RESUMO
Folate-aminocaproic acid-doxorubicin (FA-AMA-hyd-DOX) was firstly synthesized by our group. It was indicated that FA-AMA-hyd-DOX was pH-responsive, and had strong cytotoxicity on a folate receptor overexpressing cell line (KB cells) in vitro. The aim of our study was to further explore the potential use of FA-AMA-hyd-DOX as a new therapeutic drug for breast cancer. The cellular uptake and the antiproliferative activity of the FA-AMA-hyd-DOX in MDA-MB-231 cells were measured. Compared with DOX, FA-AMA-hyd-DOX exhibited higher targeting ability and cytotoxicity to FR-positive tumor cells. Subsequently, the tissue distribution of FA-AMA-hyd-DOX was studied, and the result confirmed that DOX modified by FA can effectively increase the selectivity of drugs in vivo. After determining the maximum tolerated dose (MTD) of FA-AMA-hyd-DOX in MDA-MB-231 tumor-bearing nude mice, the antitumor effects and the in vivo safety of FA-AMA-hyd-DOX were systematically evaluated. The data showed that FA-AMA-hyd-DOX could effectively increase the dose of DOX tolerated by tumor-bearing nude mice and significantly inhibit MDA-MB-231 tumor growth in vivo. Furthermore, FA-AMA-hyd-DOX treatment resulted in almost no obvious damage to the mice. All the positive data suggest that FA-targeted FA-AMA-hyd-DOX is a promising tumor-targeted compound for breast cancer therapy.
Assuntos
Ácido Aminocaproico/farmacologia , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacologia , Ácido Fólico/farmacologia , Ácido Aminocaproico/síntese química , Ácido Aminocaproico/química , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/síntese química , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Feminino , Ácido Fólico/síntese química , Ácido Fólico/química , Humanos , Camundongos , Polietilenoglicóis/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
To study the biopharmaceutics characteristics of paris saponin VII (PSVII). The solubility of PSVII was evaluated by measurement of the equilibrium solubility in different solvents and media. The permeability of PSVII was evaluated by measuring the oil/water partition coefficient (lgPapp) and determining the apparent permeability coefficient (PCapp) on a mono-layer Caco-2 cell model. The effects of p-glycoprotein and multidrug resistance related protein 2 on PSVII transport in mono-layer Caco-2 cell model were further investigated. Finally, the small intestinal absorption of PSVII was investigated in rat. In solvents of different pH, the equilibrium solubility of PSVII was quite low, and the dose number of PSVII was larger than 1. The lgPapp of PSVII was less than 0. The apparent permeability coefficient [PCapp(AP-BL)] of PSVII in mono-layer Caco-2 cell model was less than 14.96 × 10-6 cm·s-1, and the efflux ratio of PSVII in mono-layer Caco-2 cell model was less than 1. The transport rate of PSVII in mono-layer Caco-2 cell model was not affected by the inhibitors of p-glycoprotein and multidrug resistance related protein 2. After oral administration, PSVII could be detected in rat intestinal contents, but could not be detected in the small intestinal mucosa. PSVII showed low solubility and permeability, which would result in low oral bioavailability in clinic. PSVII belonged to Class IV compound in biopharmaceutics classification system.
Assuntos
Saponinas/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Animais , Transporte Biológico , Células CACO-2 , Relação Dose-Resposta a Droga , Humanos , Concentração de Íons de Hidrogênio , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Permeabilidade , Ratos , SolubilidadeRESUMO
The anti-neovascularization treatment is one of the effective strategies for tumor molecular target therapy. At present, the target and effect of the anti-neovascularization treatment is limited, and it is urgent to establish a new vascular targeting strategy to effectively treat tumors. In this work, we used high intensity focused ultrasound (HIFU) combined with targeted microbubbles to establish a molecular targeted ultrasound response microbubble for neovascular cells. Furthermore, the effects of drug loaded microbubbles on neovascularization and tumor cells were studied. The tumor vascular targeted and ultrasound-responsive microbubbles of 5-FU@DLL4-MBs were prepared by the thin-film dispersion method. The size and zeta potential of 5-FU@DLL4-MBs was about 1248 nm and -9.1 mV. 5-FU@DLL4-MBs released 5-FU showed an ultrasound-responsive manner, and had better vascular-targeting ability. Furthermore, the 5-FU@DLL4-MBs showed the strongest cytotoxic effect on HUVECs or HepG-2 cells and can be effectively internalized into the HUVECs cells. Thus, 5-FU@DLL4-MBs combined with HIFU can be considered as a potential method for antitumor angiogenesis in the future.
