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    • 专利摘要:
    The present invention relates to polymers, compositions thereof, and methods of producing polymers in general. Furthermore, the present invention relates to pharmaceutical compositions and uses of said polymers, compositions and pharmaceutical compositions. More particular, the present invention relates to polymers of jasmine lactone, where pendant groups of said polymers can readily be used for attaching functional moieties comprising active agents. Furthermore, the present invention relates to modified jasmine lactones that can readily be used in methods of producing polymers of the present invention. More particular, the invention relates to polymers from renewable monomers, which can be used in applications such as drug delivery and diagnosis, polymer–drug conjugates, medical devices, cosmetic products, polymers with marker unit, polymers usable as flame retardants, tissue engineering, coatings, paints, lubricants and biodegradable plastics.
    公开号:FI20195748A1
    申请号:FI20195748
    申请日:2019-09-10
    公开日:2021-03-11
    发明作者:Kuldeep Kumar Bansal；Jessica Rosenholm；Ari Rosling
    申请人:Aabo Akademi Univ；
    IPC主号:
    专利说明:

    [1] [1].
    In still one embodiment of the invention the polymers comprise at least one repeating unit, wherein the polymer has a Formula that is selected from Formulas la to leXL X O OH
    O O | | [la] Xf of +* of off
    O O | [lb] Oo” O OHO O
    S S L be [Ic]
    O X O OH 2 ok N O 0) 3 3
    OH OH o [Id]
    S ' O X O OH S < Kok KN ! O O
    O z S S a . K K N NH, NH, [le]
    LO 2 wherein N 15 each X is independently selected from a group consisting of O, OR6, S, SR6, and N(R6)2, wherein R6 is each independently selected from a group consist-
    ing of H, C1-20-alkyl, C2-20-alkenyl, C2-20-alkynyl, Ci-10-alkylenyl, Ci-10-haloalkyl, and phenyl; ois an integer from 1 to 1000; p is an integer from 10 to 2000; q is an integer from 10 to 2000; or a salt thereof.
    In yet one embodiment of the invention the polymers comprise at least one repeating unit, wherein the polymer has a Formula ly 4, wherein each X is independently selected from a group consisting of O, S, and NR6, wherein R6 is each independently selected from a group consisting of H, Ci- 20-alkyl, C2-20-alkenyl, C2-20-alkynyl, Ci-10-alkylenyl, C1-10-haloalkyl, and phenyl; p is an integer from 10 to 2000; or a salt thereof.
    The present invention also provides a novel composition comprising a polymer comprising at least one repeating unit, wherein the at least one repeating unit has Formula [I], and at least one active agent, or a salt thereof.
    In one embodiment of the invention the composition comprises a pol- ymer comprising at least one repeating unit, wherein the at least one repeating unit has Formula [I], wherein the at least one active agent(s), or derivatives thereof, is/are independently covalently attached to or form(s) ionic bond(s) with the polymer.
    In one preferred embodiment of the invention the composition com- prises a polymer comprising at least one repeating unit, wherein the at least one > repeating unit has Formula [I], wherein the at least one active agent(s) is/are in- D dependently selected from an active ingredient, an active pharmaceutical ingredi- N ent, an antibody, an aptamer, a unit having fluorescence, radioactivity or any oth- = er properties which can be detected, a protein, a peptide, and a flame retardant, A 30 and any derivatives thereof.
    E In yet one preferred embodiment the composition comprises a poly- © mer comprising at least one repeating unit, wherein the at least one repeating = unit has Formula [I], wherein the at least one active agent is an active pharmaceu- 2 tical ingredient, or a derivative thereof.
    N 35 In yet one preferred embodiment the composition comprises a poly- mer comprising at least one repeating unit, wherein the at least one repeating unit has Formula [I], wherein the at least one active agent is a unit having fluores- cence, which can be detected, or a derivative thereof.
    In yet one preferred embodiment the composition comprises a poly- mer comprising at least one repeating unit, wherein the at least one repeating unit has Formula [I], wherein the at least one active agent is a flame retardant, or a derivative thereof. In one embodiment of the invention the composition comprises a pol- ymer comprising at least one repeating unit, wherein the at least one repeating unit has Formula [I], wherein the at least one active agent(s) is/are independently — selected from doxorubicin, daunorubicin, epirubicin, idarubicin, paclitaxel, docet- axel, cabazitaxel, camptothecin, cisplatin, fluorescein, fluorescein isothiocyanate (FITC), rhodamine, biotin, folic acid, transferrin, arginylglycylaspartic acid (RGD), rituximab, trastuzumab, cetuximab, bevacizumab, 2-carboxyethyl phe- nylphosphinic acid (CEPPA), phosphoric acid (H3PO4), phosphorous acid, 9,10- dihydro-9-oxa-10-phosphaphenanthrene-10-oxide, and fludeoxyglucose ([*8F]FDG), and any derivatives thereof.
    In one preferred embodiment of the invention the composition com- prises a polymer comprising at least one repeating unit, wherein the at least one repeating unit has Formula [I], wherein the at least one active agent is doxorubi- cin, or a derivative thereof.
    In one preferred embodiment of the invention the composition com- prises a polymer comprising at least one repeating unit, wherein the at least one repeating unit has Formula [I], wherein the active agents are doxorubicin and fludeoxyglucose ([18F|FDG), or any derivatives thereof.
    In yet one preferred embodiment of the invention the composition > comprises a polymer comprising at least one repeating unit, wherein the at least D one repeating unit has Formula [I], wherein the active agent is 2-carboxyethyl N phenylphosphinic acid (CEPPA), or a derivative thereof. = The present invention also provides a method of producing polymer or A 30 a salt thereof, the method comprising the steps of E i) providing jasmine lactone as a jasmine lactone monomer, © ii) optionally modifying at least part of the jasmine lactone monomers = of i) with at least one suitable reagent to form a modified jasmine lactone mono- 2 mer with Formula (III),NO
    O Or R! [my wherein R1 and R2 are as previously defined, iii) subjecting the jasmine lactone monomer of i) and/or the modified jasmine lactone monomer of ii) to a polymerization reaction to form a polymer. In one embodiment of the invention is provided a method of producing a polymer, or a salt thereof, wherein the polymerization reaction of iii) is per- formed in the presence of at least one further monomer to form a copolymer. In one embodiment of the invention is provided a method of producing a polymer, or a salt thereof, wherein the formed polymer or the formed copoly- — mer is further reacted or brought to close contact with at least one suitable rea- gent capable of reacting or interacting with the formed polymer or the formed copolymer to form a modified polymer or a modified copolymer, respectively. In one embodiment of the invention is provided a method of producing a polymer, or a salt thereof, wherein the formed polymer, the formed copolymer, the formed modified polymer or the formed modified copolymer is further react- ed or brought to close contact with at least one active agent to form a composi- tion. In one embodiment of the invention is provided a method of producing a polymer, or a salt thereof, wherein at least a part of the jasmine lactone mono- mer of i) and/or the modified jasmine lactone monomer of ii) is reacted or brought to close contact with at least one active agent before or during the polymerization reaction of iii) to form a functionalized jasmine lactone and/or a functionalized modified jasmine lactone, respectively, and subjecting the formed = functionalized jasmine lactone and/or the functionalized modified jasmine lac- N 25 — tone to a polymerization reaction to form a composition. S In one embodiment of the invention is provided a method of producing 2 a polymer, or a salt thereof, wherein the formed functionalized jasmine lactone E and/or the functionalized modified jasmine lactone is subjected to a polymeriza- N tion reaction in the presence of at least one further monomer to form a composi- N 30 tion. 3 In one embodiment of the invention is provided a method of producing N a polymer, or a salt thereof, wherein the at least one active agent(s) is/are inde- pendently selected from an active ingredient, an active pharmaceutical ingredi-
    ent, an antibody, an aptamer, a unit having fluorescence, radioactive or any other properties which can be detected, a protein, a peptide, and a flame retardant, and any derivatives thereof.
