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1.
Adv Healthc Mater ; 11(6): e2101496, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34878725

RESUMO

The major obstacles of anti-PD therapy in metastatic tumors are limited drug delivery in primary tumors and metastatic foci, and the lack of tumor-infiltrating lymphocytes (TILs). Here, the authors constructed a novel cellular membrane nanovesicles platform (M/IR NPs) based on homologous targeting and near-infrared (NIR) responsive release strategy to potentiate PD-1/PD-L1 blockade therapy against metastatic tumors. In tumor-bearing mice, biomimetic M/IR NPs targeted both primary tumors and their lung metastases. Upon laser irradiation, M/IR NPs reduced cancer-associated fibroblasts (CAFs) in tumor microenvironment, thus increasing the penetration of TILs. When shed from homologous tumor cell membranes, positively charged nanoparticles (IR NPs) core can capture released tumor-associated antigens, thereby enhancing the antigen-presenting ability of DCs to activate cytotoxic T lymphocytes. When the photothermal conversion temperature under NIR-laser is higher than 42 °C, M/IR NPs initiated the rupture of cell membranes and the responsive release of PD-1/PD-L1 inhibitor BMS, which significantly attenuated tumor-associated immunosuppression and synergistically induced T cellular immunity to inhibit the tumor growth and metastasis. Overall, biomimetic M/IR NPs can improve the targeting and therapeutic efficacy of anti-PD therapy in primary tumors and metastases, opening up a new avenue for the diagnosis and treatment of metastatic tumors in the future.


Assuntos
Nanopartículas , Neoplasias , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Imunoterapia , Camundongos , Neoplasias/tratamento farmacológico , Microambiente Tumoral
2.
Cancer Lett ; 522: 238-254, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34571084

RESUMO

The response rate of anti-PD therapy in most cancer patients remains low. Therapeutic drug and tumor-infiltrating lymphocytes (TILs) are usually obstructed by the stromal region within tumor microenvironment (TME) rather than distributed around tumor cells, thus unable to induce the immune response of cytotoxic T cells. Here, we constructed the cationic thermosensitive lipid nanoparticles IR780/DPPC/BMS by introducing cationic NIR photosensitizer IR-780 iodide (IR780) modified lipid components, thermosensitive lipid DPPC and PD-1/PD-L1 inhibitor BMS202 (BMS). Upon laser irradiation, IR780/DPPC/BMS penetrated into deep tumor, and reduced cancer-associated fibroblasts (CAFs) around tumor cells to remodel the spatial distribution of TILs in TME. Interestingly, the cationic IR780/DPPC/BMS could capture released tumor-associated antigens (TAAs), thereby enhancing the antigen-presenting ability of DCs to activate cytotoxic T lymphocytes. Moreover, IR780/DPPC/BMS initiated gel-liquid crystal phase transition under laser irradiation, accelerating the disintegration of lipid bilayer structure and leading to the responsive release of BMS, which would reverse the tumor immunosuppression state by blocking PD-1/PD-L1 pathway for a long term. This combination treatment can synergistically exert the antitumor immune response and inhibit the tumor growth and metastasis.


Assuntos
Antígeno B7-H1/imunologia , Lipossomos/farmacologia , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/imunologia , Acetamidas/química , Acetamidas/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Tolerância Imunológica/efeitos dos fármacos , Imunoterapia/métodos , Indóis/química , Indóis/farmacologia , Lipossomos/química , Terapia com Luz de Baixa Intensidade , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos da radiação , Nanopartículas/química , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/radioterapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/efeitos da radiação , Microambiente Tumoral/efeitos dos fármacos
3.
ACS Omega ; 5(46): 30274-30281, 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33251462

