HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Dual tumor targeting with pH-sensitive and bioreducible polymer-complexed oncolytic adenovirus.

Abstract
Oncolytic adenoviruses (Ads) have shown great promise in cancer gene therapy but their efficacy has been compromised by potent immunological, biochemical, and specific tumor-targeting limitations. To take full advantage of the innate cancer-specific killing potency of oncolytic Ads but also exploit the subtleties of the tumor microenvironment, we have generated a pH-sensitive and bio-reducible polymer (PPCBA)-coated oncolytic Ad. Ad-PPCBA complexes showed higher cellular uptake at pH 6.0 than pH 7.4 in both high and low coxsackie and adenovirus receptor-(CAR)-expressing cells, thereby demonstrating Ad-PPCBA's ability to target the low pH hypoxic tumor microenvironment and overcome CAR dependence for target cell uptake. Endocytic mechanism studies indicated that Ad-PPCBA internalization is mediated by macropinocytosis instead of the CAR-dependent endocytic pathway that internalizes naked Ad. VEGF-specific shRNA-expressing oncolytic Ad complexed with PPCBA (RdB/shVEGF-PPCBA) elicited much more potent suppression of U87 human brain cancer cell VEGF gene expression in vitro, and human breast cancer MCF7 cell/Matrigel plug vascularization in a mouse model, when cancer cells had been previously infected at pH 6.0 versus pH 7.4. Moreover, intratumorally and intravenously injected RdB/shVEGF-PPCBA nanocomplexes elicited significantly higher therapeutic efficacy than naked virus in U87-tumor mouse xenograft models, reducing IL-6, ALT, and AST serum levels. These data demonstrated PPCBA's biocompatibility and capability to shield the Ad surface to prevent innate immune response against Ad after both intratumoral and systemic administration. Taken together, these results demonstrate that smart, tumor-specific, oncolytic Ad-PPCBA complexes can be exploited to treat both primary and metastatic tumors.
AuthorsChang Yoon Moon, Joung-Woo Choi, Dayananda Kasala, Soo-Jung Jung, Sung Wan Kim, Chae-Ok Yun
JournalBiomaterials (Biomaterials) Vol. 41 Pg. 53-68 (Feb 2015) ISSN: 1878-5905 [Electronic] Netherlands
PMID25522965 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Ltd. All rights reserved.
Chemical References
  • Angiogenesis Inhibitors
  • Biocompatible Materials
  • Polymers
  • Vascular Endothelial Growth Factor A
Topics
  • Adenoviridae (drug effects, physiology)
  • Angiogenesis Inhibitors (pharmacology)
  • Animals
  • Biocompatible Materials (chemistry)
  • Cell Death (drug effects)
  • Cell Line, Tumor
  • Drug Delivery Systems
  • Endocytosis (drug effects)
  • Endosomes (drug effects, metabolism)
  • HEK293 Cells
  • Humans
  • Hydrogen-Ion Concentration
  • Immune Evasion (drug effects)
  • Liver (drug effects, pathology)
  • Mice
  • Oncolytic Viruses (drug effects, physiology)
  • Polymers (chemical synthesis, chemistry, toxicity)
  • Transduction, Genetic
  • Vascular Endothelial Growth Factor A (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: