title: In vivo delivery of peptides and Toll-like receptor ligands by mannose-functionalized polymeric nanoparticles induces prophylactic and therapeutic anti-tumor immune responses in a melanoma model.
abstract: We hypothesized that the co-entrapment of melanoma-associated antigens and the Toll-like receptor (TLR) ligands Poly(I:C) and CpG, known to be Th1-immunopotentiators, in mannose-functionalized aliphatic polyester-based nanoparticles (NPs) could be targeted to mannose receptors on antigen-presenting cells and induce anti-tumor immune responses. High entrapment efficiencies of antigens and immunopotentiators in 150nm NPs were obtained. The co-entrapment of the model antigen ovalbumin and the TLR ligands was crucial to induce high IgG2c/IgG1 ratios and high levels of IFN-γ and IL-2. Mannose-functionalization of NPs potentiated the Th1 immune response. The nanoparticulate vaccines decreased the growth rate of murine B16F10 melanoma tumors in therapeutic and prophylatic settings. The combination of mannose-functionalized NPs containing MHC class I- or class II-restricted melanoma antigens and the TLR ligands induced the highest tumor growth delay. Overall, we demonstrate that the multifunctional properties of NPs in terms of targeting and antigen/adjuvant delivery have high cancer immunotherapeutic potential.
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal; Louvain Drug Research Institute, Advanced Drug Delivery & Biomaterials, Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Joana M
authors.initials: JM
authors.lastname: Silva
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal.
authors.forename: Eva
authors.initials: E
authors.lastname: Zupancic
authors.affiliation: Louvain Drug Research Institute, Advanced Drug Delivery & Biomaterials, Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Vandermeulen
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, 1649-025 Lisbon, Portugal.
authors.forename: Vanessa G
authors.initials: VG
authors.lastname: Oliveira
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Salgado
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal.
authors.forename: Mafalda
authors.initials: M
authors.lastname: Videira
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal.
authors.forename: Manuela
authors.initials: M
authors.lastname: Gaspar
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, 1649-025 Lisbon, Portugal.
authors.forename: Luis
authors.initials: L
authors.lastname: Graca
authors.affiliation: Louvain Drug Research Institute, Advanced Drug Delivery & Biomaterials, Université Catholique de Louvain, 1200 Brussels, Belgium. Electronic address: veronique.preat@uclouvain.be.
authors.forename: Véronique
authors.initials: V
authors.lastname: Préat
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal. Electronic address: hflorindo@ff.ul.pt.
authors.forename: Helena F
authors.initials: HF
authors.lastname: Florindo
mesh_terms: D000818:Animals; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D053804:Granzymes / Q000378:metabolism; D007074:Immunoglobulin G / Q000097:blood; D008024:Ligands; D058965:MART-1 Antigen / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D008297:Male; D008358:Mannose / Q000737:chemistry; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000737:chemistry; D010047:Ovalbumin / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry; D011070:Poly I-C / Q000008:administration & dosage / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D051193:Toll-Like Receptors / Q000276:immunology*; D047368:Tumor Burden / Q000187:drug effects; D058951:gp100 Melanoma Antigen / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; C423449:CpG ODN 1826; D016207:Cytokines; D007074:Immunoglobulin G; D008024:Ligands; D058965:MART-1 Antigen; D009838:Oligodeoxyribonucleotides; D010455:Peptides; D011108:Polymers; D051193:Toll-Like Receptors; D058951:gp100 Melanoma Antigen; D010047:Ovalbumin; D053804:Granzymes; D011070:Poly I-C; D008358:Mannose
keywords: Antigen presenting cells; Cancer vaccine; Mannose receptor targeting; Melanoma; Nanoparticles; PLGA; TLR