RESUMO
Metastasis is the primary cause resulting in the high mortality of breast cancer. The inherent antimetastasis bioactivity of Pluronic copolymers with a wide range of hydrophilic-lipophilic balance (HLB) including Pluronic L61, P85, P123, F127, F68, and F108 was first explored on metastatic 4T1 breast cancer cells. The results indicated that P85 and P123 could strongly inhibit the migration and invasion of 4T1 cells. The effects of the polymers on cell healing, migration, and invasion exhibited bell-shaped dependencies on HLB of Pluronic copolymers, and the better antimetastasis effects of Pluronic copolymers could be achieved with the HLB between 8 and 16. P85 and P123 themselves could significantly inhibit pulmonary metastasis in 4T1 mammary tumor metastasis model in situ. In addition, a synergetic antimetastasis effect could be achieved during drug combination of doxorubicin hydrochloride (DOX) and P85 or P123 intravenously. The metastasis effects of P85 and P123 both in vitro and in vivo were partially attributed to the downregulation of matrix metalloproteinase-9 (MMP-9). Therefore, Pluronic copolymers with moderate HLB 8-16 such as P85 and P123 could be promising excipients with therapeutics in drug delivery systems to inhibit breast cancer metastasis.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Poloxâmero/farmacologia , Polímeros/farmacologia , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Ciclo Celular , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Excipientes , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/secundário , Metaloproteinase 9 da Matriz/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Multidrug resistance (MDR) is one of the major obstacles in tumor treatment. Herein, we reported an active targeting strategy with peptide-mediated nanoparticles deep into tumor parenchyma, which iRGD conjugated d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) mediated codelivery of paclitaxel (PTX) and survivin shRNA (shSur) for the reversal of lung cancer resistance. Pluronic P85-polyethyleneimine/TPGS complex nanoparticles incorporated with iRGD-TPGS conjugate codelivering PTX and shSur systems (iPTPNs) could induce effective cellular uptake, RNAi effects, and cytotoxicity on A549 and A549/T cells. In particular, iPTPNs showed superiority in biodistribution, survivin expression, tumor apoptosis, and antitumor efficacy by simultaneously exerting an enhanced permeability and retention (EPR) effect and iRGD mediated active targeting effects. iPTPNs significantly enhanced the accumulation of PTX and shSur, down-regulated survivin expression, and induced cell apoptosis in tumor tissue. The in vivo antitumor efficacy showed the tumor volume of iPTPNs group (10 mg/kg) was only 12.7% of the Taxol group. Therefore, the iRGD mediated PTX and shSur codelivery system could be a very powerful approach for the reversal and therapy of lung cancer resistance.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , Oligopeptídeos/química , Paclitaxel/administração & dosagem , RNA Interferente Pequeno/metabolismo , Vitamina E/análogos & derivados , Animais , Antineoplásicos/química , Apoptose , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Integrina alfaVbeta3/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Nanotecnologia/métodos , Permeabilidade , Polietilenoglicóis/química , Interferência de RNA , Survivina , Vitamina E/químicaRESUMO
We report a photochemical reaction-induced antagonism between the photodynamic agent (PS) and anti-cancer drugs during combined therapy. The annihilation of singlet oxygen and alkene-containing drugs into inactive drug hydroperoxides is responsible for the antagonism, and results in decreased efficacy against several cancer cell lines. Experimental and simulation results reveal that the annihilation abates with increasing distance between the PS and drugs via confining the PS and drugs into separated vehicles. As a result, antagonism can be switched to synergism in treating both drug sensitive and resistant cancer cells.
Assuntos
Antineoplásicos/efeitos da radiação , Fármacos Fotossensibilizantes/efeitos da radiação , Porfirinas/efeitos da radiação , 1,2-Dipalmitoilfosfatidilcolina/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Incompatibilidade de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Humanos , Luz , Lipossomos/química , Peróxidos/síntese química , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/administração & dosagem , Porfirinas/química , Porfirinas/farmacologia , Oxigênio Singlete/químicaRESUMO
A stability-difference-selective bond-breakage strategy for the fabrication of largepore-sized hollow mesoporous organosilica nanoparticles (HMONs) is successfully developed. Moreover, surfacefunctionalized HMONs are successfully constructed to simultaneously deliver P-gp modulator siRNA and anticancer drug doxorubicin to reverse the multidrug resistance of cancer cells.
