WO2020052697A1 - Procedure for the preparation of selectively oxidized polysaccharides as anticancer-drug carriers - Google Patents

Procedure for the preparation of selectively oxidized polysaccharides as anticancer-drug carriers Download PDF

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WO2020052697A1
WO2020052697A1 PCT/CZ2019/050038 CZ2019050038W WO2020052697A1 WO 2020052697 A1 WO2020052697 A1 WO 2020052697A1 CZ 2019050038 W CZ2019050038 W CZ 2019050038W WO 2020052697 A1 WO2020052697 A1 WO 2020052697A1
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dcc
drug
polysaccharide
carrier
reaction
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French (fr)
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Jan VICHA
Lukas MÜNSTER
Zdenka CAPAKOVA
Ivo KURITKA
Michal MASARIK
Michaela FOJTU
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Tomas Bata University In Zlin
Masaryk University
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
    • C08B15/02—Oxycellulose; Hydrocellulose; Cellulosehydrate, e.g. microcrystalline cellulose
    • C08B15/04—Carboxycellulose, e.g. prepared by oxidation with nitrogen dioxide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
    • C08B15/02—Oxycellulose; Hydrocellulose; Cellulosehydrate, e.g. microcrystalline cellulose
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
    • C08B15/05—Derivatives containing elements other than carbon, hydrogen, oxygen, halogens or sulfur
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
    • C08B15/05—Derivatives containing elements other than carbon, hydrogen, oxygen, halogens or sulfur
    • C08B15/06—Derivatives containing elements other than carbon, hydrogen, oxygen, halogens or sulfur containing nitrogen, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B30/00—Preparation of starch, degraded or non-chemically modified starch, amylose, or amylopectin
    • C08B30/12—Degraded, destructured or non-chemically modified starch, e.g. mechanically, enzymatically or by irradiation; Bleaching of starch
    • C08B30/18—Dextrin, e.g. yellow canari, white dextrin, amylodextrin or maltodextrin; Methods of depolymerisation, e.g. by irradiation or mechanically
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0021—Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
    • C08B37/0033—Xanthan, i.e. D-glucose, D-mannose and D-glucuronic acid units, saubstituted with acetate and pyruvate, with a main chain of (beta-1,4)-D-glucose units; Derivatives thereof

Definitions

  • the invention relates to the method of preparation of selectively oxidized polysaccharides as carriers for anticancer drugs and their conjugates with adjustable drug release rates, high binding effectivity above 70% and carrier capacity up to 60 wt%, particularly for therapy and diagnosis of prostate, ovarian, endometrial, lung, head and neck cancer.
  • the most widely used and also the oldest known platinum cytostatic is cisplatin, cis- [Pt(NH 3 ) 2 Cl 2 ] .
  • the main disadvantage of cisplatin, as well as later generations of R 2 Pt n X 2 drugs, are severe side effects (neurotoxicity, ototoxicity, nephrotoxicity, myelosuppression), which results in cumulative toxicity of the drug in organism and non-specific mechanism of action.
  • the administered drug is actually not targeting only the cancer cells, but it also affects other fast-dividing cells in healthy tissues, such as bone marrow, hair follicles or sperm. Severe side-effects decrease the maximum safe dose of the drug which may lead to development of resistance of cancer cells to platinum-based cytostatics.
  • prodrugs i.e. compounds based on considerably less toxic octahedral complexes of platinum(IV) with general formula R 2 Pt IV X 2 L 2 , where R 2 represents two monodentate or one bidentate ligand(s) based on nitrogen, typically amine or diamine, X represents anionic leaving ligand or ligands, typically halide(s), nitro- group(s), carboxylic or dicarboxylic acid(s), and L 2 represents two axial ligands bound to the platinum via oxygen atoms.
  • the prodrug is reduced to the active R 2 Pt n X 2 compound directly in the cancer cell upon simultaneous elimination of axial ligands, which brings considerable decrease of side-effects and increase of effectivity, see for instance USA patent application US 2004/0235712A1.
  • Ligands L 2 may also have biological activity of their own (therapeutics, biological vectors).
  • RAPTA-type complexes with general formula [Ru(aren)L x (PTA) y ], where (aren) represents aromatic hydrocarbon non-covalently bound to the ruthenium, L x is leaving anionic ligand or ligands, typically halide(s), nitro- group, carboxylic or dicarboxylic acid(s), and PTA is (l,3,5-triaza-7-phosphatricyclo[3.3.l.l]decan) or its derivative, demonstrate high effectivity against metastasis, see patent application W00240494A1.
  • the cytotoxicity of Ru-based compounds is increasing with increasing lipophilicity of aromatic ligand (aren), albeit at the expense of selectivity.
