Poly(organophosphazene) hydrogels for drug delivery, preparation method thereof and use thereof

A poly(organophosphazene) represented by Chemical Formula 1b:

• wherein,
• p is the number of repeating units of ethylene glycol ranging from 7 to 50;
• NHCH(R1)CO2R2 is a hydrophobic amino acid ester, wherein
• R1 is selected from the group consisting of H, CH3, CH2SH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C6H4OH, and CH2C2H2C6H4, and
• R2 is selected from the group consisting of CH3, C2H5, C3H7, C4H9, CH2C6H5, and CH2CHCH2;
• NH(R3)(R4)(R5) is an amino acid, peptide, or depsipeptide ester, wherein
• R3 is CH(W),
• R4 is selected from the group consisting of CO2, CO2CH2CO2, CO2CH(CH3)CO2, and CONHCH(X)CO2,
• R5 is selected from the group consisting of H, CH3, and C2H5, and
• W and X are independently selected from the group consisting of H, HCH2, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, CO2C2H5, (CH2)2CO2C2H6, CH2OH, CH(CH3)OH, CH2C6H4OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(═NH)NH2, CH2C3N2H3, and CH2SH;
• NH(R6)(R7)(R8) and NH(R6)(R7)(R9) are substituents having a functional group, wherein
• R6 is CH(Y),
• R7 is selected from the group consisting of C2H4, C3H6, C4H8, CH2C6H4, CH2CO2, O, CONHCH(Z)O, CO, CO2, S, CONHCH(Z)S, N, CONHCH(Z)N, CON, COCHNH(Z)CON, CONHCH(Z)CO, and CONHCH(Z)CO2,
• R8 is selected from the group consisting of OH, SH, H, CH3, C2H5, C3H7, C4H9, CH2C6H5 CH2CHCH2, and a protecting group,
• Y and Z are independently selected from the group consisting of H, HCH2, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, CO2C2H5, (CH2)2CO2C2H5, CH2OH, CH(CH3)OH, CH2C6H4OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(═NH)NH2, CH2C3N2H3, and CH2SH, and
• R9 is selected from the group consisting of folic acid, hyaluronic acid, polyhistidine, cyclodextrin, heparin, and chitosan;
• a1, a2, b, c, d, and e respectively represent the content of each substituent, wherein a1, a2, b, and d are independently from 0.01 to 1.9, c and e are independently from 0 to 1.9, and a1+a2+b+c+d+e=2.0;
• and
• n is the degree of polymerization of the poly(organophosphazene) ranging from 5 to 100,000.

A delivery system of a bioactive substance, comprising:

