Oligo(Lactic Acid)8-Rapamycin Prodrug-Loaded Poly(Ethylene Glycol)-block-Poly(Lactic Acid) Micelles for Injection

PurposeTo prepare an oligo(lactic acid)(8)-rapamycin prodrug (o(LA)(8)-RAP)-loaded poly(ethylene glycol)-block-poly(lactic acid) (PEG-b-PLA) micelle for injection and characterize its compatibility and performance versus a RAP-loaded PEG-b-PLA micelle for injection in vitro and in vivo.MethodsMonodisperse o(LA)(8) was coupled on RAP at the C-40 via DCC/DMAP chemistry, and conversion of o(LA)(8)-RAP prodrug into RAP was characterized in vitro. Physicochemical properties of o(LA)(8)-RAP- and RAP-loaded PEG-b-PLA micelles and their antitumor efficacies in a syngeneic 4T1 breast tumor model were compared.ResultsSynthesis of o(LA)(8)-RAP prodrug was confirmed by H-1 NMR and mass spectroscopy. The o(LA)(8)-RAP prodrug underwent conversion in PBS and rat plasma by backbiting and esterase-mediated cleavage, respectively. O(LA)(8)-RAP-loaded PEG-b-PLA micelles increased water solubility of RAP equivalent to 3.3mg/ml with no signs of precipitation. Further, o(LA)(8)-RAP was released more slowly than RAP from PEG-b-PLA micelles. With added physical stability, o(LA)(8)-RAP-loaded PEG-b-PLA micelles significantly inhibited tumor growth relative to RAP-loaded PEG-b-PLA micelles in 4T1 breast tumor-bearing mice without signs of acute toxicity.ConclusionsAn o(LA)(8)-RAP-loaded PEG-b-PLA micelle for injection is more stable than a RAP-loaded PEG-b-PLA micelle for injection, and o(LA)(8)-RAP converts into RAP rapidly in rat plasma (t(1/2)=1h), resulting in antitumor efficacy in a syngeneic 4T1 breast tumor model.