RESUMO
Therapeutic nanoreactors are of increasing interest in precise cancer therapy, which have been explored to in situ produce therapeutic compounds from inert prodrugs or intrinsic molecules at the target sites. However, engineering a nanoreactor with tumor activable cascade reactions for efficient cooperative cancer therapy remains a great challenge. Herein, we demonstrate a polymersome nanoreactor with tumor acidity-responsive membrane permeability to activate cascade reactions for orchestrated cooperative cancer treatment. The nanoreactors are constructed from responsive polyprodrug polymersomes incorporating ultrasmall iron oxide nanoparticles and glucose oxidase in the membranes and inner aqueous cavities, respectively. The cascade reactions including glucose consumption to generate H2O2, accelerated iron ion release, Fenton reaction between H2O2 and iron ion to produce hydroxyl radicals (â¢OH), and â¢OH-triggered rapid release of parent drugs can be specifically activated by the tumor acidity-responsive membrane permeability. During this process, the orchestrated cooperative cancer therapy including starving therapy, chemodynamic therapy, and chemotherapy is realized for high-efficiency tumor suppression by the in situ consumed and produced compounds. The nanoreactor design with tumor-activable cascade reactions represents an insightful paradigm for precise cooperative cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Radical Hidroxila/farmacologia , Nanopartículas/química , Neoplasias/tratamento farmacológico , Polímeros/farmacologia , Pró-Fármacos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/química , Humanos , Concentração de Íons de Hidrogênio , Radical Hidroxila/síntese química , Radical Hidroxila/química , Estrutura Molecular , Neoplasias/patologia , Polímeros/síntese química , Polímeros/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismoRESUMO
Homeostasis of the skeletal system is maintained by a balance between bone formation and resorption. The receptor activator of NF-kappaB ligand (RANKL) induces the differentiation of bone-resorbing cells, osteoclasts. To identify genes regulated during osteoclast differentiation, we constructed a subtraction cDNA library using a mouse RAW264 macrophage cell line that differentiates into osteoclast-like multinucleated cells after treatment with RANKL. Northern blot analysis showed that RANKL treatment upregulated expression of 17 genes. Among these were the genes for five H(+)-ATPase subunits, two chemokines, and the osteoclast marker cathepsin K. In addition, a mouse homolog of human dendritic cell (DC)-specific transmembrane protein (DCSTAMP), whose function in osteoclastogenesis was recently revealed, was also included in the induced genes. Characterization of these inducible genes will provide an insight into the biology of osteoclasts and the mechanism of bone-related diseases.