysfunction, cancer, and death. For example, heavy metals include lead (Pb), cadmium (Cd), arsenic (As), chromium (Cr), mercury (Hg), cobalt (Co), aluminum (Al), antimony (Sb), barium (Ba), bismuth (Bi), gallium (Ga), germanium (Ge), gold (Au), indium (In), nickel (Ni), platinum (Pt), silver (Ag), strontium (Sr), tellurium (Te), thallium (Tl), tin (Sn), titanium (Ti), vanadium (V), and plutonium (Pb). It may be selected from the group consisting of ruthnium (Pu), cesium (Cs), cerium (Ce), zirconium (Zr), ruthenium (Ru), technetium (Tc), radium (Ra), thorium (Th), americium (Am), iridium (Ir), californium (Cf), polonium (Po), and uranium (U), or a mixture thereof, and is preferably selected from the group consisting of lead, cadmium, arsenic, chromium, and mercury, and more preferably lead or cadmium. In certain embodiments, the heavy metal may be radioactive and may be selected from the group consisting of Co(60), U(232, 233, 234, 235, 236 or even 238), Pu(238, 239, 240, 241), Sr(90), Cs(135, 137), Ce(144), Zr(93, 95), Ru(106), Tc(99), Sn(126), Am(241), Ir(192), Po(210), Ra(226), Pu(238), Am(241), Cf(252).

[0022] As used herein, the terms "chelator" or "chelating agent" or "chelating moiety" are used to define a chemical structure or moiety that exhibits a relatively high affinity for a specific element and exhibits at least two coordination sites. The affinity is such that the chelator can semi-permanently chelate the metal and remove the metal from any affinity it exhibits with biological molecules. Chelators primarily function to "neutralize" heavy metals by maintaining their chelation to these metals, preventing their reaction and interaction with other biological materials. Chelators may represent pincer-type structures or moieties with two or more opposing moieties formed by negatively charged chemical groups (sulfhydryl groups, ketone groups, carboxy groups, hydroxy groups, etc.) or neutrally charged chemical groups (amino groups) in a biological environment. These groups are appropriately spaced to comfortably accommodate a metal ion within the structure.

[0023] A chelating moiety in the context of this disclosure is DOTA: 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid; NOTA: 1,4,7-triazacyclononane-1,4,7-triacetic acid; NODAGA: 1,4,7-triazacyclononane-1-glutaric-4,7-diacetic acid; DOTAGA: 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid; DOTAM: 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclodecane; NOTAM: 1,4,7-tetrakis(carbamoylmethyl)-1,4,7-triazacyclononane; DOTP: 1,4,7,10-tetraazacyclododecane 1,4,7,10-tetrakis(methylenephosphonate); NOTP: 1,4,7-tetrakis(methylenephosphonate)-1,4,7-triazacyclononane; TETA: 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid; TETAM: 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetrakis(carbamoylmethyl); DTPA: diethylenetriaminopentaacetic acid; Bz-DFO: benzyldeferoxamine; DFO: can be deferoxamine.

[0024] As used herein, the term "effective amount" or "therapeutically effective amount" of a compound refers to an amount of a compound that elicits a biological or medical response in a subject, e.g., ameliorates symptoms, alleviates a condition, delays or slows disease progression, or prevents disease. In certain embodiments, such a therapeutically effective amount is an amount sufficient to prevent the uptake of the heavy metal into the subject's body.

[0025] As used herein, the term "independently" with respect to the Rc moieties, i.e., chelating moieties, of the functionalized statistical chitosan of formula (I) means that each Rc is a chelating moiety that can be different from one another or the same. For example, each Rc can be the same, i.e., there can be one type of Rc throughout the functionalized statistical chitosan, or there can be two or more types of Rc, i.e., two, three, four, five, or even n types of Rc throughout the functionalized statistical chitosan, where n is an integer.

[0026] The term "pharmaceutically acceptable excipients," as used herein, refers to inactive substances that are added together with a drug substance and are part of the formulation mixture. Pharmaceutically acceptable excipients include, for example, fillers, solvents, diluents, carriers, adjuvants, distributing and sensing agents, delivery agents, such as preservatives, disintegrants, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, flavorings, fragrances, antibacterial agents, fungicides, lubricants, and prolonged delivery controllers, antioxidants, and glidants. Their selection and appropriate proportions depend on the nature and method of administration and the dosage.

[0027] As used herein, "combination" refers to either a fixed combination in a single dosage unit form, or a combined administration, in which a compound of the present disclosure and a combination partner (e.g., another drug described below, also referred to as a "therapeutic agent" or "co-agent") are administered independently at the same time or separately within a time interval, particularly one that allows the combination partners to exhibit cooperativity, e.g., synergistic effects. The single components may be packaged in a kit or separately. One or both of the components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose before administration. As used herein, terms such as "co-administration" or "administration in combination" are meant to encompass the administration of selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include therapeutic regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

[0028] The terms "patient," "subject," "individual," and the like are used interchangeably herein and refer to a human. In some embodiments, a patient, subject, or individual in need of treatment includes those who already have a disease, condition, or disorder, i.e., a disease associated with heavy metal-induced toxicity or heavy metal-induced carcinogenesis.

[0029] Functionalized polymers for use according to the present disclosure A first aspect of the present disclosure relates to a functionalized polymer for use in treating a disease associated with heavy metal-induced toxicity or heavy metal-induced carcinogenesis in a subject in need thereof, wherein the functionalized polymer is soluble in aqueous solution and has a mass average molecular weight of 30 kDa to 5000 kDa, and a portion of the monomer units are functionalized with chelating moieties, and wherein a therapeutically effective amount of the functionalized polymer is orally administered to the subject.

[0030] In certain embodiments, the functionalized polymer has a weight average molecular weight of 100 kDa to 1000 kDa, preferably 150 kDa to 750 kDa, more preferably 200 kDa to 600 kDa, even more preferably 250 kDa to 400 kDa, and even more preferably about 300 kDa.

[0031] In another embodiment, the functionalized polymer has a weight average molecular weight of from 30 kDa to 100 kDa, preferably from 32 kDa to 80 kDa, more preferably from 34 kDa to 60 kDa, even more preferably from 35 kDa to 50 kDa, and even more preferably about 40 kDa.

[0032] In one embodiment, the functionalized polymer comprises at least 1 wt % of the chelating moiety, for example, 1 wt % to 40 wt %, preferably 5 wt % to 30 wt %, more preferably 10 wt % to 25 wt %, and even more preferably about 10 wt %, 17 wt %, or 22 wt % of the chelating moiety.

[0033] The chelating moieties allow for the chelation of one or more metals. Each chelating moiety may contain two or more coordination sites. Preferably, the coordination sites are nitrogen or oxygen atoms. Advantageously, each chelating moiety contains 4 to 8 coordination sites, more preferably 6 to 8 coordination sites, and even more preferably, each chelating moiety contains 6 coordination sites.

[0034] As used herein, the term "coordination site" refers to a single functional group capable of chelating a metal. For example, an amine functional group represents a coordination site through the formation of a coordination bond between the nitrogen atom and the metal, and a hydroxamic acid functional group also represents a coordination site through the formation of a coordination bond between the oxygen of the carbonyl unit and a covalent bond with the oxygen of the N-oxide unit, thus forming a five-membered ring.

[0035] In certain embodiments, each chelating moiety is selected from the group consisting of DOTA (1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), NODAGA (1,4,7-triazacyclononane-1-glutaric-4,7-diacetic acid), DOTAGA (2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane)), and DOTAGA (2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane). -1-yl)pentanedioic acid), DOTAM (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclodecane), NOTAM (1,4,7-tetrakis(carbamoylmethyl)-1,4,7-triazacyclononane), DOTP (1,4,7,10-tetraazacyclododecane 1,4,7,10-tetrakis(methylenephosphonate), NOTP (1,4,7-tetrakis(methylenephosphonate) The chelating moiety is selected from the group consisting of DOTAGA, Bz-DFO, DFO, DOTAM, and DTPA; more preferably, the chelating moiety is DOTAGA, or DOTAM, or DTPA, or a mixture of DOTAGA and Bz-DFO, or a mixture of DOTAGA and NOTAGA, or a mixture of DOTAGA and DTPA, or a mixture of DOTAGA and DOTAM.