    In one embodiment of the invention is provided a method of producing a polymer, or a salt thereof, wherein the active agent comprises doxorubicin, daunorubicin, epirubicin, idarubicin, paclitaxel, docetaxel, cabazitaxel, camptoth- ecin, cisplatin, fluorescein, fluorescein isothiocyanate (FITC), rhodamine, biotin, folic acid, transferrin, arginylglycylaspartic acid (RGD), rituximab, trastuzumab, cetuximab, bevacizumab, 2-carboxyethyl phenylphosphinic acid (CEPPA), phos- phoric acid (H3P04), phosphorous acid, 9,10-dihydro-9-oxa-10-phosphaphen- anthrene-10-oxide, and fludeoxyglucose ([18F]FDG), and any derivatives thereof.
    Objects of the invention are also achieved by a novel pharmaceutical composition comprising one or more polymer as previously defined or an effec- tive amount of one or more composition as previously defined, in combination — with one or more other active ingredient(s), wherein the salt is a pharmaceutical- ly acceptable salt.
    In one preferred embodiment of the invention the pharmaceutical composition is together with one or more pharmaceutically acceptable excipi- ent(s).
    Objects of the invention are also achieved by a pharmaceutical compo- sition as previously defined for use as a medicament.
    UTILITY OF THE INVENTION Polymers of the invention are polymers of jasmine lactone, which pen- dant groups of said polymers can readily be used for attaching functional moieties comprising active agents. Furthermore, discloses herein are modified jasmine 2 lactones that can readily be used in methods of producing polymers of the present & invention. Said modified jasmine lactones can be produced from jasmine lactone, <Q which contains a 5-carbon side group, which can readily be used for attaching > functional moieties including one or more active agent. Pharmaceutical composi- E 30 tions of polymers of jasmine lactone comprising one or more active agent may be 0 useful in the treatment and prevention of a disease, disorder, or condition, in par- = ticular diseases, conditions, and conditions that include, but are not limited to, 2 breast cancer, prostate carcinoma, ovarian cancer, uterine cancer, endometrial N cancer, endometrial hyperplasia, lung cancer, colon cancer, tissue wounds, skin wrinkles and cataracts.
    Further, compositions and pharmaceutical compositions of the present invention may be useful for the treatment of diseases and disorders described above and which may be prevented, treated, and/or ameliorated by said composi- tions and pharmaceutical compositions. Thus, the pharmaceutical compositions of the present invention may be used as a medicament. Further, the present in- vention includes methods of treating diseases or disorders as described herein of hereafter, comprising administering a pharmaceutical composition according to the claims to a patient or subject in need thereof. In addition, pharmaceutical composition of the present invention may be used for the manufacture of a me- dicament for use in treatment of diseases or disorders as described herein of hereafter.
    The term "treatment or prevention" as used herein and hereafter in- cludes prophylaxis, or prevention of, as well as lowering the individual's risk of falling ill with the named disorder or condition, or alleviation, amelioration, elim- ination, or cure of the said disorder once it has been established.
    The terms “administering” or “administered” to a subject or patient in- cludes dispensing, delivering or applying the composition or pharmaceutical composition to the subject by any suitable route for delivery of the composition or pharmaceutical composition to a site in the body where desired.
    Compositions and pharmaceutical compositions of the present inven- tion may be administered in an effective amount within the dosage range of about
    0.1 ng/kg to about 300 mg/kg, preferably between 1.0 ng/kg to 10 mg/kg body weight. Compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. > The term "effective amount" refers to an amount of a composition or a D pharmaceutical composition that confers a therapeutic effect on the treated sub- N ject. The therapeutic effect may be objective (i.e. measurable by some test or = marker) or subjective (i.e. subject gives an indication of or feels an effect). Such A 30 treatment need not necessarily completely ameliorate the condition of disease. E Further, such treatment or prevention can be used in conjunction with other tra- © ditional treatments for reducing the condition known to those skilled in the art. = Compositions and pharmaceutical compositions of the invention are 2 most preferably used alone or in combination i.e. administered simultaneously, N 35 separately or sequentially with other active ingredients, e.g. pharmaceutically active compounds or biologic products. The amounts of the composition(s) or pharmaceutical composition(s) of the invention, particularly a pharmaceutical composition comprising a polymer of Formula [I] and an active agent, or pharma- ceutically acceptable salts thereof, and the other active ingredient(s) and the rela- tive timings of administration will be selected in order to achieve the desired combined therapeutic effect. Compositions and pharmaceutical compositions of the invention may be administered by various routes, for example, parenteral, subcutaneous, intravenous, intraarticular, intrathecal, intramuscular, intraperito- neal, topical, and by intradermal injections, and via transdermal, rectal, buccal, oromucosal, nasal, ocular routes and via inhalation and via implant.
    Compositions and pharmaceutical compositions may be formulated in- to a suitable pharmaceutical formulations; suitable administration forms include, for example, solutions, dispersions, suspensions, powders, capsules, tablets, pills, controlled release capsules, controlled release tablets and controlled release pills. In addition to the pharmacologically active ingredients, the pharmaceutical for- — mulations of the compositions can contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the ac- tive agents into preparations that can be used pharmaceutically.
    Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically accepta- ble excipients and may be useful in selecting suitable pharmaceutically acceptable excipients.
