Disulfide-Linked Amphiphilic Polymer-Docetaxel Conjugates Assembled Redox-Sensitive Micelles for Efficient Antitumor Drug Delivery

Biomacromolecules. 2016 May 9;17(5):1621-32. doi: 10.1021/acs.biomac.5b01758. Epub 2016 Apr 5.

Abstract

Here, we prepared novel redox-sensitive drug delivery system based on copolymer-drug conjugates methoxy poly(ethylene glycol)-poly(γ-benzyl l-glutamate)-disulfide-docetaxel (mPEG-PBLG-SS-DTX) to realize the desirable cancer therapy. First, copolymers of methoxy poly(ethylene glycol)-poly(γ-benzyl l-glutamate) (mPEG-PBLGs) with different molecular weight (mPEG2000-PBLG1750 and mPEG5000-PBLG1750) were synthesized via the ring open polymerization (ROP) of 5-benzyl-l-glutamate-N-carboxyanhydride (γ-Bzl-l-Glu-NCA) initiated by monoamino-terminated mPEG (mPEG-NH2). Then, the docetaxel (DTX) was conjugated to the block polymers through a linkage containing disulfide bond to obtain mPEG-PBLG-SS-DTXs, including mPEG2000-PBLG1750-SS-DTX and mPEG5000-PBLG1750-SS-DTX. The obtained copolymer-drug conjugates mPEG2000-PBLG1750-SS-DTX and mPEG5000-PBLG1750-SS-DTX could self-assemble into nanosized micelles in aqueous environment via dialysis method with a low critical micelle concentration (CMC, 3.98 and 6.94 μg/mL, respectively). The size of the micelles was approximately 101.3 and 148.9 nm, respectively, with a narrow size distribution. They released approximately 40% DTX in a sustained way in the presence of 50 mM DTT after 120 h in comparison with only approximately 10% DTX released from micelles in the absence of DTT. The high cytotoxicity was identified for mPEG-PBLG-SS-DTXs micelles against MCF-7/ADR and A549 cells, and the IC50 of mPEG-PBLG-SS-DTXs micelles against MCF-7/ADR for 24 h was roughly a 15th of the value of free DTX. Moreover, the mPEG-PBLG-SS-DTXs micelles could be efficiently uptaken by MCF-7/ADR and A549 cells. Thus, the present constructed mPEG-PBLG-SS-DTXs micelles were very promising for effective cancer therapy.

MeSH terms

  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Cell Survival / drug effects
  • Disulfides / chemistry*
  • Docetaxel
  • Drug Carriers / chemistry*
  • Drug Delivery Systems*
  • Female
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Micelles
  • Oxidation-Reduction
  • Polymers / chemistry*
  • Taxoids / administration & dosage*
  • Taxoids / pharmacology
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Disulfides
  • Drug Carriers
  • Micelles
  • Polymers
  • Taxoids
  • Docetaxel