RESUMO

The encapsulation of hydrophobic drugs is a problem that many researchers are working on. The goal of this study is to achieve the delivery of hydrophobic drugs by means of prodrugs and nanoformulations for a stronger tumor cell-killing effect and explore related killing mechanisms. Lipophilic quercetin (Qu) was covalently linked to glyceryl caprylate-caprate (Gcc) via disulfide bonds-containing 3,3'-dithiodipropionic acid (DTPA) to synthesize novel lipid Qu-SS-Gcc. Qu-SS-Gcc lipid nanoparticles (Qu-SS-Gcc LNPs) were fabricated using the solvent diffusion technique. The intracellular release of Qu by cleavage of nanocarriers was determined by liquid chromatography and compared with the uptake of free Qu. Detection methods, such as fluorescent quantitation, flow cytometry, and western blot were applied to explore the action mechanism induced by Qu. It was revealed that Qu-SS-Gcc LNPs could be cleaved by the high concentrations of reduction molecules in MCF-7/ADR (human multidrug-resistant breast cancer) cells, followed by the release of Qu. The intracellular Qu content produced by dissociation of Qu-SS-Gcc LNPs was higher than that produced by internalization of free Qu. The resulting release of Qu exerted superior cell-killing effects on MCF-7/ADR cells, such as P-gp inhibition by binding to P-gp binding sites, blocking the cell cycle in the G2 phase, and causing cell apoptosis and autophagy. Moreover, it was revealed autophagy triggered by a low concentration of Qu-SS-Gcc LNPs was beneficial to cell survival, while at a higher concentration, it acted as a cell killer. Qu-SS-Gcc LNPs can realize massive accumulation of Qu in tumor cells and exert a multifaceted killing effect on tumor cells, which is a reference for the delivery of hydrophobic drugs.

4.
J Zhejiang Univ Sci B ; 21(3): 218-233, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32133799

RESUMO

Metastasis is one of the main reasons causing death in cancer patients. It was reported that chemotherapy might induce metastasis. In order to uncover the mechanism of chemotherapy-induced metastasis and find solutions to inhibit treatment-induced metastasis, the relationship between epithelial-mesenchymal transition (EMT) and doxorubicin (DOX) treatment was investigated and a redox-sensitive small interfering RNA (siRNA) delivery system was designed. DOX-related reactive oxygen species (ROS) were found to be responsible for the invasiveness of tumor cells in vitro, causing enhanced EMT and cytoskeleton reconstruction regulated by Ras-related C3 botulinum toxin substrate 1 (RAC1). In order to decrease RAC1, a redox-sensitive glycolipid drug delivery system (chitosan-ss-stearylamine conjugate (CSO-ss-SA)) was designed to carry siRNA, forming a gene delivery system (CSO-ss-SA/siRNA) downregulating RAC1. CSO-ss-SA/siRNA exhibited an enhanced redox sensitivity compared to nonresponsive complexes in 10 mmol/L glutathione (GSH) and showed a significant safety. CSO-ss-SA/siRNA could effectively transmit siRNA into tumor cells, reducing the expression of RAC1 protein by 38.2% and decreasing the number of tumor-induced invasion cells by 42.5%. When combined with DOX, CSO-ss-SA/siRNA remarkably inhibited the chemotherapy-induced EMT in vivo and enhanced therapeutic efficiency. The present study indicates that RAC1 protein is a key regulator of chemotherapy-induced EMT and CSO-ss-SA/siRNA silencing RAC1 could efficiently decrease the tumor metastasis risk after chemotherapy.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/patologia , Doxorrubicina/efeitos adversos , Sistemas de Liberação de Medicamentos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , RNA Interferente Pequeno/administração & dosagem , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores , Aminas/química , Quitosana/química , Doxorrubicina/administração & dosagem , Feminino , Humanos , Células MCF-7 , Metástase Neoplásica/prevenção & controle , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Proteínas rac1 de Ligação ao GTP/fisiologia
5.
Carbohydr Polym ; 230: 115613, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31887935

RESUMO

Targeted and sensitive drug release at the colitis site is critical for the effective therapy of ulcerative colitis and reduction of side effects from the drug. Herein, we used 3,3'-dithiodipropionic acid (DTPA) to covalently link quercetin (Qu) and glyceryl caprylate-caprate (Gcc) via ester bonds to prepare Qu-SS-Gcc lipid nanoparticles (Qu-SS-Gcc LNPs). Dexamethasone (Dex) was used as a model drug, and chitosan (CSO) was modified on the surface of Qu-SS-Gcc LNPs to obtain CSO-modified Dex-loaded Qu-SS-Gcc LNPs (CSO/Dex/LNPs). The encapsulation efficiency and drug loading of CSO/Dex/LNPs were 93.1 % and 8.1 %, respectively. The in vitro release results showed that CSO/Dex/LNPs had esterase-responsive characteristics and could release the drug rapidly in esterase-containing artificial intestinal fluid. A human colorectal adenocarcinoma cell (Caco-2) monolayer was used as the intestinal cell barrier model. Transmembrane resistance measurements and permeation experiments showed that CSO/Dex/LNPs had a protective effect on the lipopolysaccharide (LPS)-stimulated Caco-2 cell monolayer and increased the expression of E-cadherin in LPS-stimulated Caco-2 cells. Moreover, CSO/Dex/LNPs could significantly reduce the expression of the inflammatory factors TNF-α, IL-6 and NO in LPS-stimulated RAW 264.7 cells. The ulcerative colitis mouse model was constructed by using C57BL/6 mice. The in vivo distribution results showed that CSO/Dex/LNPs had colon-targeting effects and strong retention ability in the colons of mice with colitis. The results also showed that CSO/Dex/LNPs had better anti-inflammatory effects than free Dex, which could reduce colonic atrophy, reduce histomorphological changes and increase the expression of E-cadherin in the colon. Furthermore, the expression levels of TNF-α, IL-6 and NO in the CSO/Dex/LNP-treated group were 37.4 %, 35.5 % and 33.2 % of those in mice with colitis, respectively.


