Segmented degradable polymers and conjugates made therefrom
View Patent ↗The present invention provides, among other things, segmented, degradable polymeric reagents suitable for reaction with biologically active agents to form conjugates, the polymeric reagents comprising one or more polymer chains divided or separated by one or more degradable linkages into polymer segments having a molecular weight suitable for renal clearance. The polymeric reagents can have a substantially linear structure, a branched structure, or a multiarm structure. Each structure includes one or more linkages capable of degradation in vivo.
1. A polymer reagent having a structure according to the following formula:
wherein:
each POLY 1 , which may be the same or different, is a water-soluble and non-peptidic poly(alkylene glycol);
each X 1 , X 2 , and X 3 , which may be the same or different, is a spacer moiety;
each L 3 , which may be the same or different, are linkages that are optionally cleavable in vivo;
each Z 4 , which may be the same or different, is a capping group or a functional group;
each a, b, and c, which may be the same or different, is either zero or one;
R comprises two lysine residues linked by amide linkages to a linker of an aliphatic carbon chain comprising a disulfide bond; and
p is an integer in the range of 2-32,
wherein the polymeric reagent is not in the form of a hydrogel.
2. The polymer reagent of claim 1 , wherein each POLY 1 has a number average molecular weight of less than or equal to about 20,000 Da.
3. The polymer reagent of claim 1 , wherein each POLY 1 has a number average molecular weight of less than or equal to about 10,000 Da.
4. The polymer reagent of claim 1 , wherein each of POLY 1 has a number average molecular weight of less than or equal to about 8,000 Da.
5. The polymer reagent of claim 1 , wherein each POLY 1 is a poly(ethylene glycol).
6. The polymer reagent of claim 1 , wherein each of X 1 , X 2 , and X 3 , is selected from the group consisting —C(O)—, —C(O)—NH—, —NH—C(O)—NH—, —O—C(O)—NH—, —C(S)—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 , —O—CH 2 —, —CH 2 —O—, —O—CH 2 —CH 2 —, —CH 2 —O—CH 2 —, —CH 2 —CH 2 —O—, —O—CH 2 —CH 2 —CH 2 —, —CH 2 —O—C H 2 —CH 2 —, —CH 2 —CH 2 —O—CH 2 —, —CH 2 —CH 2 —CH 2 —O—, —O—CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —O—CH 2 —CH 2 -C H 2 —, —CH 2 —CH 2 —O—CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —O—CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —O—, —C(O)—NH—CH 2 —, —C(O)—NH—CH 2 —CH 2 —, —CH 2 —C(O)—NH—CH 2 —, —CH 2 —CH 2 —C(O)—NH—, —C(O)—NH—CH 2 —CH 2 —CH 2 —, —CH 2 —C(O)—NH—CH 2 —CH 2 —, —CH 2 —CH 2 —C(O)—NH—CH 2 —, —CH 2 —CH 2 —CH 2 —C(O)—NH—, —C(O)—NH—C H 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —C(O)—NH—CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —, —CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—NH—, —C( O)—O—CH 2 —, —CH 2 —C(O)—O—CH 2 —, —CH 2 —CH 2 —C(O)—O—CH 2 —, —C(O)—O—CH 2 —CH 2 —, —NH—C(O)—CH 2 —,—CH 2 —NH—C(O)—CH 2 —, —CH 2 —CH 2 —NH—C(O)—CH 2 —, —NH—C(O)—CH 2 —CH 2 —, —CH 2 —NH—C(O)—CH 2 —CH 2 —, —CH 2 —CH 2 —NH—C(O)—CH 2 —CH 2 —, —C(O)—NH—CH 2 —, —C(O)—NH—CH 2 —CH 2 —, —O—C(O)—NH—CH 2 —, —O—C(O)—NH—CH 2 —CH 2 —, -NH—CH 2 —, —NH—CH 2 —CH 2 —, —CH 2 —NH—CH 2 —, —CH 2 —CH 2 —NH—CH 2 —, —C(O)—CH 2 —, —C(O)—CH 2 —CH 2 —, —CH 2 —C(O)—CH 2 —, —CH 2 —CH 2 —C(O)—CH 2 —, —CH 2 —CH 2 —C(O)—CH 2 —CH 2 —, —CH 2 —CH 2 —C(O)—, —CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —NH—, —CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —NH—C(O)—, —CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —NH—C (O)—CH 2 —, —CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —NH—C(O)—CH 2 —CH 2 —, —C(O)—NH—(CH 2 ) 1-6 —NH—C(O)—, —NH—C(O)—NH—(CH 2 ) 1-6 —NH—C(O)—, and —O—C(O)—NH—(CH 2 ) 1-6 —NH—C(O)—, —O—C(O)—NH—[CH 2 ] h —(OCH 2 CH 2 ) j —, —NH—C(O)—O—[CH 2 ] h —(OCH 2 CH 2 ) j —, bivalent cycloalkyl group, —O—, —S—, —N(R 6 )—, and combinations thereof, wherein R 6 is H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl, (h) is zero to six, and (j) is zero to 20.
7. The polymer reagent of claim 1 , wherein each POLY 1 is a branched poly(ethylene glycol) polymer.
8. The polymer reagent of claim 1 , wherein L 3 is a linkage that is cleavable in vivo.
9. The polymer reagent of claim 8 , wherein L 3 is selected from the group consisting of amide linkages, urethane linkages, disulfide linkages, dipeptide linkages, and tripeptide linkages.
10. The polymer reagent of claim 1 , wherein L 3 is a urethane linkage having the structure —O—C(O)—NH—CHY—C(O)—NH—Y′—, where Y is selected from H, alkyl, substituted alkyl, and aryl, and Y′ is alkyl or substituted alkyl.
11. A conjugate comprising the reaction product of a biologically active agent and a polymeric reagent according to claim 1 .
12. The polymer reagent of claim 1 , having the following structure
wherein each PEG(5K) is a poly(ethylene oxide) having a weight-average molecular weight of 5,000 Daltons and each LYS is a lysine residue.