RESUMO
Docetaxel (DTX) has become widely accepted as a first-line treatment for metastatic breast cancer; however, the frequent development of resistance provides challenges in treating the disease.C60 fullerene introduces a unique molecular form of carbon, exhibiting attractive chemical and physical properties. Our study aimed to develop dicarboxylic acid-derivatized C60 fullerenes as a novel DTX delivery carrier. This study investigated the potential of water-soluble fullerenes to deliver the anti-cancer drug DTX through a hydrophilic linker. The synthesis was carried out using the Prato reaction. The spectroscopic analysis confirmed the successful conjugation of DTX molecules over fullerenes. The particle size of nanoconjugate was reported to be 122.13 ± 1.63 nm with a conjugation efficiency of 76.7 ± 0.14%. The designed conjugate offers pH-dependent release with significantly less plasma pH, ensuring maximum release at the target site. In-vitro cell viability studies demonstrated the enhanced cytotoxic nature of the developed nanoconjugate compared to DTX. These synthesized nanoscaffolds were highly compatible with erythrocytes, indicating the safer intravenous route administration. Pharmacokinetic studies confirmed the higher bioavailability (~ 6 times) and decreased drug clearance from the system vis-à-vis plain drug. The histological studies reveal that nanoconjugate-treated tumour cells exhibit similar morphology to normal cells. Therefore, it was concluded that this developed formulation would be a valuable option for clinical use.
Assuntos
Antineoplásicos , Neoplasias da Mama , Ácidos Carboxílicos , Sobrevivência Celular , Docetaxel , Sistemas de Liberação de Medicamentos , Fulerenos , Fulerenos/química , Fulerenos/administração & dosagem , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Docetaxel/farmacologia , Docetaxel/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Humanos , Feminino , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Ácidos Carboxílicos/química , Tamanho da Partícula , Portadores de Fármacos/química , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Nanoconjugados/química , Ratos , Células MCF-7 , Disponibilidade BiológicaRESUMO
Docetaxel (DTX), a widely prescribed anticancer agent, is now associated with increased instances of multidrug resistance. Also, being a problematic BCS class IV drug, it poses challenges for the formulators. Henceforth, it was envisioned to synthesize an analogue of DTX with a biocompatible lipid, i.e., palmitic acid. The in-silico studies (molecular docking and simulation) inferred lesser binding of docetaxel palmitate (DTX-PL) with P-gp vis-à-vis DTX and paclitaxel, indicating it to be a poor substrate for P-gp efflux. Solid lipid nanoparticles (SLNs) of the conjugate were prepared using various lipids, viz. palmitic acid, stearic acid, cetyl palmitate and glyceryl monostearate. The characterization studies for the nanocarrier were performed for the surface charge, drug payload, micromeritics, release pattern of drug and surface morphology. From the cytotoxicity assays on resistant MCF-7 cells, it was established that the new analogue offered substantially decreased IC50 to that of DTX. Further, apoptosis assay also corroborated the results obtained in IC50 determination wherein, SA-SLNs showed the highest apoptotic index than free DTX. The conjugate not only enhanced the solubility but also offered lower plasma protein binding and improved pharmacokinetic and pharmacodynamic effect for DTX loaded SA-SLNs in apt animal models, and lower affinity to P-gp efflux. The studies provide preliminary evidence and a ray of hope for a better candidate in its nano version for safer and effective cancer chemotherapy.