[0036] In certain embodiments, the chelating moiety is

[0037] [ka] [ka]

[0038] is selected from the group consisting of:

[0039] In certain embodiments, the heavy metal chelated by the chelating moiety or mixtures thereof is lead (Pb), cadmium (Cd), arsenic (As), chromium (Cr), mercury (Hg), cobalt (Co), aluminum (Al), antimony (Sb), barium (Ba), bismuth (Bi), gallium (Ga), germanium (Ge), gold (Au), indium (In), nickel (Ni), platinum (Pt), silver (Ag), strontium (Sr), tellurium (Te), thallium (Tl), tin (Sn), thiamine (Tb), thiamine (Tc), thiamine (Td), thiamine (Te), thiamine (Te), thiamine (Tc ... The metal is selected from the group consisting of tungsten (Ti), vanadium (V), plutonium (Pu), cesium (Cs), cerium (Ce), zirconium (Zr), ruthenium (Ru), technetium (Tc), radium (Ra), thorium (Th), americium (Am), iridium (Ir), californium (Cf), polonium (Po), and uranium (U), or mixtures thereof, and is preferably selected from the group consisting of lead, cadmium, arsenic, chromium, and mercury, and more preferably lead or cadmium.

[0040] In certain embodiments, the heavy metal is radioactive, for example, selected from the group consisting of Co(60), U(232, 233, 234, 235, 236 or even 238), Pu(238, 239, 240, 241), Sr(90), Cs(135, 137), Ce(144), Zr(93, 95), Ru(106), Tc(99), Sn(126), Am(241), Ir(192), Po(210), Ra(226), Pu(238), Am(241), Cf(252).

[0041] The functionalized polymer may be selected from the group consisting of polysaccharides, polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyacrylic acid (PAA), polyallylamine (PAH), where some of the monomer units are functionalized with chelating moieties.

[0042] In certain embodiments, the polysaccharide may be selected from digestible polysaccharides, such as starch, or non-digestible polysaccharides, such as chitosan, cellulose, chitin, β-glucan, xylan, pectin, mucilage, gum, lignin, galactan, agar, fructan, fucoidan, galactoglucan, sulfated polysaccharides, or mixtures thereof, preferably chitosan. In a preferred embodiment, the polysaccharide is selected from non-digestible polysaccharides. In fact, non-digestible polysaccharides have beta-glycosidic bonds, which are less easily digested than digestible polysaccharides with alpha-glycosidic bonds, which are more rapidly digested by alpha-amylases present in the digestive tract.

[0043] In one embodiment, the functionalized polymer is polyethylene glycol (PEG), preferably polyethylene glycol (PEG) having DTPA or DOTAM or a mixture thereof as the chelating moiety, more preferably polyethylene glycol (PEG) having a weight average molecular weight of 30 kDa to 100 kDa, preferably 32 kDa to 80 kDa, more preferably 34 kDa to 60 kDa, even more preferably 35 kDa to 50 kDa, and even more preferably about 40 kDa.

[0044] In certain embodiments, the functionalized polymers of the present disclosure are selected from among polymers that do not reach the bloodstream after oral administration. As used herein, a polymer is considered not to reach the bloodstream after oral administration when less than 5%, preferably less than 3%, and more preferably less than 1% of the polymer is found in the blood after oral administration, typically as determined by the animal assay described in the Examples, i.e., fluorescence studies in a red filter for gadolinium quantification using ICPMS.

[0045] Indeed, without wishing to be bound by any theory, the inventors believe that by remaining in the gastrointestinal tract, the polymer advantageously acts locally by chelating some of the heavy metals present in water and / or food and / or air contamination, e.g., from combat zones, pollution, pollution, accidents, dirty bombs, etc., prior to their assimilation, thus preventing their passage through the intestinal barrier. The fact that the polymer does not cross the intestinal barrier allows for local action in the gastrointestinal tract, avoiding the typical adverse effects of the presence of chelating moieties in systemic compartments as observed with prior art treatments.

[0046] In one embodiment, at least 90%, preferably at least 95%, and more preferably at least 99% of the polymer is excreted in the feces within 7 days after oral administration to the subject.

[0047] In another embodiment, the polymer for use according to the present disclosure is selected from among polymers that are resistant to degradation in the gastrointestinal tract, such that its weight average molecular weight remains substantially unchanged after passage through the gastrointestinal tract.

[0048] Preferred embodiment of the polymer: functionalized PEG In certain embodiments, the functionalized polymer is polyethylene glycol (PEG), more preferably a polymer having the following formula (V):

[0049] [ka]

[0050] wherein n is 100 to 120, more preferably 105 to 115, even more preferably 109 to 113, and even more preferably about 111.

[0051] In one embodiment, the 8-arm PEG of formula V is represented by formula (VI):

[0052] [ka]

[0053] (wherein n is 100 to 120, more preferably 105 to 115, even more preferably 109 to 113, and even more preferably about 111), functionalized PEG, PEG-DTPA.

[0054] In another embodiment, the 8-arm PEG of formula V is represented by formula (VII):

[0055] [ka]

[0056] (wherein n is 100-120, more preferably 105-115, even more preferably 109-113, and even more preferably about 111), functionalized PEG, PEG-DOTAM.

[0057] Preferred embodiment of the polymer: functionalized statistical chitosan In certain embodiments, the functionalized polymer is chitosan, preferably having a weight average molecular weight of 100 kDa to 1000 kDa and formula (I):

[0058] [ka]

[0059] (In the formula, each Rc is a chelating moiety; each Z is independently a single bond or a linker which is a hydrocarbon chain containing 1 to 12 carbon atoms, said hydrocarbon chain being linear or branched, optionally containing one or more unsaturations, and preferably containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and halogen; x is 0.005 to 0.7, preferably 0.05 to 0.7, y is 0.01 to 0.7, preferably 0.05 to 0.2, the ratio y / x is 0.05 or more, preferably 0.15 or more; The sum x+y is 0.15 or more, preferably 0.30 or more, and more preferably 0.35 or more).

[0060] In the above formula I, it is understood that two or more Rc groups can be present in the functionalized statistical chitosan. These Rc groups can be the same or different from each other. They are all independently selected from groups having chelating moieties. The same applies to Z-linkers, and there can be several Z-linkers, which can be the same or different from each other.

[0061] In some embodiments, in Formula I, x is between 0.005 and 0.6; y is between 0.1 and 0.9; the ratio y / x is greater than 0.16; and the sum x+y is greater than 0.30.

[0062] In certain embodiments, the functionalized statistical chitosan of the present disclosure has at least 10 15 has a complex formation constant of

[0063] In one embodiment, the functionalized statistical chitosan of formula I has formula (II):

[0064] [ka]

[0065] (In the formula, Rc1 and Rc2 are different chelating moieties, Z1 and Z2, which may be the same or different, are a linker which is a single bond or a hydrocarbon chain containing 1 to 12 carbon atoms, said hydrocarbon chain being linear or branched, optionally containing one or more unsaturations and preferably one or more heteroatoms selected from nitrogen, oxygen, sulfur, and halogen; x is 0.005 to 0.7, preferably 0.05 to 0.7, and more preferably 0.2 to 0.6; y=z+w is 0.01 to 0.7, preferably 0.05 to 0.2, the ratio y / x is 0.05 or more, preferably 0.15 or more; the sum x+y is 0.15 or greater, preferably 0.30 or greater, and more preferably 0.35 or greater; z / y is 0.5 to 1).

[0066] In this embodiment, the functionalized statistical chitosan of formula (II) can contain either a single type of moiety, including a chelating moiety, Rc1, when z is equal to 1, or two types of moieties, including a chelating moiety, Rc1, and Rc2, when 0.5≦z<1.

[0067] In some embodiments, z / y is 0.8 to 0.99, and therefore the Rc1 moiety is the majority.

[0068] In another embodiment, in Formula II, x is from 0.005 to 0.6; y is from 0.1 to 0.9; the ratio y / x is greater than 0.3; and z is from 0.5 to 1.

