Cleavable polymer drug conjugates

A method for preparation of polymer drug conjugate of formula I

• wherein:
• R1 and R2 are independently selected from H or —CH3;
• R3 is selected from —H or —CH3;
• x is a natural number between 1-100;
• y is a natural number between 1-100;
• n is a natural number between 1-200 and
• L is a cleavable linker and
• D is at least one therapeutic agent;
• Z is selected from —O or —NH;
• A is an end group that is optionally a polymerization initiator or a fragment thereof;
• or A is null;
• and
• B is an end group that is optionally a polymerization initiator or a fragment thereof or B is null;
• and further wherein the method comprises (i) polymerization of PEG (meth)acrylate monomer (formula II) and (meth)acrylate-L monomer (Formula IIIb)
• wherein R1 and R2 are independently selected from —H or —CH3;
• R3 is selected from —H or —CH3;
• L is a cleavable linker and n is a natural number between 1-200 to give a copolymer of formula IV
• wherein x is a natural number between 1-100 and y is a natural number between 1-100, Z is selected from —O or —NH, A is an end group that is optionally a polymerization initiator or a fragment thereof or A may be null, B is an end group that is optionally a polymerization initiator or a fragment thereof or B may be null and then (ii) reacting formula IV with at least one therapeutic agent (D) to give formula I.

A method for preparation of polymer drug conjugate of formula I

• wherein:
• R1 and R2 are independently selected from —H or —CH3;
• R3 is selected from —H or —CH3;
• x is a natural number between 1-100;
• y is a natural number between 1-100;
• n is a natural number between 1-200 and
• L is a cleavable linker and
• D is at least one therapeutic agent;
• Z is selected from —O or —NH;
• A is an end group that is optionally a polymerization initiator or a fragment thereof;
• or A is null;
• and
• B is an end group that is optionally a polymerization initiator or a fragment thereof or B is null;
• wherein the method comprises (i) polymerization of PEG (meth)acrylate monomer (Formula II) and (meth)acrylate monomer (formula IIIc)
• wherein R1 and R2 are independently selected from —H or —CH3;
• R3 is selected from —H or —CH3;
• R4 is selected from carbonyl activating groups such as perfluorophenoxy, maleimide, carbonate, thiazolidone-2-thione, N-oxybenzotriazole, imidazolyl, o/p-nitrophenoxy, pentachloro-phenoxy, N-hydroxysuccinimide, acetates, formates, 2,3,5-trichlorophenol, 8-hydroxyquinoline, and —OH, —OCH3, —OCH2CH3, Cl, F, Br, H, —SH, —NH2, —NHR5 or —OR5, R5 is C1-C10 saturated or unsaturated hydrocarbon and n is a natural number between 1-200 to give a copolymer of formula V
• wherein x is a natural number between 1-100 and y is a natural number between 1-100, Z is selected from —O or —NH, A is an end group that is optionally a polymerization initiator or a fragment thereof or A may be null, B is an end group that is optionally a polymerization initiator or a fragment thereof or B may be null and then (ii) reacting formula V with at least one type of therapeutic agent attached to a linker (L-D) to give formula I

A method for preparation of polymer drug conjugate of formula I

• wherein:
• R1 and R2 are independently selected from —H or —CH3;
• R3 is selected from —H or —CH3;
• x is a natural number between 1-100;
• y is a natural number between 1-100;
• n is a natural number between 1-200 and
• L is a cleavable linker and
• D is at least one therapeutic agent;
• Z is selected from —O or —NH;
• A is an end group that is optionally a polymerization initiator or a fragment thereof;
• or A is null;
• and
• B is an end group that is optionally a polymerization initiator or a fragment thereof or B is null;
• and further wherein the method comprises (i) polymerization of PEG (meth)acrylate monomer (Formula II) and (meth)acrylate monomer (formula IIIc)
• wherein R1 and R2 are independently selected from —H or —CH3;
• R3 is selected from —H or —CH3 or —CH2CH3;
• R4 is selected from carbonyl activating groups such as perfluorophenoxy, maleimide, carbonate, thiazolidone-2-thione, N-oxybenzotriazole, imidazolyl, o/p-nitrophenoxy, pentachloro-phenoxy, N-hydroxysuccinimide, acetates, formates, 2,3,5-trichlorophenol, 8-hydroxyquinoline and —OH, —OCH3, —OCH2CH3, Cl, F, Br, H, —SH, —NH2, —NHR5 or —OR5, R5 is C1-C10 saturated or unsaturated hydrocarbon and n is a natural number between 1-200 to give a copolymer of formula V
• wherein x is a natural number between 1-100 and y is a natural number between 1-100, A is an end group that is optionally a polymerization initiator or a fragment thereof or A may be null, B is an end group that is optionally a polymerization initiator or a fragment thereof or B may be null and then (ii) reacting formula V with a linker (L) to give a copolymer of formula IV and (iii) reacting formula IV with at least one type of therapeutic agent (D) to give polymer conjugate of formula I.