Assuntos
Antineoplásicos/farmacologia , Fluoruracila/farmacologia , Microbolhas , Neovascularização Patológica/tratamento farmacológico , Ultrassonografia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila/química , Células Hep G2 , Humanos , Estrutura Molecular , Neovascularização Patológica/patologia , Tamanho da Partícula , Relação Estrutura-AtividadeRESUMO
AIM: The objective of this study was to deliver a ring-closed form of 10-hydroxycamptothecin (HCPT) to the mitochondria and nucleus to treat colorectal cancer. MATERIALS & METHODS: HCPT-loaded nanoparticle HCPT@PLGA-PEG2k-triphenylphosphonium/PLGA-hyd-PEG4k-folic acid (PT/PHF) and HCPT@PT/PLGA-SS-PEG4k-folic acid (PSF) were prepared by using emulsion-solvent evaporation method. RESULTS: In vitro experimental results indicated HCPT@PT/PHF and HCPT@PT/PSF maintained a large amount of HCPT in active form, and delivered more HCPT to the nucleus and mitochondria of the tumor cell, which resulted in the enhancement of cytotoxicity of HCPT. In vivo experimental results indicated that HCPT@PT/PHF and HCPT@PT/PSF delivered more ring-closed form of HCPT to tumor tissue, which led to strong antitumor activity. CONCLUSION: HCPT@PT/PHF and HCPT@PT/PSF could enhance therapeutic efficacy of HCPT to colorectal cancer.
Assuntos
Camptotecina/análogos & derivados , Núcleo Celular/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Portadores de Fármacos/química , Mitocôndrias/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacologia , Transporte Biológico , Camptotecina/farmacologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Emulsões/química , Ácido Fólico/química , Ácido Fólico/metabolismo , Humanos , Camundongos , Camundongos Nus , Modelos Animais , Nanopartículas/química , Tamanho da Partícula , Poliésteres/química , Polietilenoglicóis/química , Propriedades de Superfície , Distribuição TecidualRESUMO
In order to inhibit the growth of lung cancer bone metastasis and reduce the bone resorption at bone metastasis sites, a bone metastasis target micelle DOX@DBMs-ALN was prepared. The size and the zeta potential of DOX@DBNs-ALN were about 60 nm and -15 mV, respectively. DOX@DBMs-ALN exhibited high binding affinity with hydroxyapatite and released DOX in redox-responsive manner. DOX@DBMs-ALN was effectively up taken by A549 cells and delivered DOX to the nucleus of A549 cells, which resulted in strong cytotoxicity on A549 cells. The in vivo experimental results indicated that DOX@DBMs-ALN specifically delivered DOX to bone metastasis site and obviously prolonged the retention time of DOX in bone metastasis site. Moreover, DOX@DBMs-ALN not only significantly inhibited the growth of bone metastasis tumour but also obviously reduced the bone resorption at bone metastasis sites without causing marked systemic toxicity. Thus, DOX@DBMs-ALN has great potential in the treatment of lung cancer bone metastasis.
