RESUMO
We report herein a novel delivery system, derived from the facile enzymatic synthesis of oligorutin (OR), for cancer cell targeting and pH-responsive drug delivery. In this study, we demonstrate that OR could preferentially penetrate cancer cells via the lipid raft-mediated endocytosis pathway, and cell membrane cholesterol was critical to the internalization of OR. The accumulation of OR in the tumor region was further confirmed by an in vivo biodistribution study. Considering the tumor-targeting property of OR, a pH-responsive drug delivery system (OR-BTZ) was developed by covalent conjugation of the catechol groups on OR with antitumor drug bortezomib (BTZ) through a pH-sensitive borate ester bond. OR-BTZ exerted cytotoxicity as well as inhibition of the migration and invasion to hepatoma carcinoma cells and showed no apparent cytotoxicity with liver normal cells. The OR-BTZs also presented significant therapeutic efficacy and low systematic toxicity in the murine hepatocellular carcinoma model. To our knowledge, this study presents the first attempt to exploit the potential of oligoflavonoids for cancer cell-targeted drug delivery and will motivate the development of flavonoids and their derivatives as a new type of biomaterials for tumor-targeted therapy.
Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Preparações Farmacêuticas , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Concentração de Íons de Hidrogênio , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Distribuição TecidualRESUMO
The success in the application of nanomedicines for tumor therapy is largely dependent on the development of efficient tumor targeting, specific and effective drug delivery systems. Here, through a simple synthetic process, we developed a type of novel glucose transporter 1 (GLUT1)-targeting, tumor microenvironment responsive and near infrared irradiation (NIR) induced cytosolic drug delivery nanoparticles (NPs). Our design was based on polydopamine (PDA) NPs as the photothermal agent and drug delivery carrier, glucosyl functional ligands as the GLUT1 targeting agents, and the conjugation of anticancer drug bortezomib (BTZ) to the catechol groups of PDA NPs in a pH-dependent manner. The in vitro and in vivo studies demonstrated that the functionalized PDA NPs could efficiently accumulate in tumor site and localize in subcellular endo/lysosomes of tumor cells, and they could respond to tumor microenvironment and endo/lysosomal pH as well as NIR to promote the robust release of BTZ. Furthermore, the functionalized PDA NPs were first demonstrated to overcome the endo/lysosomal barrier for the enhanced cytosolic BTZ drug delivery through NIR-triggered endo/lysosomal release, achieving the integration of NIR-triggered photothermal effect and chemotherapy for synergistic tumor ablation. The significant suppression and even complete regression of 4 T1 tumor was observed in mice given only single treatment. Therefore, the GLUT1-targeting, pH and photothermal responsive drug delivery NPs show a great potential for broadly applicable chemo-photothermal tumor therapy.
Assuntos
Hipertermia Induzida , Nanopartículas , Animais , Doxorrubicina , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Glucose , Indóis , Camundongos , Fototerapia , Polímeros , Microambiente TumoralRESUMO
Cancer cells possess some inherent characteristics, such as glucose-dependence and intolerance to heat and exogenous reactive oxygen species (ROS). In this study, a strategy has been developed to target these vulnerable weaknesses of cancer cells using glucose oxidase (GOx) and polydopamine (PDA) functionalized iron oxide nanoparticles (Fe3O4@PDA/GOx NPs). PDA is first deposited on the surfaces of iron oxide NPs through self-polymerization, and then GOx is covalently linked with PDA upon mixing the enzyme and Fe3O4@PDA under alkaline conditions. In this system, the PDA layer along with iron oxide NPs serves as a photothermal transfer material converting near infrared (NIR) radiation into heat. The covalently linked GOx can competitively consume glucose and spontaneously generate ROS H2O2 that can be further converted by the iron oxide NPs into more toxic ËOH, inducing apoptosis of cancer cells. The selective toxicity of Fe3O4@PDA/GOx NPs on cancer cells is demonstrated both in vitro and in vivo. In particular, a single injection rather than multiple doses results in significant suppression of tumors, and does not induce apparent histological lesions in the 4T1 tumor-bearing Balb/c mice. The versatility of the functionalization strategy reported in this study will contribute to developing efficient therapies for selective cancer treatment.