RESUMO
A novel thioether-terminated triazole bridge-containing covalent organic framework (TCOF) was constructed via a simple click chemistry between alkyne and azide monomers for dual-sensitive [pH and glutathione (GSH)] anticancer drug delivery systems. The synthesized TCOFs were crystalline in nature with a pore size of approximately 10-30 nm, as confirmed by powder X-ray diffraction spectroscopy and Brunauer-Emmett-Teller technique. Owing to the flexible nature of the synthesized COF, polyethylene glycol (PEG) modification was easily performed to yield a stable TCOF (TCOF-PEG) colloidal solution. Doxorubicin (DOX)-loaded TCOF-PEG (TCOF-DOX-PEG) exhibited sensitivity to lysosomal pH 5 and GSH environments. DOX release was four times higher under GSH environment (relative to pH 7.4) and three times higher under pH 5 condition because of the dynamic nature of triazole. In contrast, DOX-loaded COF without the triazole ring (I-COF) did not show any significant drug release in pH 7.4 and acidic pH; however, drug release was observed in GSH environment. MTT drug internalization data demonstrated sustained release of DOX from TCOF-DOX-PEGs. Finally, we demonstrated the utility of TCOF-PEG as an in vitro drug delivery system in HeLa cells. TCOF-DOX-PEG exhibited time-dependent release of DOX followed by internalization. Thus, the novel TCOF system reported here opens a new window in COF research for sensitive drug carrier systems.
Assuntos
Estruturas Metalorgânicas , Doxorrubicina , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Polietilenoglicóis , Sulfetos , TriazóisRESUMO
In this study, we prepared ferulic acid (FA) and paclitaxel (PTX) co-loaded polyamidoamine (PAMAM) dendrimers conjugated with arginyl-glycyl-aspartic acid (RGD) to overcome P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). FA was released in greater extent (80%) from the outer layer of the dendrimers compared with PTX (70%) from the interior of the dendrimers. FA improved intracellular availability of PTX via P-gp modulation in drug-resistant cells. In vitro drug uptake data show higher PTX delivery with RGD-PAMAM-FP than with PAMAM-FP in drug resistant KB CH-R 8-5 cell lines. This indicates that RGD facilitates intracellular PTX accumulation through active targeting in multidrug-resistant KB CH-R 8-5 cells. The terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick-end labeling assay data and membrane potential analysis in mitochondria confirm the enhanced anticancer potential of RGD-PAMAM-FP nanoaggregates in drug-resistant cells. We also confirmed by the increased protein levels of proapoptotic factors such as caspase 3, caspase 9, p53, and Bax after treatment with RGD-PAMAM-FP nanoaggregates and also downregulates antiapoptotic factors. Hence, FA-PTX co-loaded, RGD-functionalized PAMAM G4.5 dendrimers may be considered as an effective therapeutic strategy to induce apoptosis in P-gp-overexpressing, multidrug-resistant cells.
Assuntos
Ácidos Cumáricos , Dendrímeros , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Neoplasias , Paclitaxel , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacologia , Dendrímeros/química , Dendrímeros/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Paclitaxel/química , Paclitaxel/farmacologiaRESUMO
Electroactive polypyrrole-molybdenum disulfide (MoP) nanocomposites were synthesized and used for modifying screen-printed carbon electrodes (SPCEs) for ultrasensitive detection of berberine, an anticancer drug, in rat plasma. The electroactive nanocomposites were fabricated by exfoliating MoS2 followed by pyrrole polymerization. The effect of polypyrrole in the MoP nanocomposite was evaluated by varying the pyrrole concentration during polymerization, and the resulting nanocomposites prepared with pyrrole concentrations of 10, 20, 30 µL were named as MoP-1, MoP-2, and MoP-3, respectively. The electrochemical characterization of the three MoP nanocomposite sensors revealed that MoP-2/SPCE exhibited the highest electroactivity. The detection of berberine by the three MoP-coated SPCEs revealed that MoP-2/SPCE exhibited the highest activity against berberine due to a two-electron transfer mechanism on the MoP-2/SPCE electrode surface. The detection limit of berberine using the MoP-2/SPCE sensor was found to be about 0.05 µM, which is remarkably lower than the reported detection limits. The interference study proved the selectivity of the MoP-2/SPCE sensor toward berberine in the presence of other bioactive molecules and metal ions. The designed MoP-2/SPCE sensor retained 92% of its initial activity after 15 days of storage at room temperature, with RSD values of about 2.95% and 3.68% for the repeatability and reproducibility studies. Finally, the detection limit of berberine in a rat plasma sample determined using the MoP-2/SPCE sensor was found to be about 5 µM.