title: Multifunctional nanoparticles co-delivering Trp2 peptide and CpG adjuvant induce potent cytotoxic T-lymphocyte response against melanoma and its lung metastasis.
abstract: Immunotherapy has shown the potential to become an essential component of the successful treatment of various malignancies. In many cases, such as in melanoma, however, induction of a potent and specific T-cell response against the endogenous antigen or self-antigen still remains a major challenge. To induce a potent MHC I-restricted cytotoxic T-lymphocyte (CTL) response, cytosol delivery of an exogenous antigen into dendritic cells is preferred, if not required. Lipid-calcium-phosphate (LCP) nanoparticles represent a new class of intracellular delivery systems for impermeable drugs. We are interested in exploring the potential of LCP NPs for use as a peptide vaccine delivery system for cancer therapy. To increase the encapsulation of Trp2 peptide into the calcium phosphate precipitate core of LCP, two phosphor-serine residues were added to the N-terminal of the peptide (p-Trp2). CpG ODN was also co-encapsulated with p-Trp2 as an adjuvant. The NPs were further modified with mannose to enhance and prolong the cargo deposit into the lymph nodes (LNs), which ensured persistent antigen loading and stimulation. Compared with free Trp2 peptide/CpG, vaccination with LCP encapsulating p-Trp2 and CpG resulted in superior inhibition of tumor growth in both B16F10 subcutaneous and lung metastasis models. An IFN-γ production assay and in vivo CTL response study revealed that the improved efficacy was a result of a Trp2-specific immune response. Thus, encapsulation of phospho-peptide antigens into LCP may be a promising strategy for enhancing the immunogenicity of poorly immunogenic self-antigens for cancer therapy.
authors.affiliation: Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ramishetti
authors.affiliation: Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Tseng
authors.affiliation: Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Shutao
authors.initials: S
authors.lastname: Guo
authors.affiliation: Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: leafh@unc.edu.
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D002130:Calcium Phosphates / Q000737:chemistry; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005260:Female; D007167:Immunotherapy; D008055:Lipids / Q000737:chemistry; D008168:Lung / Q000276:immunology / Q000473:pathology; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000556:secondary* / Q000628:therapy*; D008358:Mannose / Q000737:chemistry; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008565:Membrane Proteins / Q000008:administration & dosage* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000473:pathology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D002130:Calcium Phosphates; D019496:Cancer Vaccines; D008055:Lipids; D008565:Membrane Proteins; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; C500290:peptide SVYDFFVWL; C020243:calcium phosphate; D008358:Mannose
keywords: 1,2-dioleoyl-3-trimethylammonium-propane chloride salt; 1,2-distearoryl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethyleneglycol-2000)] ammonium salt; APCs; CFSE; CTL; CaP; Calcium phosphate; DOPA; DOTAP; DSPE-PEG; Immunotherapy; MHC; Melanoma; Nanoparticle; Peptide vaccine; Trp2; antigen presenting cells; calcium phosphate; carboxyfluorescein succinimidyl ester; cytotoxic T lymphocyte; dioleoylphosphatydic acid; major histocompatibility complex; tyrosinase-related protein 2