    Suitable pharmaceutically acceptable excipients include but are not limited to the following types of excipients: diluents (for example starches, man- > nitol), fillers (for example lactose, microcrystalline cellulose or calcium hydrogen D phosphate), binders (for example pre-gelatised corn starch, polyvinylpyrrolidone N or methylcellulose), additives (for example magnesium stearate, talc, silica), dis- = integrants (for example potato starch), lubricants (for example sodium lauryl sul- A 30 phate), glidants (for example fumed silica, talc, magnesium carbonate), granulat- E ing agents (for example water, ethanol), coating agents (for example hydroxypro- © pyl methylcellulose, gelatin, waxes, shellac, plastics, plant fibers), wetting agents = (for example sorbitan monopalmitate, poloxamer 407), solvents (for example wa- 2 ter), co-solvents (for example ethanol, propylene glycol), suspending agents (for N 35 example sorbitol, cellulose derivatives, edible hydrogenated fats), emulsifiers (for example lecithin or acacia), sweeteners (for example sucrose), flavoring agents
    (for example cherry, lime), flavor masking agents (for example vanilla, citrus), coloring agents (for example titanium oxide), anti-caking agents (for example sili- con dioxide), humectants (for example glycerine, sorbitol), chelating agents (for example EDTA salts, histidine, aspartic acid), plasticizers (for example tributyl citrate, diethyl phthalate), viscosity increasing agents (for example methylcellu- lose), antioxidants (for example (ascorbic acid, cysteine), preservatives (for ex- ample methyl or propyl p-hydroxybenzoates, sorbic acid or ascorbic acid), stabi- lizers (for example polysorbate 20 & 80, poloxamer 407), surfactants (for exam- ple polyethylene glycol, polysorbate 80), and buffering agents (for example sodi- um and potassium phosphates, citrate, acetate, carbonate or glycine buffers de- pending on the targeted pH-range). The skilled artisan will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is pre- sent in the composition or pharmaceutical composition and what other ingredi-
    ents are present in the composition.
    The compositions and pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art.
    Compositions and pharmaceutical compositions of the invention include, but are not limited to, for parenteral and topical administration that include, but are not limited to, sterile aqueous or non-aqueous solvents, suspensions and emulsions.
    Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, veg- etable oil, fish oil, and injectable organic esters.
    Aqueous carriers include, but are not limited to, water, water-alcohol solutions, including saline and buffered medi- al parenteral vehicles including sodium chloride solution, Ringer’s dextrose solu- — tion, dextrose plus sodium chloride solution, Ringer's solution containing lactose, > or fixed oils.
    Intravenous vehicles include, but are not limited to, fluid and nutri- D ent replenishers, electrolyte replenishers, such as those based on Ringer's dex- N trose and the like.
    Agueous compositions and agueous pharmaceutical composi- = tions according to the invention may comprise suitable buffer agents, such as so- A 30 dium and potassium phosphates, citrate, acetate, carbonate or glycine buffers de- E pending on the targeted pH-range.
    The use of sodium chloride as a tonicity ad- © juster is also useful.
    Compositions and pharmaceutical compositions may include = other excipients, such as stabilizing agents or preservatives.
    Useful stabilizing 2 excipients include surfactants (polysorbate 20 & 80, poloxamer 407), polymers N 35 (polyethylene glycols, povidones), carbohydrates (sucrose, mannitol, glucose, lac- tose), alcohols (sorbitol, glycerol propylene glycol, ethylene glycol), suitable pro-
    teins (albumin), suitable amino acids (glycine, glutamic acid), fatty acids (ethano- lamine), antioxidants (ascorbic acid, cysteine etc.), chelating agents (EDTA salts, histidine, aspartic acid) or metal ions (Ca, Ni, Mg, Mn). Among useful preservative agents are benzyl alcohol, chlorbutanol, benzalkonium chloride and possibly parabens. The composition and pharmaceutical composition according to the pre- sent invention may be provided in concentrated form or in form of a powder to be reconstituted on demand. In such cases formulations of powder for solution for injection /infusion excipients mentioned above may be used. In case of lyophiliz- ing, certain cryoprotectants are preferred, including polymers (povidones, poly- ethylene glycol, dextran), sugars (sucrose, glucose, lactose), amino acids (glycine, arginine, glutamic acid) and albumin. If solution for reconstitution is added to the packaging, it may consist e.g., of pure water for injection or sodium chloride solu- tion or dextrose or glucose solutions. Furthermore, polymers of formula [1] and [II] can be used as synthesis intermediates for the preparation of other compounds, in particular of other pharmaceutically active compositions, which are obtainable from polymers of formula [I] and [II] and, for example by introduction of substituents or modifica- tion of functional moieties. Further, compositions and pharmaceutical compositions of the present invention that show reduced toxicities and/or enhanced efficacy of active agents may be useful in drug delivery and diagnosis. E.g., compositions and pharmaceuti- cal compositions of the invention may be useful as drug deliver carriers as e.g. nanocarriers (NCs). The polymer-drug conjugates of the invention forming NCs show beneficial drug release and/or targeting properties, especially stimuli sensi- tive NCs offer improved drug release at the desired target site. Polymers compris- > ing active pharmaceutical ingredient(s) and/or unit(s) that can be detected, e.g. D units having fluorescence, may therefore be useful in drug diagnosis. N The polymers and compositions of the invention may also be useful in = medical devices, cosmetic products, flame retardants, tissue engineering, coat- A 30 ings, paints, lubricants and biodegradable plastics.