[0069] Rc portion (Rc, Rc1, and Rc2) As used herein, the term "Rc moiety" refers to the Rc moiety of Formula I, and the term "Rc1 and Rc2 moieties" refers to Rc1 and Rc2 of Formula II when Rc2 is present. According to the present disclosure, the Rc1 and Rc2 groups are chelating moieties. In other words, the Rc, Rc1, and Rc2 moieties enable chelation of one or more metals by forming a complex.

[0070] Each of the Rc, Rc1, and Rc2 moieties can contain two or more coordination sites. Preferably, the coordination sites are nitrogen or oxygen atoms. Advantageously, each of the Rc, Rc1, and Rc2 moieties contains 4 to 8 coordination sites, more preferably 6 to 8 coordination sites, and even more preferably, each of the Rc, Rc1, and Rc2 moieties contains 6 coordination sites.

[0071] As used herein, the term "coordination site" refers to a single functional group capable of chelating a metal. For example, an amine functional group represents a coordination site through the formation of a coordination bond between the nitrogen atom and the metal, and a hydroxamic acid functional group also represents a coordination site through the formation of a coordination bond between the oxygen of the carbonyl unit and a covalent bond with the oxygen of the N-oxide unit, thus forming a five-membered ring.

[0072] In one embodiment, for the functionalized statistical chitosan of formula I, each Rc moiety is independently selected from the group consisting of DOTA (1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), NODAGA (1,4,7-triazacyclononane-1-glutaric-4,7-diacetic acid), DOTAGA (2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid), DOTAM (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecan-1-yl), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid ... cyclodecane), NOTAM (1,4,7-tetrakis(carbamoylmethyl)-1,4,7-triazacyclononane), DOTP (1,4,7,10-tetraazacyclododecane 1,4,7,10-tetrakis(methylenephosphonate), NOTP (1,4,7-tetrakis(methylenephosphonate)-1,4,7-triazacyclononane), TETA (1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid), TETAM (1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetrakis(carbamoylmethyl)), DTPA (diethylenetriaminopentaacetic acid), Bz-DFO (benzyldeferoxamine), and DFO (deferoxamine), preferably selected from the group consisting of DOTAGA, Bz-DFO, DFO, DOTAM, and DTPA, more preferably the Rc group is DOTAGA.

[0073] In another embodiment, for the functionalized statistical chitosan of formula II, Rc1 and Rc2 are independently selected from the group consisting of DOTA, NOTA, NODAGA, DOTAGA, DOTAM, NOTAM, DOTP, NOTP, TETA, TETAM, DTPA, Bz-DFO, and DFO, preferably selected from the group consisting of DOTAGA, Bz-DFO, DFO, DOTAM, and DTPA.

[0074] In certain embodiments, the chelating moiety is

[0075] [ka] [ka]

[0076] is selected from the group consisting of:

[0077] In one embodiment, for the functionalized statistical chitosan of formula I, the Rc group is DOTAGA, preferably where z / y=1.

[0078] In another embodiment, for the functionalized statistical chitosan of formula II, the Rc1 group is DOTAGA and the Rc2 group is Bz-DFO.

[0079] Z Linkers (Z, Z1, and Z2) As used herein, the term "Z linker" refers to the Z linker of Formula I, and the term "Z1 and Z2 linkers" refers to the Z1 and Z2 linkers of Formula II when a Z2 binder is present.

[0080] The choice of Z, Z1, and Z2 linkers in formulas I and II essentially depends on the Rc, Rc1, and Rc2 moieties and the metal to be chelated. Indeed, for steric reasons in particular, the Rc, Rc1, and Rc2 moieties may be more or less close to the six-membered ring of the nitrogen of the glucosamine unit.

[0081] In Formula I, each Z is independently a single bond or a linker that is a hydrocarbon chain containing 1 to 12 carbon atoms, the hydrocarbon chain being linear or branched, optionally containing one or more unsaturations and preferably one or more heteroatoms selected from nitrogen, oxygen, sulfur, and halogen.

[0082] In one embodiment, in Formula I, each Z is independently selected from the group consisting of a bond, a linear or branched alkyl chain having 1 to 12 carbon atoms, and a linear or branched alkenyl chain having 2 to 12 carbon atoms, wherein the alkyl and alkenyl chains are separated by one or more C6 to C10 aryl groups and / or by one or more -O-, -S-, -C(O)-, -NR'-, -C(O)NR'-, -NR'-C(O)-, -NR'-C(O)-NR'-, The alkyl and alkenyl chains may be optionally interrupted by one or more heteroatoms or groups selected from the group consisting of -NR'-C(O)-O-, -OC(O)NR', -C(S)NR'-, -NR'-C(S)-, and -NR'-C(S)-NR, and the alkyl and alkenyl chains may be optionally substituted with one or more groups selected from the group consisting of halogen, -OR', -COOR', -SR', and -NR'2, and each R' is independently H or a C1-C6 alkyl.

[0083] Advantageously, in formula I, each Z is independently selected from the group consisting of a bond and a linear or branched alkyl chain having 1 to 12 carbon atoms, said alkyl chain optionally interrupted by one or more C6-C10 aryl groups and / or by one or more heteroatoms or groups selected from the group consisting of -O-, -S-, -C(O)-, -NR'-, -C(O)NR'-, -NR'-C(O)-, -C(S)NR'-, -NR'-C(S)-NR', and each R' is independently H or a C1-C6 alkyl.

[0084] In certain embodiments, each Z is an alkyl chain having 1 to 12 carbon atoms.

[0085] In another embodiment, each Z is polyethylene glycol (PEG).

[0086] Advantageously, in formula II, Z1 and Z2 are independently a single bond or a hydrocarbon chain having 1 to 12 carbon atoms, said chain may be linear or branched, may contain one or more unsaturations, and may contain one or more heteroatoms, preferably selected from nitrogen, oxygen, sulfur, and halogen.

[0087] In one embodiment, in Formula II, Z1 and Z2 are independently selected from the group consisting of a bond, a linear or branched alkyl chain having 1 to 12 carbon atoms, and a linear or branched alkenyl chain having 2 to 12 carbon atoms, wherein the alkyl and alkenyl chains are separated by one or more C6 to C10 aryl groups and / or by one or more -O-, -S-, -C(O)-, -NR'-, -C(O)NR'-, -NR'-C(O)-, -NR'-C(O)-NR and each R' is independently H or a C1-C6 alkyl.

[0088] In certain embodiments, in Formula II, Z1 and Z2 are independently selected from the group consisting of a bond and a straight or branched alkyl chain having 1 to 12 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more C6-C10 aryl groups and / or by one or more heteroatoms or groups selected from the group consisting of -O-, -S-, -C(O)-, -NR'-, -C(O)NR'-, -NR'-C(O)-, -C(S)NR'-, and -NR'-C(S)-NR', and each R' is independently H or a C1-C6 alkyl.

[0089] In certain embodiments, Z1 and / or Z2 are alkyl chains having 1 to 12 carbon atoms.

[0090] In another particular embodiment, Z1 and / or Z2 is polyethylene glycol (PEG).

[0091] Monomeric units of functionalized statistical chitosans. The functionalized statistical chitosan of formula I of the present disclosure is composed of three types of monomer units: N-acetylglucosamine A-type units, glucosamine B-type units, and glucosamine C-type units functionalized with a chelating moiety (Rc-type) linked to the nitrogen of the glucosamine by a linker (Z-type).

[0092] The functionalized statistical chitosan is a statistical polymer, in other words, the arrangement of the individual monomer units A, B, and C types is random.

[0093] The functionalized statistical chitosan of formula II of the present disclosure is composed of four types of monomer units, namely, an N-acetylglucosamine A-type unit, a glucosamine B-type unit, and two glucosamine C-type units, namely, C1 and C2, functionalized with a chelating moiety (of type Rc1 or Rc2) linked to the glucosamine nitrogen by a linker (of type Z1 or Z2).

[0094] The functionalized statistical chitosan in Formula II is a statistical polymer, in other words, the arrangement of the individual monomer units A, B, C1, and C2 is random.

