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

  • Yu Tong Tam
  • Lauren Repp
  • Zhi-Xiong Ma
  • John B. Feltenberger
  • Glen S. KwonEmail author
Research Paper
  • 181 Downloads
Part of the following topical collections:
  1. Nanomedicines in Cancer

Abstract

Purpose

To 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.

Methods

Monodisperse 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.

Results

Synthesis 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.

Conclusions

An 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.

KEY WORDS

block copolymer mTOR oligo(lactic acid) polymeric micelle prodrug sirolimus 

Abbreviations

ACN

Acetonitrile

Bn

Benzyl

CH2Cl2

Methylene chloride

DCC

1,3-dicyclohexylcarbodiimide

DMAP

4-dimethylaminopyridine

EtOAc

Ethyl acetate

HF/Pyr

Hydrogen fluoride/pyridine

mTOR

Mammalian target of rapamycin

Na2SO4

Sodium sulphate

NaHCO3

Sodium bicarbonate

O(LA)n

Oligo(lactic acid)n

O(LA)n-RAP

Oligo(lactic acid)n-rapamycin

PBS

Phosphate buffered saline

Pd/C

Palladium on carbon

PEG-b-PLA

Poly(ethylene glycol)-block-poly(lactic acid)

RAP

Rapamycin

Sn(Oct)2

Tin(II)-ethylhexanoate

TES

Triethylsilyl ether

THF

Tetrahydrofuran

TLC

Thin layer chromatography

Notes

Supplementary material

11095_2019_2600_MOESM1_ESM.docx (566 kb)
ESM 1 (DOCX 565 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Pharmaceutical Sciences DivisionUniversity of Wisconsin-MadisonMadisonUSA
  2. 2.Discovery Pharmaceutical Sciences Merck Research LaboratoriesCaliforniaUSA
  3. 3.Medicinal Chemistry Center, School of PharmacyUniversity of Wisconsin-MadisonMadisonUSA

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