Assuntos
Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Reabsorção Óssea/tratamento farmacológico , Doxorrubicina/química , Doxorrubicina/farmacologia , Neoplasias Pulmonares/patologia , Micelas , Células A549 , Animais , Neoplasias Ósseas/patologia , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapêutico , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Camundongos Nus , Terapia de Alvo Molecular , Oxirredução/efeitos dos fármacos , Fosfatidiletanolaminas/química , Distribuição TecidualRESUMO
Bone is an especially prone metastatic site for breast cancer, and to block the vicious cycle between bone resorption and tumor growth is an important strategy for the treatment of breast cancer bone metastasis. In this paper, pH- and redox-sensitive as well as breast cancer bone metastasis-targeting nanoparticles (DOX@ALN-(HA-PASP)CL) were prepared, and also their anti-tumor activity and anti-bone resorption effect were investigated in detail. The in vitro experimental results indicated that DOX released from DOX@ALN-(HA-PASP)CL exhibited a GSH-, DTT- and pH-dependent manner. Moreover, in an in vitro 3D breast cancer bone metastasis model, DOX@ALN-(HA-PASP)CL decreased bone resorption through inhibiting the proliferation of human breast cancer cells (MDA-MB-231 cells) and reducing the activity of osteoclasts. The in vivo experimental results indicated that a large amount of DOX was delivered to a breast cancer bone metastasis site after tumor-bearing mice were treated with DOX@ALN-(HA-PASP)CL; meanwhile, DOX@ALN-(HA-PASP)CL significantly decreased the tumor volume and bone resorption in tumor-bearing mice without causing obvious systemic toxicity. In conclusion, the in vitro and in vivo experimental results indicate that DOX@ALN-(HA-PASP)CL has great potential in the treatment of breast cancer bone metastasis.
Assuntos
Neoplasias Ósseas/tratamento farmacológico , Reabsorção Óssea/tratamento farmacológico , Neoplasias da Mama/patologia , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Nanopartículas , Animais , Neoplasias Ósseas/secundário , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Feminino , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Nus , Oxirredução , Células RAW 264.7 , RatosRESUMO
Doxorubicin (DOX) is a broad-spectrum chemotherapy drug to treat tumors. However, severe side effects and development of DOX resistance hinder its clinical application. In order to overcome DOX resistance, DOX/TPP-DOX@Pasp-hyd-PEG-FA micelles were prepared by using newly synthesized comb-like amphiphilic material Pasp-hyd-PEG-FA. Drug released in vitro from micelles showed a pH-dependent manner. DOX/TPP-DOX@Pasp-hyd-PEG-FA induced more apoptosis in KB cell and MCF-7/ADR cell than DOX@Pasp-hyd-PEG-FA. Confocal laser scanning microscopy experiment indicated that DOX/TPP-DOX@Pasp-hyd-PEG-FA delivered TPP-DOX and DOX to the nucleus and mitochondria of the tumor cell simultaneously. Thus, DOX/TPP-DOX@Pasp-hyd-PEG-FA could significantly damage the mitochondrial membrane potential. DOX/TPP-DOX@Pasp-hyd-PEG-FA markedly shrinked the tumor volume in tumor-bearing nude mice grafted with MCF-7/ADR cell as compared with the same dose of free DOX. DOX was mainly accumulated in tumor tissue after DOX/TPP-DOX@Pasp-hyd-PEG-FA was injected to tumor-bearing nude mice by tail vein. After free DOX was injected to tumor-bearing nude mice by tail vein, DOX widely distributed through the whole body. Therefore, mitochondria and nucleus dual delivery system has potential in overcoming DOX resistance.
