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

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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.

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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

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Author information

Author notes

  1. Yu Tong Tam

    Present address: Discovery Pharmaceutical Sciences Merck Research Laboratories, South San Francisco, California, 94080, USA

Authors and Affiliations

  1. Pharmaceutical Sciences Division, University of Wisconsin-Madison, 777 Highland Avenue, Madison, Wisconsin, 53705-2222, USA

    Yu Tong Tam, Lauren Repp & Glen S. Kwon

  2. Medicinal Chemistry Center, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, Wisconsin, 53705-2222, USA

    Zhi-Xiong Ma & John B. Feltenberger

Authors
  1. Yu Tong Tam
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  2. Lauren Repp
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  3. Zhi-Xiong Ma
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  4. John B. Feltenberger
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  5. Glen S. Kwon
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Corresponding author

Correspondence to Glen S. Kwon.

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Tam, Y.T., Repp, L., Ma, ZX. et al. Oligo(Lactic Acid)8-Rapamycin Prodrug-Loaded Poly(Ethylene Glycol)-block-Poly(Lactic Acid) Micelles for Injection. Pharm Res 36, 70 (2019). https://doi.org/10.1007/s11095-019-2600-0

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  • DOI: https://doi.org/10.1007/s11095-019-2600-0

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