Epimorphic regeneration and related hydrogel delivery systems
Methods and compositions are described for enhancing tissue regeneration or wound repair in a mammalian subject comprising a composition comprising (a) a proline hydroxylase inhibitor component or molecule that increases or upregulates HIF1a and (b) a carrier component comprising a hydrogel.
1. A drug delivery system for epimorphic regeneration, said system comprising a first macromonomer component of a formula
a second macromonomer component of a formula
wherein Cys is an N-terminal cysteine residue, each of R 1 and R 2 is independently selected from hexaglycolic and tripentaerythritolic moieties, each of n1 and n2 is an integer independently selected from 1 to about 201; and a drug component for up-regulation of hypoxia inducible factor 1a (H1F1a), said drug component selected from proline hydroxylase inhibitor compounds and prodrugs thereof, a said prodrug comprising a said proline hydroxylase inhibitor compound coupled to a cleavable polymer component, said drug component in an amount to produce a regenerative response.
2. The drug delivery system of claim 1 wherein each said macromonomer component is in a fluid medium.
3. The drug delivery system of claim 2 wherein said first and second macromonomer components are cross-linked to provide a hydrogel, and said drug component is dispersed therein.
4. The drug delivery system of claim 1 wherein a said drug component is selected from 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (1,4-DPCA), a poly(alkylene oxide) coupled prodrug of 1,4-DPCA, dimethyloxallyl glycine (DMOG), 30-amino-3,14,25-trihydroxy-3,9,14,20,25-pentaazatriacontane-2,10,13,21,24-pentone (DFX), 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (Imiquimod) and CoCl 2 .
5. The drug delivery system of claim 4 wherein a said drug component is a poly(alkylene oxide) prodrug of 1,4-DPCA.
6. A drug delivery system for epimorphic regeneration, said system comprising a first macromonomer component of a formula
a second macromonomer component of a formula
wherein Cys is an N-terminal cysteine residue, each of R 1 and R 2 is independently selected from hexaglycolic and tripentaerythritolic moieties, each of n1 and n2 is an integer independently selected from 1 to about 201; and a drug component for up-regulation of hypoxia inducible factor 1a (H1F1a), said drug component selected from proline hydroxylase inhibitor compounds and prodrugs thereof, a said prodrug comprising a said proline hydroxylase inhibitor compound coupled to a cleavable poly(alkene oxide) block copolymer component, said drug component in an amount to provide an H1F1a level for induction of a regenerative response.
7. The drug delivery system of claim 6 wherein said first and second macromonomer components are cross-linked to provide a hydrogel, and said drug component is dispersed therein.
8. The drug delivery system of claim 6 wherein a said drug component is selected from 1,4-DPCA, a poly(alkylene oxide) coupled prodrug of 1,4-DPCA, DMOG, DFX, Imiquimod and CoCl 2 .