[0095] In Formulas I and II, x represents the proportion of A units, and x is 0.005 to 0.7, preferably 0.05 to 0.7, more preferably 0.2 to 0.6, even more preferably 0.25 to 0.4, typically about 0.3. In one embodiment, x is 0.025 to 0.075, more preferably 0.04 to 0.06, typically about 0.05.

[0096] In Formulas I and II, y represents the proportion of C-type units, and is 0.01 to 0.7, preferably 0.05 to 0.2. In one embodiment, y is 0.03 to 0.2, preferably 0.05 to 0.1, even more preferably 0.07 to 0.08, and typically about 0.072. In another embodiment, y is 0.05 to 0.3, more preferably 0.1 to 0.2, and typically about 0.15 or about 0.12.

[0097] In another embodiment, when Rc1 and Rc2 of formula II are independently selected from the group consisting of DOTA, NOTA, NODAGA, DOTAGA, DOTAM, NOTAM, DOTP, NOTP, TETA, TETAM, DTPA, Bz-DFO, and DFO, preferably DOTAGA, Bz-DFO, DFO, DOTAM, and DTPA, y is 0.05 to 0.3, more preferably 0.1 to 0.2, and typically about 0.12; Rc1 is 0.06 to 0.08, and typically about 0.07; and Rc2 is 0.04 to 0.06, and typically about 0.05.

[0098] The remaining monomer units in Formulas I and II are B units. Thus, in Formulas I and II, the proportion of B units is equal to 1-xy.

[0099] According to the present disclosure, in formulas I and II, the ratio y / x is 0.05 or more, preferably 0.15 or more. Indeed, the effectiveness of functionalized statistical chitosan is determined by the number of chelation sites, which is directly related to the number of metals required to reduce local inflammation induced by and / or inducing deregulation of metal homeostasis and to reduce oxidative stress in a subject in need thereof.

[0100] To be effective and yet be administered as a solution to a subject in need thereof, the functionalized statistical chitosan must be soluble at physiological pH, i.e., pH 4.8 to 8. To this end, the sum of x + y can be 0.15 or greater, preferably 0.30 or greater, and more preferably 0.35 or greater.

[0101] The specific ratio of the number of A units to the number of C units, in combination with the sum of the proportion of A units and the proportion of C units, makes it possible to obtain sufficient chelation and solubility that allows the functionalized statistical chitosan to be used in the treatment of diseases characterized by local inflammation and increased oxidative stress induced by and / or inducing deregulation of metal homeostasis in subjects in need thereof.

[0102] According to the present invention, z / y is between 0.5 and 1. In other words, the C-type units can be exclusively units having Z1 as a linker and Rc1 as a group bearing a chelating moiety.

[0103] The functionalized statistical chitosan has a weight average molecular weight of 100 kDa to 1000 kDa, preferably 150 kDa to 750 kDa, more preferably 200 kDa to 600 kDa, even more preferably 250 kDa to 400 kDa, and even more preferably about 300 kDa.

[0104] In certain embodiments, the functionalized statistical chitosan is selected from the following functionalized statistical chitosans: - functionalized statistical chitosan of formula II, in which z / y=1, Rc1 is DOTAGA and Z1 is a bond; - functionalized statistical chitosan of formula II, in which z / y=1, Rc1 is DTPA and Z1 is a bond; - a functionalized statistical chitosan of formula II, wherein 0.5≦z / y<1, Rc1 is DOTAGA, Z1 is a bond, Rc2 is Bz-DFO, and Z2 is selected from the group consisting of a bond and a linear or branched alkyl chain having 1 to 12 carbon atoms, said alkyl chain being optionally interrupted by one or more C6-C10 aryl groups and / or by one or more heteroatoms or groups selected from the group consisting of -O-, -S-, -C(O)-, -NR'-, -C(O)NR'-, -NR'-C(O)-, -C(S)NR'-, -NR'-C(S)-NR', and each R' is independently H or a C1-C6 alkyl.

[0105] In one embodiment, the functionalized statistical chitosan has the following formula (III):

[0106] [ka]

[0107] (wherein x is 0.25 to 0.4, typically about 0.3, and y is 0.05 to 0.2, typically about 0.07).

[0108] In one embodiment, the functionalized statistical chitosan is soluble in aqueous solution at physiological pH, i.e., pH 4.8 to 8, and reacts as follows: (DS DOTAGA (%)+3.5)*(DA(%)+8)≧150, where DS is the degree of substitution of DOTAGA and DA is the degree of acetylation of the functionalized statistical chitosan.

[0109] In another embodiment, the functionalized statistical chitosan has formula (III), where x is 0.025 to 0.075, more preferably 0.04 to 0.06, typically about 0.05, and y is 0.05 to 0.3, more preferably 0.1 to 0.2, typically about 0.15.

[0110] In another embodiment, the functionalized statistical chitosan has the following formula (IV):

[0111] [ka]

[0112] (wherein x is 0.2 to 0.6, more preferably 0.25 to 0.4, typically about 0.3, and y=z+w is 0.05 to 0.3, more preferably 0.1 to 0.2, typically about 0.12).

[0113] Synthesis of functionalized polymers of formulas I and II Compounds of formula I and II can be synthesized using the methods disclosed in WO 2022 / 023677 and references such as Natuzzi, M., Grange, C., Grea, T. et al. Feasibility study and direct extraction of endogenous free metallic cations combining hemodialysis and chelating polymer. Sci Rep 11, 19948 (2021).

[0114] Pharmaceutical compositions of functionalized polymers The functionalized polymer for use may be administered orally by itself or may be formulated with one or more pharmaceutically acceptable excipients.

[0115] Any excipient suitable for use in pharmaceutical compositions known to those of skill in the art may be used in the compositions described herein.

[0116] In certain embodiments, the pharmaceutical composition can be in a liquid form suitable for oral administration, such as an aqueous solution of the functionalized polymer. In another particular embodiment, the pharmaceutical composition can be in a solid dosage form suitable for oral administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In a preferred embodiment, the pharmaceutical composition is a capsule or tablet.

[0117] In some embodiments, release of the contents of the capsule or tablet may be immediate or modified, such as delayed, targeted, or sustained. In a preferred embodiment, the solid dosage form is an immediate release dosage form.

[0118] A second object of the present disclosure relates to oral formulations comprising the functionalized polymers of the present disclosure and one or more pharmaceutically acceptable excipients.

[0119] In certain embodiments, the pharmaceutically acceptable excipients include fillers, disintegrants, lubricants, and glidants.

[0120] Filler A filler (also called a diluent, dilutant, or thinner) is a substance added to a drug substance to make it suitable for oral administration (e.g., capsules, tablets). The filler itself should not have any pharmacological effect in humans. Examples of fillers include mannitol, microcrystalline cellulose, lactose monohydrate, anhydrous lactose, corn starch, xylitol, sorbitol, sucrose, dicalcium phosphate, maltodextrin, and gelatin.

[0121] Disintegrant Disintegrants are added to oral solid dosage forms to aid in deagglomeration. Disintegrants are formulated to rapidly disintegrate the solid dosage form when it comes into contact with moisture. Disintegration is usually considered to be the first step in the dissolution process. Examples of disintegrants include modified starches, such as sodium starch glycolate, sodium carboxymethyl starch, and pregelatinized starch, cross-linked polymers, such as cross-linked polyvinylpyrrolidone (crospovidone) or cross-linked sodium carboxymethylcellulose (croscarmellose sodium), and calcium silicate.

[0122] lubricant Lubricants are substances used in tablet and capsule formulations to reduce friction. They facilitate the extrusion of the tablet from the matrix, thereby preventing scratches from forming on its surface. Originally, lubricants can be divided into two groups: a) fats and fat-like substances; and b) powdery substances. Powdery substances are more applicable than fat-like substances because the latter affect the solubility and chemical stability of the tablet. Powdery lubricants are introduced by powdering the granules. This ensures a constant flow of the tableting mass from the hopper to the matrix, ensuring the accuracy and consistency of the drug substance dosage.