Assuntos
Caprilatos/química , Quitosana/análogos & derivados , Colite Ulcerativa/tratamento farmacológico , Portadores de Fármacos/química , Nanopartículas/química , Polímeros Responsivos a Estímulos/química , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Células CACO-2 , Colo/efeitos dos fármacos , Colo/metabolismo , Reagentes para Ligações Cruzadas/química , Citocinas/genética , Citocinas/metabolismo , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Portadores de Fármacos/efeitos adversos , Esterases/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/efeitos adversos , Óxido Nítrico/metabolismo , Quercetina/administração & dosagem , Quercetina/química , Quercetina/uso terapêutico , Células RAW 264.7
6.
RSC Adv ; 10(35): 20445-20459, 2020 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35517758

RESUMO

An insufficient drug concentration at the target site and drug efflux resulting in poor efficacy are recognized as important obstacles in osteoporosis treatment. Simvastatin (SIM), which can treat osteoporosis by promoting osteoblast differentiation and mineralization through the bone morphogenetic proteins (BMP)-Smad signaling pathway, has lower bioavailability, and less bone tissue distribution. Herein, novel lipid nanoparticles (LNPs) delivering SIM (SIM/LNPs) for osteoporosis therapy were developed with aspartic oligopeptide (ASP n , here ASP6)-based bone-targeting moieties grafted to the nanoparticles (SIM/ASP6-LNPs) in an attempt to increase the concentration of SIM in bones with a relatively low dose to minimize adverse effects. In vivo experiments indicated that the ASP6-LNPs exhibited ideal bone-targeting characteristics, and in vitro cell evaluation experiments showed LNPs have good biocompatibility with MC3T3-E1 cells. The cell mineralization experiment revealed that the SIM-loaded LNPs induced osteoblast differentiation and the formation of mineralized nodules in MC3T3-E1 cells, achieving the same efficacy as that of SIM. Pharmacodynamic experiments revealed that SIM/ASP6-LNPs improved the efficacy of SIM on the recovery of bone mineral density when compared to SIM/LNPs or to SIM alone. Therefore, SIM/ASP6-LNPs may represent a potential bone-targeting drug delivery system (DDS) that contributes to the development of a novel osteoporosis treatment.

7.
Carbohydr Polym ; 212: 215-221, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30832850

RESUMO

DrzBC and DrzBS (10-23 DNAzyme) could block the expression of HBV e- and s- gene respectively. But the application of 10-23 DNAzyme was limited owing to the lack of appropriate delivery vehicles. Chitosan oligosaccharide-SS-Octadecylamine (CSSO), a redox-responsive nano-sized polymeric carrier, could self-aggregate and bind with DNA by electrostatic interaction at proper mass ratio. Compared with the traditional commercial carrier Lipo2000, CSSO exhibited lower cytotoxicity, efficient cellular uptake by targeting cells, and rapidly DNA released in cytoplasm after escaping from endosomes. Including the same DNA concentration, Lipo2000/(DrzBC or DrzBS) showed maximum inhibitory rate on HBeAg (47.29 ±â€¯1.86%) and HBsAg (33.58 ±â€¯0.72%) secretion after 48 h incubation, and then both decreased. In contrast, HBeAg secretion inhibition by CSSO/DrzBC and HBsAg secretion inhibition by CSSO/DrzBS were up to 73.86 ±â€¯1.77% and 67.80 ±â€¯2.51% at 48 h, and further increased to 83.83 ±â€¯2.34% and 76.79 ±â€¯2.18% at 72 h, respectively. CSSO is a promising redox-responsive polymeric carrier for efficient anti-Hepatitis B Virus gene therapy.