  • transition metal-based drugs can be enhanced by their conjugation to the macromolecular carrier.
  • Conjugate formation offers a number of advantages in the comparison with the administration of free drug, namely reduced systemic toxicity, prolonged circulation time in blood and enhanced cellular uptake.
  • Another advantage of macromolecular carriers is their passive accumulation in the tumor tissue due to the so-called enhanced permeability and retention (EPR) effect.
  • EPR effect is a result of higher permeability of defective endothelium, which allows macromolecules to easily diffuse into the tumor, where they accumulate due to the poor effectivity of lymphatic system caused by the uncontrolled cell division. The drug is thus predominantly released from the carrier directly in the target area.
  • Biologically active targeting vector is a compound, which predominantly binds to tumor cells, e.g. due to the overexpression of receptors in the cellular membrane.
  • a typical example is folic acid, which a- receptors (FRa) are overexpressed in number of cancer cell lines since they co-regulate the cell division. Active targeting of FRa by using carriers decorated by folic acid leads to the considerable increase of cellular uptake and thus to increase of effectivity of the drug.
  • the most important characteristics of macromolecular drug carriers are besides low toxicity and biocompatibility also good solubility, well defined molecular weight, number of functional (binding) groups per monomeric unit, their respective position and orientation, and nature of drug binding (covalent, ionic). Density, position, and orientation of binding groups are of particular importance because they determine the mode of drug binding and thus also influence the carrier capacity and drug release characteristics.
  • the carrier may bind the drug in mono- or bidentate manner.
  • the most common R 2 Pt n X 2 , R 2 Pt IV X 2 L 2 platinum (pro)drugs contain two binding places.
  • Polysaccharides are highly promising drug carriers. Their main advantages are excellent biocompatibility, low toxicity, and simple modifications. These advantages led to a number of applications of polysaccharides and polysaccharide-based biomaterials, particularly hydrogels, for drug delivery, see for instance USA patents US6338843B 1, US4931553A and US4793986A, USA patent application US2008300389A1, international patent application W09637519A1, and European patent application EP1722714A1.
  • Acidic polysaccharides containing at least one -COOH group in their structure are particularly suited for drug delivery applications. This is due to possible direct binding of the drug to the -COOH group and in its relatively simple modifications, e.g. esterification and amidation reactions.
  • Acidic polysaccharides can be of natural origin, e.g. hyaluronic acid, alginate (USA patent US4695462A), or they can be synthetically prepared from common polysaccharides such as cellulose or dextrin.
  • An example of the latter is the succinic acid ester of dextrin, which was claimed in patent US6338843B 1 as a carrier for doxorubicin-based anticancer drugs.
  • the major disadvantage of most of the natural acidic polysaccharides is relatively low density of carboxylic groups. Usually, the degree of substitution is ⁇ 1, i.e. they contain one or less -COOH group per monomeric unit. This leads to the low binding effectivity and limits the carrier capacity due to the undesirable crosslinking reactions described above. For instance, conjugation of cisplatin (CP) to the hyaluronic acid has only 30% binding effectivity and maximum carrier capacity of only 25 wt% even when using a very high weight ratio of reactants 16 : 10 (CP : HA). These disadvantages can be partially remedied by using linkers, i.e.
  • Yet another alternative solution lies in highly selective oxidation of polysaccharide hydroxyl groups to aldehydes in positions 2 and 3 of pyranose cycle using NaI0 4 , which is accompanied with the simultaneous breaking of C2 - C3 bond.
  • This allows to achieve much higher density of functional groups (up to two per each pyranose unit).
  • Resulting aldehyde is however not suitable as a drug carrier due to its highly complex structure and tendency for degradation.
  • this method was used to activate the polysaccharides for binding with linkers based on amino acid and carboxylic acid derivatives, to which Pt(II) and Pt(IV) complexes were subsequently bound, as claimed by the USA patent US4793986A.
  • the disadvantage of this solution is potential toxicity of dialdehyde further enhanced by synthesis involving extremely toxic cyanide salts as reducing agents.
  • 2,3-dicarboxypolysaccharides Secondary oxidation of 2,3-dialdehydepolysaccharides by NaCl0 2 leads to the preparation of 2,3-dicarboxypolysaccharides.
  • cellulose Assuming cellulose as a starting material, 2,3- dicarboxycellulose (DCC) is prepared.
  • the DCC has, on contrary to non- selectively oxidized cellulose, well-defined structure and good solubility in water when oxidized above 70%.
  • Proposed applications of 2,3-dicarboxypolysaccharides focused in the past mostly on their polyanionic character.