[0123] Examples of lubricants include magnesium stearate, hydrogenated castor oil, glyceryl behenate, calcium stearate, zinc stearate, mineral oil, silicone fluid, sodium lauryl sulfate, L-leucine, and sodium stearyl fumarate.

[0124] Glidants Glidants are blended with formulations to enhance the flow characteristics of tablet core blend materials. During the early stages of compression, glidants are mixed into the particle arrangement of the tablet powder blend to improve flow and uniformity within the die cavity of the tablet press. Glidants promote the flow of tablet granulations by reducing interparticle friction. The effect of a glidant on granule flow depends on the size and shape of the granule particles and the glidant. Above a certain concentration, glidants actually act as a flow inhibitor. In tablet manufacturing, glidants are usually added just before compression. Examples of glidants include colloidal silicon dioxide, starch, magnesium stearate, and talc.

[0125] Any suitable excipient in pharmaceutical compositions known to those skilled in the art may further be used in the compositions described herein.

[0126] The unit dose of the functionalized polymer is between 0.1 mg and 500 mg, preferably between 1 mg and 100 mg, more preferably between 2 mg and 10 mg, and even more preferably about 5 mg.

[0127] Subject populations preferably targeted by the treatment method The methods of treatment disclosed herein are suitable for subjects with diseases associated with heavy metal-induced toxicity or heavy metal-induced carcinogenesis.

[0128] Without wishing to be bound by any theory, it is believed that the methods of treatment disclosed herein prevent the uptake of such heavy metals into the subject's body.

[0129] In certain embodiments, the subject is a mammal, eg, a human subject.

[0130] Thus, the methods of the present disclosure are particularly suitable for subjects exposed to heavy metals present in contaminated water and / or food and / or air pollution, for example, from combat zones due to contamination, pollution, accidents, dirty bombs, etc.

[0131] Examples of diseases associated with heavy metal-induced toxicity or carcinogenesis include, but are not limited to, kidney disease, liver disease, gastrointestinal disease, cardiovascular disease, respiratory disease, bone disease, brain disease, developmental abnormalities, neurological and neurobehavioral disorders, diabetes, hearing loss, blood and immune disorders, and cancer disorders.

[0132] The renal disease may in particular be selected from the group consisting of chronic tubulointerstitial nephritis, end-stage renal disease, Fanconi syndrome, chronic kidney disease.

[0133] The liver disease may in particular be selected from the group consisting of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis.

[0134] Said gastrointestinal disease may in particular be selected from the group consisting of dysbiosis, inflammatory bowel diseases such as Crohn's disease or ulcerative colitis.

[0135] Said cardiovascular disease may in particular be selected from the group consisting of hypertension, stroke, atherosclerosis, peripheral vascular or arterial disease, coronary artery disease, congestive heart failure.

[0136] Said respiratory disease may in particular be selected from the group consisting of pneumonia, pulmonary edema, acute tracheobronchitis, pulmonary fibrosis, asthma, lung cancer.

[0137] The bone disease may in particular be selected from the group consisting of osteomalacia, osteoarthritis, degenerative disk disease, and osteoporosis.

[0138] The brain disease may in particular be selected from the group consisting of dementia.

[0139] Said developmental abnormality may in particular be selected from the group consisting of congenital and neurological abnormalities, developmental delays, and learning disabilities.

[0140] Said neurological and neurobehavioral disorders may in particular be selected from the group consisting of autism spectrum disorders.

[0141] The blood and immune disorders may in particular be selected from the group consisting of autoimmune diseases.

[0142] In certain embodiments, the disease is end-stage renal disease or inflammatory bowel disease.

[0143] In certain embodiments, such diseases associated with heavy metal-induced toxicity or heavy metal-induced carcinogenesis result from the absorption of radioactive isotopes of heavy metals listed herein in contaminated areas following a nuclear accident or terrorist or war, resulting in contamination of water and / or air and / or food.

[0144] Treatment methods The functionalized polymers, more preferably functionalized statistical chitosans, and pharmaceutical compositions thereof disclosed in the preceding paragraphs are useful as drugs in methods for treating diseases associated with heavy metal-induced toxicity or heavy metal-induced carcinogenesis in subjects in need thereof, more particularly in the subpopulations of subjects defined above.

[0145] The functionalized polymer is orally administered to a subject in an amount sufficient to prevent uptake of the heavy metal into the subject's body.

[0146] The pharmaceutical compositions may be orally administered by any means appropriate to the disease or disorder being treated, as determined by one of ordinary skill in the medical arts.

[0147] The appropriate dose and the appropriate duration and frequency of administration will be determined by factors such as those discussed herein, including the subject's condition, the type and severity of the subject's disease, the particular form of the active ingredient, and the method of administration.

[0148] In general, an appropriate dose (or effective dose) and treatment regimen provides a sufficient amount of the pharmaceutical composition to provide a therapeutic effect, e.g., an improved clinical outcome such as frequent complete or partial remission, or longer disease-free and / or overall survival, or reduced severity of symptoms, or other benefits as described in detail herein.

[0149] In some embodiments, the functionalized polymer is administered to a subject in need thereof once, twice, or three times daily.

[0150] A typical daily dose may comprise from 0.1 mg to 500 mg, preferably from 1 mg to 100 mg, more preferably from 2 mg to 10 mg, and even more preferably about 5 mg, preferably functionalized statistical chitosan. [Example]

[0151] Hereinafter, the present disclosure will be described in more detail and specifically with reference to examples, which are not intended to limit the present invention.

[0152] Materials and Methods Preparation of solutions: Solution 1: 10 g / L MEX-CD1 Lyophilized MEX-CD1 was dissolved in ultrapure water at a concentration of 10 g / L.

[0153] Solution 2: 10 g / L MEX-DTPA Lyophilized MEX-DTPA was dissolved in ultrapure water at a concentration of 10 g / L.

[0154] Solution 3: 10 g / L MEX-DOTAM Lyophilized MEX-DOTAM was dissolved in ultrapure water at a concentration of 10 g / L.

[0155] Solution 4: Biodistribution of MEX-CD1 mixture Lyophilized MEX-CD1, synthesized as described below and further labeled with gadolinium, was dissolved in ultrapure water at a concentration of 10 g / L. Lyophilized MEX-CD1 labeled with cyanine 5.5 was dissolved in ultrapure water at a concentration of 10 g / L. 1 mL of each solution was combined to prepare a mixed solution containing 5 g / L of each labeled MEX-CD1.

[0156] Solution 6: 5 g / L MEX-CD1 + 3.5 g / L NaCl 3.5 g / L of NaCl was dissolved in ultrapure water. Lyophilized MEX-CD1 was then dissolved in this solution to a final concentration of 5 g / L. This solution was sterilized at 121°C for 20 minutes.

[0157] Solution A: Concentrated salt solution for in vitro laboratory testing In ultrapure water: 263 g / L NaCl, 3.35 g / L KCl, 6.24 g / L CaCl2, 2.14 g / L MgCl2, 10.8 g / L acetic acid, 45 g / L glucose

[0158] Solution B: 0.1 M acetate buffer, pH 4.6 The acetate buffer contains 11.4 mL of acetic acid (MS grade), 15.4 g of ammonium acetate, and 2 L of ultrapure water.

[0159] Experimental Protocol: Protocol 1: High-pressure liquid chromatography-mass spectrometry (HPLC-MS) The eluent used in this method was acetate buffer (solution B, prepared using MS-grade certified products), the injection volume was 10 μL, and the flow rate was fixed at 0.4 mL / min. The column used was a SEC Polysep GFC-P 4000 series. The HPLC was coupled to an inductively coupled plasma mass spectrometer (ICP-MS) for the detection of selected isotopes.

[0160] Protocol 2: Vivaspin ultrafiltration experiments We used 20 mL Vivaspin centrifuge tubes with a 30 kDa inner membrane. Centrifugation was performed at 4000 rpm for 10-30 min cycles. After each centrifugation, the solution that passed through the membrane was collected for each sample and henceforth referred to as the undernatant. This was done in a single pass, ideally leaving approximately 0.5 mL of supernatant, which was collected for ICP-MS analysis.