    E 2 >N
    EXAMPLES Synthesis of poly(jasmine lactone) homopolymer (PJL, 1y'): SN o O OH
    TS | | Ty' Poly(jasmine lactone) (PJL) was synthesized via ring opening polymerization (ROP) of jasmine lactone in bulk. The dried monomer jasmine lactone (5.00 g,
    30.0 mmol) was transferred into a flask containing the initiating alcohol propar- gyl alcohol (0.07 g, 1.3 mmol) and stirred for 10-15 minutes to make a homoge- neous mixture. 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD) (0.08 g, 0.6 mmol) was then added under a nitrogen atmosphere and the mixture was allowed to react for 11 h at room temperature. The obtained viscous liquid (91% conversion as per 1H NMR) was subsequently quenched by adding 5 mL of a solution of benzoic acid in acetone (0.03 g/mL), the polymer was precipitated in cold methanol and the residual solvent was evaporated under vacuum. Polymer PJL was recovered as colorless viscous liquid with 4.4 g yield. FTIR: 2960 (C-H stretching), 1727 (C=0), 1157 (C-O, ester), 722 (C=C) cm. 1H NMR (500 MHz, CDCI3): 8ppm 5.50 — 5.38 (m, 18H), 5.30 - 5.18 (m, 19H), 4.91 -
    4.78 (m, 19H), 4.64 (d, J = 2.4 Hz, 2H), 4.05 - 3.97 (m, 1H), 3.63 - 3.53 (m, 1H),
    2.49 - 2.42 (m, 1H), 2.39 - 2.11 (m, 80H), 2.08 - 1.90 (m, 40H), 1.75 - 1.30 (m, 81H), 1.02 - 0.83 (m, 60H). Synthesis of Boc-protected amine terminated homopolymer (PJL-NHBoc, o SN o O OH 2 O O v S S 2 O NHB00 L_NHBoc 4. E To prepare Boc-protected amine terminated polymer, PJL (1ya’, 2 g, 0.65 mmol) < and 2-(Boc-amino)ethanethiol (0.23 g, 1.33 mmol) were dissolved in DCM (5 ml). 5 25 2,2-Dimethoxy-2-phenylacetophenone (DMPA), 0.33 g, 13 mmol) was added to 2 the mixture and the reaction mixture was stirred for 4 h in a UV cabinet fitted N with a UV A/B bulb. The reaction mixture was precipitated in cold methanol and the solvent was removed under vacuum to yield Boc-protected amine terminated homopolymer PJL-NHBoc (1x'). NMR analysis confirmed consumption of double bonds of PJL (1ya'). Synthesis of poly(jasmine lactone) (PJL) copolymer (mPEG-b-PJL, 1a'): mr S
    O O | I A di-block (AB type) copolymer of jasmine lactone was synthesized using meth- oxy-PFG (mPEG) as initiator. Dried mPEG (5.0 kDa, 5 g, 1.0 mmol) was added in a flask containing dry jasmine lactone (5.04 g 30.0 mmol) and the mixture was heated to 50 °C and stirred for 10 minutes, until a homogeneous mixture was ob- tained. TBD (0.11 g, 0.8 mmol) was added and the mixture was allowed to react for 7 hours at 50°C (88% conversion as per IH NMR). The reaction mixture was then cooled, quenched by adding 5 mL of a solution of benzoic acid in acetone (0.3 g/5 mL) and the resulting polymer was precipitated in cold methanol followed by removal of residual solvent in vacuum. The obtained dry material was dissolved in a minimum quantity of acetone and re-precipitated in petroleum ether. Any residual solvent was evaporated under vacuum to yield the desired copolymer. The copolymer mPEG-b-PJL (1a’) was recovered as wax-like material (8.2 g yield). FTIR: 2885 (C-H stretching), 1730 (C=O), 1341 (C-H bending), 1105 (C-O, ester and ether overlapped), 730 (C=C) cm. 1H NMR (500 MHz, CDCls): öppm 5.52 -
    5.42 (m, 22H), 5.32 - 5.21 (m, 23H), 4.94 - 4.81 (m, 23H), 4.22 (dd, J = 10.8, 5.9 Hz 2H), 4.03 (s, 2H), 3.64 (s, 495H), 3.38 (s, 3H), 2.43 - 2.13 (m, 101H), 2.13 -
    1.94 (m, 50H), 1.75 - 1.38 (m, 100H), 0.96 (dt, J = 11.5, 5.0 Hz, 75H). Post-polymerization modification of copolymer (mPEG-b-PJL) to insert o functional moiety of choice (mPEG-b-PJL-COOH, 1c’): : SN 3 O O 2 S S | LL a 2 0” OH 0” OH 1c' 2 25 Thiol-ene click reaction was utilized to modify the available ene -groups of the > mPEG-b-PJL chain. Briefly, mPEG-b-PJL (1a’, 1.0 g, 0.11 mmol) and 3- mercaptopropionic acid (1.07 g, 10.1 mmol) were dissolved in DCM (5 mL). DMPA (0.097 g, 0.38 mmol) was added to the above mixture and stirred overnight in a
    UV cabinet fitted with a stirrer and UV A/B bulb. The reaction mixture was then precipitated in cold diethyl ether followed by removal of residual solvent in vacu- um to recover the product as a white sticky solid (1.1 g yield). FTIR: 2884 (C-H stretching), 1726 (C=0), 1342 (C-H bending), 1107 (C-O0) cm1. 1H NMR (500 MHz, CDCIl3): éppm 5.25 - 4.75 (m, 22H), 4.30 - 4.16 (m, 2H), 4.06 (s, 2H), 3.64 (s, 523H), 3.38 (s, 3H), 2.73 (d, / = 6.5 Hz, 44H), 2.62 (t, J = 6.9 Hz, 44H),
    2.54 (s, 21H), 2.32 (s, 44H), 1.97 - 1.31 (m, 238H), 0.93 (ddd, J = 22.6, 11.1, 6.3 Hz, 70H). Post-polymerization modification of copolymer (mPEG-b-PJL, 1a’) to insert — functional moiety of choice (mPEG-b-PJL-OH, 1d’): aN O 0)
    S S K a w Thiol-ene click reaction was utilized to modify the available ene -groups of the mPEG-b-PJL chain. Briefly, mPEG-b-PJL (1a’, 1.0 g, 0.11 mmol) and 2- mercaptoethanol (0.8 g, 10.1 mmol) was dissolved in DCM (5 mL). 2,2- Dimethoxy-2-phenylacetophenone (DMPA) (0.097 g, 0.38 mmol) was added to the above mixture and stirred overnight in a UV cabinet fitted with a stirrer and UV A/B bulb. The reaction mixture was then precipitated in cold diethyl ether followed by removal of residual solvent in vacuum to recover the product as a white sticky solid (1.1 g yield). FTIR: 3433 (O-H), 2886 (C-H stretching), 1727 (C=0), 1341 (C-H bending), 1106 > (C-0) cm1. TH NMR (500 MHz, CDCI3) ppm 5.32 — 4.80 (m, 23H), 4.27 - 4.17 (m, S 2H), 4.02 (d, J = 29.8 Hz, 2H), 3.75 - 3.67 (m, 41H), 3.64 (s, 518H), 3.38 (s, 3H), > 2.85 — 2.63 (m, 47H), 2.63 — 2.45 (m, 23H), 2.32 (s, 47H), 1.82 - 1.31 (m, 238H), = 1.07 — 0.82 (m, 76H). x a sSN
    Post-polymerization modification of copolymer (mPEG-b-PJL, 1a’) to insert functional moiety of choice (mPEG-b-PJL-NH2 HCI, 1e'): N 0 o OHO OJ J
