RESUMO
Breast cancer consists of heterogenic subpopulations, which determine the prognosis and response to chemotherapy. Among these subpopulations, a very limited number of cancer cells are particularly problematic. These cells, known as breast cancer stem cells (BCSCs), are thought responsible for metastasis and recurrence. They are thus major contributor to the unfavorable outcomes seen for many breast cancer patients. BCSCs are more prevalent in the hypoxic niche. This is an oxygen-deprived environment that is considered crucial to their proliferation, stemness, and self-renewal but also one that makes BCSCs highly refractory to traditional chemotherapeutic regimens. Here we report a small molecule construct, AzCDF, that allows the therapeutic targeting of BCSCs and which is effective in normally refractory hypoxic tumor environments. A related system, AzNap, has been developed that permits CSC imaging. Several design elements are incorporated into AzCDF, including the CAIX inhibitor acetazolamide (Az) to promote localization in MDA-MB-231 CSCs, a dimethylnitrothiophene subunit as a hypoxia trigger, and a 3,4-difluorobenzylidene curcumin (CDF) as a readily released therapeutic payload. This allows AzCDF to serve as a hypoxia-liable molecular platform that targets BCSCs selectively which decreases CSC migration, retards tumor growth, and lowers tumorigenesis rates as evidenced by a combination of in vitro and in vivo studies. To the best of our knowledge, this is the first time a CSC-targeting small molecule has been shown to prevent tumorigenesis in an animal model.
Assuntos
Antineoplásicos/uso terapêutico , Inibidores da Anidrase Carbônica/uso terapêutico , Carcinogênese/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Acetazolamida/análogos & derivados , Acetazolamida/uso terapêutico , Animais , Antineoplásicos/síntese química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Curcumina/análogos & derivados , Curcumina/síntese química , Curcumina/uso terapêutico , Diarileptanoides/síntese química , Diarileptanoides/uso terapêutico , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/uso terapêutico , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/diagnóstico por imagem , Esferoides Celulares/efeitos dos fármacos , Tiofenos/síntese química , Tiofenos/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Multifunctional nanoparticles that carry chemotherapeutic agents can be innovative anticancer therapeutic options owing to their tumor-targeting ability and high drug-loading capacity. However, the nonspecific release of toxic DNA-intercalating anticancer drugs from the nanoparticles has significant side effects on healthy cells surrounding the tumors. Herein, we report a tumor homing reactive oxygen species nanoparticle (THoR-NP) platform that is highly effective and selective for ablating malignant tumors. Sodium nitroprusside (SNP) and diethyldithiocarbamate (DDC) were selected as an exogenous reactive oxygen species (ROS) generator and a superoxide dismutase 1 inhibitor, respectively. DDC-loaded THoR-NP, in combination with SNP treatment, eliminated multiple cancer cell lines effectively by the generation of peroxynitrite in the cells (>95% cell death), as compared to control drug treatments of the same concentration of DDC or SNP alone (0% cell death). Moreover, the magnetic core (ZnFe2O4) of the THoR-NP can specifically ablate tumor cells (breast cancer cells) via magnetic hyperthermia, in conjunction with DDC, even in the absence of any exogenous RS supplements. Finally, by incorporating iRGD peptide moieties in the THoR-NP, integrin-enriched cancer cells (malignant tumors, MDA-MB-231) were effectively and selectively killed, as opposed to nonmetastatic tumors (MCF-7), as confirmed in a mouse xenograft model. Hence, our strategy of using nanoparticles embedded with ROS-scavenger-inhibitor with an exogenous ROS supplement is highly selective and effective cancer therapy.
Assuntos
Ditiocarb , Nanopartículas , Neoplasias Experimentais , Nitroprussiato , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase-1 , Animais , Ditiocarb/química , Ditiocarb/farmacologia , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/economia , Nanopartículas/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Nitroprussiato/química , Nitroprussiato/farmacologia , Superóxido Dismutase-1/química , Superóxido Dismutase-1/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Mitochondria are organelles that are readily susceptible to temperature elevation. We selectively delivered a coumarin-based fluorescent iron oxide nanoparticle, Mito-CIO, to the mitochondria. Upon 740 nm laser irradiation, the intracellular temperature of HeLa cells was elevated by 2.1 °C within 5 min when using Mito-CIO, and the treatment resulted in better hyperthermia and a more elevated cytotoxicity than HeLa cells treated with coumarin iron oxide (CIO), which was missing the mitochondrial targeting unit. We further confirmed these results in a tumor xenograft mouse model. To our knowledge, this is the first report of a near-infrared laser irradiation-induced hyperthermic particle targeted to mitochondria, enhancing the cytotoxicity in cancer cells. Our present work therefore may open a new direction in the development of photothermal therapeutics.