• the poly(organophosphazene) represented by Chemical Formula 1b, or a poly(organophosphazene) hydrogel comprising a solution where the poly(organophosphazene) represented by Chemical Formula 1a is dissolved in one or more solvents selected from the group consisting of water, a buffer solution, an acid solution, a basic solution, a salt solution, a saline solution, water for injection, and a glucose salt solution, at a concentration of 1 to 50 wt %;
• and
• a bioactive substance selected from the group consisting of proteins, polypeptides, peptides, vaccines, genes, hormones, anti-cancer drugs, angiogenesis inhibitors, treating cells, and a combination thereof:
• wherein
• p is the number of repeating units of ethylene glycol ranging from 7 to 50;
• NHCH(R1)CO2R2 is a hydrophobic amino acid ester, wherein
• R1 is selected from the group consisting of H, CH3, CH2SH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C6H4OH, and CH2C2H2C6H4, and
• R2 is selected from the group consisting of CH3, C2H5, C3H2, C4H9, CH2C6H5, and CH2CHCH2;
• NH(R3)(R4)(R5) is an amino acid, peptide, or depsipeptide ester, wherein
• R3 is CH(W),
• R4 is selected from the group consisting of CO2, CO2CH2CO2, CO2CH(CH3)CO2, and CONHCH(X)CO2,
• R5 is selected from the group consisting of H, CH3, and C2H5, and
• W and X are independently selected from the group consisting of H, HCH2, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, CO2C2H5, (CH2)2CO2C2H5, CH2OH, CH(CH3)OH, CH2C6H4OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(═NH)NH2, CH2C3N2H3, and CH2SH;
• NH(R6)(R7)(R8) and NH(R6)(R7)(R9) are substituents having a functional group, wherein
• R6 is CH(Y),
• R7 is selected from the group consisting of CH2, C2H4CO2, CONHCH(Z)CONHCH(M)O, CONHCH(Z)CONHCH(L)CONHCH(L)O, CONHCH(Z)CONHCH(M)S, CONHCH(Z)CONHCH(M)CONHCH(L)S, CONHCH(Z)CONHCH(M)N, CONHCH(Z)CONHCH(M)CONHCH(L)N, COCHNH(Z)CONHCH(M)CON, COCHNH(Z)CONHCH(M)CONHCH(L)CON, COCHNH(Z)CONHCH(M)CO, COCHNH(Z)CONHCH(M)CONHCH(L)CO, COCHNH(Z)CONHCH(M)CO2, and COCHNH(Z)CONHCH(M)CONHCH(L)CO2,
• R8 is selected from the group consisting of OH, SH, H, CH3, C2H5, C3H7, C4H9, CH2C6H5CH2CHCH2, and a protecting group,
• Y, Z, L, and M are independently selected from the group consisting of H, HCH2, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, CO2C2H5, (CH2)2CO2C2H5, CH2OH, CH(CH3)OH, CH2C6H4OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(═NH)NH2, CH2C3N2H3, and CH2SH,
• R9 is selected from the group consisting of OH, SH, H, NH2, CH3, C2H5, C3H7, CH2C6H5, CH2CHCH2, NHCH(SH)CO2H, NH(CH2)qSH, NH(CH2CH2NH)rH, [NHCH(C4H8NH2)CO]rOH, [NHCH[(CH2)3C(═NH)(NH2)]CO]rOH, folic acid, hyaluronic acid, polyhistidine, cyclodextrin, heparin, chitosan, and protamines, and
• q is the number of repeating units of methylene ranging from 1 to 20;
• r is the number of repeating units of ethylenimine, lysine, or arginine, ranging from 1 to 18,000;
• a1, a2, b, c, d, and e respectively represent the content of each substituent, wherein a1, a2, b, and d are independently from 0.01 to 1.9, c and e are independently from 0 to 1.9, and a1+a2+b+c+d+e=2.0;
• and
• n is the degree of polymerization of the poly(organophosphazene) ranging from 5 to 100,000,
• wherein,
• p is the number of repeating units of ethylene glycol ranging from 7 to 50;
• NHCH(R1)CO2R2 is a hydrophobic amino acid ester, wherein
• R1 is selected from the group consisting of H, CH3, CH2SH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C6H4OH, and CH2C2H2C6H4, and
• R2 is selected from the group consisting of CH3, C2H5, C3H7, C4H9, CH2C6H5, and CH2CHCH2;
• NH(R3)(R4)(R5) is an amino acid, peptide, or depsipeptide ester, wherein
• R3 is CH(W),
• R4 is selected from the group consisting of CO2, CO2CH2CO2, CO2CH(CH3)CO2, and CONHCH(X)CO2,
• R5 is selected from the group consisting of H, CH3, and C2H5, and
• W and X are independently selected from the group consisting of H, HCH2, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, CO2C2H5, (CH2)2CO2C2H5, CH2OH, CH(CH3)OH, CH2C6H4OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(═NH)NH2, CH2C3N2H3, and CH2SH;
• NH(R6)(R7)(R8) and NH(R6)(R7)(R9) are substituents having a functional group, wherein
• R6 is CH(Y),
• R7 is selected from the group consisting of C2H4, C3H6, C4H8, CH2C6H4, CH2CO2, O, CONHCH(Z)O, CO, CO2, S, CONHCH(Z)S, N, CONHCH(Z)N, CON, COCHNH(Z)CON, CONHCH(Z)CO, and CONHCH(Z)CO2,
• R8 is selected from the group consisting of OH, SH, H, CH3, C2H5, C3H7, C4H9, CH2C6H5 CH2CHCH2, and a protecting group,
• Y and Z are independently selected from the group consisting of H, HCH2, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, CO2C2H5, (CH2)2CO2C2H5, CH2OH, CH(CH3)OH, CH2C6H4OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(═NH)NH2, CH2C3N2H3, and CH2SH, and
• R9 is selected from the group consisting of folic acid, hyaluronic acid, polyhistidine, cyclodextrin, heparin, and chitosan;
• a1, a2, b, c, d, and e respectively represent the content of each substituent, wherein a1, a2, b, and d are independently from 0.01 to 1.9, c and e are independently from 0 to 1.9, and a1+a2+b+c+d+e=2.0;
• and
• n is the degree of polymerization of the poly(organophosphazene) ranging from 5 to 100,000.