    NH NH Pe Pe’ 10 To prepare amine terminated polymer, mPEG-b-PJL (1a’, 0.5 g, 0.06 mmol) and —cysteamine hydrochloride (0.58 g, 5.1 mmol) was dissolved in ethanol (5 mL) containing one mL of DCM. DMPA (0.05 g, 0.2 mmol) and stirred overnight in UV cabinet fitted with a stirrer and UV A/B bulb. The reaction mixture was filtered, and the solvent of the filtrate was removed under vacuum. The dried product was dissolved in water and dialyzed (molecular weight cut off (MWCO): 2kDa) for 4 — days against water and freeze dried to obtain the purified product as a light yel- low colored solid (0.52 g yield). FTIR: 2877 (C-H stretching), 1727 (C=0), 1342 (C-H bending), 1107 (C-0) cm”. 1H NMR (500 MHz, DMSO-ds): ppm 5.42 (s, 7H), 5.27 (d, J = 36.6 Hz, 7H), 5.07 - 4.58 (m, 15H), 3.49 (s, 495H), 3.22 (d, J = 3.5 Hz, 3H), 2.89 (d, J = 6.8 Hz, 32H), 2.72 -
    2.56 (m, 31H), 2.35 — 2.05 (m, 58H), 1.90 (s, 14H), 1.71 — 1.19 (m, 159H), 1.04 -
    0.60 (m, 70H). Conjugation of doxorubicin (DOX) to mPEG-b-PJL-OH (1d’) via disulfide linkage (mPEG-b-PJL-S-S-DOX, 1dx'): oOO
    N oIO
    I a a © +KKLOOON
    TrgO O
    S S ve Br Ss gS TCs. OH k A 0 OH o o o H : mn LLE
    OH HO Xx LI O OH O ° (3 OH (> O 1dx' Carbodiimide coupling reaction was utilized to conjugate doxorubicin to the pen- dant group of the polymer. A reduction sensitive linker (3,3’-dithiodipropionic acid) was utilized to synthesize polymer-drug conjugate in order to achieve site- specific controlled drug release. The disulfide linker was first converted into its anhydride form using reported procedure. Briefly, 3,3’-dithiodipropionic acid (3.0 g, 48 mmol) was dissolved in acetyl chloride (30 mL) and the reaction mixture was refluxed for 12 h at 70 °C. The solvent was removed under vacuum and the residue was washed with ethyl ether and vacuum-dried to afford the anhydride o 10 form of dithiodipropionic acid (DTPA, 2.6 g) as a white solid. FTIR: 1793 (C=0, > anhydride) , 1043 (CO-0-CO) cm". 2 Subsequently, doxorubicin HCI (DOX, 0.1 g, 0.18 mmol), DTPA (0.04 g, 0.22 mmol) oO and triethylamine (0.08 mL, 0.54 mmol) were dissolved in DMF (10 ml), stirred > for 24 h in dark and the reaction was monitored by Thin-layer chromatography a 15 (TLC). After completion of reaction, the mixture was cooled to 0 °C and N-(3- 2 dimethylaminopropyl)-N'-ethylcarbodiimide (EDC, 0.14 g, 0.9 mmol) was added Lo to the reaction mixture and the reaction mixture was stirred for 1 h. A solution of o mPEG-b-PJL-OH (1d’, 0.16 g, 0.018 mmol) and 4-(dimethylamino)pyridine N (DMAP, 0.01 g, 0.09 mmol) in DMF (5 mL) was added to the above reaction mix- ture. The reaction mixture was stirred for 2 days at room temperature and then dialyzed against water for one week to remove unreacted DOX, DTPA, EDC, and DMAP. The purified solution was freeze dried to obtain a dark red solid as the product mPEG-b-PJL-S-S-DOX (1dx', 0.22 g yield).
    Synthesis of thioketal linker (TK, reactive oxygen species responsive linker, 1Z): HOS TS a
    FAT Anhydrous acetone (5.8 g, 98.2 mmol) and anhydrous 3-mercaptopropionic acid (5.2 g 49.1 mmol) were mixed with dry hydrogen chloride and stirred for 6 h at room temperature. The reaction mixture was then placed on an ice-salt mixture and to achieve crystallization. The crystallized product was then washed several times with cold hexane and ice cold water. The white colored product was then dried in vacuum to acquire TK (1z’, 3.6 g yield).
    NMR (400 MHz, CDCI3): &ppm 2.91 (4H), 2.68 (4H), 1.60 (6H).
    Synthesis of doxorubicin-TK (DOX-TK, 17x’):O OH O
    O Oo O OH ö N SLS OH
    SA KY TL TY A YY 1zx’'
    O O O < NOH z Coupling of drugs to the TK linker was performed via carbodiimide coupling.
    Briefly, TK (1z’, 0.07 g, 0.28 mmol), N-(3-dimethylaminopropyl)-N’-ethylcarbodi- imide (EDC, 0.064 g, 0.33 mmol) and N-hydroxysuccinimide (0.038 g, 0.33 mmol) o were dissolved in DCM (10 mL), and the mixture was cooled to 0 °C and stirred > 20 for 1 h. Doxorubicin HCI (DOX, 0.15 g, 0.28 mmol) was dissolved separately in 2 DCM (10 mL) containing 100 pL of triethylamine and added to the above mixture. oO The reaction mixture was then stirred for 24 h in dark and the reaction was moni- > tored by TLC. After completion of reaction, the reaction mixture was filtered and a solvent was evaporated to afford DOX-TK (1zx'). o 25KKLOOON
    Synthesis of docetaxel-TK (DTX-TK, 1zy'): < > 7O
    O OH AA e © NH Hon A, , O +) Y [ JA 9 IK ÖH 6 OH 1zy' To prepare DTX-TK, TK (1z, 0.047 g, 0.18 mmol) and N-(3-dimethyl- aminopropyl)-N'-ethylcarbodiimide (EDC, 0.069 g, 0.36 mmol) were dissolved in DCM (10 mL), and the mixture was cooled to 0 °C and stirred for 30 min. Docet- axel (DTX, 0.15 g, 0.18 mmol) and DMAP (0.044 g, 0.36 mmol) was dissolved sep- arately in DCM and added to the above mixture, stirred in dark for 36 h and the reaction was monitored by TLC. After completion of reaction, the reaction mix- ture was filtered and solvent was evaporated to afford DTX-TK (1zy’). Conjugation of doxorubicin (DOX) and docetaxel (DTX) to mPEG-b-PJL-OH (1d’) using DOX-TK (1zx’) and DTX-TK (1zy’) to synthesize mPEG-b-PJL-TK- DOXDTX (1dxy’): oOO
    N oIO
    I a a 00 +KKLOOON
    Afro O OH
    O O 3 J O ,0 ON 0)
    O OH O ALOT A vd 6 6 OH Ö N S S «K < TOT A
    O O O 2 OH Wo = O = O , >O
    OH o oO OH > X a O (J 1dxy' © ‘OH
    H To a solution of intermediates DOX-TK (1zx') and DTX-TK (1zy’) in DMF (10 mL) was added EDC (0.04 g, 0.2 mmol) at 0° C and the reaction mixture was stirred for 30 min. A solution of mPEG-b-PJL-OH (1d’, 0.5 g, 0.056 mmol) and DMAP (0.007 g,
    0.056 mmol) in DMF (10 mL) was added to the reaction mixture and the reaction mixture was stirred for 40 h at room temperature while monitored by TLC. After reaction completion, the mixture was transferred to a dialysis tubing and dialyzed against water for two weeks to remove reactants and reagents. The purified solu- D tion was freeze dried to obtained ROS responsive polymer drug conjugate mPEG- i 10 b-PJL-TK-DOXDTX (1dxy’) (0.68 g).