Assuntos
Aminas/administração & dosagem , Quitosana/administração & dosagem , Terapia Genética/métodos , Vírus da Hepatite B/efeitos dos fármacos , Oligossacarídeos/administração & dosagem , Polímeros/administração & dosagem , Aminas/metabolismo , Quitosana/metabolismo , DNA Viral/efeitos dos fármacos , DNA Viral/genética , DNA Viral/metabolismo , Relação Dose-Resposta a Droga , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/metabolismo , Células Hep G2 , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Humanos , Oligossacarídeos/metabolismo , Oxirredução/efeitos dos fármacos , Polímeros/metabolismo
8.
Adv Healthc Mater ; 7(17): e1800485, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29995353

RESUMO

An insufficient drug concentration at the target site and drug efflux resulting in poor efficacy is recognized as important obstacles in tumor treatment. Herein, novel lipid nanoparticles (LNPs) with redox-responsive properties based on disulfide bond-contained, quercetin (Qu)-grafted glyceryl caprylate-caprate (Gcc) are introduced (Qu-SS-Gcc LNPs). Qu-SS-Gcc LNPs show good entrapment of paclitaxel (PTX) due to π-π stacking between the aromatic rings of Qu and PTX. In vitro experiments indicate that Qu-SS-Gcc LNPs can selectively respond to high levels of reducing substances by breakdown of disulfide bonds, thus achieving rapid and efficient drug release, and only dissociate rapidly in tumor cells rather than in normal cells. Meanwhile, the Qu released concomitantly with the breakdown of disulfide bonds combines with P-gp and inhibits the drug efflux triggered by P-gp. Using an orthotopic 4T1 mouse mammary tumor model in BALB/c mice, PTX/Qu-SS-Gcc LNPs exhibit superior antitumor efficacy compared to Taxol, in addition better biosafety and inhibition of chemotherapy-triggered P-gp overexpression are achieved. Taken together, this work designs and implements redox-responsive drug release and drug efflux inhibition in tumor cells via modified LNPs, which not only leads to efficient drug release but also solves the problem of drug efflux that exists in stimulus-responsive systems.


Assuntos
Antineoplásicos Fitogênicos/química , Nanopartículas/química , Paclitaxel/química , Animais , Antineoplásicos Fitogênicos/farmacocinética , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Oxirredução , Paclitaxel/farmacocinética , Paclitaxel/farmacologia
9.
Inorg Chem ; 56(24): 15216-15230, 2017 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-29188999

RESUMO

On the basis of preparation and characterization of [Fe]-H2ase models (2-COCH2-6-HOCH2C5H3N)Fe(CO)2L (A, L = η1-SCOMe; B, L = η1-2-SC5H4N), the chemical reactivities of A and B with various electrophilic and nucleophilic reagents have been investigated, systematically. Thus, when A reacted with 1 equiv of MeCOCl in the presence of Et3N in MeCN to give the η2-SCOMe-coordinated acylation product (2-COCH2-6-MeCO2CH2C5H3N)Fe(CO)2(η2-SCOMe) (1), treatment of A with excess HBF4·Et2O in MeCN gave the cationic MeCN-coordinated complex [(2-COCH2-6-HOCH2C5H3N)Fe(CO)2(MeCN)](BF4) (2). In addition, when 2 was treated with 1 equiv of 2,6-(p-4-MeC6H4)2C6H3SK or PPh3 in CH2Cl2 to give the thiophenolato- and PPh3-substituted derivatives (2-COCH2-6-HOCH2C5H3N)Fe(CO)2[2,6-(p-MeC6H4)2C6H3S] (3) and [(2-COCH2-6-HOCH2C5H3N)Fe(CO)2(PPh3)](BF4) (4), treatment of B with 1 equiv of PMe3 or P(OMe)3 in THF afforded the phosphine- and phosphite-substituted complexes (2-COCH2-6-HOCH2C5H3N)(η1-2-SC5H4N)Fe(CO)2L (5, L = PMe3; 6, L = P(OMe)3). Interestingly, in contrast to A, when B reacted with excess HBF4·Et2O in MeCN to afford the BF3 adduct [2-COCH2-6-HO(BF3)CH2C5H3N]Fe(CO)2(η1-2-SC5H4N) (7), reaction of B with 1 equiv of p-MeC6H4COCl in the presence of Et3N in MeCN gave not only the expected 2-acylmethyl-6-p-toluoyloxomethylpyridine-containing complex (2-COCH2-6-p-MeC6H4CO2CH2C5H3N)Fe(CO)2(η2-2-SC5H4N) (8), but also gave the unexpected 2-toluoyloxovinyl-6-toluoyloxomethylpyridine-containing complex (2-p-MeC6H4CO2C2H-6-p-MeC6H4CO2CH2C5H3N)Fe(CO)2(η2-2-SC5H4N) (9). While the possible pathways for the novel reactions leading to complexes 1, 2, and 7-9 are suggested, the structures of complexes B, 1-4, and 6-9 were unambiguously confirmed by X-ray crystallography. In addition, model complexes A and B have been found to be catalysts for proton reduction to H2 from TFA under CV conditions.


