Highly specific in vivo gene delivery for p53-mediated apoptosis and genetic photodynamic therapies of tumour

Nat Commun. 2015 Mar 5;6:6456. doi: 10.1038/ncomms7456.

Abstract

Anticancer therapies are often compromised by nonspecific effects and challenged by tumour environments' inherent physicochemical and biological characteristics. Often, therapeutic effect can be increased by addressing multiple parameters simultaneously. Here we report on exploiting extravasation due to inherent vascular leakiness for the delivery of a pH-sensitive polymer carrier. Tumours' acidic microenvironment instigates a charge reversal that promotes cellular internalization where endosomes destabilize and gene delivery is achieved. We assess our carrier with an aggressive non-small cell lung carcinoma (NSCLC) in vivo model and achieve >30% transfection efficiency via systemic delivery. Rejuvenation of the p53 apoptotic pathway as well as expression of KillerRed protein for sensitization in photodynamic therapy (PDT) is accomplished. A single administration greatly suppresses tumour growth and extends median animal survival from 28 days in control subjects to 68 days. The carrier has capacity for multiple payloads for greater therapeutic response where inter-individual variability can compromise efficacy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Carcinoma, Non-Small-Cell Lung / therapy*
  • Cell Line, Tumor
  • Dimethyl Sulfoxide
  • Endosomes / metabolism
  • Gene Transfer Techniques*
  • Glutamates
  • Green Fluorescent Proteins / metabolism*
  • Humans
  • Hydrogen-Ion Concentration
  • In Situ Nick-End Labeling
  • Indoles
  • Magnetic Resonance Spectroscopy
  • Mice
  • Mice, Inbred BALB C
  • Photochemotherapy / methods*
  • Tumor Microenvironment / physiology*
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Glutamates
  • Indoles
  • Tumor Suppressor Protein p53
  • killer red protein, Anthomedusae
  • Green Fluorescent Proteins
  • 3-aminoglutaric acid
  • DAPI
  • Dimethyl Sulfoxide