EGFR-Targeted Polymeric Mixed Micelles Carrying Gemcitabine for Treating Pancreatic Cancer

Biomacromolecules. 2016 Jan 11;17(1):301-13. doi: 10.1021/acs.biomac.5b01419. Epub 2015 Dec 17.

Abstract

The objective of this study was to design GE11 peptide (YHWYGYTPQNVI) linked micelles of poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-gemcitabine-graft-dodecanol (PEG-b-PCC-g-GEM-g-DC) for enhanced stability and target specificity of gemcitabine (GEM) to EGFR-positive pancreatic cancer cells. GE11-PEG-PCD/mPEG-b-PCC-g-GEM-g-DC mixed micelles showed EGFR-dependent enhanced cellular uptake, and cytotoxicity as compared to scrambled peptide HW12-PEG-PCD/mPEG-b-PCC-g-GEM-g-DC mixed micelles and unmodified mPEG-b-PCC-g-GEM-g-DC micelles. Importantly, GE11-linked mixed micelles preferentially accumulated in orthotopic pancreatic tumor and tumor vasculature at 24 h post systemic administration. GE11-linked mixed micelles inhibited orthotopic pancreatic tumor growth compared to HW12-linked mixed micelles, unmodified mPEG-b-PCC-g-GEM-g-DC micelles, and free GEM formulations. Tumor growth inhibition was mediated by apoptosis of tumor cells and endothelial cells as determined by immunohistochemical staining. In summary, GE11-linked mixed micelles is a promising approach to treat EGFR overexpressing cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / administration & dosage
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use
  • Disease Models, Animal
  • Drug Carriers / chemical synthesis
  • Drug Carriers / therapeutic use*
  • ErbB Receptors / antagonists & inhibitors*
  • Gemcitabine
  • Humans
  • Mice
  • Micelles*
  • Pancreatic Neoplasms / drug therapy*
  • Peptides / chemistry
  • Polyesters / chemistry
  • Polyethylene Glycols / chemistry
  • Polymers / chemistry

Substances

  • Antimetabolites, Antineoplastic
  • Drug Carriers
  • GE11 peptide
  • Micelles
  • Peptides
  • Polyesters
  • Polymers
  • poly(ethylene glycol)-block-poly(2-methyl-2-carboxylpropylene carbonate-graft-dodecanol)
  • Deoxycytidine
  • Polyethylene Glycols
  • monomethoxypolyethylene glycol
  • EGFR protein, human
  • ErbB Receptors
  • Gemcitabine