Theranostics 2020; 10(6):2744-2758. doi:10.7150/thno.40902

Research Paper

Oligopeptide-modified poly(beta-amino ester)s-coated AdNuPARmE1A: Boosting the efficacy of intravenously administered therapeutic adenoviruses

Pau Brugada-Vilà3, Anna Cascante2, Miguel Ángel Lázaro2, Cristina Castells-Sala2, Cristina Fornaguera3, Maria Rovira-Rigau1, Lorenzo Albertazzi4,5, Salvador Borros3✉, Cristina Fillat1✉

1. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Facultat de Medicina i Ciències de la Salut. Universitat de Barcelona, 08036 Barcelona, Spain
2. Sagetis Biotech SL, 08017 Barcelona, Spain
3. Grup d'Enginyeria de Materials (GEMAT) Institut Químic de Sarrià (IQS) Universitat Ramon Llull (URL), 08017 Barcelona, Spain
4. Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute for Science and Technology (BIST), Barcelona, Spain
5. Department of Biomedical Engineering and the Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands

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Citation:
Brugada-Vilà P, Cascante A, Lázaro MÁ, Castells-Sala C, Fornaguera C, Rovira-Rigau M, Albertazzi L, Borros S, Fillat C. Oligopeptide-modified poly(beta-amino ester)s-coated AdNuPARmE1A: Boosting the efficacy of intravenously administered therapeutic adenoviruses. Theranostics 2020; 10(6):2744-2758. doi:10.7150/thno.40902. Available from http://www.thno.org/v10p2744.htm

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Abstract

Oncolytic adenoviruses are used as agents for the treatment of cancer. However, their potential is limited due to the high seroprevalence of anti-adenovirus neutralizing antibodies (nAbs) within the population and the rapid liver sequestration when systemically administered. To overcome these challenges, we explored using nanoparticle formulation to boost the efficacy of systemic oncolytic adenovirus administration.

Methods: Adenovirus were conjugated with PEGylated oligopeptide-modified poly(β-amino ester)s (OM-pBAEs). The resulting coated viral formulation was characterized in terms of surface charge, size, aggregation state and morphology and tested for anti-adenovirus nAbs evasion and activity in cancer cells. In vivo pharmacokinetics, biodistribution, tumor targeting, and immunogenicity studies were performed. The antitumor efficacy of the oncolytic adenovirus AdNuPARmE1A coated with OM-pBAEs (SAG101) in the presence of nAbs was evaluated in pancreatic ductal adenocarcinoma (PDAC) mouse models. Toxicity of the coated formulation was analyzed in vivo in immunocompetent mice.

Results: OM-pBAEs conjugated to adenovirus and generated discrete nanoparticles with a neutral charge and an optimal size. The polymeric coating with the reporter AdGFPLuc (CPEG) showed enhanced transduction and evasion of antibody neutralization in vitro. Moreover, systemic intravenous administration of the formulation showed improved blood circulation and reduced liver sequestration, substantially avoiding activation of nAb production. OM-pBAEs coating of the oncolytic adenovirus AdNuPARmE1A (SAG101) improved its oncolytic activity in vitro and enhanced antitumor efficacy in PDAC mouse models. The coated formulation protected virions from neutralization by nAbs, as antitumor efficacy was preserved in their presence but was completely lost in mice that received the non-formulated AdNuPARmE1A. Finally, coated-AdNuPARmE1A showed reduced toxicity when high doses of the formulation were administered.

Conclusions: The developed technology represents a promising improvement for future clinical cancer therapy using oncolytic adenoviruses.

Keywords: oncolytic adenovirus, polymer-coated viral vectors, poly(β-amino ester)s, pancreatic cancer, systemic delivery