RESUMEN
Several FDA-approved adjuvants signal through the NLRP3 inflammasome and IL-1ß release. Identifying small molecules that induce IL-1ß release could allow targeted delivery and structure-function optimization, thereby improving safety and efficacy of next-generation adjuvants. In this work, we leverage our existing high throughput data set to identify small molecules that induce IL-1ß release. We find that ribociclib induces IL-1ß release when coadministered with a TLR4 agonist in an NLRP3- and caspase-dependent fashion. Ribociclib was formulated with a TLR4 agonist into liposomes, which were used as an adjuvant in an ovalbumin prophylactic vaccine model. The liposomes induced antigen-specific immunity in an IL-1 receptor-dependent fashion. Furthermore, the liposomes were coadministered with a tumor antigen and used in a therapeutic cancer vaccine, where they facilitated rejection of E.G7-OVA tumors. While further chemical optimization of the ribociclib scaffold is needed, this study provides proof-of-concept for its use as an IL-1 producing adjuvant in various immunotherapeutic contexts.
Asunto(s)
Quinasa 4 Dependiente de la Ciclina , Inflamasomas , Interleucina-1beta , Proteína con Dominio Pirina 3 de la Familia NLR , Purinas , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Interleucina-1beta/metabolismo , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Animales , Humanos , Ratones , Purinas/farmacología , Purinas/química , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Linfocitos T/inmunología , Ratones Endogámicos C57BL , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Liposomas/química , Vacunas contra el Cáncer/farmacología , Vacunas contra el Cáncer/inmunología , Femenino , AminopiridinasRESUMEN
This roadmap outlines the potential roles of metallic nanoparticles (MNPs) in the field of radiation therapy. MNPs made up of a wide range of materials (from Titanium, Z = 22, to Bismuth, Z = 83) and a similarly wide spectrum of potential clinical applications, including diagnostic, therapeutic (radiation dose enhancers, hyperthermia inducers, drug delivery vehicles, vaccine adjuvants, photosensitizers, enhancers of immunotherapy) and theranostic (combining both diagnostic and therapeutic), are being fabricated and evaluated. This roadmap covers contributions from experts in these topics summarizing their view of the current status and challenges, as well as expected advancements in technology to address these challenges.