  • the DCC was considered as one of the potential alternatives of alginates for preparation of injectable and biodegradable hydrogels for sustained delivery of proteins, as was claimed in USA patents US6432449B 1, US 6656508B2, European patents EP1079811B 1 and EP0975333B 1. DCC was thus only mentioned as an alternative to one component of the gel network. DCC is also mentioned as an alternative of alginate derivatives in the international patent application W02005079703A1, which relates to the development of two-phase system for sustained delivery of quinazolin derivatives and treatment of fibrosis. The positively charged drug is bound in these systems by ionic interactions with negatively charged polymer. DCC is also mentioned in the patent application US2005020813A1 as one of possible alternatives for preparation of hydrophilic coating of hydrophobic core in systems designed for transport of compounds with poor water solubility.
  • the polysaccharides may be contaminated by employed organic solvents, which are very difficult to remove by standard procedures (vacuum drying) probably due to the formation of strong hydrogen bridges with polycarboxylate anion.
  • polysaccharides for metallodrug-delivery applications should have well- defined structure and composition, simple and easy-to-control synthesis, defined (and definable) molecular weight and high solubility. They should also be non-toxic, biodegradable or at least biocompatible. They should also possess the highest possible density of drug-binding groups in the distance and the orientation suitable for chelation/binding of respective metal complexes. Other functional groups, usable for biding of targeting vectors and other biologically active compounds should also be available in the positions, where their modifications do not influence the amount of carried compound.
  • the shortcomings of the prior art described above can be overcame by using the method for the preparation of selectively oxidized polysaccharides as drug-delivery carriers according to the present invention.
  • the invention features, in accordance with previous procedures, polysaccharides with at least one pyranose cycle in their basic structural unit bearing hydroxyl groups in positions 2 and 3, and these are at least partially, but preferably completely, oxidized to 2,3-dialdehydepolysaccharides by selective oxidation using periodate alkali metal salt, followed by secondary oxidation of dialdehyde and formation of 2,3-dicarboxypolysaccharide by chlorite alkali metal salt in the presence of acetic acid.
  • the essence of the invention resides in the fact, that for the preparation of fully oxidized polysaccharide with adjustable molecular weight is necessary to use in the first step the periodate : polysaccharide molar ratio 1.0- 1.5 : 1 and reaction time from 24 to 72 h, depending on the crystallinity of the material and its particle size, and for subsequent quantitative conversion of resulting 2,3-dialdehydexypolysaccharide to 2,3-dicarboxypolysaccharide it is advantageous to use the molar ratio of aldehyde groups : chlorite salt : acetic acid between 1 : 2 : 1 and 1 : 8 : 1 and reaction time at least 7 h, while for the preparation of materials with weight- average molecular weight (M w ) lower than that of the original polysaccharide it is necessary to add sulfamic acid into the reaction mixture before secondary oxidation, as M w of the product is inversely dependent on the molar amount of sulfa
  • Bioconjugation reactions are used to bind biologically or diagnostically active compounds to the carrier via a spacer.
  • the -COOH group of the biologically active compound is activated by using carbodiimide such as EDC (l-ethyl-3-(3- dimethylaminopropyljcarbodiimide) and N-hydroxysuccinimide (NHS), which is followed by amidation reaction with amino- group of the spacer (NH 2 -PEG-COOH).
  • carbodiimide such as EDC (l-ethyl-3-(3- dimethylaminopropyljcarbodiimide) and N-hydroxysuccinimide (NHS), which is followed by amidation reaction with amino- group of the spacer (NH 2 -PEG-COOH).
  • Molar ratio of individual components is preferably between 1 : 1 : 1 : 1 and 1 : 10 : 1 : 10 (vector : EDC : NHS : spacer) if the vector contains only a single -COOH group, or between 1 : 0.1 : 1 : 0.1 and 1 : 0.99 : 1 : 0.99 if the vector contains two or more -COOH groups.
  • EDC : NHS spacer ratio below 1 : 1 : 1 : 1 the probability of undesirable side reactions is reduced.
  • the -COOH group of the spacer is in the next step activated by carbodiimide (EDC) and in the presence of 4-dimethylaminopyridine (DMAP) as a catalyst (EDC : DMAP ratio between 10 : 1 and 100 : 1) the esterification of hydroxyl group of the 2,3- dicarboxypolysaccharide is performed.
  • EDC carbodiimide
  • DMAP 4-dimethylaminopyridine
  • Conjugate with adjustable drug release rate, drug binding effectivity above 70% and carrier capacity up to 80 wt% is composed of carrier prepared according to the invention and conjugated by active compounds, which are an anticancer drugs based on transition metal complex, particularly bidentate-bound platinum complexes of general formulas R 2 Pt n X 2 and R 2 Pt IV X 2 L 2 , ruthenium complexes of general formula [Ru(aren)L x (PTA) y ], and monofunctional platinum salts of general formula [R 3 Pt n X]Y, while the control over the drug release rates is achieved by using the carrier with different M w , particularly lower than that of starting polysaccharide, and by using the variety of weight ratios between the drug and the carrier between 1: 100 and 10: 1 during the conjugate preparation.
  • active compounds which are an anticancer drugs based on transition metal complex, particularly bidentate-bound platinum complexes of general formulas R 2 Pt n X 2 and R 2 Pt IV X 2 L 2
  • the starting material for the preparation of 2,3-dicarboxypolysaccharide carriers can be any non-toxic and biocompatible polysaccharide, which structure allows for selective oxidation of hydroxyl groups at C2 and C3 of pyranose cycle to aldehydes by using periodate salt and their subsequent oxidation to carboxylic acids by using chlorite salt.
  • the presence of at least one pyranose cycle composed of -CHOH groups in positions 2 and 3 is thus required in the basic structural unit of the polysaccharide.
  • Polysaccharides fulfilling these requirements include, but are not limited to, cellulose, amylose, starch, pectin, dextrin, dextran, xanthan, and acidic polysaccharides such as hyaluronic acid, carboxymethylcellulose, carboxymethyldextran, chondroitin, and alginate, with the preferred material being cellulose.
  • Polysaccharide can be oxidized entirely or partially.
  • 2,3-dicarboxypolysaccharides can be further decorated by additional groups and ligands for improving their therapeutic or diagnostic qualities preferably at the hydroxyl, carboxyl or another suitable functional group at C6 of pyranose cycle, if present. The reason being that substitution at C6 of pyranose cycle has minimal impact on the conjugate formation with biologically active compound in the positions 2 and 3.
  • Conjugated biologically active compound means therapeutically active neutral or positively charged complex of transition metal, which is bound to the carrier either in a covalent or ionic manner or by the combination of thereof. Presence of at least one (monodentate binding) but preferably two leaving anionic ligands X in cis orientation (bidentate biding) is required for covalent conjugation to the carrier.
  • ligands are typically anions of inorganic and organic acids (halides, carboxylates). Alternatively, instead of two leaving ligands, single bidentate ligand, i.e. dicarboxylate, may be present.
  • the essential condition is the sufficient lability of these ligand(s), which is required for their substitution by carboxylic group(s) of the carrier during the conjugation. This condition ensures the spontaneous progress of the conjugation.
  • activation of the complex may be employed, e.g. by silver nitrate in the case of halide(s).
  • the complex For the ionic or combined (ionic and covalent) binding of the complex with the carrier, the complex must bear the positive charge in order to bind to the negatively charged carrier.
  • Ligands L 2 may be biological
  • biologically active transition metal complexes can also be monodentate platinum R 3 Pt n X]Y salts, where R 3 are three nitrogen-based ligand(s) of variable composition, X represents anionic leaving ligand or ligands, typically halide(s), nitro- group(s), carboxylic or dicarboxylic acid(s), Y is an anion of inorganic or organic acid, and platinum moiety bears a positive charge.
  • RAPTA-type complexes with general formula [Ru(aren)L x (PTA) y ], where (aren) represents aromatic hydrocarbon non-covalently bound to the ruthenium, L x is leaving anionic ligand or ligands (typically halide(s), nitro- group(s), carboxylic or dicarboxylic acids) and PTA is (l,3,5-triaza- 7-phosphatricyclo[3.3.l. l]decan) or its derivative.
  • Another possibility are square-planar complexes of Au 111 with antitumor effect, known as peptidomimetics, and other complexes of transition metals, which fulfill the requirements.
  • the invention relates to the preparation of high-purity carriers for transition metal-based anticancer drugs with an adjustable weight- average molecular weight (M w ).
  • M w weight- average molecular weight
  • the presented invention allows for synthesis of carriers capable of transporting a broad spectrum of metallodrugs, including non platinum cytostatics, the higher drug-binding effectiveness due to possibility of bidentate binding and high loading capacity due to high density of binding groups, while still maintaining good solubility.
  • Presented invention further allows for the advanced drug targeting by combination of both passive (EPR effect) and active tumor targeting (biologically active vectors), the adjustable drug release rates, while simultaneously avoiding the contamination of the product by organic solvents as step involving precipitation of the product by alcohols is avoided, and other contaminants are removed by dialysis.
  • EPR effect passive
  • active tumor targeting biologically active vectors
  • Fig. 1 General structure of 2,3-dicarboxypolysaccharides
  • Fig. 2 Portion of 1 H NMR spectra of DCC prepared according to Example 1 (25°C, D 2 0), degree of oxidation 95%.
