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Published on: November 24, 2014
pH-sensitive oncolytic adenovirus hybrid targeting acidic tumor microenvironment and angiogenesis
Joung-Woo Choi1, Soo-Jung Jung1, Dayananda Kasala1
1Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsinmi-ro, Seongdong-gu, Seoul, Republic of Korea.
Abstract:
Although oncolytic adenoviruses (Ads) are an attractive option for cancer gene therapy, the intravenous administration of naked Ad still encounters unfavorable host responses, non-specific interactions, and heterogeneity in targeted cancer cells. To overcome these obstacles and achieve specific targeting of the tumor microenvironment, Ad was coated with the pH-sensitive block copolymer, methoxy poly(ethylene glycol)-b-poly(l-histidine-co-l-phenylalanine) (PEGbPHF). The physicochemical properties of the generated nanocomplex, Ad/PEGbPHF, were assessed. At pH6.4, GFP-expressing Ad/PEGbPHF induced significantly higher GFP expression than naked Ad in both coxsackie and adenovirus receptor (CAR)-positive and -negative cells. To assess the therapeutic efficacy of the Ad/PEGbPHF complex platform, an oncolytic Ad expressing VEGF promoter-targeting transcriptional repressor (KOX) was used to form complexes. At pH6.4, KOX/PEGbPHF significantly suppressed VEGF gene expression, cancer cell migration, vessel sprouting, and cancer cell killing effect compared to naked KOX or KOX/PEGbPHF at pH7.4, demonstrating that KOX/PEGbPHF can overcome the lack of CAR that is frequently observed in tumor tissues. The antitumor activity of KOX/PEGbPHF systemically administered to a tumor xenograft model was significantly higher than that of naked KOX. Furthermore, KOX/PEGbPHF showed lower hepatic toxicity and did not induce an innate immune response against Ad. Altogether, these results demonstrate that pH-sensitive polymer-coated Ad complex significantly increases net positive charge upon exposure to hypoxic tumor microenvironment, allowing passive targeting to the tumor tissue. It may offer superior potential for systemic therapy, due to its improved tumor selectivity, increased therapeutic efficacy, and lower toxicity compared to naked KOX.
Insights
pH-sensitive polymer-coated adenoviruses (Ads) improve cancer gene therapy by targeting tumors specifically. This novel Ad/PEGbPHF complex enhances therapeutic efficacy and reduces toxicity for systemic cancer treatment.
Area of Science:
- Biotechnology
- Nanomedicine
- Cancer Gene Therapy
Background:
- Oncolytic adenoviruses (Ads) show promise for cancer gene therapy but face challenges with intravenous administration, including host responses and non-specific targeting.
- Tumor microenvironments often exhibit heterogeneity and lack specific receptors like the coxsackie and adenovirus receptor (CAR), limiting naked Ad efficacy.
Purpose of the Study:
- To develop a pH-sensitive polymer-coated adenovirus complex (Ad/PEGbPHF) for targeted delivery to the tumor microenvironment.
- To evaluate the physicochemical properties, cellular uptake, and therapeutic efficacy of the Ad/PEGbPHF complex in preclinical cancer models.
Main Methods:
- Adenoviruses (Ads) were coated with methoxy poly(ethylene glycol)-b-poly(l-histidine-co-l-phenylalanine) (PEGbPHF), a pH-sensitive block copolymer.
- Physicochemical properties and GFP expression of Ad/PEGbPHF were assessed at different pH levels.
- Therapeutic efficacy was evaluated using an oncolytic Ad expressing a VEGF promoter-targeting transcriptional repressor (KOX), assessing VEGF gene expression, cancer cell migration, and tumor xenograft models.
Main Results:
- Ad/PEGbPHF demonstrated enhanced GFP expression at pH 6.4 compared to naked Ad in both CAR-positive and -negative cells.
- KOX/PEGbPHF significantly suppressed VEGF gene expression, cancer cell migration, and exhibited enhanced cancer cell killing at pH 6.4.
- Systemic administration of KOX/PEGbPHF in a tumor xenograft model showed superior antitumor activity, lower hepatic toxicity, and no innate immune response compared to naked KOX.
Conclusions:
- The pH-sensitive polymer coating enables Ad/PEGbPHF to target the hypoxic tumor microenvironment by increasing net positive charge.
- This targeted delivery system overcomes CAR heterogeneity in tumors, offering improved tumor selectivity and therapeutic efficacy.
- Ad/PEGbPHF represents a promising platform for systemic cancer therapy with enhanced efficacy and reduced toxicity.
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