Polymeric enkephalin prodrugs

An enkephalin-polymer conjugate of the formula:

• [Enkephalin-C(O)—X]n-P
• wherein P is polymer, polymer-lipid or polymer derivative attached to the C terminus carboxyl group without spacer between terminal amino acid and polymer;
• wherein X is an atom or a chemical moiety selected from the group consisting of O, S, imidazo, and phosphate;
• wherein C(O)—X is the hydrolysable linkage comprising the functional group selected from carboxylic ester, thioester, acylimidazo, and phosphonic ester;
• wherein n≧1;
• wherein enkephalins attached to polymer is selected from the group consisting of endogenous enkephalins (including OGF (met-enkephalin) and leu-enkephalin), opioid peptides, proenkephalins, endorphins, dynorphins, proenkephalins and synthetic enkephalin analogues.

A peptide-PEG conjugate having the formula:

• [Peptide-C(O)—O]n—PEG
• wherein n≧1 ;
• wherein —C(O)—O is the peptide C-terminus carboxylic ester linkage connected directly to a PEG polymer;
• and
• wherein PEG is selected from the group consisting of mPEG (monomethoxy polyethylene glycol), linear PEG, branched PEG, multiple-arm PEG, PEG-lipid, PEG copolymers, PEG block copolymers, PEG terpolymers, and PEG polymer derivatives capable of forming hydrogels, liposomes or nanoparticles.

A pre-synthesized C-terminal amino acid-PEG ester derivative having the formula:

• Pm-AA-m PEG
• or
• (Pm-AA)q-PEG
• wherein PEG is linear PEG, branched PEG or multiple-arm PEG;
• wherein mPEG is monomethoxy polyethylene glycol and having structure —O—(CH2CH2O)n—CH3;
• wherein n is about 4 to about 1000;
• wherein m is 0 or 1;
• wherein q≧1;
• wherein P-AA comprises a polypeptide;
• and
• wherein AA is the C-terminal amino acid of the peptide, or a desired amino acid, and said AA is selected from the group consisting of glycine, alanine, phenylalanine, leucine, isoleucine, serine, threonine, glutamine, asparagine, aspartic acid, glutamic acid, histidine, cysteine, tyrosine, lysine, arginine, proline, tryptophan, valine and other homo-amino acids.