Assuntos
Materiais Biomiméticos/química , Hidrogenase/química , Compostos de Ferro/química , Proteínas Ferro-Enxofre/química , Piridinas/química , Catálise , Cristalografia por Raios X , Técnicas Eletroquímicas , Ligantes , Modelos Moleculares , Oxirredução , Prótons
10.
Nanomedicine (Lond) ; 12(5): 511-534, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28178869

RESUMO

AIM: Whether PEI2k-HAuNS could promote gene transfection efficiency controlled by near-infrared (NIR) light. MATERIALS & METHODS: This safe nonviral gene delivery system was obtained by conjugating low molecular weight (2 kDa) polyethylenimine (PEI) onto hollow gold nanospheres (PEI2k-HAuNS). Upon NIR laser irradiation, there was a conspicuous increase both in the in vitro and in vivo transfection achieved by the nanocomplexes. Furthermore, a plasmid encoding the tumor suppressor TP53 (pTP53) was applied to test antitumor activity. RESULTS: The enhanced gene transfection efficiency and therapy of PEI2k-HAuNS were achieved via the mediation of an NIR laser compared with the other treatments in vitro and in vivo. CONCLUSION: The application of NIR laser irradiated PEI2k-HAuNS can be used as a promising gene delivery systems in vitro and in vivo.


Assuntos
Técnicas de Transferência de Genes , Terapia Genética , Nanosferas/administração & dosagem , Neoplasias/terapia , Animais , Ouro/química , Humanos , Raios Infravermelhos , Células MCF-7 , Camundongos , Peso Molecular , Nanosferas/química , Neoplasias/genética , Polietilenoimina/química , Transfecção , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto
11.
ACS Appl Mater Interfaces ; 8(9): 5929-40, 2016 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-26860241

RESUMO

Solid lipid nanoparticles (SLNs) have been extensively investigated and demonstrated to be a potential nanocarriers for improving oral bioavailability of many drugs. However, the molecular mechanisms related to this discovery are not yet understood. Here, the molecular transport mechanisms of the SLNs crossing simulative intestinal epithelial cell monolayers (Caco-2 cell monolayers) were studied. The cytotoxicology results of the SLNs in Caco-2 cells demonstrated that the nanoparticles had low cytotoxicity, had no effect on the integrity of the cell membrane, did not induce oxidative stress, and could significantly reduce cell membrane fluidity. The endocytosis of the SLNs was time-dependent, and their delivery was energy-dependent. For the first time, the transport of the SLNs was directly verified to be a vesicle-mediated process. The internalization of the SLNs was mediated by macropinocytosis pathway and clathrin- and caveolae (or lipid raft)-related routes. Transferrin-related endosomes, lysosomes, endoplasmic reticulum (ER), and Golgi apparatus were confirmed to be the main destinations of the SLNs in Caco-2 cells. As for the transport of the SLNs in Caco-2 cell monolayers, the results demonstrated that the SLNs transported to the basolateral side were intact, and the transport of the nanoparticles did not destroy the structure of tight junctions. The transcytosis of the SLNs across the Caco-2 cell monolayer was demonstrated to be mediated by the same routes as that in the endocytosis study. The ER, Golgi apparatus, and microtubules were confirmed to be important for the transport of the SLNs to both the basolateral and apical membrane sides. This study provides a more thoroughly understand of SLNs transportation crossing intestinal epithelial cell monolayers and could be beneficial for the fabrication of SLNs.