  • Fig. 3 Schematics of oxidation and modification of cellulose by spacer bearing folic acid and preparation of the cisplatin-DCC conjugate (CP-DCC).
  • Fig. 4 Structure of CP-DCC conjugate based on spectroscopic analysis (DFT optimized)
  • Fig. 5 a) Cisplatin binding effectivity as a function of the weight ratio of reactants.
  • Fig. 6 Cumulative release rates for PhPt-DCC conjugates prepared by different procedures (PhDCC - spontaneous reaction, PhDCC Ag - activation by AgN0 3 )
  • Fig. 7 a) Structural formula of RAPTA-C
  • Fig. 8 Univariate analysis of overall survival of mice treated with CP (blue line) and CP-DCC (red line), M w of the carrier: 18 kDa, 44 wt% of CP in the conjugate.
  • Fig. 9 Distribution of platinum in tumor tissue of mice treated with CP (Fig. 9a) and CP-DCC (Fig. 9b)
  • Starting material for the synthesis is a high-purity polysaccharide (cellulose) subsequently mixed with solution of sodium periodate.
  • the molar ratio of reactants and oxidation time depends on degree of conversion required and the type of the polysaccharide.
  • 72 h reaction at 30°C in the absence of light is used, employing the molar ratio of reactants 1.2 : 1 (NaI0 4 : cellulose).
  • the oxidation reaction is terminated by the addition of ethylenglycol.
  • Obtained 2,3-dialdehydecellulose (DAC) is purified by filtration and centrifugation and degree of DAC conversion is determined by oxime reaction and alkalimetric titration.
  • the DAC prepared according to this procedure reaches degree of conversion above 90%.
  • DAC is further oxidized by NaCl0 2 in the presence of acetic acid, using optimal reaction ratio of 1 : 4 : 2 (-CHO : NaCl0 2 : CH3COOH).
  • the reaction is finished after 7 h at 30°C in the absence of light.
  • the reaction stoichiometry and its duration can be modified based on the material characteristic of the substrate and required properties of the product.
  • the reaction is subsequently terminated by addition of NaOH and reaction mixture dialyzed against distilled water for at least 48 h or until the pH equilibrium is reached.
  • the dialysis step is followed by titration of the product by NaOH to neutral pH and resulting solution of 2,3-dicarboxycellulose is filtered and lyophilized.
  • the product prepared by this procedure has high purity, degree of oxidation above 95% (see 1 H NMR spectrum of DCC in Fig. 2) and M w corresponding to that of original substrate since degradation of polymeric chains does not practically occur during the oxidation.
  • the low- intensity signals in the NMR spectrum in Fig. 2 belong to un-oxidized anhydroglucose units of cellulose.
  • the solution of sulfamic acid is added to the reaction mixture before the secondary oxidation.
  • the presence of sulfamic acid directly influences the M w of the product, because the molecular weight of the product is inversely dependent on its molar amount in reaction mixture.
  • the salts of 2,3-dcarboxypolysaccharides prepared according to the examples 1 and 2 can be used directly for the preparation of conjugates with metallodrugs, or they can be further modified by biologically active compounds for enhanced tumor targeting or by compounds for diagnostic applications.
  • Partially oxidized CMC is subsequently used for secondary oxidation by sodium chlorite in the presence of acetic acid with slightly modified reaction stoichiometry defined by the molar ratio of CMC to other reaction components (CMC : NaCl0 2 : CH3COOH 1 : 2 : 2) and using reaction time of 3.5 h.
  • the sulfamic acid solution can be used during the preparation to adjust the molecular weight of the product in order to obtain material with different properties, particularly drug-release rates. Further steps are the same as in preparation of DCC in Example 1. Yield of the reaction 94 %, degree of CMC oxidation: 55 %.
  • Example 3 one can prepare anticancer drug carriers from other water-soluble polysaccharides, particularly from dextran, dextrin, and xanthan. To ensure the full conversion, one should increase the duration of primary oxidation to 24 h and that of secondary oxidation to 7 h and follow the procedure described in Examples 1 and 2.
  • Biologically or diagnostically active compounds can be attached to the carrier either directly, or by using a spacer, which is a (macro)molecular chain of suitable length, i.e. modified polyethylene glycol (PEG) with M w between 100 and 20000 Da.
  • PEG polyethylene glycol
  • the only condition is the presence of carboxylic group in the structure of bound active compound.
  • the first, more simple method of direct binding of the compound is suitable for compounds that do not directly interact with living organisms, e.g. fluorescence probes.
  • the second method is preferred for biological vectors, as the spacer reduces the steric hindrance of the vector caused by the presence of the macromolecular chain of the carrier. Vector thus may bind to the receptor of the target cell more easily.