    O I Drug Content:
    O T The amount of DOX presented in polymer conjugate was determined using UV-Vis z spectroscopy. mPEG-b-PJL-S-S-DOX (1dx', 1 mg) was dissolved in 1 mL of phos- o phate buffer saline (PBS) and the absorption at Amax 481 nm was recorded using 5 15 NanoDrop 2000c spectrophotometer (Thermo Fisher Scientific, USA). The drug 2 concentration was calculated using pre-prepared standard calibration curve and N it was found that each mg of conjugate contains about 0.3 mg of DOX. Figure 1 represent the overlapped UV-Vis spectra of DOX and its polymer conjugate mPEG-
    b-PJL-S-S-DOX (1dx'). Size of drug-polymer -conjugates: The size and polydispersity index of DOX conjugate mPEG-b-PJL-S-S-DOX (1dx’) was measured by dynamic light scattering (DLS) using a ZetaSizer NanoZS® (Malvern Instruments, UK). Samples were diluted (50 pg/mL with respect to pol- ymer) with MilliQ water and transferred into cuvettes for analysis. Measurements were performed at 25°C and data analysis was carried out using the Malvern ZetaSizer software version 7.12. Figure 2a represents size distribution by volume (volume (%) vs size (d.nm)) of DOX conjugate mPEG-b-PJL-S-S-DOX (1dx') from a size distribution measurement using DLS. Transmission Electron Microscopy (TEM) images were taken to confirm the size and to determine the surface mor- phology. Sample (50 ng/mL) was imaged on TEM grids without staining. TEM images were taken using a JEM 1400-Plus (JEOL Ltd., Tokyo, Japan). To perform the TEM observations, a drop of the diluted sample was directly deposited on the copper grid and observed in TEM after drying. Figure 2b represents an example of a TEM-image of a drug-polymer conjugate (mPEG-b-PJL-S-S-DOX, 1dx') after re- dispersion of said conjugate in water. In-vitro drug release: The release profile of DOX from conjugate mPFEG-b-PJL-S-S-DOX (1dx') was de- termined by a dialysis method at pH 5.0 in the presence of different quantity of dithiothreitol (DTT). Briefly, a calculated quantity of mPEG-b-PJL-S-S-DOX (1dx’, 5 mg) was dissolved in release media i.e. acetate buffer (pH 5.0 containing either 10 uM or 100 uM of DTT). The solution was then placed in dialysis tubing (Float-A- Lyzer) having the molecular weight cut off (mwco) of 3.5-5 kDa. The samples > 25 — were dialysed against 500 mL of release media at 37 °C. The release media was D replaced with fresh release media every 24 h. The volume of solution in the dialy- N sis tubing was measured at appropriate time intervals (~6 h), and restored to the = original with release media, if necessary. Samples (5 pL) were withdrawn directly A from the dialysis tubing at predetermined time intervals and the volume of solu- E 30 tion in the dialysis tubing was restored with fresh release media. Samples were o analysed using a UV-Vis spectrophotometer at Amax 492 nm to calculate the 5 amount of DOX remaining in the dialysis bag. Figure 3 represents results from a 2 release profile determination of DOX from conjugate mPEG-b-PJL-S-S-DOX (1dx').N
    In-vitro cell studies: Triple negative breast cancer cells MDAMB-231, and healthy cells of mouse em- bryonic fibroblasts (MEF) (ATCC) were used for in vitro studies. The cells were cultured in high-glucose Dulbecco’s Modified Eagle Medium (DMEM) supple- mented with 10% fetal bovine serum (FBS), 1% penicillin-streptomycin and 2 mM L-glutamine at 37°C, in a humidified incubator with 5% COz2. Cells were pas- saged 2-3 times a week once they reached 90-100% confluency. A WST-1 cell viability assay was used to determine cytotoxicity of polymer and DOX efficacy in cancerous and healthy cells. MDAMB-231 and MEF cells were in- cubated overnight in a 96-well-plate (7000 cells per well) in cell growth media at 37°C with 5% COz. The following day, the cell growth media were replaced with fresh media containing different concentrations of mPEG-b-PJL-OH polymer (1d’;
    0.5, 1.0, or 2.0 mg/mL), DOX HCI (25, 50, 100, or 150 pg/mL) or DOX-PJL conju- gate mPEG-b-PJL-S-S-DOX (1dx'; 25, 50, 100, or 150 pg/mL) and incubated for 48 hor 72 h. Sample stocks were prepared in PBS and all the dilutions for the cell viability assay were prepared in cell growth media. After 48 h and 72 h incubation at 37°C, 5% COz2, 10 uL of WST-1 cell proliferation reagent was added and the plate was incubated for additionally 2 h. The absorbance of samples was then read according to the manufacturer protocol (420-480 nm). The percentage cell proliferation was reported relative to untreated cells (100% viability). To elimi- nate the background due to doxorubicin, doxorubicin controls without cells were prepared and absorbance values were measured and subtracted prior to the plot- ting. Figures 4A and 4B represents results from the in-vitro toxicity profiles of a MPEG-b-PJL-OH polymer (1d’) on the MEF and MDAMB-231 cell lines. Figures 5B and 5B represents results from the in-vitro toxicity profiles of DOX and mPEG-b- o PJL-S-S-DOX (DOX-PJL, (1dx')) on the MEF and MDAMB-231 cell lines. S Cellular uptake (by confocal microscopy): 3 Cellular uptake was evaluated by fixed cell confocal imaging at 0.5 h time point. 2 The microscopy setup consisted of Leica TCS SP5 STED (Leica Microsystems), = 30 LASAF software (Leica application suite), photo multiplier tube (PMT) and 100x N oil objectives. The imaging was performed using seguential scanning option con- J sisting of single-photon excitation for free DOX and DOX conjugate mPEG-b-P]L-S- 3 S-DOX (1dx’). Samples were excited by argon laser at 488 nm, and emission from DOX was collected between 510 nm and 600 nm. MDAMB-231 and MEF cells — were grown as described earlier at 60%-70% confluent over coverslips. Samples (2 pg/mL equivalent to DOX) were prepared in 1 mL of cell growth media and were added to cells growing over coverslips.
