Perivascular drug delivery system
The present technology provide compositions that are drug delivery systems for the sustained release of anti-stenotic drugs for the treatment and prevention of occlusion of blood vessels, particularly after perivascular surgery. The compositions include a hydrogel, unimolecular micelles dispersed within the hydrogel, and an effective amount of anti-stenotic drug dispersed within the unimolecular micelle. The hydrogel may be a di-or tri-block copolymer comprising one block of poly(ethylene glycol) (PEG) and one or two blocks of poly(lactic-co-glycolic acid) (PLGA). The unimolecular micelle may include three domains: a dendritic polymer core, hydrophobic block polymers (e.g., PVL, PVCL, and/or PCL) attached to the core and PEG attached to the hydrophobic block polymers.
1. A composition comprising a hydrogel, unimolecular micelles dispersed within the hydrogel, and an effective amount of anti-stenotic drug dispersed within the unimolecular micelles, wherein
the hydrogel is a di-or tri-block copolymer comprising one block of poly(ethylene glycol) (PEG) and one or two blocks of poly(lactic-co-glycolic acid) (PLGA), wherein the hydrogel is a PLGA-b-PEG-b-PLGA copolymer having a molecular weight of 2,500 to 3,500 Da, wherein the hydrogel is a thermogel that is water soluble below a gelation temperature of from about 10° C. to about 20° C., and wherein the thermogel forms a stable thermogel above the gelation temperature;
the unimolecular micelle comprises
a polyamidoamine (PAMAN) having a molecular weight of 500 to 10,000 Da,
hydrophobic block polymers attached to at least a majority of the terminating groups of the dendritic polymer, wherein the hydrophobic block polymers have a molecular weight from about 1,000 to about 5,000 Da and which are selected from the group consisting of poly(valerolactone) (PVL), poly(valerolactone-co-lactic acid) (PVCL), and poly(caprolactone) (PCL), and
poly(ethylene glycol) attached to the hydrophobic block polymer and terminating in OH, O-alkyl, NH2, or biotin, and having a molecular weight of about 1,000 to about 15,000 Da; wherein the unimolecular micelle comprises PAMAM-PVL-PEG-O(C1-3 alkyl) and has a molecular weight of about 100,000 to about 350,000 Da, wherein the PAMAM is a 4-generation dendrimer; and
the anti-stenotic drug is selected from the group consisting of rapamycin, resveratrol, halofuginone, idarubicin, (S)-tent-butyl 2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate, 1-[5-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)indolin-1-yl]-2-(3-trifluoromethylphenyl)ethanone, and a combination of any two or more thereof.
2. The composition of claim 1 wherein the each PLGA block comprises from 1:4 to 4:1 lactic acid to glycolic acid residues on a molar basis.
3. The composition of claim 1 wherein the each PLGA block comprises from 2:1 to 4:1 lactic acid to glycolic acid residues on a molar basis.
4. The composition of claim 1 wherein the anti-stenotic drug is rapamycin.
5. The composition of claim 1 wherein the loading of anti-stenotic drug is about 1 to about 35 wt % of the unimolecular micelles.
6. The composition of claim 1 wherein the loading of anti-stenotic drug is about 15 to about 25 wt % of the unimolecular micelles.
7. The composition of claim 1 , wherein the composition is for delivery to a blood vessel.