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.
| Original language | English |
|---|---|
| Pages (from-to) | 2744-2758 |
| Number of pages | 15 |
| Journal | Theranostics |
| Volume | 10 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 1 Jan 2020 |
Funding
We are grateful to the Servei de Microscopia Electrònica from the CCiTUB Universitat de Barcelona. This work was supported by grants to CF from the Spanish Ministry of Economia y Competitividad BIO2017-89754-C2-2R, RTC-2015-3751-1 with partial support from the Generalitat de Catalunya SGR17/861, and co-funded by the European Regional Development Fund (FEDER). CIBERER is an initiative of the ISCIII. The CF group acknowledges the support of the Spanish Adenovirus Network (AdenoNet, BIO2015-68990-REDT). We also acknowledge the support of CERCA Programme/Generalitat de Catalunya. This work was developed at the Centro Esther Koplowitz, Barcelona, Spain. MR-R was recipient of an FPI predoctoral contract from MINECO, Spain. Financial support from MINECO/ FEDER (grants RTC-2015-3751-1, SAF2015-64927-C2-1-R and SAF2015-64927-C2-2-R) is acknowledged. C. Fornaguera is grateful to MINECO for the Postdoctoral Fellowship (grant Torres Quevedo 2015). The Support of Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) from Generalitat de Catalunya for their support trough SGR 2017 1559 grant. The authors acknowledge the kind support of Irene Porcar and Elena García-Ollé in performing experiments.
| Funders | Funder number |
|---|---|
| Federación Española de Enfermedades Raras | |
| Ministerio de Economía y Competitividad | SAF2015-64927-C2-1-R, SAF2015-64927-C2-2-R |
| Instituto de Salud Carlos III | |
| European Regional Development Fund |
Keywords
- Oncolytic adenovirus
- Pancreatic cancer
- Poly(β-amino ester)s
- Polymer-coated viral vectors
- Systemic delivery
