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Oncolytic Adenovirus Coated with Multidegradable Bioreducible Core-Cross-Linked Polyethylenimine for Cancer Gene

Joung-Woo Choi1, Joung-Pyo Nam1, Kihoon Nam1

  • 1†Center for Controlled Chemical Delivery (CCCD), Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah 84112, United States.

Biomacromolecules
|June 23, 2015
PubMed

Insights

Researchers developed a new adenoviral vector using bioreducible polyethylenimine (rPEI) for safer and more effective cancer gene therapy. This optimized vector shows enhanced cancer cell killing and gene delivery, overcoming previous limitations of adenoviral therapies.

Area of Science:

  • Biotechnology
  • Gene Therapy
  • Nanomedicine

Background:

  • Adenovirus (Ad) vectors are promising for gene delivery but face challenges with immunogenicity and toxicity.
  • Oncolytic adenovirus (oAd) therapies are hindered by these safety concerns, limiting clinical translation.

Purpose of the Study:

  • To create a novel adenoviral vector complexed with multidegradable bioreducible core-cross-linked polyethylenimine (rPEI).
  • To enhance transduction efficacy and stability while reducing immunogenicity and toxicity for improved cancer gene therapy.

Main Methods:

  • Synthesized various molecular weight rPEIs and complexed them with adenovirus at different molar ratios.
  • Characterized the size and surface charge of the resulting Ad/rPEI complexes.
  • Evaluated transduction efficiency, cellular uptake, cancer cell killing, viral production, and gene expression in cancer cells.

Main Results:

  • Ad/rPEI complexes demonstrated significantly enhanced transduction efficiency in both CAR-positive and CAR-negative cancer cells compared to naked Ad.
  • Smaller Ad/16 kDa rPEI complexes (under 200 nm) showed improved cellular internalization.
  • Complexation with 16 kDa rPEI significantly increased cancer cell killing and viral production, particularly in CAR-negative cells.
  • Treatment with oAd/16 kDa rPEI led to decreased Met and VEGF expression in cancer cells.

Conclusions:

  • Multidegradable bioreducible core-cross-linked PEI effectively complexes with adenovirus, enhancing gene delivery and oncolytic efficacy.
  • The optimized Ad/rPEI vector shows potential as an efficient and safe platform for cancer gene therapy, applicable to a broad range of cancers.
  • This approach addresses key limitations of current adenovirus-based therapies, paving the way for clinical advancements.

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