  • the method for the preparation of vector-decorated 2,3- dicarboxypolysaccharide relies on bioconjugation reactions, optimized for the modifications of 2,3- dicarboxypolysaccharides.
  • the -COOH group of the vector is activated in the first step, by using (l-ethyl-3-(3-dimethylaminopropyl)carbodiimide) and NHS (N-hydroxysuccinimide) and subsequent amidation reaction with the NH 2 - group of the spacer (Nfh-PEG-COOH).
  • the -COOH group of the spacer is selectively activated by EDC in the presence of DMAP (4-dimethylaminopyridine) as a catalyst and esterification reaction with -OH group of the 2,3-dicarboxypolysaccharide is performed.
  • DMAP dimethylaminopyridine
  • the carboxylic group of the vector is activated by EDC and in the presence of DMAP reacts directly with -OH group of the 2,3-dicarboxypolysaccharide.
  • folic acid is first dissolved in dry DMSO, mixed with 1 molar equivalent of NHS and activated by EDC. Due to the presence of two -COOH groups in the folic acid structure, the molar ratio between folic acid and EDC is reduced to 1 : 0.95 or less to lower the chance of undesirable side reactions, and the duration of the reaction is increased to 6 h. Higher-purity product is thus achieved in exchange for minor decrease of yield. In case that only a single -COOH group is present in the activated molecule, one should use higher amount of EDC, preferably > 1.2 equivalent and reduced duration of the activation.
  • Activated folate is subsequently precipitated in the acetone/ether mixture (1 : 3), filtrated, washed, and immediately re-dissolved in dry DMSO.
  • the 0.95 molar equivalent (relative to folate) of NH 2 - PEG-COOH of suitable M w (2 kDa) is added and the reaction mixture is gently stirred at 40°C for 18 h under the nitrogen atmosphere to prevent the hydrolysis and in the absence of light.
  • reaction mixture is dialyzed against distilled water by using a membrane with molecular- weight cut-off, MWCO, 1.5 kDa.
  • the product (F-PEG) was obtained by lyophilization.
  • F-PEG is subsequently dissolved in dry pyridine and activated by 0.95 molar equivalent of EDC for 24 h.
  • the DMAP as a catalyst for esterification is subsequently added to the reaction mixture (molar ratio EDC : DMAP can be between 10 : 1 and 100 : 1) together with DCC dissolved in dry DMSO.
  • the molar ratio of F-PEG and DCC is dependent on the desired degree of substitution.
  • the biological targeting effect of folate was observed already for 5% substitution.
  • the reaction is terminated after 24 h by addition of water.
  • the reaction mixture was dialyzed (MWCO 14 kDa) to remove unreacted F-PEG and lyophilized.
  • the amount of folate in final product was determined by UV/VIS spectroscopy (5%).
  • the general procedure involves dissolution of the 2,3-dicarboxypolysaccharide of desired M w in distilled water and drop-wise addition of the solution of biologically active transition metal complex (drug) under the continuous stirring in the absence of light.
  • the metal complex must contain at least one easily leaving ligand. If the lability of leaving ligand is sufficient, reaction is spontaneous.
  • the reaction ratio depends on the desired amount of compound loading and it relates also to the desired release rates. Typically, weigh to weight ratios of compound : carrier can be from 1 : 100 to 10 : 1.
  • reaction time can be increased to 96 h.
  • the reaction can be performed between 0 and 50°C depending on the reactivity of the drug.
  • reaction temperature can prevent undesirable precipitation of the product which may occur due to high reactivity of the compound resulting in oversaturation of the carrier and uneven reaction progress.
  • leaving ligands are halides, one may perform activation by silver nitrate. After the filtration or centrifugation of precipitated silver halide, the solution of activated complex is mixed with the solution of the carrier, as described above. After the termination of reaction, residual unconjugated complexes are removed by dialysis.
  • the duration of dialysis should be 4 to 8 -times longer than the period during which free complex is quantitatively dialyzed, typically 2 - 4 h. Longer duration leads to unnecessary loses, while shorter does not guarantee sufficient purity of the conjugate.
  • the whole process of preparation of the carrier and its conjugate decorated by folic acid is schematically summarized in Figure 3 for DCC and cisplatin.
  • cisplatin-DCC (F-DCC) conjugate To prepare cisplatin-DCC (F-DCC) conjugate, the aqueous solution of cisplatin (2 mg/mL) was gradually added into the gently stirred solution of DCC or F-DCC (2 mg/mL), and the reaction mixture was left for 72 h in the dark. After that, the reaction mixture was dialyzed for 4 h against distilled water (membrane with MWCO 3.5 kDa) and lyophilized. Reactions were performed using DCC of M w of 18 kDa and 76 kDa, respectively, and F-DCC of M w of 18 kDa.