A delivery system of a bioactive substance containing

• a bioactive substance, and
• a poly(organophosphazene) represented by the following Chemical Formula 1c, or a hydrogel containing a solution of the poly(organophosphazene) represented by following Chemical Formula 1c,
• wherein the bioactive substance is one or more selected from the group consisting of:
• one or more proteins, polypeptides, or peptides selected from the group consisting of exendin-4, fibroblast growth factor (FGF), insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-β), nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5, neurotensin, tachykinin, neuropeptide Y (NPY), peptide YY (PYY), vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), and their synthetic analogs, monoclonal antibodies, and antibodies;
• one or more anti-cancer drugs selected from the group consisting of imatinib, floxuridine, gemcitabine, hydroxyurea, zoledronate, flutamide, valrubicin, and streptozocin;
• one or more angiogenesis inhibitors selected from the group consisting of rebimastat, matrix metalloproteinases (MMPs) inhibitor (S-3304), protein kinase C beta inhibitor (LY317615), endostatin, vatalanib (PTK787/ZK 222584), sunitinib malate (SU11248), cilenqitide (EMD-121974), humanized monoclonal antibody MEDI-522, EOS-200-4, and integrin alpha-5-beta-1 antagonist (ATN-161);
• and
• synthetic analogs thereof,
• wherein
• p ranges from 7 to 50;
• NHCH(R1)CO2R2 is a hydrophobic amino acid ester, wherein
• R1 is selected from the group consisting of H, CH3, CH2SH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C6H4OH, and CH2C2H2C6H4, and
• R2 is selected from the group consisting of CH3, C2H5, C3H7, C4H5, CH2C6H5, and CH2CHCH2;
• NH(R3)(R4)(R5) is an amino acid, peptide, or depsipeptide ester, wherein
• R3 is CH(W),
• R4 is selected from the group consisting of CO2, CO2CH2CO2, CO2CH(CH3)CO2, and CONHCH(X)CO2,
• R5 is selected from the group consisting of H, CH3, and C2H5, and
• W and X are independently selected from the group consisting of H, HCH2, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, CO2C2H5, (CH2)2CO2C2H5, CH2OH, CH(CH3)OH, CH2C6H4OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(═NH)NH2, CH2C3N2H3, and CH2SH;
• NH(R6)(R7)(R8) and NH(R6)(R7)(R9) are substituents having a functional group, wherein
• R6 is CH(Y),
• R7 is selected from the group consisting of C2H4, C3H6, C4H8, CH2C6H4, CH2CO2, O, CONHCH(Z)O, CO, CO2, S, CONHCH(Z)S, N, CONHCH(Z)N, CON, COCHNH(Z)CON, CONHCH(Z)CO, and CONHCH(Z)CO2,
• R8 is selected from the group consisting of OH, SH, H, CH3, C2H5, C3H7, C4H9, CH2C6H5 CH2CHCH2, and a protecting group,
• Y and Z are independently selected from the group consisting of H, HCH2, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, CO2C2H5, (CH2)2CO2C2H5, CH2OH, CH(CH3)OH, CH2C6H4OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(═NH)NH2, CH2C3N2H3, and CH2SH,
• R9 is selected from the group consisting of OH, SH, H, NH2, CH3, C2H5, C3H2, C4H9, CH2C6H5, CH2CHCH2, NHCH(SH)CO2H, NH(CH2)qSH, NH(CH2CH2NH)rH, [NHCH(C4H8NH2)CO]rOH, [NHCH[(CH2)3C(═NH)(NH2)]CO]rOH, and protamine,
• q ranges from 1 to 20, and
• r ranges from 1 to 18,000;
• a1, az, b, c, d, and e respectively represent the content of each substituent, wherein a1, a2, b, and d are independently 0.01 to 1.9, c and e are independently 0 to 1.9, and a1+a2+b+c+d+e=2.0;
• and
• n ranges from 5 to 100,000.