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

Purpose: To prepare an oligo(lactic acid)-rapamycin prodrug (o(LA)-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.

Methods: Monodisperse o(LA) was coupled on RAP at the C-40 via DCC/DMAP chemistry, and conversion of o(LA)-RAP prodrug into RAP was characterized in vitro. Physicochemical properties of o(LA)-RAP- and RAP-loaded PEG-b-PLA micelles and their antitumor efficacies in a syngeneic 4 T1 breast tumor model were compared.

Results: Synthesis of o(LA)-RAP prodrug was confirmed by H NMR and mass spectroscopy. The o(LA)-RAP prodrug underwent conversion in PBS and rat plasma by backbiting and esterase-mediated cleavage, respectively. O(LA)-RAP-loaded PEG-b-PLA micelles increased water solubility of RAP equivalent to 3.3 mg/ml with no signs of precipitation. Further, o(LA)-RAP was released more slowly than RAP from PEG-b-PLA micelles. With added physical stability, o(LA)-RAP-loaded PEG-b-PLA micelles significantly inhibited tumor growth relative to RAP-loaded PEG-b-PLA micelles in 4 T1 breast tumor-bearing mice without signs of acute toxicity.

Conclusions: An o(LA)-RAP-loaded PEG-b-PLA micelle for injection is more stable than a RAP-loaded PEG-b-PLA micelle for injection, and o(LA)-RAP converts into RAP rapidly in rat plasma (t = 1 h), resulting in antitumor efficacy in a syngeneic 4 T1 breast tumor model.