  • Tested reaction ratio (CP : DCC) was between 4 : 10 and 12 : 10 (28 - 55 wt% of CP). Formation of the conjugate was observed using IR spectroscopy in far-infrared region (FIR), 13 C and 195 Pt NMR and X-ray fluorescence spectroscopy (XRF). FIR spectra revealed disappearance of vibration bands at 315 cm 1 and 323 cm 1 which corresponds to Cl-Pt-Cl vibrations of free cisplatin and simultaneous appearance of bands at 338 cm 1 and 387 cm 1 , which corresponds to O-Pt-O vibrations.
  • FIR far-infrared region
  • XRF X-ray fluorescence spectroscopy
  • the conjugate formation is manifested in 13 C NMR spectra by appearance of broad signal at 175.3 ppm, which was assigned to C2 and C3 carbon atoms bearing cisplatin residue. Bidentate binding of cisplatin is than evident from 195 Pt NMR spectra, where cisplatin signal shifted from -2149 ppm to -1605 ppm, i.e. into the region where square-planar complexes of platinum coordinated by two nitrogen and two oxygen atoms resonate.
  • a model of structure of conjugate, optimized using density functional theory (DFT) with RBE0 functional and split-valence basis set, is given in Fig. 4. Amount of cisplatin bound in the conjugate was determined by XRF spectroscopy. Cisplatin binding effectivity was above 90% even for reactant ratio 12 : 10 (CP : DCC). Cisplatin binding effectivity as a function of reactant ratio is given in Fig. 5a.
  • the drug release rates can be adjusted from ⁇ l0%/24 h to >70%/24 h by changing the amount of cisplatin in the conjugate and the M w of the carrier. Selected examples are given in Fig. 5b.
  • Cisplatin release rates were determined in the following manner: 20 mg of CP-DCC with different molecular weight and content of cisplatin were dissolved at 37°C in 5 mL of phosphate-buffered saline (PBS) with pH 7.4 and 5.5, respectively, and dialyzed against 95 mL of the same medium (membrane MWCO 3.5 kDa). The aliquots (5 mL) were collected in predetermined times and the content of cisplatin determined by XRF spectroscopy. After each step, 5 mL of fresh medium was added to the solution to keep constant volume.
  • PBS phosphate-buffered saline
  • Phenanhriplatin cA-[Pt(NH3)2-(phenanthridin)Cl]NC)3, PhPt
  • DCC aqueous cellulose
  • PhPt was dissolved in cold water (0°C, 0.8 mg/mL) and added dropwise to the cooled solution of DCC (0°C, 1 mg/mL).
  • the reaction mixture was gently stirred in the absence of light and left to slowly warm up to the ambient temperature in an insulated container for 96 h.
  • the solution was then dialyzed and lyophilized as described for CP-DCC in Example 6.
  • Tested PhPt DCC weight ratios were between 2 : 10 and 8 : 10.
  • PhPt can be activated by 0.95 molar equivalent of AgNCE at 50°C for 16 h. The solution is then cooled to 0°C and precipitated AgCl is removed by repeated cycles of centrifugation and filtration. The solution containing activated PhPt 2+ ions is used for the preparation of the conjugate (Ph-DCC) as described in previous paragraph. The same procedure was used for the preparation of PhPt conjugate with F-DCC (M w 76 kDa). The prepared conjugate was characterized by XRF and 13 C NMR spectroscopy. The partially covalent character of conjugate binding is substantiated by signal of C2 and C3 carboxylic carbon atoms at 171 ppm. PhPt binding effectivity to DCC is somewhat lower than of cisplatin, although still very high with 87% at weight ratio 4: 10 and 77% at 8 : 10 ratio (PhPt : DCC, w/w).
  • PhPt Drug release rates of PhPt, in this case, depend not only on the M w of the carrier and loading of the drug but also on the method of preparation of the conjugate, see Fig. 6. While 20% of active compound is released from conjugate prepared by direct reaction between PhPt and DCC during the first hour, only 3% are released from conjugate prepared using AgNCF activation (see PhDCC Ag in Fig. 6). Delayed-release has the potential to further reduce the side effects of the drug because the release outside the target tissue is limited.
  • the RAPTA-C, Ru 11 complex representing non-platinum anticancer drugs is bearing two chloride ligands in cis orientation with Cl-Ru-Cl angle ⁇ 90° and with Cl - Cl distance 3.3 A, parameters similar to cisplatin (for structural formula and presumed structure of conjugate between RAPTA-C and DCC, the R-DCC, see Fig. 7). Figands are thus in an ideal position for substitution by carboxylic groups of the carrier.
