Engineering of cell microenvironment-responsive polypeptide nanovehicle co-encapsulating a synergistic combination of small molecules for effective chemotherapy in solid tumors

Acta Biomater. 2017 Jan 15:48:131-143. doi: 10.1016/j.actbio.2016.10.034. Epub 2016 Oct 26.

Abstract

In this study, we report a facile method to construct a bioactive (poly(phenylalanine)-b-poly(l-histidine)-b-poly(ethylene glycol) polypeptide nanoconstruct to co-load doxorubicin (DOX) and quercetin (QUR) (DQ-NV). The smart pH-sensitive nanovehicle was fabricated with precisely tailored drug-to-carrier ratio that resulted in accelerated, sequential drug release. As a result of ratiometric loading, QUR could significantly enhance the cytotoxic potential of DOX, induced marked cell apoptosis; change cell cycle patterns, inhibit the migratory capacity of sensitive and resistant cancer cells. In particular, pro-oxidant QUR from DQ-NV remarkably reduced the GSH/GSSG ratio, indicating high oxidative stress and damage to cellular components. DQ-NV induced tumor shrinkage more effectively than the single drugs in mice carrying subcutaneous SCC-7 xenografts. DQ-NV consistently induced high expression of caspase-3 and PARP and low expression of Ki67 and CD31 immunomarkers. In summary, we demonstrate the development of a robust polypeptide-based intracellular nanovehicle for synergistic delivery of DOX/QUR in cancer chemotherapy.

Statement of significance: In this study, we report a facile method to construct bioactive and biodegradable polypeptide nanovehicles as an advanced platform technology for application in cancer therapy. We designed a robust (poly(phenylalanine)-b-poly(l-histidine)-b-poly(ethylene glycol) nanoconstruct to co-load doxorubicin (DOX) and quercetin (QUR) (DQ-NV). The conformational changes of the histidine block at tumor pH resulted in accelerated, sequential drug release. QUR could significantly enhance the cytotoxic potential of DOX, induce marked cell apoptosis, change cell cycle patterns, and inhibit the migratory capacity of sensitive and resistant cancer cells. DQ-NV induced tumor shrinkage more effectively than the single drugs and the 2-drug cocktail in tumor xenografts. In summary, we demonstrate the development of an intracellular nanovehicle for synergistic delivery of DOX/QUR in cancer chemotherapy.

Keywords: Combination; Doxorubicin; Nanovehicle; Polypeptide; Quercetin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Blotting, Western
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cellular Microenvironment / drug effects*
  • Doxorubicin / pharmacology
  • Drug Carriers / chemistry*
  • Drug Synergism
  • Endocytosis / drug effects
  • Flow Cytometry
  • Hydrodynamics
  • Hydrogen-Ion Concentration
  • Immunohistochemistry
  • Mice
  • Nanoparticles / chemistry*
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Oxidative Stress / drug effects
  • Particle Size
  • Peptides
  • Quercetin
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / therapeutic use*
  • Tissue Engineering / methods*
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Drug Carriers
  • Peptides
  • Small Molecule Libraries
  • Doxorubicin
  • Quercetin