Assuntos
Antineoplásicos/administração & dosagem , Docetaxel/administração & dosagem , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Lipídeos/administração & dosagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Nanopartículas/administração & dosagem , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/química , Docetaxel/farmacocinética , Liberação Controlada de Fármacos , Eritrócitos/efeitos dos fármacos , Feminino , Humanos , Lipídeos/química , Lipídeos/farmacocinética , Células MCF-7 , Masculino , Camundongos Endogâmicos BALB C , Nanopartículas/química , Ratos Wistar , Albumina Sérica Humana/químicaRESUMO
Despite the fact that protein and peptide therapeutics are widely employed in the treatment of various diseases, their delivery is posing an unembellished challenge to the scientists. It was discovered that delivery of these therapeutic systems through oral route is easy with high patient compliance. However, proteolytic degradation and absorption through the mucosal epithelium are the barriers in this route. These issues can be minimized by the use of enzyme inhibitors, absorption enhancers, different carrier systems or either by direct modification. In the process of investigation, it was found that transdermal route is not posing any challenges of enzymatic degradation, but, still absorption is the limitation as the outer layer of skin acts as a barrier. To suppress the effect of the barrier and increase the rate of the absorption, various advanced technologies were developed, namely, microneedle technology, iontophoresis, electroporation, sonophoresis and biochemical enhancement. Indeed, even these molecules are targeted to the cells with the use of cell-penetrating peptides. In this review, delivery of the peptide and protein therapeutics using oral, transdermal and other routes is discussed in detail.
Assuntos
Sistemas de Liberação de Medicamentos , Peptídeos/farmacologia , Preparações Farmacêuticas/metabolismo , Proteínas/metabolismo , Animais , Humanos , Peptídeos/administração & dosagem , Peptídeos/química , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/química , Proteínas/administração & dosagem , Proteínas/químicaRESUMO
Chemotherapy is one of the most frequently employed and reliable treatment options for the management of a variety of cancers. Taxanes (paclitaxel, docetaxel and cabazitaxel) are frequently prescribed to treat breast cancer, hormone refractory prostate cancer, non-small cell lung cancer and ovarian cancer. Most of the commercial products of taxanes are available as injectables, which are not patient compliant and are associated with frequent side effects like ototoxicity, baldness and neurotoxicity. Most of these concerns are ascribable to the presence of toxic solvents in these commercial formulations, which are used to solubilize these drug(s). However, there have been several attempts to develop toxic solvent free taxane formulations, especially employing novel drug delivery systems (NDDS). These systems have been reported to result in the advancement of anticancer activity, therapeutic index, stability, biocompatibility, tissue or organ targeting, encapsulation capacity, tissue permeability, oral bioavailability, reduced toxicity and reduced incidences of abnormal reactions, sustained and controlled release in comparison to the conventional solvent-based formulations. The review is an attempt to analyze the potential of NDDS-mediated taxane delivery for safer and effective cancer chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Taxoides/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/química , Hidrocarbonetos Aromáticos com Pontes/química , Coloides/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Masculino , Taxoides/químicaRESUMO
Docetaxel is one of the promising drugs and employed for the management of variety of cancers. However, challenges like poor-bioavailability, low tissue-permeability, compromised aqueous solubility and dose-dependent side-effects limit its clinical applications. Whereas, PLGA-based polymeric micelles possess the ability to enhance the tissue permeability of drugs and increase their biocompatibility. Henceforth, it was aimed to fabricate the dextran-PLGA-based polymeric-micelles loaded with docetaxel to explore the potential benefits in drug delivery. Dextran was chemically linked to PLGA and the linkage was confirmed by FT-IR, UV and NMR-spectroscopy. Critical-micelle-concentration of amphiphilic polymer was determined and drug was encapsulated by diffusion technique and erythrocyte compatibility. The system was evaluated for drug release profile and in vitro cytotoxicity studies. The pharmacokinetic profile was studied in rats. The micelles obtained were of 96.5±2.5nm and offered drug encapsulation of order of 54.85±1.21%.The cytotoxicity of drug against MCF-7 and MDA-MB-231 cell lines was enhanced by approx. 100%. The pharmacokinetic profile was substantially modified and about 16-folds enhancement in bioavailability was observed vis-à-vis plain drug. The approach was not only able to control the drug release, but also offered promise to enhance the pharmacokinetic and pharmacodynamic potential of docetaxel and similar anticancer agents.