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Oligopeptide-modified poly(beta-amino ester)s-coated AdNuPARmE1A: Boosting the efficacy of intravenously administered
Pau Brugada-Vilà1, Anna Cascante2, Miguel Ángel Lázaro2
1Grup d'Enginyeria de Materials (GEMAT) Institut Químic de Sarrià (IQS) Universitat Ramon Llull (URL), 08017 Barcelona, Spain.
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.
Insights
Nanoparticle formulation of oncolytic adenoviruses overcomes antibody neutralization and liver sequestration, enhancing cancer treatment efficacy. This novel approach improves adenovirus delivery and antitumor activity in preclinical models.
Area of Science:
- Biotechnology
- Nanomedicine
- Oncolytic Virus Therapy
Background:
- Oncolytic adenoviruses show promise for cancer treatment but face challenges from pre-existing neutralizing antibodies (nAbs) and rapid liver sequestration upon systemic administration.
- These limitations hinder the therapeutic potential of adenoviral vectors, necessitating strategies to improve their systemic delivery and efficacy.
Purpose of the Study:
- To investigate the use of nanoparticle formulation with PEGylated oligopeptide-modified poly(β-amino esters) (OM-pBAEs) to enhance the systemic efficacy of oncolytic adenoviruses.
- To evaluate the ability of the OM-pBAEs coating to evade nAbs, improve pharmacokinetics, target tumors, and reduce toxicity of oncolytic adenoviruses.
Main Methods:
- Adenoviruses were conjugated with OM-pBAEs to create nanoparticle formulations.
- Formulations were characterized for physical properties and tested *in vitro* for antibody evasion and cancer cell transduction.
- *In vivo* studies assessed pharmacokinetics, biodistribution, tumor targeting, immunogenicity, antitumor efficacy in pancreatic ductal adenocarcinoma (PDAC) models, and toxicity.
Main Results:
- OM-pBAE coated adenoviruses formed stable nanoparticles with neutral charge and optimal size, demonstrating enhanced *in vitro* transduction and antibody evasion.
- Systemic administration resulted in improved circulation, reduced liver sequestration, and suppressed nAb activation.
- The coated oncolytic adenovirus (SAG101) exhibited enhanced *in vitro* oncolytic activity and superior *in vivo* antitumor efficacy in PDAC models, preserving activity in the presence of nAbs and showing reduced toxicity.
Conclusions:
- Nanoparticle formulation using OM-pBAEs effectively shields oncolytic adenoviruses from neutralizing antibodies and improves systemic delivery.
- This technology significantly enhances antitumor efficacy in preclinical models and demonstrates reduced toxicity.
- The developed formulation represents a promising advancement for the clinical application of oncolytic adenoviruses in cancer therapy.
