RESUMEN
The therapeutic efficacy of chemotherapy in many types of hematological malignancies and solid tumors is dramatically hindered by multidrug resistance (MDR). This work presents a combination strategy of pretreatment of MDA-MB-231/MDR1 cells with quercetin (QU) followed by doxorubicin (DOX) to overcome MDR, which can be delivered by mixed micelles composed of the reduction-sensitive hyaluronic acid-based conjugate and d-α-tocopheryl poly(ethylene glycol) 1000 succinate. The combination strategy can enhance the cytotoxicity of DOX on MDA-MB-231/MDR1 cells by increasing intracellular DOX accumulation and facilitating DOX-induced apoptosis. The probable MDR reversal mechanisms are that the pretreatment cells with QU-loaded mixed micelles downregulate P-glycoprotein expression to decrease DOX efflux as well as initiate mitochondria-dependent apoptotic pathways to accelerate DOX-induced apoptosis. In addition, this combination strategy can not only potentiate in vivo tumor-targeting efficiency but also enhance the antitumor effect in MDA-MB-231/MDR1-bearing nude mice without toxicity or side effects. This research suggests that the co-administration of natural compounds and chemotherapeutic drugs could be an effective strategy to overcome tumor MDR, which deserves further exploration.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Ácido Hialurónico/química , Polietilenglicoles/química , Quercetina/farmacología , Vitamina E/química , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Productos Biológicos/farmacología , Mama/efectos de los fármacos , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Ratones , Ratones Desnudos , Micelas , Transducción de Señal/efectos de los fármacosRESUMEN
Multidrug resistance (MDR) remains a significant impediment to chemotherapy during cancer therapy. In this study, the amphiphilic biomaterials PEI-TOS and HA-QU were synthesized to self-assemble into PEI-TOS/HA-QU core-shell micelles for the targeted codelivery of paclitaxel (PTX) and quercetin (QU) to alleviate multidrug drug resistance and enhance therapeutic efficacy. The PTX-loaded micelles possessed a uniform particle size (167.60 ± 8.185 nm), stable negative charge (-19.13 ± 0.321 mV), and pH-responsive drug release with good compatibility. The drug-loaded micelles increased the chemosensitivity of MDR tumor cells (MDA-MB-231/MDR1) to PTX and activated mitochondria-dependent apoptotic pathways (the IC50 was 2.22-fold lower than that of PTX alone). Moreover, PEI-TOS/HA-QU micelles increased the cellular uptake of lipophilic antitumor drugs by downregulating P-gp expression in MDA-MB-231/MDR1 cells. Compared with Taxol, PTX-loaded PEI-TOS/HA-QU micelles presented excellent antitumor efficacy in tumor-bearing mice, with an average tumor size that was 3.7-fold lower than that of the control group. The drug-loaded formulation showed low in vitro / in vivo toxicity and better tumor accumulation than the free drug, which led to a high tumor inhibition rate of 80.56% and considerable biocompatibility. This work describes a new platform for the codelivery of lipophilic anticancer drugs and natural active ingredients such as PTX and QU for the treatment of MDR cancer cells.
Asunto(s)
Neoplasias de la Mama , Paclitaxel , Animales , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Resistencia a Múltiples Medicamentos , Humanos , Ácido Hialurónico , Hidrógeno , Ratones , Micelas , Polietileneimina , Quercetina , Succinatos , alfa-TocoferolRESUMEN
Oral administration of the uveitogenic peptide (aa 336-351) derived from human HSP60 induced clinical and histological manifestations of uveitis in 65.8% (48/73) of Lewis rats. Uveitis was significantly decreased to 16.7% (11/66) in parallel experiments with the peptide linked to recombinant cholera toxin B subunit (rCTB), also given by mouth (chi(2)=34.2, p<0.0001). The protective efficacy between tolerized and immunized animals was 74.7%. Adoptive transfer of mesenteric lymph node cells from tolerized rats prevented the development of uveitis. A significantly higher proportion of regulatory CD4(+)CD45RC(low)RT6(+) subset of Th2 memory cells were found in the mesenteric lymph nodes (p<0.005) and spleens (p=0.05) of tolerized rats without uveitis, as compared with immunized rats and uveitis. In situ hybridization studies of mesenteric lymph nodes and/or the uveal tract showed significant increases in IL-10 and TGF-beta mRNA but decreases in IFN-gamma and IL-12 mRNA in tolerized, as compared with immunized animals. Thus, the mechanism of tolerance, preventing the development of uveitis may involve a regulatory subset of memory cells and a shift from Th1 to Th2 and Th3 cytokines. We suggest that mucosally induced uveitis can be prevented by oral administration of the peptide-rCTB conjugate.