Assuntos
Portadores de Fármacos/química , Técnicas de Transferência de Genes , Dióxido de Silício/química , Ligas/química , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Catálise , Humanos , Metais/química , Nanotubos/química , Neoplasias/tratamento farmacológico , Oxirredução , Óxidos/química , Espectroscopia Fotoeletrônica , PorosidadeRESUMO
A novel micelle/precursor co-templating assembly strategy is successfully developed to synthesize large-pore ultrasmall mesoporous organosilica nanoparticles (MONs). Furthermore, elaborately designed MONs with a cell-penetrating peptide (TAT) (MONs-PTAT) are constructed for highly efficient intranuclear gene delivery. They exhibit a high loading capacity, improved protection for the loaded gene, and enhanced transfection efficiencies of EGFP plasmid (pEGFP).
Assuntos
Técnicas de Transferência de Genes , Micelas , Nanopartículas/química , Materiais Biocompatíveis/química , Sobrevivência Celular , Produtos do Gene tat/genética , Terapia Genética/métodos , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Plasmídeos/genética , Porosidade , Dióxido de Silício/química , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral RamanRESUMO
Breast cancer is the most vicious killer for women's health, while metastasis is the main culprit, which leads to failure of treatment by increasing relapse rate. In this work, a new complexes nanoparticles loading two siRNA (Snail siRNA (siSna) and Twist siRNA (siTwi)) and paclitaxel (PTX) were designed and constructed using two new amphiphilic polymer, polyethyleneimine-block-poly[(1,4-butanediol)-diacrylate-ß-5-hydroxyamylamine] (PEI-PDHA) and polyethylene glycol-block-poly[(1,4-butanediol)-diacrylate-ß-5-hydroxyamylamine] (PEG-PDHA) by self-assembly. The experimental results showed that in the 4T1 tumor-bearing mice models, PEI-PDHA/PEG-PDHA/PTX/siSna/siTwi) complex nanoparticles (PPSTs) raised the accumulation and retention of both PTX and siRNA in tumor after administrated intravenously, resulted in the strong inhibition of the tumor growth and metastasis simultaneously. It was found that co-delivery of siSna and siTwi had more significant anti-metastasis effect than delivering a single siRNA, as a result of simultaneously inhibiting the motility of cancer cells and degradation of ECM. Therefore, PPSTs could be a promising co-delivery vector for effective therapy of metastatic breast cancer.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Nanopartículas , Metástase Neoplásica/prevenção & controle , Paclitaxel/farmacologia , Poliésteres/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Animais , Feminino , Humanos , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Metastasis is one of the major obstacles for the successful therapy of breast cancer. To inhibit the metastasis and growth of breast cancer simultaneously, a new docetaxel (DTX) loaded shrapnel nano delivery system with the reduction- and enzyme-sensitive properties was designed and developed. Firstly, methoxy polyethylene glycol-peptide-vitamin E succinate (PPV), a matrix metalloproteinases (MMPs)-sensitive copolymer, was synthesized by conjugating mPEG and vitamin E succinate (VES) using an enzyme-sensitive peptide. Then, DTX loaded methoxy polyethylene glycol-s-s-vitamin E succinate (PSV) micelles (DPM) @ PPV-based liposomes (DPM@PL) were prepared by the incorporation of DPM into the PPV-based liposomes. DPM@PL showed a shrapnel structure with average particle size 113.3 ± 2.7 nm. The drug loading and encapsulation efficiency of DPM@PL were 1.93% and 99.02%, respectively. An obvious burst release (>90%) of drug was observed in the simulated tumor microenvironment with MMPs and reductive glutathione. The cellular uptake and cytotoxicity of DPM@PL in 4T1 cells were significantly enhanced after the pre-treatment of activated MMP-9. Compared with Taxotere(®), DPM@PL remarkably increased the distribution of DTX in lung and tumor of 4T1 tumor-bearing mice, and inhibited the in situ tumor growth and pulmonary metastasis formation effectively through the enhanced DTX-induced apoptosis and the reduced metastasis-promoting proteins expression. Compared with saline group, the inhibitory rates of DPM@PL against tumor volume and lung metastasis were about 81% and 92%, respectively, and it didn't produce the significant systemic toxicity. As a result, DPM@PL could be a promising nano delivery system for the successful therapy of breast cancer.