[0161] The original solution, supernatant, and samples containing the undercontant were analyzed by ICP-MS to determine the concentration of the metal of interest in each solution. Samples were diluted (at least) 10-fold using 1% HNO3. An internal standard (indium) was added to each sample at a final concentration of 2 ppb In. Analysis was performed either in KED (kinetic energy discrimination) mode, which introduces a helium flow into the chamber, or in standard mode. KED was used with other analyses for more sensitive elements, but the majority of samples were run in standard mode for 208Pb, 206Pb, 111Cd, 112Cd, and 114Cd.

[0162] Calibration curves ranging from 0.01 to 10 ppb for lead and cadmium were prepared, allowing the system to convert the counts per second recorded for each sample into concentrations in ppb.

[0163] Synthesis of the functionalized polymer of the present invention: MEX-CD1 (chitosan as the polymer and DOTAGA as the chelating moiety) In the first step, 60 g of chitosan, 4 L of ultrapure water, and 45 mL of glacial acetic acid are added to a 10 L reactor and stirred at pH 4.5±0.5 for 16 hours. A pale yellow solution is observed.

[0164] In the second step, 1.2 L of 1,2-propanediol is added to the pale yellow solution obtained from step 1 and stirred for 1 hour. A solution consisting of 14 mL of acetic anhydride in 600 mL of 1,2-propanediol is slowly added over 10 minutes to obtain uniform acetylation along the polymer chain. The mixture is maintained under stirring for 4 hours.

[0165] The acetylation rate can be determined by elemental analysis. The non-acetylated monomer of the polymer (monomer B) has a molar mass of 161.2 gmol -1 (C6NO4H 11 ), while the acetylated monomer of the polymer (monomer A) has a molar mass of 203.2 gmol -1 (C8NO5H 13 ) The elemental analysis of the polysaccharide obtained after step 2 is as follows: C 39.22%; H 7.55%; and N 6.77%, which is 1 This corresponds to a 29% acetylation rate (x=0.29) confirmed by 1 H NMR.

[0166] In the third step, 2 L of the solution obtained after the second step is placed under stirring. 120 g of DOTAGA anhydride is added and stirred for 16 hours. At the end of this reaction, the solution is diluted 10 times with ultrapure water and purified by tangential purification using a 100 kDa membrane. After the first dilution step is completed at a volume of 16 L, the solution is filtered with 480 L of 0.1 M acetic acid, maintaining a constant volume of 16 L, and then with 320 L of ultrapure water. This purification is completed by reconcentration to a volume of 8 L. The successful removal of unreacted DOTAGA from the solution can be verified by HPLC-UV. The solution at a concentration of 10 g / L is then filtered using a nylon filter (0.4 μm) before being lyophilized.

[0167] 1By 1 H NMR it is possible to determine the percentage of DOTAGA functionalized monomers (y) in a polymer known to have a percentage of acetylation x.

[0168] The amount of grafted DOTAGA is determined by spectrophotometric UV absorption at 295 nm. MEX-CD1 contains 0.345 mmol of DOTAGA per gram of polymer.

[0169] The mole fraction x of N-acetylglucosamine repeat units is x = 0.29 using 1H-NMR, and the mole fraction y of DOTAGA-grafted repeat units is y = 0.075 using 1H-NMR and copper absorption using HPLC-SEC.

[0170] MEX-DTPA (chitosan as the polymer and DTPA as the chelating moiety) In the first step, 1 g of chitosan, 66 mL of ultrapure water, and 0.84 mL of glacial acetic acid are added and stirred at pH 4.5±0.5 for 16 hours. A pale yellow solution is observed.

[0171] In the second step, 20 mL of 1,2-propanediol is added to the pale yellow solution obtained from step 1 and stirred for 1 hour. A solution consisting of 0.704 mL of acetic anhydride in 30 mL of 1,2-propanediol is slowly added over 10 minutes to obtain uniform acetylation along the polymer chain. The mixture is maintained under stirring for 4 hours.

[0172] In the third step, 0.8 g of DTPA bisanhydride is added to the previous solution and stirred for 16 hours. At the end of this reaction, the solution is diluted 10 times with ultrapure water and purified by tangential purification using a 100 kDa membrane. After the first dilution step is completed to a volume of 1 L, the solution is filtered with 5 L of 0.1 M acetic acid, and then with 5 L of ultrapure water, while maintaining a constant volume of 1 L. This purification is completed by reconcentration to a volume of approximately 100 mL. It can be verified by HPLC-UV that the unreacted DTPA has been successfully removed from the solution.

[0173] The amount of grafted DTPA is determined by spectrophotometric UV absorption at 295 nm. MEX-DTPA contains 0.21 mmol of DTPA per gram of polymer.

[0174] The mole fraction x of N-acetylglucosamine repeat units is x=0.58 using 1H-NMR, and the mole fraction y of DTPA-grafted repeat units is y=0.045 using 1H-NMR.

[0175] The MEX-DTPA synthesized herein is useful for the therapeutic methods described in this disclosure.

[0176] MEX-DOTAM (chitosan as the polymer and DOTAM as the chelating moiety) In the first step, 1 g of chitosan, 66 mL of ultrapure water, and 0.84 mL of glacial acetic acid are added and stirred at pH 4.5±0.5 for 16 hours. A pale yellow solution is observed.

[0177] In the second step, 20 mL of 1,2-propanediol is added to the pale yellow solution obtained from step 1 and stirred for 1 hour. A solution consisting of 0.704 mL of acetic anhydride in 30 mL of 1,2-propanediol is added slowly over 10 minutes to obtain uniform acetylation along the polymer chain. The medium is maintained and stirred for 4 hours. The solution is then purified by tangential purification using a 100 kDa membrane and 7 L of ultrapure water to remove the solvent and reconcentrated to approximately 100 mL. The pH of the solution is increased to 7 ± 0.1 using NaOH. 8 mL of DMSO is added to the solution to create a 5% DMSO in water environment and stirred for 1 hour.

[0178] In the third step, 11 mL of a 100 g / L solution of DOTAM NHS-ester in DMSO is added over 10 min. The solution is then diluted 2-fold with ultrapure water and stirred for 16 h. At the end of this reaction, the solution is diluted 10-fold with ultrapure water and purified by tangential purification using a 100 kDa membrane. After completing the first dilution step to a volume of 1 L, the solution is filtered with 5 L of 0.1 M acetic acid, maintaining a constant volume of 1 L, and then with 5 L of ultrapure water. This purification is completed by reconcentration to a volume of approximately 100 mL. It can be verified by HPLC-UV that unreacted DOTAM has been successfully removed from the solution.

[0179] The amount of grafted DOTAM is determined by spectrophotometric UV absorption at 295 nm. MEX-DOTAM contains 0.049 mmol of DOTAM per gram of polymer.

[0180] The mole fraction x of N-acetylglucosamine repeat units is x=0.58 using 1H-NMR, and the mole fraction y of DOTAGA-grafted repeat units is y=0.0097 using 1H-NMR.

[0181] MEX-DOTAM synthesized herein is useful for the therapeutic methods described in this disclosure.

[0182] PEG-DTPA (PEG as the polymer and DTPA as the chelating moiety) The PEG used has the following formula (V):

[0183] [ka]

[0184] where n is 111.3, Purchased from Creative PEGWork. DTPA bis anhydride was provided by Chematech. Synthesis was performed in DMSO (Fischer Chemicals). Cassette VIVAFLOW 30 kDa used for purification was purchased from Sartorius.

[0185] 0.36 g of DTPA bis anhydride was dissolved in 10.26 mL of DMSO (35 g / L) at 40°C under stirring for 1 hour. Meanwhile, 0.27 g of PEG was weighed and dissolved in 43.36 mL of DMSO. Next, this PEG solution was added directly to the DTPA solution and stirred at 40°C for 1.5 hours. Next, the solution was purified with ultrapure water and 10% DMSO using a VIVAFLOW 30 kDa cassette to a final purification factor of approximately 10,000. -2 Purified using HCl at 200 M.

