Ligand-modified nanoparticles as a multifunctional cancer

J.M. Silva, G. Vandermeulen, V.G. Oliveira, S. Pinto, E. Zupancic, L. Graca, V. Préat, H. Florindo
Faculty of Pharmacy University of Lisbon, PT

Keywords: cancer vaccine, nanoparticles, PLGA, mannose receptor targeting, TLR, dendritic cells

Summary:

With this study we demonstrate that the combination of active targeting of NP with their multifuctional properties in terms of antigen and adjuvant delivery has high cancer immunotherapeutic potential. Our strategy was to combine APC-targeting properties of mannose-functionalized polymeric NP and their capacity to codeliver simultaneously cancer antigens and Toll-like receptor ligands (TLRl). We also address the interaction of NP with different APC types, as well as the endocytic and intracellular trafficking pathways followed by NP. We are able to produce NP with high entrapment efficiencies of both antigens and adjuvants and potential to avoid lysosomal degradation. Mannose residues are exposed at NP surface and available for biding. Considerable levels of colocalization with endolysosomal vesicles, with a tendency to accumulate in the endoplasmic reticulum, demonstrate the potential of NP to induce the activation of TLR and to cross-present the antigens to CD8+ T cells. In vivo, mannosylated NP containing two TLRl and the antigen tested on OT II mice induced superior levels of IFN-γ and IL-2, as well as higher IgG2c/IgG1 ratios, when compared to non-functionalized NP. The administration of two melanoma antigens in different mannose-functionalyzed NP containing two TLRl induced the highest B16F10 tumor growth delayment.