Polymeric oncolytic adenovirus for cancer gene therapy

Abstract

Oncolytic adenovirus (Ad) vectors present a promising modality to treat cancer. Many clinical trials have been done with either naked oncolytic Ad or combination with chemotherapies. However, the systemic injection of oncolytic Ad in clinical applications is restricted due to significant liver toxicity and immunogenicity. To overcome these issues, Ad has been engineered physically or chemically with numerous polymers for shielding the Ad surface, accomplishing extended blood circulation time and reduced immunogenicity as well as hepatotoxicity. In this review, we describe and classify the characteristics of polymer modified oncolytic Ad following each strategy for cancer treatment. Furthermore, this review concludes with the highlights of various polymer-coated Ads and their prospects, and directions for future research.

Keywords: Active targeting; Cancer gene therapy; Clinical trials; Oncolytic Ad/polymer hybrid vector; Oncolytic adenovirus; Systemic administration; Tumor microenvironment targeting.

Fig. 1

Schematic diagram of the cancer cell-specific killing of oncolytic adenovirus (Ad). Oncolytic Ad can replicate and destroy cancer cells by cancer-specific oncolysis while sparing normal cells.

Fig. 2

Overview of strategies used for surface modification of Ad. The free amines on the viral surface can be easily reacted with functional polymers (top). Ad coated with a cationic polymer effectively interacts with the negatively charged Ad surface (bottom).

Fig. 3

Active targeting of oncolytic Ad/polymers. Active targeting strategy. Ligands grafted at the surface of polymers, which complexed with oncolytic Ad, bind to receptors overexpressed cancer cells. After endocytosis, Ad/polymer enters into the endosome, then escape from endosome when pH value of endosome becomes acidic.

Fig. 4

Tumor microenvironment targeting. At normal physiological condition such as blood, oncolytic Ad/pH sensitive polymer complex is stable and deprotonated. PEGylation of pH sensitive polymer prolongs blood retention time of the complex and facilitates intratumoral accumulation. At acidic tumor microenvironment, pH sensitive complex is protonated and net surface charge of the complex becomes cationic and is internalized into the tumor cells through charge-mediated internalization.