[0186] The amount of grafted DTPA was determined by spectrophotometric UV absorption at 295 nm. PEG-DTPA contained 0.18 mmol of DTPA per gram of polymer. The mole fraction y of DTPA-grafted repeat units was determined to be y = 1 using 1H-NMR.

[0187] The structure of the synthesized PEG-DTPA is shown in the following formula (VI):

[0188] [ka]

[0189] where n is 111.3.

[0190] The PEG-DTPA synthesized herein is useful for the therapeutic methods described in this disclosure.

[0191] PEG-DOTAM (PEG as the polymer and DOTAM as the chelating moiety) The PEG used was an 8-arm PEG amine with a molecular weight of 40 kDa, purchased from Creative PEGWorks. DOTAM NHS-ester was provided by Chematech as a 100 g / L solution in DMSO. Synthesis was performed in DMSO (Fischer Chemicals). The VIVAFLOW 30 kDa cassette used for purification was purchased from Sartorius.

[0192] 3.5 mL of a 100 g / L DOTAM NHS-ester / DMSO solution was added to a round-bottom flask under stirring at 40°C for 1 hour. Meanwhile, 0.27 g of PEG was weighed and dissolved in 43.36 mL of DMSO. This PEG solution was then added directly to the DTPA solution and stirred at 40°C for 1.5 hours. The solution was then purified using a VIVAFLOW 30 kDa cassette with ultrapure water and 0.1 M acetic acid to a final purification factor of approximately 10,000.

[0193] The amount of grafted DOTAM is determined by spectrophotometric UV absorption at 295 nm. PEG-DOTAM contains 0.036 mmol of DOTAM per gram of polymer. The mole fraction y of DOTAM grafted to the amine functional groups of the ethylene glycol monomer is y = 0.21 using 1H-NMR.

[0194] The structure of the synthesized PEG-DOTAM is shown in the following formula (VII):

[0195] [ka]

[0196] where n is 111.3.

[0197] The PEG-DOTAM synthesized herein is useful for the therapeutic methods described in this disclosure.

[0198] Example 1 Biodistribution of orally administered MEX-CD1 in mice Eight mice were orally administered 0.2 mL of solution 4. Two mice were sacrificed at 1, 2, 4, and 24 hours. Fluorescence studies were performed using a CCD camera and the following parameters: two sets of spotlights for excitation at 633 nm and 470 nm, and two sets of filters at 680±20 nm and 520±20 nm. Organs were then digested with nitric acid for gadolinium quantification using ICPMS.

[0199] result Qualitative biodistribution using fluorescence As shown in Figure 1, no fluorescence is observed in the kidney, liver, brain, spleen, heart, urine, lung, bone, skin, blood, and muscle at any time point after 1, 2, 4, and 24 hours. Fluorescence is observed only in the stomach, intestine, and colon after 1, 2, and 4 hours. A slight level of autofluorescence is seen in the stomach of control mice.

[0200] The fluorescence results indicate that MEX-CD1 is present only in the stomach, intestines, and colon (gastrointestinal tract). Some autofluorescence was observed in the stomachs of control mice, which explains the remaining fluorescence in the two stomachs at 24 hours.

[0201] Quantitative biodistribution using ICP-MS As shown in Figure 2, because there were two experimental mice at each time point, the average percent gadolinium was taken and then plotted along with the standard deviation in Figure 1. The trend indicates that within the first hour, the majority of MEX-CD1 was already found in the intestine, and by 24 hours, all of the MEX-CD1 had been eliminated from the mouse's digestive system.

[0202] Other organs were also evaluated, and all showed concentrations less than 1% of the administered gadolinium and were therefore considered zero.

[0203] Thus, orally administered MEX-CD1 remains in the gastrointestinal tract, does not cross the intestinal membrane into the blood, and is completely excreted after 1 day.

[0204] Example 2 Orally administered MEX-CD1 in mice exposed to heavy metals The study was carried out as described below: Control group - no treatment and regular rodent chow and water Saline group - fed contaminated rodent chow, regular water, and oral saline once daily for 14 days MEX-CD1 group - fed contaminated rodent chow, regular water, and oral administration of MEX-CD1 solution once daily for 14 days Contaminated rodent food = 7 ppm (mg / kg) Cd + 50 ppm (mg / kg) Pb Oral administration = 0.2 mL of 3.5 g / L NaCl in H2O or 5 g / L MEX-CD1 in H2O + 0.2 mL of 3.5 g / L NaCl

[0205] result body weight As shown in Figure 3, the weight loss observed in the saline- and MEX-CD1-treated groups can be attributed to exposure to the contaminated rodent chow. The groups then stabilized in weight after 6 days. This demonstrates that oral administration of MEX-CD1 does not affect the health of the mice, as reflected by changes in weight over time.

[0206] Liver enzyme activity

[0207] [Table 1]

[0208] In all groups, the enzyme activity levels in the mice remained statistically insignificant, providing evidence that oral administration of MEX-CD1 does not affect liver function.

[0209] hematology As shown in Figure 4, acute heavy metal intoxication was evidenced in several hematological parameters in saline-treated mice (specifically, significantly different white blood cells (WBC) and MCHC, and slight changes in platelets (PLT) and MCH). This onset of acute heavy metal intoxication occurred in a manner similar to observations previously described in the literature. This intoxication was restored to normal levels by oral administration of MEX-CD1. This not only provides evidence that this treatment does not adversely affect blood parameters, but also demonstrates the beneficial impact of this oral administration therapy in protecting against heavy metal exposure.

[0210] Blood levels of lead and cadmium As shown in Figure 5, exposure of mice to contaminated rodent food significantly increases blood lead and cadmium levels. In the case of lead, MEX-CD1, administered orally once daily, helps mitigate the levels found in the mice's blood. MEX-CD1 has only a small effect on cadmium levels due to trace levels.

[0211] Example 3 In vitro chelation of lead and cadmium in complex environments by MEX-polymers Polymer 1-MEX-CD1 The samples were prepared using solution A defined in the Materials and Methods section. Metal standards purchased from SCP Science, Pb in 5% HNO3 2+ or Cd 2+ Four samples were prepared using solution 1, with a concentration of 1000 ppm, and solution 1. The pH was adjusted using 1 M NaOH. The samples were experimentally analyzed according to protocol 2.

[0212] [Table 2]

[0213] [Table 3]

[0214] Polymer 2-MEX-DTPA Samples were prepared using solution A. Metal standards purchased from SCP Science, Pb in 5% HNO3 2+ or Cd 2+ Seven samples were prepared using solution 1, 2, and 3. The pH was adjusted using 1 M NaOH. The samples were experimentally analyzed according to protocol 2.

[0215] [Table 4]

[0216] [Table 5]

[0217] Polymer 3-MEX-DOTAM Samples were prepared using solution A. Metal standards purchased from SCP Science, Pb in 5% HNO3 2+ or Cd 2+ Seven samples were prepared using solution 3, with a concentration of 1000 ppm. The pH was adjusted using 1 M NaOH. The samples were experimentally analyzed according to protocol 2.

[0218] [Table 6]

[0219] [Table 7]

[0220] Because the original solutions were centrifuged and passed through the membrane in one step, the original and undertandant concentrations are comparable. For each polymer, efficient chelation of cadmium and lead was observed at pH 4 and 5, as indicated by lower metal concentrations in the undertandant compared to the original. For MEX-DOTAM and MEX-DTPA, minimal lead chelation was observed at pH 2 and 3, but efficient chelation was observed at pH 4 and 5. Due to the more efficient chelating ability of MEX-DTPA and MEX-DOTAM in low pH environments compared to MEX-CD1, these polymers may exhibit similar or improved chelation capabilities in vivo compared to MEX-CD1.

[0221] Example 4 In vitro chelation of lead and cadmium by MEX-CD1 in simple and complex environments MEX-CD1 chelation in water Using a metal mixture of Pb and Cd purchased from SCP Science, both at 10 ppm in 5% HNO3, and Solution 1, the following six samples were prepared in ultrapure water and analyzed by HPLC-MS according to Protocol 1:

[0222] [Table 8]

[0223] Figures 6, 6a, and 6b show that the polymer at a concentration of 0.1 g / L is effective at chelating lead in a concentrated solution composed of salt and acid. As the metal concentration increases, a larger polymer peak is observed at 11 minutes in Figures 6a and 6b, corresponding to greater chelation of these metals to the polymer. A linear relationship can be seen in Figure 6, providing evidence that MEX-CD1 chelates these metals within the desired concentration range.