Assuntos
Membrana Celular/metabolismo , Lipídeos/química , Nanopartículas/química , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Endossomos/metabolismo , Recuperação de Fluorescência Após Fotodegradação , Ouro/química , Complexo de Golgi/metabolismo , Humanos , Lisossomos/metabolismo , Nanopartículas/metabolismo , Nanopartículas/toxicidade , Espécies Reativas de Oxigênio/metabolismo
12.
Int J Nanomedicine ; 10: 5671-85, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26388691

RESUMO

PURPOSE: Nanoparticles (NPs) that target bone tissue were developed using poly(lactic-co-glycolic acid) (PLGA) copolymers and tetracycline (TC)-based bone-targeting moieties. These NPs are expected to enable the transport of drugs, such as simvastatin (SIM), for the treatment of osteoporosis. METHODS: The molecular structures of TC-PLGA were validated by (1)H-NMR, and the SIM-loaded NPs were prepared using the solvent emulsification method. The surface properties, cytotoxicity, cellular uptake, cell mineralization, bone targeting potential, and animal pharmacodynamics of the TC-PLGA NPs were evaluated and compared to those of PLGA NPs. RESULTS: It was confirmed that the average particle size of the NPs was approximately 220 nm. In phosphate-buffered saline (PBS, pH 7.4), the SIM-loaded NPs exhibited a cumulative release of up to 80% within 72 hours. An in vitro cell evaluation indicated that the NPs had an excellent cellular uptake capacity and showed great biocompatibility with MC3T3-E1 cells, thereby reducing the cytotoxic effects of SIM. The cell mineralization assay showed that the SIM-loaded NPs induced osteogenic differentiation and mineralized nodule formation in MC3T3-E1 cells, thereby achieving the same effect as SIM. Preliminary findings from in vitro and in vivo bone affinity assays indicated that the TC-PLGA NPs may display increased bone-targeting efficiency compared to PLGA NPs lacking a TC moiety. The use of SIM-loaded TC-PLGA NPs in treating osteoporosis was tested through animal pharmacodynamics analyses performed in ovariectomized rats, and the results suggested that the SIM-loaded TC-PLGA NPs can improve the curative effects of SIM on the recovery of bone mineral density compared to either SIM-loaded PLGA NPs or SIM alone. CONCLUSION: Bone-targeting NPs, which were based on the conjugation of TC to PLGA copolymers, have the ability to target bone. These NPs may be developed as a delivery system for hydrophobic drugs, and they are expected to improve the curative effects of drugs, reduce the administered drug doses, and reduce side effects in other organs.


Assuntos
Osso e Ossos/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Ácido Láctico/química , Nanopartículas/química , Osteogênese/efeitos dos fármacos , Ácido Poliglicólico/química , Sinvastatina/química , Tetraciclina/química , Células 3T3 , Animais , Diferenciação Celular , Cromatografia Líquida de Alta Pressão , Feminino , Fluoresceína/química , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos ICR , Osteoporose/tratamento farmacológico , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos , Ratos Sprague-Dawley , Solventes , Propriedades de Superfície
13.
Nanomedicine ; 11(4): 855-66, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25725489

RESUMO

UNLABELLED: The amphiphilic graft copolymer poly (lactic-co-glycolic acid)-g-dextran (Dex-PLGA) was successfully synthesized to fabricate micelles for the delivery of paclitaxel with low critical micelle concentration (CMC). The sizes of paclitaxel-loaded Dex-PLGA (Dex-PLGA/PTX) micelles were kept below 100nm with a relatively narrow size distribution. This novel PTX nano-formulation was found to exhibit slightly stronger in vitro cytotoxicity against SKOV-3, OVCAR-8 and MCF-7 cells with Taxol®. However, it could overcome the drug resistance of multi-drug resistant human breast carcinoma cells (MCF-7/Adr cells). The maximum tolerated dose (MTD) of Dex-PLGA/PTX after a single dose was more than 200mg PTX/kg, which were 8-fold higher than that of Paclitaxel Injection. The in vivo antitumor activity results indicated that Dex-PLGA/PTX micelles treatments effectively suppressed the tumor growth and highly reduced the toxicity against animals than Taxol® and could eliminate the SKOV-3 tumor by highly increasing the drug dose. FROM THE CLINICAL EDITOR: Chemotherapy for cancer has always been hampered the toxic side effect of the drugs. Nanotechnology has helped to produce various drug delivery systems to minimize these side effects. In this article, the authors designed dextran-based micelles loaded with paclitaxel. They showed effective anti-tumor activity in both in vitro and in vivo experiments with significant lower systemic toxicity.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Dextranos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ácido Láctico/farmacologia , Micelas , Paclitaxel/farmacologia , Ácido Poliglicólico/farmacologia , Animais , Neoplasias da Mama/patologia , Dextranos/química , Feminino , Ácido Láctico/química , Células MCF-7 , Camundongos , Paclitaxel/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico
14.
J Control Release ; 206: 91-100, 2015 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-25796347

