Stereocomplex Prodrugs of Oligo(lactic acid)_n-Gemcitabine in Poly(ethylene glycol)-block-poly(d,l-lactic acid) Micelles for Improved Physical Stability and Enhanced Antitumor Efficacy

Herein we demonstrate the formation of stereocomplex prodrugs of oligo( l -lactic acid) n -gemcitabine (o(LLA) n -GEM) and oligo( d -lactic acid) n -gemcitabine (o(DLA) n -GEM) for stable incorporation in poly(ethylene glycol)- block -poly( d, l -lactic acid) (PEG- b -PLA) micelles. O(LLA) n or o(DLA) n was attached at the amino group (4-( N )) of GEM via an amide linkage. When n = 10, a 1:1 mixture of o(LLA) 10 -GEM and o(DLA) 10 -GEM (o(L+DLA) 10 -GEM) was able to form a stereocomplex with a distinctive crystalline pattern. Degradation of o(L+DLA) 10 -GEM was driven by both backbiting conversion and esterase contribution, generating primarily o(L+DLA) 1 -GEM and GEM. O(L+DLA) 10 -GEM stably loaded in PEG- b -PLA micelles in the size range of 140–200 nm with an unexpected elongated morphology. The resulting micelles showed improved physical stability in aqueous media and inhibited backbiting conversion of o(L+DLA) 10 -GEM within micelles. Release of o(L+DLA) 10 -GEM from micelles was relatively slow, with a t 1/2 at ca . 60 h. Furthermore, weekly administration of o(L+DLA) 10 -GEM micelles i.v. displayed potent antitumor activity in an A549 human non-small-cell lung carcinoma xenograft model. Thus, stereocomplexation of isotactic o(LLA) n and o(DLA) n acts as a potential prodrug strategy for improved stability and sustained drug release in PEG- b -PLA micelles.