[0224] MEX-CD1 chelation in solution A 77 ppb Pb 2+was added to the solution. This dope solution, along with Solution 1, Solution B, and ultrapure water, were used to create different acidic environments. Chelation was tested in these different environments: concentrated acid (pH 2), pH 5, and pH 7.4. The pH was adjusted with NaOH, and the samples were analyzed by HPLC-MS according to Protocol 1.

[0225] [Table 9]

[0226] Figure 7 above shows that the polymer at a concentration of 0.1 g / L is effective in chelating lead in concentrated solutions composed of salt and acid. At pH 5 and 7.4, a large proportion of the lead is chelated and bound to the polymer, as evidenced by the HPLC / SEC-ICP-MS (lead detection) chromatogram with an increase in peak area at 15 minutes, specifically corresponding to the polymer.

[0227] MEX-CD1 in water The samples were prepared in ultrapure water, solution 1, and 50,000 ppm Pb in 5% HNO3. 2+ The samples were experimentally analyzed according to protocol 2.

[0228] [Table 10]

[0229] Figure 8 above shows the linear relationship between increasing lead concentrations and chelation by MEX-CD1.

[0230] MEX-CD1 in water, ultra-trace chelation A metal mixture solution containing 10 ppm of both Pb and Cd in 5% HNO3, purchased from SCP Science, was used with Solution 1 and ultrapure water to prepare the samples. These samples were experimentally analyzed using Protocol 2.

[0231] [Table 11]

[0232] Figure 9 demonstrates that the chelation efficiency of lead and cadmium by ICP-MS analysis begins at 0.05 ppb (50 ppt). Lead also shows efficient chelation in the 0.01 ppb (10 ppt) range.

Claims

1. 1. A functionalized polymer for use in treating a disease associated with heavy metal-induced toxicity or heavy metal-induced carcinogenesis in a subject in need thereof, wherein the functionalized polymer is soluble in aqueous solution and has a mass average molecular weight of 30 kDa to 5000 kDa, and a portion of the monomer units are functionalized with chelating moieties, and wherein a therapeutically effective amount of the functionalized polymer is orally administered to the subject.

2. 2. The functionalized polymer for use according to claim 1, wherein the subject in need thereof is a subject exposed to heavy metals present in contaminated water and / or food and / or air pollution.

3. 3. A functionalized polymer for use according to claim 1 or 2, comprising at least 1 wt% of chelating moieties, for example 1 wt% to 40 wt% of chelating moieties.

4. 4. The functionalized polymer for use according to any one of claims 1 to 3, wherein the chelating moiety is selected from the group consisting of DOTA, NOTA, NODAGA, DOTAGA, DOTAM, NOTAM, DOTP, NOTP, TETA, TETAM, DTPA, Bz-DFO, DFO, and mixtures thereof, preferably selected from the group consisting of DOTAGA, Bz-DFO, DFO, DOTAM, DTPA, and mixtures thereof.

5. 5. The functionalized polymer for use according to any one of claims 1 to 4, wherein the disease associated with heavy metal induced toxicity or heavy metal induced carcinogenesis is selected from the group consisting of kidney disease, liver disease, gastrointestinal disease, cardiovascular disease, respiratory disease, bone disease, brain disease, developmental abnormalities, neurological and neurobehavioral disorders, diabetes, hearing loss, blood and immune disorders, and cancer disorders.

6. a. the renal disease is selected from the group consisting of chronic tubulointerstitial nephritis, end-stage renal disease, Fanconi syndrome, and chronic kidney disease; b. the liver disease is selected from the group consisting of nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and liver fibrosis; c. the gastrointestinal disorder is selected from the group consisting of dysbiosis, inflammatory bowel disease such as Crohn's disease or ulcerative colitis; d. the cardiovascular disease is selected from the group consisting of hypertension, stroke, atherosclerosis, peripheral vascular or arterial disease, coronary artery disease, and congestive heart failure; e. the respiratory disease is selected from the group consisting of pneumonia, pulmonary edema, acute tracheobronchitis, pulmonary fibrosis, asthma, and lung cancer; f. the bone disease is selected from the group consisting of osteomalacia, osteoarthritis, osteodiscopathy, and osteoporosis; g. the brain disease is selected from the group consisting of dementia; h. the developmental abnormality is selected from the group consisting of congenital and neurological abnormalities, developmental delays, and learning disabilities; i. the neurological and neurobehavioral disorder is selected from the group consisting of autism spectrum disorders; or j. The functionalized polymer for use according to claim 5, wherein the blood and immune disorders are selected from the group consisting of autoimmune diseases.

7. The heavy metals are lead (Pb), cadmium (Cd), arsenic (As), chromium (Cr), mercury (Hg), cobalt (Co), aluminum (Al), antimony (Sb), barium (Ba), bismuth (Bi), gallium (Ga), germanium (Ge), gold (Au), indium (In), nickel (Ni), platinum (Pt), silver (Ag), strontium (Sr), tellurium (Te), thallium (Tl), tin (Sn), titanium (Ti), vanadium (V), plutonium (Pu), cesium (C), 7. The functionalized polymer for use according to any one of claims 1 to 6, wherein the metal is selected from the group consisting of cerium (Ce), zirconium (Zr), ruthenium (Ru), technetium (Tc), radium (Ra), thorium (Th), americium (Am), iridium (Ir), californium (Cf), polonium (Po), and uranium (U), or mixtures thereof, preferably selected from the group consisting of lead, cadmium, arsenic, chromium, and mercury, more preferably lead or cadmium.

8. 8. The functionalized polymer for use according to any one of claims 1 to 7, which is administered to a subject in a unit dose of 0.1 mg to 500 mg, preferably 1 mg to 100 mg, more preferably 2 mg to 10 mg, even more preferably about 5 mg.

9. 9. A functionalized polymer for use according to any one of claims 1 to 8, wherein the functionalized polymer is selected from the group consisting of polysaccharides, such as chitosan, polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyacrylic acid (PAA), polyallylamine (PAH), and some of the monomer units are functionalized with chelating moieties.

10. A polymer having a mass average molecular weight of 100 kDa to 1000 kDa and formula (I): 【Chemical 1】 (In the formula, each Rc is a chelating moiety; each Z is independently a single bond or a linker which is a hydrocarbon chain containing from 1 to 12 carbon atoms, said hydrocarbon chain being linear or branched, optionally containing one or more unsaturations and preferably one or more heteroatoms selected from nitrogen, oxygen, sulfur, and halogen; x is 0.005 to 0.7, preferably 0.05 to 0.7; y is 0.005 to 0.5, preferably 0.01 to 0.2; the ratio y / x is 0.01 or more, preferably 0.02 or more; 10. A functionalized polymer for use according to any one of claims 1 to 9, which is a functionalized statistical chitosan, wherein the sum x+y is greater than or equal to 0.15, preferably greater than or equal to 0.

30.

11. Formula (III): 【Chemistry 2】 11. The functionalized polymer for use according to claim 10, having the formula: wherein x is between 0.25 and 0.4, typically about 0.3, and y is between 0.05 and 0.2, typically about 0.

07.

12. 12. The functionalized polymer for use according to any one of claims 1 to 11, formulated as a solid dosage form.

13. 13. The functionalized polymer for use according to any one of claims 1 to 12, administered once, twice or three times daily.

14. 14. An oral formulation comprising the functionalized polymer of any one of claims 1 to 13 and one or more pharmaceutically acceptable excipients, wherein the unit dose of the functionalized polymer is between 0.1 mg and 500 mg, preferably between 1 mg and 100 mg, more preferably between 2 mg and 10 mg, and even more preferably about 5 mg.

15. Formula (III): 【Chemistry 3】 15. The oral formulation of claim 14, having the formula: wherein x is between 0.25 and 0.4, typically about 0.3, and y is between 0.05 and 0.2, typically about 0.07.

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