    After incubation 0.5 h, the medium was removed, and cells were washed 1x with phosphate-buffered saline (PBS). Cells were then fixed with 4% paraformaldehyde (PFA) for 10 min at room tem- perature.
    After 10 min, cells were washed 3x with PBS.
    Figure 6 represents ex- amples of confocal images showing cellular uptake of DOX and DOX-conjugate PJL-DOX (mPEG-b-PJL-S-S-DOX, 1dx') in MDAMB-231 cells.
    Figure 7 represents an example of fluorescence spectra of free DOX and DOX conjugated with polymer (mPEG-b-PJL-S-S-DOX, 1dx'). Figure 8 represents examples of confocal images showing cellular uptake of DOX and DOX-conjugate PJL-DOX (mPEG-b-PJL-S-S- DOX,1dx')in MEF cells.
    In vivo studies - animals: All animal experiments were done with the approval of Institutional Animal Ethi- cal Committee (IAEC), National Institute of Immunology, New Delhi.
    Murine breast cancer (4T1) cells (1.5 x 106) in 200 uL of FBS were injected subcutane- — ously into the right flanks of 5-week-old female Balb/c mice.
    Mice were random- ized into four groups (6 mice in each group) after they developed a tumor of ~75 mm3. Groups were then subjected to different treatments of (a) PBS (control group); (b) free doxorubicin; (c) PJL-DOX conjugate (mPEG-b-PJL-S-S-DOX (1dx')) and (d) Adrisome (marketed liposomal DOX formulation) with an equivalent dox- — orubicin dose of 7.5 mg/kg, intravenously through a lateral tail vein on alternate day (total 10 doses). Tumor measurements were made every alternate day using a digital caliper, and tumor volume was calculated using the formula L x B2/2 where L and B are the length and breadth of the tumor.
    Fach mouse was weighed before dosing and weight loss with respect to dosing.
    The survival study was con- tinued until the last mouse was found live in all the groups.
    Figure 9A represents > an example of the effect of PBS, DOX, PJL-DOX (mPEG-b-PJL-S-S-DOX (1dx’)) and N Adrisome on the tumor volume of murine breast cancer (4T1) cells in Balb/c mice 2 vs injection day.
    Figure 9B represents an example of the weight change (%) of o Balb/c mice vs injection day when treated as above.
    Figure 10 represents an ex- I 30 ample of the effect of PBS, DOX, PJL-DOX (mPEG-b-PJL-S-S-DOX (1dx’)) and = Adrisome on the survivability (%) of Balb/c mice vs injection day when treated as i above.
    S It will be obvious to a person skilled in the art that, as the technology > advances, the inventive concept can be implemented in various ways.
    The inven- tion and its embodiments are not limited to the examples described above but may vary within the scope of the claims.
    权利要求:
    Claims (22)
    [1] 1. A polymer comprising at least one repeating unit, wherein the at least one repeating unit has Formula [I] oh
    RS R [1] wherein each R1 and R2 is independently selected from a group consisting of H, R6, R21, SR6, SR21, SC(0)R6, SC(0)R21, OR6, OR21, OC(0)R6, OC(0)R21, OC(O)NHR6, OC(O)NHR21, NR6R21, N(R6), NHC(O)R6, NHC(O)R21, NHC(O)NHR6, NHC(O)NHRZ21, N*(R6)3, N3, NO2, NOR6, CN, and halogen; or R1 and RZ, together with the carbon atoms to which they are attached to, form a saturated or partly unsaturated mono-, bi-, tri- or tetracyclic cycloalkyl or heterocycle optionally substituted with one or more SR21, SR6, SC(0)R6, SC(0)R21, OR21, OR6, OC(0)R6, OC(O0)R21, OC(O)NHR6, OC(O)NHR21, NR6R21, N(R6)2, N*(R6)3, R6, R21, halogen, N3, NO2, NOR6, CN, C1-10-alkyl, C2-10-alkenyl, Ca- — 10-alkynyl, Ci-s-haloalkyl; a mono-, bi-, tri-, tetra- or pentacyclic aryl or heteroaryl optionally substituted with one or more SR21, SR6, SC(O)R6, SC(O)R21, OR21, OR6, OC(0)R6, OC(0)R21, OC(O)NHR6, OC(O)NHR21, NR6R21, N(R6)2, N*(R6)3, Re, R21, halogen, N3, NO2, NOR6, CN, Ci-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-5- haloalkyl; R6 is each independently selected from a group consisting of H, C1-20- alkyl, C2-20-alkenyl, C2-20-alkynyl, Ci-10-alkylenyl, Ci-10-haloalkyl, and phenyl; R21 is each independently selected from C1-10-alkylenyl-CO2H, C1-10- o alkylenyl-OH, C1-10-alkylenyl-NHR6, C1-10-alkylenyl-SH, Ci-10-alkylenyl- > N(0=CC=0)C=O, Ci-10-alkylenyl-S-Ci-10-alkylenyl-S-Ci-10-alkylenyl-N(O=CC=C)C=0, 2 25 (CH2CH20)mCH2CH2-N(0=CC=C)C=0, C1-10-alkylenyl-S-S-C1-10-alkylenyl-CO2H, Oo (CH2CH20)m-C1-10-alkylenyl-S-S-C1-10-alkylenyl-CO2H, C2-20-alkynyl, (CH2CH20)mH, > (CH2CH20)nCH2CH2SH, (CH2CH20)nCH2CH2N(R6)2, Ci-10-alkylenyl, Ci-10-haloalkyl, E optionally substituted with one or more halogen, CO2R6, OR6, N(R6)2, N+(R6)3, 3 SR6, N3, NO2, NOR6, CN, Ci-10-alkyl, Cz-10-alkenyl, Ci-10-haloalkyl, Ci-10-alkylenyl- 9 30 CO2H, Ci-10-alkylenyl-OH, Ci-10-alkylenyl-N(R6)2, phenyl; > m is an integer from 1 to 100; n is an integer from 1 to 100; or
    R1 and R2 together form a double bond between the carbon atoms they are attached to, and with the proviso that R1 and R2 are not all hydrogen at the same time, or a salt thereof.
    [2] 2. The polymer of claim 1, wherein the polymer is a copolymer formed from monomers comprising lactones, carbonates, esters, lactams, alkenes and epoxides.
