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

Authors
  • Tam, Yu Tong1, 2
  • Repp, Lauren1
  • Ma, Zhi-Xiong3
  • Feltenberger, John B.3
  • Kwon, Glen S.1
  • 1 University of Wisconsin-Madison, Pharmaceutical Sciences Division, 777 Highland Avenue, Madison, Wisconsin, 53705-2222, USA , Madison (United States)
  • 2 Discovery Pharmaceutical Sciences Merck Research Laboratories, South San Francisco, California, 94080, USA , California (United States)
  • 3 University of Wisconsin-Madison, Medicinal Chemistry Center, School of Pharmacy, 777 Highland Avenue, Madison, Wisconsin, 53705-2222, USA , Madison (United States)
Type
Published Article
Journal
Pharmaceutical Research
Publisher
Springer-Verlag
Publication Date
Mar 19, 2019
Volume
36
Issue
5
Identifiers
DOI: 10.1007/s11095-019-2600-0
Source
Springer Nature
Keywords
License
Yellow

Abstract

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 4 T1 breast tumor model were compared.ResultsSynthesis of o(LA)8-RAP prodrug was confirmed by 1H 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 3.3 mg/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 4 T1 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 (t1/2 = 1 h), resulting in antitumor efficacy in a syngeneic 4 T1 breast tumor model.

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