Hydrogels with biodegradable crosslinking

A method to prepare a drug-releasing degradable hydrogel, which method comprises:

• (a) providing a first multi-armed polyethylene glycol (PEG) polymer wherein each arm is terminated by a group comprising orthogonal first and second functional groups, which first orthogonal functional group is different from said second orthogonal functional group, and wherein the group comprising said first orthogonal functional group and said second orthogonal functional group comprises cysteine, lysine, or aspartate;
• (b) reacting said first multi-armed PEG polymer of step (a) with a linker-drug conjugate wherein said conjugate comprises a third functional group that reacts with only the first orthogonal functional group to obtain a derivatized first polymer;
• and
• (c) reacting the derivatized first polymer obtained in step (b) with a crosslinker coupled to a second multi-armed PEG polymer wherein said crosslinker comprises a fourth functional group that reacts with only the second orthogonal functional group present on said derivatized first polymer to obtain said drug-releasing degradable hydrogel, or
• (d) reacting said first multi-armed PEG polymer of step (a) with a crosslinker coupled to a second multi-armed PEG polymer wherein said crosslinker comprises a fourth functional group that reacts only with the second orthogonal functional group of said first multi-armed PEG polymer to obtain a crosslinked polymer, and
• (e) reacting the crosslinked polymer of step (d) with a linker-drug conjugate, wherein said conjugate comprises a third functional group that reacts with only the first orthogonal functional group of said first multi-armed PEG polymer to obtain a said drug-releasing degradable hydrogel,
• wherein the crosslinker of step (c) or step (d) is of formula (1)
• wherein
• m of formula (1) is 0 or 1;
• X of formula (1) is
• wherein
• T* is O, S, or NR6;
• z is 1-6;
• Y is (OCH2CH2)p, wherein p is 1-100;
• and
• Z2 is a functional group coupled to the second multi-armed PEG polymer, and one of R1, R2 and R5 of formula (1) comprises the fourth functional group that reacts with only the second orthogonal functional group present on said first multi-armed PEG polymer of step (a) or said derivatized first multi-armed PEG polymer of step (b);
• or
• Z2 is the fourth functional group that reacts with only the second orthogonal functional group present on said first multi-armed PEG polymer of step (a) or said derivatized first multi-armed PEG polymer of step (b), and one of R1, R2 and R5 of formula (1) comprises a functional group coupled to the second multi-armed PEG polymer;
• with the proviso that:
• (1) when one of R5 of formula (1) comprises the fourth functional group or the functional group coupled to the second multi-armed PEG polymer, the remaining R5 of formula (1) is H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, (OCH2CH2)p O-alkyl wherein p=1-1000, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• and
• (a) R1 and R2 of formula (1) are independently CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4;
• (b) R1 and R2 of formula (1) may be joined to form a 3-8 membered ring;
• (c) R1 of formula (1) is CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4;
• and R2 of formula (1) is H, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl;
• or
• (d) R2 of formula (1) is CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4;
• and R1 of formula (1) is H, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl;
• or
• (2) when R1 of formula (1) comprises the fourth functional group or the functional group coupled to the second multi-armed PEG polymer:
• R2 of formula (1) is CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4;
• and each R1 of formula (1) is independently H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, (OCH2CH2)p O-alkyl wherein p=1-1000, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• or
• (3) when R1 of formula (1) comprises the fourth functional group or the functional group coupled to the second multi-armed PEG polymer:
• R1 of formula (1) is CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4;
• and each R5 of formula (1) is independently H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, (OCH2CH2)p O-alkyl wherein p=1-1000, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• wherein the linker-drug conjugate of step (b) or step (e) is of formula (3)
• wherein
• m of formula (3) is 0 or 1;
• D of formula (3) is a drug;
• Y of formula (3) is NH or NBCH2, wherein B is H, optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• either R1, R2 or one of R5 of formula (3) comprises the third functional group coupled to the first orthogonal functional group of the first multi-armed PEG polymer;
• with the proviso that:
• (1) when one of R5 of formula (3) comprises the third functional group, the remaining R5 of formula (3) is H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, (OCH2CH2)p O-alkyl wherein p=1-1000, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• and
• (a) R1 and R2 of formula (3) are independently CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4;
• (b) R1 and R2 of formula (3) may be joined to form a 3-8 membered ring;
• (c) R1 of formula (3) is CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4;
• and R2 of formula (3) is H, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl;
• or
• (d) R2 of formula (3) is CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4;
• and R1 of formula (3) is H, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl;
• or
• (2) when R1 of formula (3) comprises the third functional group:
• R2 of formula (3) is CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4;
• and each R5 of formula (3) is independently H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, (OCH2CH2)p O-alkyl wherein p=1-1000, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• or
• (3) when R2 of formula (3) comprises the third functional group:
• R1 of formula 3) is CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4;
• and each R5 of formula (3) is independently H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, (OCH2CH2)p O-alkyl wherein p=1-1000, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl,
• wherein each said orthogonal functional group independently comprises N3, NH2, NH-CO2tBu, SH, StBu, maleimide, CO2H, CO2tBu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctyne, acrylate, or acrylamide, and wherein
• when one orthogonal functional group comprises N3 the other does not comprise alkyne or cyclooctyne,
• when one orthogonal functional group comprises SH the other does not comprise maleimide, acrylate, or acrylamide, when one orthogonal functional group comprises NH2 the other does not comprise CO2H,
• when one orthogonal functional group comprises 1,3-diene or cyclopentadiene the other does not comprise furan.