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Stereocomplex Prodrugs of Oligo(lactic Acid)

Stereocomplex Prodrugs of Oligo(lactic Acid)

Yu Tong Tam, Chengbin Huang, Michael Poellmann, Glen S Kwon

ACS Nano. 2018 Jul 24;12(7):7406-7414.

PMID: 29957934

Abstract:

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 t1/2 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
LS74316	Poly(D,L-lactide-block-acrylic acid)			Price

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