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Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
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Dual tumor targeting with pH-sensitive and bioreducible polymer-complexed oncolytic adenovirus

Chang Yoon Moon1, Joung-Woo Choi1, Dayananda Kasala1

  • 1Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, Republic of Korea.

Biomaterials
|December 20, 2014
PubMed

Insights

Novel polymer-coated oncolytic adenoviruses (Ads) enhance tumor targeting and efficacy by exploiting the tumor microenvironment. This smart nanotherapy overcomes limitations of traditional Ads, offering improved cancer treatment potential.

Area of Science:

  • Biotechnology
  • Nanomedicine
  • Cancer Gene Therapy

Background:

  • Oncolytic adenoviruses (Ads) show promise for cancer gene therapy but face limitations like immune response and poor tumor targeting.
  • The tumor microenvironment presents unique challenges, including low pH and specific receptor dependencies, which can hinder viral efficacy.

Purpose of the Study:

  • To develop a pH-sensitive, bio-reducible polymer (PPCBA)-coated oncolytic Ad to improve tumor targeting and therapeutic efficacy.
  • To overcome the limitations of naked Ads, including immune recognition and CAR-dependent uptake, by utilizing the tumor microenvironment's characteristics.

Main Methods:

  • Generated PPCBA-coated oncolytic Ads (Ad-PPCBA) and evaluated their cellular uptake at different pH levels (6.0 vs. 7.4).
  • Investigated the internalization mechanism of Ad-PPCBA complexes, comparing it to naked Ads.
  • Assessed the efficacy of VEGF-specific shRNA-expressing oncolytic Ad complexed with PPCBA (RdB/shVEGF-PPCBA) in vitro and in vivo models, including tumor xenografts.

Main Results:

  • Ad-PPCBA demonstrated enhanced cellular uptake at pH 6.0, targeting the acidic tumor microenvironment and overcoming CAR dependence.
  • Internalization of Ad-PPCBA occurred via macropinocytosis, distinct from the CAR-dependent pathway of naked Ads.
  • RdB/shVEGF-PPCBA significantly suppressed VEGF gene expression and vascularization in vitro and in vivo, showing superior therapeutic efficacy compared to naked Ads.
  • PPCBA coating shielded Ads from immune response and improved biocompatibility, reducing serum levels of IL-6, ALT, and AST.

Conclusions:

  • Smart, tumor-specific, oncolytic Ad-PPCBA complexes represent a promising strategy to enhance cancer gene therapy.
  • This nanotherapy effectively targets the tumor microenvironment, overcomes viral limitations, and demonstrates significant therapeutic potential for primary and metastatic tumors.
Keywords:
Bioreducible polymerCancer gene therapyOncolytic adenovirusSystemic administrationTumor microenvironmentpH-sensitive

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