RESUMO
The present study was performed to investigate the therapeutic performance of polymer-lipid hybrid nanoparticles towards the delivery of lapatinib (LPT) in breast cancers. We have successfully developed the lapatinib-loaded polymer-lipid hybrid nanosystem and showed its therapeutic potential in in vitro and in vivo models of breast cancer. The nanoformulations consisted of a polymeric core (poly[lactide-co-glycolide]-D-a-tocopheryl polyethylene glycol 1000 succinate [PLGA-TPGS]), which was then enveloped by a PEGylated lipid layer (DSPE-PEG) (PLPT) to maintain the structural integrity. The PLPT formulation controlled the drug release in pH 7.4 conditions and accelerated the release at pH 5.5 conditions. The PLPT showed a remarkable cellular internalization and efficiently killed the MCF-7 cancer cells in a time- and concentration-dependent manner. Moreover, LPT-loaded nanoparticles effectively induced apoptosis of cancer cells than compared to free LPT. Pharmacokinetic data suggested that nanoparticles could significantly enhance the blood circulation time of LPT by reducing the uptake by a reticuloendothelial system (RES). The prolonged blood circulation of PLPT could allow the preferential accumulation of drug in the tumor tissues. Importantly, PLPT significantly reduced the tumor burden of cancerous mice and effectively controlled the tumor cell proliferation. TUNEL assay further showed a greater apoptosis of tumor tissues in the PLPT treated mice group. Our results suggest that the use of a hybrid system may allow a decrease in the dosage regimen without the loss of therapeutic effect. Overall, lapatinib-loaded hybrid nanoparticles hold great potential for achieving an optimal therapeutic effect in breast cancer treatment. The present anticancer drug delivery system could be potentially applied for the treatment of other cancers.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Portadores de Fármacos , Nanopartículas , Quinazolinas/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Ácido Láctico/uso terapêutico , Lapatinib , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Sistema Fagocitário Mononuclear/metabolismo , Fagocitose/efeitos dos fármacos , Polietilenoglicóis/uso terapêutico , Ácido Poliglicólico/uso terapêutico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Quinazolinas/administração & dosagem , Quinazolinas/farmacocinética , Carga Tumoral/efeitos dos fármacos , Vitamina E/análogos & derivados , Vitamina E/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Oral squamous cell carcinoma (OSCC) or cancers of oral cavity is one of the most common cancers worldwide with high rate of mortality and morbidity. At present, chemotherapy is one of the most effective treatments; however it often fails to meet the requirements in the clinical therapy. In the present study, we have successfully formulated ligand-decorated cancer-targeted CDDP-loaded PLGA-PEG/NR7 nanoparticles and demonstrated the feasibility of using NR7 peptide for targeted delivery, rapid intracellular uptake, and enhanced cytotoxic effect in receptor-overexpressed OSCC cancer cells. RESULTS: Nanosized particles were formed and sustained release patterns were observed for PLGA/NR7 nanoparticles. Significantly higher cellular uptake was observed in HN6 OSCC cancer cells and superior anticancer effects are observed from the optimized targeted nanoparticles. Furthermore, Live/Dead assay showed a higher extent of red fluorescence was observed for the cells exposed with PLGA/NR7 than compared with non-targeted PLGA NP. The presence of the NR7-targeting moiety on the surface of PLGA carriers could allow the specific receptor-mediated internalization, enhanced cellular uptake, and higher cell killing potency. Especially, PLGA/NR7 NP exhibited a superior apoptosis effect in HN6 cancer cells with around ~45 % (early and late apoptotic stage) and ~59 % after 24 and 48 h incubation, respectively. It is apparent that the actively targeted micelles will deliver more anticancer agent to cancer cell than non-targeted one. CONCLUSION: Altogether, our results show the feasibility and promise of a cell-targeted anticancer nanomedicine strategy that can be effective for the treatment of oral squamous cell carcinoma. The present work might be of great importance to the further exploration of the potential application of PLGA/NR7 in the clinically relevant animal models.
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/administração & dosagem , Portadores de Fármacos/química , Ácido Láctico/química , Neoplasias Bucais/tratamento farmacológico , Nanopartículas/química , Ácido Poliglicólico/química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Sistemas de Liberação de Medicamentos , Humanos , Nanomedicina , Peptídeos/química , Copolímero de Ácido Poliláctico e Ácido PoliglicólicoRESUMO
Colon cancer is one of the leading causes of cancer-related death worldwide, and the therapeutic application of 5-fluorouracil (5-FU) is limited due to its nonspecificity, low bioavailability, and overdose. The present study is an attempt to improve the chemotherapeutic efficacy of 5-FU in colon cancers. Therefore, we have prepared 5-FU-loaded hyaluronic acid (HA)-conjugated silica nanoparticles (SiNPs) to target to colon cancer cells. In this study, we have showed the specific binding and intracellular accumulation of targeted nanoparticles based on HA surface modifications in colon carcinoma cells. The particles had spherical shapes with sizes of approximately 130 nm. HA-conjugated nanoparticles showed a sustained release pattern for 5-FU and continuously released for 120 hours. We have further investigated the cytotoxicity potential of targeted and nontargeted nanoparticles in colo-205 cancer cells. IC50 value of 5-FU/hyaluronic acid-conjugated silica nanoparticles (HSNP) was 0.65 µg/mL compared with ~2.8 µg/mL for 5-FU/SNP after 24 hours of incubation. The result clearly showed that HA-conjugated NP was more effective in inducing apoptosis in cancer cells than nontargeted NP. The 5-FU/HSNP showed ~45% of cell apoptosis (early and late apoptosis stage) compared with only 20% for 5-FU/silica nanoparticles (SNP)-treated group. The HA-conjugated nanoparticles provide the possibility of efficient drug transport into tumors that could effectively reduce the side effects in the normal tissues. 5-FU/HSNP was highly efficient in suppressing the tumor growth in xenograft tumor model. The proportion of Ki67 in 5-FU/HSNP-treated group was significantly lower than that of either free drug or nontargeted SiNPs. Altogether, we have showed that conjugation of HA to SiNPs could result in enhanced uptake of 5-FU through CD44-mediated endocytosis uptake and could result in significant antitumor efficacy. Thus, 5-FU/HSNP could be a promising drug delivery system for colon cancer therapy.