Assuntos
Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Doxorrubicina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Feminino , Ácido Fólico/química , Humanos , Concentração de Íons de Hidrogênio , Células KB , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Nus , Micelas , Polietilenoglicóis/químicaRESUMO
In order to overcome drug resistant and enhance antitumor activity of DOX, a new pH-sensitive micelle (DOX/DQA-DOX@DSPE-hyd-PEG-AA) was prepared to simultaneously deliver DOX to nucleus and mitochondria. Drug released from DOX/DQA-DOX@DSPE-hyd-PEG-AA showed a pH-dependent manner. DOX/DQA-DOX@DSPE-hyd-PEG-AA induced the depolarization of mitochondria and apoptosis in MDA-MB-231/ADR cells and A549 cells, which resulted in the high cytotoxicity of DOX/DQA-DOX@DSPE-hyd-PEG-AA against MDA-MB-231/ADR cells and A549 cells. Confocal microscopy confirmed that DOX/DQA-DOX@DSPE-hyd-PEG-AA simultaneously delivered DQA-DOX and DOX to the mitochondria and nucleus of tumor cell. After DOX/DQA-DOX@DSPE-hyd-PEG-AA was injected to the tumor-bearing nude mice by the tail vein, DOX was mainly found in tumor tissue. But DOX was widely distributed in the whole body after the administration of free DOX. Compared with free DOX, the same dose of DOX/DQA-DOX@DSPE-hyd-PEG-AA significantly inhibited the growth of DOX-resistant tumor in tumor-bearing mice without obvious systemic toxicity. Therefore, dual subcellular compartment delivery of DOX greatly enhanced the antitumor activity of DOX on DOX-resistant tumor. DOX/DQA-DOX@DSPE-hyd-PEG-AA has the potential in target therapy for DOX-resistant tumor.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Animais , Antibióticos Antineoplásicos/metabolismo , Antibióticos Antineoplásicos/uso terapêutico , Antibióticos Antineoplásicos/toxicidade , Caspase 3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/metabolismo , Doxorrubicina/uso terapêutico , Feminino , Humanos , Concentração de Íons de Hidrogênio , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Distribuição Tecidual , Transplante HeterólogoRESUMO
In order to increase the therapeutic effect of doxorubicin (DOX) on bone metastases, a multifunctional micelle was developed by combining pH-sensitive characteristics with bone active targeting capacity. The DOX loaded micelle was self-assembled by using doxorubicin-poly (ethylene glycol)-alendronate (DOX-hyd-PEG-ALN) as an amphiphilic material. The size and drug loading of DOX loaded DOX-hyd-PEG-ALN micelle was 114 nm and 24.3%. In pH 5.0 phosphate buffer solution (PBS), the micelle released DOX significantly faster than in pH 7.4 PBS. In addition, with the increase of incubation time, more red DOX fluorescence was observed in tumor cells and trafficked from cytoplasm to nucleus. The IC50 of DOX loaded DOX-hyd-PEG-ALN micelle on A549 cells was obviously lower than that of free DOX in 48 h. Furthermore, the in vivo image experimental results indicated that a larger amount of DOX was accumulated in the bone metastatic tumor tissue after DOX loaded DOX-hyd-PEG-ALN micelle was intravenously administered, which was confirmed by histological analysis. Finally, DOX loaded DOX-hyd-PEG-ALN micelle effectively delayed the tumor growth, decreased the bone loss and reduced the cardiac toxicity in tumor-bearing nude mice as compared with free DOX. In conclusion, DOX loaded DOX-hyd-PEG-ALN micelle had potential in treating bone metastatic tumor.
Assuntos
Alendronato/administração & dosagem , Antibióticos Antineoplásicos/administração & dosagem , Conservadores da Densidade Óssea/administração & dosagem , Neoplasias Ósseas/secundário , Doxorrubicina/administração & dosagem , Micelas , Polietilenoglicóis , Alendronato/química , Alendronato/farmacocinética , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/farmacocinética , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Doxorrubicina/química , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Cinética , Camundongos , Terapia de Alvo Molecular , Ressonância Magnética Nuclear Biomolecular , Tamanho da Partícula , Polietilenoglicóis/química , Microtomografia por Raio-X , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Alendronate-monoethyl adipate-(hydrazone)-doxorubicin conjugate (ALN-MA-hyd-DOX) was synthesized to specifically deliver doxorubicin (DOX) to bone tumor tissue. The binding kinetics of ALN-MA-hyd-DOX with hydroxyapatite (HA) and natural bone were detected by using spectrophotometer. Cytotoxicity of ALN-MA-hyd-DOX on tumor cells was determined by MTT [3-(4,5-dimethylthiaol-2-yl)-2,5-diphenyl-tetrazolium bromide] method. The cellular uptake of ALN-MA-hyd-DOX was observed by using fluorescence microscopy. The in vivo antitumor activity of ALN-MA-hyd-DOX was investigated by using tumor-bearing nude mice model. The results indicated that ALN-MA-hyd-DOX was able to quickly bind with HA and natural bone. ALN-MA-hyd-DOX immobilized on the natural bone released more DOX in pH 5.0 medium than that in pH 6.0 or 7.4 medium. The cytotoxicity of ALN-MA-hyd-DOX toward A549 cells and MDA-MB-231/ADR cells was greater than DOX. ALN-MA-hyd-DOX was rapidly uptaken by A549 cells and MDA-MB-231/ADR cells. Compared with the same dose of free DOX, ALN-MA-hyd-DOX significantly decreased tumor volume of tumor-bearing nude mice. DOX mainly distributed in bone tumor tissue after ALN-MA-hyd-DOX was intravenously administered to tumor-bearing nude mice, whereas DOX distributed through the whole body after DOX was intravenously administered to tumor-bearing nude mice. These findings implied that the ALN-MA-hyd-DOX was a promising bone-targeted conjugate for treating bone neoplasms.