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/tratamento farmacológico , Nanopartículas/administração & dosagem , Polietilenoglicóis/administração & dosagem , Taxoides/administração & dosagem , Tocoferóis/administração & dosagem , Animais , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/uso terapêutico , Antineoplásicos Fitogênicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Docetaxel , Portadores de Fármacos/administração & dosagem , Composição de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Lipossomos/administração & dosagem , Neoplasias Pulmonares/prevenção & controle , Masculino , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Estrutura Molecular , Nanopartículas/uso terapêutico , Nanopartículas/toxicidade , Proteínas de Neoplasias/biossíntese , Tamanho da Partícula , Fosfatidilcolinas , Polietilenoglicóis/síntese química , Distribuição Aleatória , Ratos Sprague-Dawley , Taxoides/farmacocinética , Taxoides/uso terapêutico , Taxoides/toxicidade , Distribuição Tecidual , Tocoferóis/síntese química , Microambiente TumoralRESUMO
Metastasis is one of the major obstacles for the successful therapy of breast cancer. Although increased candidate drugs targeting cancer metastasis are tested, their clinical translation is limited by either serve toxicity or low efficacy. In present work, a nano-drug delivery system loading atorvastatin calcium (Ator) was developed for the efficient suppression of the metastasis of breast cancer. The nano-drug delivery system was constructed by a amphiphilic copolymer of methoxy polyethylene glycol-s-s-vitamin E succinate (mPEG-s-s-VES, PSV), which was consisted of a hydrophilic mPEG1k segment and a hydrophobic VES head, which were conjugated with a linker bearing amide and disulfide groups simultaneously. Self-assembly of PSV and Ator formed Ator-loaded PSV micelles (ASM) with good colloidal stability, high drug loading content (up to 50%) and great encapsulation efficiency (99.09 ± 0.28%). In cellular level, it was found that the ASM could efficiently release the Ator payload into cytosol due to detachment of PEG shell at high intracellular glutathione condition. ASM could significantly inhibit the migration and invasion of 4T1 breast cancer cells with inhibitory rates of 79.2% and 88.5%, respectively. In a 4T1 orthotropic mammary tumor metastatic cancer model, it was demonstrated that ASM could completely blocked the lung and liver metastasis of breast cancer with minimal toxicity owing to enhanced Ator accumulation in tumor and lung as compared with that of free Ator. The down-regulations of metastasis-promoting MMP-9, Twist and uPA proteins were demonstrated as the main underlying mechanism. As a result, ASM could be a promising drug delivery system for the efficient therapy of breast cancer metastasis.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Ácidos Heptanoicos/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Polietilenoglicóis/química , Pirróis/administração & dosagem , Vitamina E/análogos & derivados , Animais , Atorvastatina , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Preparações de Ação Retardada/química , Feminino , Ácidos Heptanoicos/uso terapêutico , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/prevenção & controle , Pulmão/efeitos dos fármacos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/prevenção & controle , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Oxirredução , Pirróis/uso terapêuticoRESUMO
To maximize the interference efficacy of pGPU6/Neo-p65 shRNA-expressing pDNA (p65 shRNA) and subsequently more effectively inhibit tumor growth and lymphatic metastasis through blocking the nuclear factor-kappa B (NF-κB) signaling pathway, seven Tween 85-polyethyleneimine (PEI) conjugates (TnPs, n=2, 3, 4, 5, 6, 7 and 8), which differed in the length of the polymethylene [-(CH2)n-] spacer between Tween 85 and PEI, were synthesized and investigated. The results showed that the transfection efficiency and cytotoxicity both increased with the spacer chain length. Then, TnPs with a [-(CH2)6-] spacer (T6P) were chosen to deliver p65 shRNA to a tumor and subsequently inhibit tumor growth and lymphatic metastasis. The T6P/p65 shRNA complex nanoparticles (T6Ns) could significantly down-regulate p65 expression in breast cancer cells, and consequently inhibit cell invasion and disrupt the tube formation. Most importantly, T6Ns accumulated greatly in tumor tissue, and as a result, significantly inhibited the growth and lymphatic metastasis of breast cancer xenograft. All these results indicated that the transfection efficacies of cationic amphiphiles could be significantly modulated by minor structural variations, and that T6P was promising for the effective delivery of p65 shRNA to knock down the expression of the key metastasis-driving genes and inhibit tumor growth and metastasis.