| Popis: |
Traditional approaches to cancer vaccines elicit weak CD8(+) T cell responses and have largely failed to meet clinical expectations. This is in part due to inefficient antigen cross-presentation, inappropriate selection of adjuvant and its formulation, poor vaccine pharmacokinetics, and/or suboptimal coordination of antigen and adjuvant delivery. Here, we describe a nanoparticle vaccine platform for facile co-loading and dual-delivery of antigens and nucleic acid adjuvants that elicits robust antigen-specific cellular immune responses. The nanovaccine design is based on diblock copolymers comprising a poly(ethylene glycol)-rich first block that is functionalized with reactive moieties for covalent conjugation of antigen via disulfide linkages, and a pH-responsive second block for electrostatic packaging of nucleic acids that also facilitates endosomal escape of associated vaccine cargo to the cytosol. Using polyIC, a clinically-advanced nucleic acid adjuvant, we demonstrated that endosomolytic nanoparticles promoted the cytosolic co-delivery of polyIC and protein antigen, which acted synergistically to enhance antigen cross-presentation, co-stimulatory molecule expression, and cytokine production by dendritic cells. We also found that the vaccine platform increased the accumulation of antigen and polyIC in the local draining lymph nodes. Consequently, dual-delivery of antigen and polyIC with endsomolytic nanoparticles significantly enhanced the magnitude and functionality of CD8(+) T cell responses relative to a mixture of antigen and polyIC, resulting in inhibition of tumor growth in a mouse tumor model. Collectively, this work provides a proof-of-principle for a new cancer vaccine platform that strongly augments anti-tumor cellular immunity via cytosolic co-delivery of antigen and nucleic acid adjuvant. |
Full Text from ScienceDirect