ABSTRACT
BACKGROUND: Delivery of PLGA (poly [D, L-lactide-co-glycolide])-based biodegradable nanoparticles (NPs) to antigen presenting cells, particularly dendritic cells, has potential for cancer immunotherapy. MATERIALS & METHODS: Using a PLGA NP vaccine construct CpG-NP-Tag (CpG-ODN-coated tumor antigen [Tag] encapsulating NP) prepared using solvent evaporation technique we tested the efficacy of ex vivo and in vivo use of this construct as a feasible platform for immune-based therapy. RESULTS: CpG-NP-Tag NPs were avidly endocytosed and localized in the endosomal compartment of bone marrow-derived dendritic cells. Bone marrow-derived dendritic cells exposed to CpG-NP-Tag NPs exhibited an increased maturation (higher CD80/86 expression) and activation status (enhanced IL-12 secretion levels). In vivo results demonstrated attenuation of tumor growth and angiogenesis as well as induction of potent cytotoxic T-lymphocyte responses. CONCLUSION: Collectively, results validate dendritic cells stimulatory response to CpG-NP-Tag NPs (ex vivo) and CpG-NP-Tag NPs' tumor inhibitory potential (in vivo) for therapeutic applications, respectively.
Subject(s)
Cancer Vaccines/administration & dosage , Dendritic Cells/drug effects , Nanoparticles/administration & dosage , Neoplasms/therapy , Cancer Vaccines/chemistry , Cancer Vaccines/immunology , Dendritic Cells/immunology , Endocytosis/immunology , Humans , Immunotherapy/methods , Lactic Acid/administration & dosage , Lactic Acid/chemistry , Molecular Targeted Therapy , Nanoparticles/chemistry , Neoplasms/immunology , Polyglycolic Acid/administration & dosage , Polyglycolic Acid/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunologyABSTRACT
AIM: Low immunogenicity remains a major obstacle in realizing the full potential of cancer vaccines. In this study, we evaluated CpG-coated tumor antigen (Tag)-encapsulating 'bacteriomimetic' nanoparticles (CpG-nanoparticle [NP]-Tag NPs) as an approach to enhance anti-tumor immunity. MATERIALS & METHODS: CpG-NP-Tag NPs were synthesized, characterized for their physicochemical properties and tested in vivo. RESULTS: We found CpG predosing followed by intraperitoneal (IP) immunization with CpG-NP-Tag NPs significantly attenuated tumor growth in female BALB/c mice compared with respective controls. Histopathological and Immunofluorescence data revealed CpG-NP-Tag tumors had lower proliferation, higher apoptotic activity, greater CD4(+) and CD8(+) T cell infiltration as well as higher IFN-γ levels as compared with control groups. CONCLUSION: Our findings suggest CpG-NP-Tag NPs can enhance anti-tumor effect of nanoparticulate tumor vaccination system.
Subject(s)
Antigens, Neoplasm/chemistry , Antineoplastic Agents/therapeutic use , Cancer Vaccines/immunology , CpG Islands/genetics , Lactic Acid/chemistry , Nanoparticles/chemistry , Polyglycolic Acid/chemistry , Animals , Antineoplastic Agents/chemistry , Apoptosis , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Cell Line, Tumor , Cell Proliferation , Drug Delivery Systems , Female , Interferon-gamma/metabolism , Ki-67 Antigen/metabolism , Luminescence , Mice , Mice, Inbred BALB C , Microscopy, Electron, Transmission , Microscopy, Fluorescence , Nanomedicine/methods , Neoplasms/immunology , Neoplasms/therapy , Particle Size , Polylactic Acid-Polyglycolic Acid Copolymer , Spectrometry, FluorescenceABSTRACT
Environmental electrophilic chemical carcinogens are detoxified via mercapturic acid pathway to be excreted as mercapturic acid derivatives. Mercapturic acid pathway is also involved in the metabolism of pro-apoptotic and toxic endogenous electrophiles such as 4-hydroxynonenal (HNE). HNE is a common denominator in stress induced signaling and is a pro-apoptotic second messenger that affects cell cycle signaling in a concentration dependent manner. It can regulate signaling for apoptosis, differentiation, and gene expression by interacting with the transcriptional factors, transcriptional repressors, membrane receptors and other proteins. First two rate limiting enzymes of the mercapturic acid pathway, GSTs that conjugate HNE to glutathione (GSH), and RLIP76 that excludes GHS-HNE conjugate from cells, regulate the intracellular concentration of HNE. Thus GSTs and RLIP76 can have a profound effect on cell cycle signaling. Our studies have established that increased HNE levels in cells promote apoptotic signaling while at decreased levels below its basal constituted levels HNE promote proliferation. A major outcome of these findings is that by blocking the mercapturic acid pathway mediated detoxification of HNE through the inhibition of RLIP76 catalyzed transport of GS-HNE, a complete remission of many human cancer xenografts in mice can be achieved.