pH-sensitive oncolytic adenovirus hybrid targeting acidic tumor microenvironment and angiogenesis

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 pH 6.4, 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 pH 6.4, 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 pH 7.4, 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.

Hepatoma targeting peptide conjugated bio-reducible polymer complexed with oncolytic adenovirus for cancer gene therapy

“…The adenoviral transduction efficiency was examined with a green fluorescence protein (GFP)-expressing replication-incompetent Ad (Ad/GFP). The Ad/GFP was constructed and characterized in our previous study [9, 28]. The construction and generation of oncolytic Ad backbone was previously described (RdB) [19, 29].…”

Evolving Lessons on Nanomaterial-Coated Viral Vectors for Local and Systemic Gene Therapy

“…Alternatively, active tumor targeting of viral vectors can be achieved by complexation with tumor microenvironment-responsive polymers, which can be activated by tumor-specific conditions. Under tumor-specific conditions, such as hypoxia and high levels of MMPs, nanocomplex can be internalized into cancer cells [152,155]. Modification of viral vectors by nanomaterials Review was sufficient to protect Ad from Ad-specific neutralizing Ab, whereas less than 10% PEGylation offered no protection, suggesting that a critical threshold of Ad surface must be PEGylated to achieve protection from interactions with the host immune response [138].…”

“…Choi et al have examined the therapeutic profile of oncolytic Ad expressing VEGF promoter-targeting transcriptional repressor (KOX) complexed with a pH-sensitive block copolymer (methoxy poly(ethylene glycol)-b-poly(L-histidine-co-L-phenylalanine; PEGbPHF) [152]. At pH 6.4, KOX/PEG bPHF significantly suppressed VEGF gene expression, cancer cell migration and vessel sprouting compared with naked KOX or KOX/PEG bPHF at pH 7.4, demonstrating that an acidic cellular environment enhances the antiangiogenic efficacy of KOX/PEG bPHF.…”

Polymeric oncolytic adenovirus for cancer gene therapy

“…For example, the HER2/neu receptor is only overexpressed in 20 to 30% of breast cancer patients; therefore, the active targeting moiety-conjugated Ad/polymer based platform strategy is ineffective for treating all cancer types. To improve this approach, recently several studies developed a tumor microenvironment targeting strategy that utilizes pH sensitive polymers to target acidic tumor microenvironment [121,122]. …”

“…Recently, Choi et al investigated tumor microenvironment specific targeting with oncolytic Ad complexed with the pH-sensitive block copolymer, and methoxy poly(ethylene glycol)- b -poly(L-histidine-coLphenylalanine) (PEG b PHF) [122]. Poly(L-histidine) (pHis) is a promising pH-sensitive polybase for stimuli-responsive polymeric carrier due to the imidazole ring of its backbone.…”