Assuntos
Neoplasias Ósseas/tratamento farmacológico , Doxorrubicina/administração & dosagem , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
A PEG-based, folate mediated, active tumor targeting drug delivery system using DOX-hyd-PEG-FA nanoparticles (NPs) were prepared. DOX-hyd-PEG-FA NPs showed a significantly faster DOX release in pH 5.0 medium than in pH 7.4 medium. Compared with DOX-hyd-PEG NPs, DOX-hyd-PEG-FA NPs increased the intracellular accumulation of DOX and showed a DOX translocation from lysosomes to nucleus. The cytotoxicity of DOX-hyd-PEG-FA NPs on KB cells was much higher than that of free DOX, DOX-ami-PEG-FA NPs and DOX-hyd-PEG NPs. The cytotoxicity of DOX-hyd-PEG-FA NPs on KB cells was attenuated in the presence of exogenous folic acid. The IC50 of DOX-hyd-PEG-FA NPs and DOX-hyd-PEG NPs on A549 cells showed no significant difference. After DOX-hyd-PEG-FA NPs were intravenously administered, the amount of DOX distributed in tumor tissue was significantly increased, while the amount of DOX distributed in heart was greatly decreased as compared with free DOX. Compared with free DOX, NPs yielded improved survival rate, prolonged life span, delayed tumor growth and reduced the cardiotoxicity in tumor bearing mice model. These results indicated that the acid sensitivity, passive and active tumor targeting abilities were likely to act synergistically to enhance the drug delivery efficiency of DOX-hyd-PEG-FA NPs. Therefore, DOX-hyd-PEG-FA NPs are a promising drug delivery system for targeted cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Ácido Fólico/análogos & derivados , Ácido Fólico/farmacologia , Nanopartículas/administração & dosagem , Polietilenoglicóis/farmacologia , Animais , Linhagem Celular Tumoral , Portadores de Fármacos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Células KB , Camundongos , Camundongos Nus , Taxa de SobrevidaRESUMO
Doxorubicin (DOX) is a broad-spectrum antitumor drug used in the clinic. However, it can cause serious heart toxicity. To increase the therapeutic index of DOX and to attenuate its toxicity toward normal tissues, we conjugated DOX with either α-linolenic acid (LNA) or palmitic acid (PA) by a hydrazone or an amide bond to produce DOX-hyd-LNA, DOX-ami-LNA, DOX-hyd-PA, and DOX-ami-PA. The cytotoxicity of DOX-hyd-LNA on HepG2, MCF-7, and MDA-231 cells was higher compared to that of DOX, DOX-ami-LNA, DOX-hyd-PA, and DOX-ami-PA. The cytotoxicity of DOX-hyd-LNA on HUVECs was lower than that of DOX. DOX-hyd-LNA released significantly more DOX in pH 5.0 medium than it did in pH 7.4 medium. DOX-hyd-LNA induced more apoptosis in MCF-7 and HepG2 cells than DOX or DOX-ami-LNA. Significantly more DOX was released from DOX-hyd-LNA in both MCF-7 and HepG2 cells compared with DOX-ami-LNA. Compared to free DOX, a biodistribution study showed that DOX-hyd-LNA greatly increased the content of DOX in tumor tissue and decreased the content of DOX in heart tissue after it was intravenously administered. DOX-hyd-LNA improved the survival rate, prolonged the life span, and slowed the growth of the tumor in tumor-bearing nude mice. These results indicate that DOX-hyd-LNA improved the therapeutic index of DOX. Therefore, DOX-hyd-LNA is a potential compound for use as a cancer-targeting therapy.
Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Ácido alfa-Linolênico/química , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Feminino , Células Hep G2 , Humanos , Hidrazonas/química , Concentração de Íons de Hidrogênio , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Camundongos Nus , Ácido Palmítico/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The experiment aimed to increase the drug-delivery efficiency of poly-lactic-co-glycolic acid (PLGA) nanoparticles. Lipid-polymer hybrid nanoparticles (LPNs-1) were prepared using PLGA as a hydrophobic core and FA-PEG-hyd-DSPE as an amphiphilic shell. Uniform and spherical nanoparticles with an average size of 185 nm were obtained using the emulsification solvent evaporation method. The results indicated that LPNs-1 showed higher drug loading compared with naked PLGA nanoparticles (NNPs). Drug release from LPNs-1 was faster in an acidic environment than in a neutral environment. LPNs-1 showed higher cytotoxicity on KB cells, A549 cells, MDA-MB-231 cells, and MDA-MB-231/ADR cells compared with free doxorubicin (DOX) and NNPs. The results also showed that, compared with free DOX and NNPs, LPNs-1 delivered more DOX to the nuclear of KB cells and MDA-MB-231/ADR cells. LPNs-1 induced apoptosis in KB cells and MDA-MB-231/ADR cells in a dose-dependent manner. The above data indicated that DOX-loaded LPNs-1 could kill not only normal tumor cells but also drug-resistant tumor cells. These results indicated that modification of PLGA nanoparticles with FA-PEG-hyd-DSPE could considerably increase the drug-delivery efficiency and LPNs-1 had potential in the delivery of chemotherapeutic agents in the treatment of cancer.
Assuntos
Antineoplásicos/farmacologia , Ácido Fólico/análogos & derivados , Nanopartículas/química , Fosfatidilcolinas/química , Polietilenoglicóis/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos , Ácido Fólico/química , Ácido Fólico/metabolismo , Humanos , Ácido Láctico/química , Ácido Láctico/metabolismo , Nanopartículas/metabolismo , Fosfatidilcolinas/metabolismo , Polietilenoglicóis/metabolismo , Ácido Poliglicólico/química , Ácido Poliglicólico/metabolismo , Copolímero de Ácido Poliláctico e Ácido PoliglicólicoRESUMO
Folate-aminocaproic acid-doxorubicin (FA-AMA-DOX) was synthesized and characterized by H NMR spectroscopy and mass spectrometry. Cytotoxicity and cellular uptake experiments were performed in KB and HepG2 cells, which express folic acid receptor, and the cell line A549, which does not express folic acid receptor. Cytotoxicity was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cellular uptake was monitored using fluorescence microscopy. The amount of DOX released from FA-AMA-DOX was much greater at pH 5.0 than that at pH 6.5 or 7.4. The cytotoxicity of FA-AMA-DOX toward KB and HepG2 cells was greater than that of DOX or AMA-DOX at the same concentrations, and cytotoxicity could be attenuated by FA in a dose-dependent manner. On the contrary, the cytotoxicity of FA-AMA-DOX and AMA-DOX toward A549 cells was lower than that of DOX at the same concentration, and cytotoxicity could not be reduced by FA. Compared with FA-AMA, FA-AMA-DOX increased the intracellular accumulation of DOX in KB cells. These results suggested that FA-AMA-DOX have suitable attributes for the active targeting of folate-receptor-positive tumor cells and for releasing the chemotherapeutic agent, DOX, in situ; it therefore has potential as a novel cancer therapeutic.