RESUMEN
The efficacy of photodynamic therapy (PDT)-related cancer therapies is significantly restricted by two irreconcilable obstacles, i.e., low reactive oxygen species (ROS) generation capability and hypoxia which constrains the immune response. Herein, this work develops a self-assembled clinical photosensitizer indocyanine green (ICG) and the HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) nanoparticles (ISDN) without any excipient. This work discovers that the hydrophobic interaction forces between ICG and 17-DMAG promote the photostability of ICG and its intersystem crossing (ISC) process, thereby improving the ROS quantum yield from 0.112 to 0.46. Augmented ROS generation enhances PDT efficacy and further enhances immunogenic cell death (ICD) effects. 17-DMAG inhibits the HSP90/hypoxia-inducible factor 1α (HIF-1α) axis to dramatically reverse the immunosuppressive tumor microenvironment caused by PDT-aggravated hypoxia. In a mouse model of pancreatic cancer, ISDN markedly improve cytotoxic T lymphocyte infiltration and MHC I and MHC II activation, demonstrating the superior ICD effects in situ tumor and the powerful systematic antitumor immunity generation, eventually achieving vigorous antitumor and recurrence resistance. This study proposes an unsophisticated and versatile strategy to significantly improve PDT efficacy for enhancing systemic antitumor immunity and potentially extending it to multiple cancers.
Asunto(s)
Inmunoterapia , Verde de Indocianina , Nanopartículas , Fotoquimioterapia , Fármacos Fotosensibilizantes , Especies Reactivas de Oxígeno , Fotoquimioterapia/métodos , Animales , Especies Reactivas de Oxígeno/metabolismo , Ratones , Verde de Indocianina/química , Verde de Indocianina/farmacología , Línea Celular Tumoral , Nanopartículas/química , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Humanos , Nanomedicina Teranóstica , Proteínas HSP90 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Microambiente Tumoral/efectos de los fármacos , Benzoquinonas/química , Benzoquinonas/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/metabolismo , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacología , Muerte Celular Inmunogénica/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Neoplasias/metabolismoRESUMEN
Extracellular vesicles (EVs) are a class of lipid bilayer membranes, containing lipids, nucleic acids (DNA and RNA), proteins, and other substances. They are produced by almost all types of cells and act as signaling intermediaries between cells and/or tissues through different mechanisms involving complex signals. EVs produced by each type of cells are composed of highly heterogeneous and inhomogeneous subgroups with different biological functions. Therefore, in the past few decades, researchers have tried to use different "labels" to define the subgroups of EVs, and explore the differences in them. However, a unified standard for defining the populations of EVs has not yet been established so far. In this study, we review and summarize the use of different "labels" to define subgroups of EVs.