    [3] 3. The polymer of claim 2, wherein said monomers are selected from a group consisting of jasmine lactone, lactide, glycolide, caprolactone, decalactone, butyrolactone, ethylene oxide, ethylene, pentadecalactone, hydroxybutanoate, ethylene carbonate, and caprolactam.
    [4] 4. The polymer of claim 1, wherein the polymer is a homopolymer.
    [5] 5. The polymer according to any of claims 1 to 4, wherein the at least one repeating unit has Formula [11] Oh 0) | [N].
    [6] 6. The polymer according to any of claims 1 to 3, wherein the polymer has a Formula that is selected from Formulas Ia to le Xp” o OH 0) 0) | | al Xf of +* oy off
    O O > | [Ib] O N 20 3 ON X O s OH
    O O O
    I = S S : k k +
    KK S 07 OH 07 COH [lc] O
    N
    N
    O O
    S S Sh 0) O
    S S IM & [le] wherein each X is independently selected from a group consisting of O, ORS, S, SR6, and N(R6)2, wherein R6 is as defined in claim 1; ois an integer from 1 to 1000; pisan integer from 10 to 2000; g is an integer from 10 to 2000; or a salt thereof.
    [7] 7. The polymer according to claim 1 or claims 4 to 5, wherein the pol- ymer has a Formula ly
    YT 0) | [ly], o wherein > 15 each X is independently selected from a group consisting of O, S, and 2 NR6, wherein R6 is as defined in claim 1; oO pisan integer from 10 to 2000; > or a salt thereof. a
    [8] 8. A composition comprising a polymer according to any of claims 1 to 2 20 7 and at least one active agent, or a salt thereof. Lo
    [9] 9. The composition of claim 8, wherein the at least one active agent(s) o is/are independently covalently attached to or form(s) ionic bond(s) with said N polymer.
    [10] 10. The composition according to claim 8 or 9, wherein the at least one active agent(s) is/are independently selected from an active ingredient, an active pharmaceutical ingredient, an antibody, an aptamer, a unit having fluorescence, radioactivity or any other properties which can be detected, a protein, a peptide, and a flame retardant.
    [11] 11. The composition according to any of claims 8 to 10, wherein the at least one active agent(s) is/are independently selected from doxorubicin, dauno- rubicin, epirubicin, idarubicin, paclitaxel, docetaxel, cabazitaxel, camptothecin, cisplatin, fluorescein, fluorescein isothiocyanate (FITC), rhodamine, biotin, folic acid, transferrin, arginylglycylaspartic acid (RGD), rituximab, trastuzumab, cetux- = imab, bevacizumab, 2-carboxyethyl phenylphosphinic acid (CEPPA), phosphoric acid (H3P04), phosphorous acid, 9,10-dihydro-9-oxa-10-phosphaphenanthrene- 10-oxide, and fludeoxyglucose ([18F]FDG), and any derivative thereof.
    [12] 12. A method for producing a polymer or a salt thereof, the method comprising the steps of i) providing jasmine lactone as a jasmine lactone monomer, ii) optionally modifying at least part of the jasmine lactone monomers of i) with at least one suitable reagent to form a modified jasmine lactone mono- mer with Formula (III),
    O
    O Os R! [my wherein R1 and R2 are as defined as in claim 1, iii) subjecting the jasmine lactone monomer of i) and/or the modified jasmine lactone monomer of ii) to a polymerization reaction to form a polymer.
    [13] 13. The method according to claim 12, wherein the polymerization re- = action of iii) is performed in the presence ofat least one further monomer to form N 25 acopolymer. 3
    [14] 14. The method according to claim 12 or 13, wherein the formed pol- 2 ymer or the formed copolymer is further reacted or brought to close contact with Ek at least one suitable reagent capable of reacting or interacting with the formed N polymer or the formed copolymer to form a modified polymer or a modified co- J 30 polymer, respectively. 3
    [15] 15. The method according to any of claims 12 to 14, wherein the formed polymer, the formed copolymer, the formed modified polymer or the formed modified copolymer is further reacted or brought to close contact with at least one active agent to form a composition.
    [16] 16. The method according to claim 12, wherein at least a part of the jasmine lactone monomer of i) and/or the modified jasmine lactone monomer of ii) is reacted or brought to close contact with at least one active agent before or during the polymerization reaction of iii) to form a functionalized jasmine lactone and/or a functionalized modified jasmine lactone, respectively, and subjecting the formed functionalized jasmine lactone and/or the functionalized modified jas- mine lactone to a polymerization reaction to form a composition.
    [17] 17. The method according to claim 16, wherein the formed functional- ized jasmine lactone and/or the functionalized modified jasmine lactone is sub- jected to a polymerization reaction in the presence of at least one further mono- mer to form a composition.
    [18] 18. The method according to any of claims 15 to 17, wherein the at least one active agent(s) is/are independently selected from an active ingredient, an active pharmaceutical ingredient, an antibody, an aptamer, a unit having fluo- rescence, radioactive or any other properties which can be detected, a protein, a peptide, and a flame retardant.
    [19] 19. The method according to any of claims 15 to 18, wherein the active agent comprises doxorubicin, daunorubicin, epirubicin, idarubicin, paclitaxel, docetaxel, cabazitaxel, camptothecin, cisplatin, fluorescein, fluorescein isothiocy- anate (FITC), rhodamine, biotin, folic acid, transferrin, arginylglycylaspartic acid (RGD), rituximab, trastuzumab, cetuximab, bevacizumab, 2-carboxyethyl phe- nylphosphinic acid (CEPPA), phosphoric acid (H3PO4), phosphorous acid, 9,10- dihydro-9-oxa-10-phosphaphenanthrene-10-oxide, and fludeoxyglucose ([18F]FDG).
    [20] 20. A pharmaceutical composition comprising one or more polymer as > claimed in any one of claims 1 to 7 or an effective amount of one or more compo- O sition as claimed in any one of claims 8 to 11, in combination with one or more N other active ingredient(s), wherein the salt is a pharmaceutically acceptable salt. =
    [21] 21. The pharmaceutical composition as claimed in claim 20, together A 30 — with one or more pharmaceutically acceptable excipient(s).
    E
    [22] 22. A pharmaceutical composition as claimed in any one of claims 20 o to 21 for use as a medicament.
    3
    N
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    US7018655B2|2002-03-18|2006-03-28|Labopharm, Inc.|Amphiphilic diblock, triblock and star-block copolymers and their pharmaceutical compositions|
    ES2834916T3|2006-08-11|2021-06-21|Starpharma Pty Ltd|Polylysine dendrimer targeted therapeutic agent|
    SI2285350T1|2008-06-16|2018-03-30|Pfizer Inc.|Methods for the preparation of targeting agent functionalized diblock copolymers for use in fabrication of therapeutic nanoparticles|
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