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.

Research paper by Yu Tong YT Tam, Chengbin C Huang, Michael M Poellmann, Glen S GS Kwon

Indexed on: 30 Jun '18Published on: 30 Jun '18Published in: ACS Nano


Herein we demonstrate the formation of stereocomplex prodrugs of oligo(L-lactic acid)-gemcitabine (o(LLA)-GEM) and oligo(D-lactic acid)-gemcitabine (o(DLA)-GEM) for stable incorporation in poly(ethylene glycol)- block-poly(D,L-lactic acid) (PEG- b-PLA) micelles. O(LLA) or o(DLA) was attached at the amino group (4-(N)) of GEM via amide linkage. When n = 10, 1:1 mixture of o(LLA)-GEM and o(DLA)-GEM (o(L+DLA)-GEM) were able to form stereocomplex with a distinctive crystalline pattern. Degradation of o(L+DLA)-GEM was driven by both backbiting conversion and esterase contribution, generating primarily o(L+DLA)-GEM and GEM. O(L+DLA)-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)-GEM within micelles. Release of o(L+DLA)-GEM from micelles was relatively slow, with t at ca. 60 hours. Furthermore, weekly administration of o(L+DLA)-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) and o(DLA) acts as a potential prodrug strategy for improved stability and sustained drug release in PEG- b-PLA micelles.