RESUMO

The redox responsive nanocarriers have made a considerable progress in achieving triggered drug release by responding to the endogenous occurring difference between the extra- and intra- cellular redox environments. Despite the promises, this redox difference exists both in normal and tumor tissue. So a non-selective redox responsive drug delivery system may result in an undesired drug release in normal cells and relevant side-effects. To overcome these limitations, we have developed a chitosan based glycolipid-like nanocarrier (CSO-ss-SA) which selectively responded to the reducing environment in tumor cells. The CSO-ss-SA showed an improved reduction-sensitivity which only fast degraded and released drug in 10mM levels of glutathione (GSH). The CSO-ss-SA could transport the drug fast into the human ovarian cancer SKOV-3 cells and human normal liver L-02 cells by internalization, but only fast release drug in SKOV-3 cells. By regulating the intracellular GSH concentration in SKOV-3 cells, it indicated that the cellular inhibition of the PTX-loaded CSO-ss-SA showed a positive correlation with the GSH concentration. The CSO-ss-SA was mainly located in the liver, spleen and tumor in vivo, which evidenced the passive tumor targeting ability. Despite the high uptake of liver and spleen, drug release was mainly occurred in tumor. PTX-loaded CSO-ss-SA achieved a remarkable tumor growth inhibition effect with rather low dose of PTX. This study demonstrates that a smartly designed glycolipid-like nanocarrier with selective redox sensitivity could serve as an excellent platform to achieve minimal toxicity and rapid intracellular drug release in tumor cells.


Assuntos
Quitosana/análogos & derivados , Preparações de Ação Retardada/química , Glicolipídeos/química , Animais , Linhagem Celular , Linhagem Celular Tumoral , Quitosana/metabolismo , Preparações de Ação Retardada/metabolismo , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Glicolipídeos/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Micelas , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Oxirredução , Ácidos Esteáricos
15.
Int J Nanomedicine ; 10: 665-75, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25653517

RESUMO

The delivery of chemotherapeutics into tumor cells is a fundamental knot for tumor-target therapy to improve the curative effect and avoid side effects. Here, A54 peptide-functionalized poly(lactic-co-glycolic acid)-grafted dextran (A54-Dex-PLGA) was synthesized. The synthesized A54-Dex-PLGA self-assembled to form micelles with a low critical micelle concentration of 16.79 µg·mL(-1) and diameter of about 50 nm. With doxorubicin (DOX) base as a model antitumor drug, the drug-encapsulation efficiency of DOX-loaded A54-Dex-PLGA micelles (A54-Dex-PLGA/DOX) reached up to 75%. In vitro DOX release from the A54-Dex-PLGA/DOX was prolonged to 72 hours. The A54-Dex-PLGA micelles presented excellent internalization ability into hepatoma cells (BEL-7402 cell line and HepG2 cell line) in vitro, and the cellular uptake of the micelles by the BEL-7402 cell line was specific, which was demonstrated by the blocking experiment. In vitro antitumor activity studies confirmed that A54-Dex-PLGA/DOX micelles suppressed tumor-cell (BEL-7402 cell) growth more effectively than Dex-PLGA micelles. Furthermore, in vivo biodistribution testing demonstrated that the A54-Dex-PLGA micelles had a higher distribution ability to BEL-7402 tumors than that to HepG2 tumors.


Assuntos
Antineoplásicos , Dextranos , Ácido Láctico , Ácido Poliglicólico , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dextranos/química , Dextranos/farmacocinética , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Humanos , Ácido Láctico/química , Ácido Láctico/farmacocinética , Micelas , Ácido Poliglicólico/química , Ácido Poliglicólico/farmacocinética , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Distribuição Tecidual
16.
Mol Pharm ; 12(4): 1072-83, 2015 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-25490413