  • the R-DCC conjugate was prepared by using lower temperature as described in Example 7 for Ph-DCC and by using lower weight to weight ratio of reactants (4 : 10, RAPTA-C : DCC). The amount of bound ruthenium was determined by XRF spectroscopy. The reaction effectivity was 80%. The release of RAPTA-C from the R- DCC is faster than in the case of cisplatin (85%/24 h), presumably due to the higher lability of Ru-0 bonds.
  • Biological tests were performed in vitro using a panel of cell lines representing healthy tissues, primary, and metastatic cancer cells. Cytotoxicity of tested compounds for individual cell lines was determined by metabolic MTT assay. The assay is in principle based on the reduction of tetrazolium salt MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) by mitochondrial reductase to insoluble formazan. Purple formazan is dissolved in an organic solvent, and cell viability is determined by spectrophotometry since conversion of MTT to formazan occurs only in metabolically active (living) cells.
  • MTT tetrazolium salt
  • Healthy tissues are represented by cell lines NIH/3T3 (mouse embryonic fibroblasts), HFF (human fibroblasts) and PNT1A (healthy prostate cells).
  • PNT1A primary tumor
  • A2780/CP primary tumor
  • metastatic H1299, 22RV1
  • Cytotoxicity of CP-DCC is 3 - 9-times lower for healthy cells (3 -9-times higher IC50) than for free CP.
  • the cytotoxicity for primary and metastatic cancer cell lines is on average only around 40% lower than for free cisplatin. In some cases (PC-3 cell line, Table 1) it is even slightly higher. For about 40% lower cytotoxicity agrees well with the cumulative drug release from the conjugate, which is in this particular case between 60 - 70% after 48 h (Fig. 5b). Based on data obtained, it is assumed that in the case of equitoxic dose, the CP-DCC would have considerably higher cytotoxicity against cancer cell lines than free cisplatin.
  • PhPt and Ph-DCC are comparable for healthy cells, while Ph-DCC is on average more effective against tumor cell lines than free PhPt.
  • the IC50 of Ph-DCC is even several times lower, see Table 2. Better effectivity of the conjugate in comparison with a free drug, the trend opposite to that of CP and CP-DCC, correlates with faster release of active compound from Ph-DCC in comparison with CP-DCC, see Fig. 5b and 6.
  • Table 2 ICsovalues for free phenanthriplatin (PhPt) and phenanthriplatin-DCC conjugate (Ph- DCC, M w of the carrier 76 kDa, 26 wt% of PhPt) for healthy (NIH/3T3, HFF, PNT1A), primary tumor (A2780, A2780/CP, A549) and metastatic (22RV1 ) cell lines.
  • CP and CP-DCC conjugate (M w of the carrier 18 kDa, 44 wt% of CP) was performed according to the experimental plan approved by the Committee on the Protection of Animals, Faculty of Medicine, Masaryk University on 10 female athymic Nu/Nu mice weighing between 19.7 and 25.9 g, which were 8 weeks old.
  • Tumor induction was performed by s.c. injection of ovarian carcinoma A2780 in the interscapular area (200 pL, 5 ⁇ 10 6 cells/mice in 100 mL PBS). Twenty-five days after tumor induction, when tumors reached sizes of about 6 mm, the CP and CP-DCC conjugate were i.v. administered in 200 pL of physiological solution. Concentrations of CP and CP-DCC were set to 1.5 mg/mL and 3 mg/mL, respectively, which corresponds to the same overall dose of cisplatin.
  • FIG. 9 illustrates the relative distribution of platinum (local concentration of platinum) in the tumor tissue of mice treated with CP (Fig. 9a) and CP-DCC (Fig. 9b), respectively.
  • the color scale corresponds to the average concentration of platinum in mice tumor tissue (pg/g) that ranges between 0 - 18 pg/g (Fig. 9a) and 0-25 pg/g (Fig. 9b).
  • the accumulation of platinum in the tumor tissue was significantly higher, up to 25 pg/g, in the case of mice treated with CP-DCC. Conjugation of CP to the DCC positively influences the accumulation of Pt in the tumor tissue.

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FR3116820A1 (fr) * 2020-12-02 2022-06-03 Centre Technique Du Papier Procede de solubilisation et de regeneration de la cellulose
CN114957510A (zh) * 2022-07-19 2022-08-30 西安超磁纳米生物科技有限公司 一种功能化修饰的聚葡萄糖山梨醇羧甲醚及制备方法

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CN114957510A (zh) * 2022-07-19 2022-08-30 西安超磁纳米生物科技有限公司 一种功能化修饰的聚葡萄糖山梨醇羧甲醚及制备方法

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