RESUMO

To improve the gene transfection efficiency mediated by chitosan-g-stearic acid (CS) micelles, poly(ethylene glycol)-b-poly(γ-glutamic acid) (PG) was incorporated into a CS-based gene delivery system. CS/PG/pDNA complexes were prepared by ionic interaction. CS and PEGylated CS (PCS) micelles were introduced to prepare binary complexes for use as controls. CS/PG/pDNA complexes possessed similar sizes and presented as irregular spheroids in shape. The incorporation of PG into CS/pDNA complexes did not affect the ability of CS to compact pDNA and also showed a protective effect against DNase I based degradation of pDNA. Importantly, PG could increase gene transfection efficiency, which was also affected by the mixing methods used for the preparation of CS/PG/pDNA ternary complexes. The transfection efficiencies mediated by CS/PG/pDNA complexes against HEK293 and EC-1 cells reached up to 40.8% and 11.6%, respectively, which were much higher than those of CS/pDNA complexes (1.3% and 4.0%) and PCS/pDNA complexes (0.8% and 2.4%). In addition, the incorporation of PG into CS/pDNA complexes significantly enhanced cellular uptake in HEK293 and EC-1 cells and, additionally, improved endosomal escape and intracellular vector unpacking. However, the incorporation of PG reduced the cellular uptake of CS/PG/pDNA complexes in macrophages (RAW264.7 cells). It was further demonstrated that, in addition to a nonspecific charge-mediated binding to cell membranes, a γ-PGA-specific receptor-mediated pathway was involved in the internalization of CS/PG/pDNA complexes. These results indicated that PG played multiple important roles in enhancing the transfection efficiency of CS/PG/pDNA complexes.


Assuntos
Glicolipídeos/química , Micelas , Peptídeos/química , Polietilenoglicóis/química , Animais , Ânions , Quitosana/química , DNA/química , Eletroforese em Gel de Ágar , Endossomos/metabolismo , Técnicas de Transferência de Genes , Genes Reporter , Células HEK293 , Humanos , Macrófagos/metabolismo , Camundongos , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Ácido Poliglutâmico/análogos & derivados , Ácido Poliglutâmico/química , Polímeros/química , Ácidos Esteáricos/química , Transfecção
17.
Int J Nanomedicine ; 9: 4597-608, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25298734

RESUMO

Nowadays, a real challenge in cancer therapy is to design drug delivery systems that can achieve high concentrations of drugs at the target site for improved therapeutic effect with reduced side effects. In this research, we designed and synthesized a homing peptide-(TNYLFSPNGPIA, TNYL) modified chitosan-g-stearate (CS) polymer micelle (named T-CS) for targeting delivery. The peptide displayed specific binding affinity to EphB4 which is a member of the Eph family of receptor tyrosine protein kinases. The amphiphilic polymer T-CS can gather into micelles by themselves in an aqueous environment with a low critical micelle concentration value (91.2 µg/L) and nano-scaled size (82.1 ± 2.8 nm). The drug encapsulation efficiency reached 86.43% after loading the hydrophobic drug doxorubicin (DOX). The cytotoxicity of T-CS/DOX against SKOV3 cells was enhanced by approximately 2.3-fold when compared with CS/DOX. The quantitative and qualitative analysis for cellular uptake indicated that TNYL modification can markedly increase cellular internalization in the EphB4-overexpressing SKOV3 cell line, especially with a short incubation time. It is interesting that relatively higher uptake of the T-CS/DOX micelles by SKOV3 cells (positive-EphB4) than A549 cells (negative-EphB4) was observed when the two cells were co-incubated. Furthermore, in vivo distribution experiment using a bilateral-tumor model showed that there was more fluorescence accumulation in the SKOV3 tumor than in the A549 tumor over the whole experiment. These results suggest that TNYL-modified CS micelles may be promising drug carriers as targeting therapy for the EphB4-overexpressing tumor.


Assuntos
Antineoplásicos/farmacocinética , Quitosana/química , Doxorrubicina/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Peptídeos/química , Ácidos Esteáricos/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quitosana/farmacocinética , Doxorrubicina/química , Doxorrubicina/farmacologia , Humanos , Masculino , Camundongos , Camundongos Nus , Micelas , Microscopia Confocal , Peptídeos/farmacocinética , Ácidos Esteáricos/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Mol Pharm ; 11(10): 3716-26, 2014 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-25197948

RESUMO

An understanding of drug delivery system transport across epithelial cell monolayer is very important for improving the absorption and bioavailability of the drug payload. The mechanisms of epithelial cell monolayer transport for various nanocarriers may differ significantly due to their variable components, surface properties, or diameter. Solid lipid nanoparticles (SLNs), conventionally formed by lipid materials, have gained increasing attention in recent years due to their excellent biocompatibility and high oral bioavailability. However, there have been few reports about the mechanisms of SLNs transport across epithelial cell monolayer. In this study, the molecular mechanisms utilized by SLNs of approximately 100 nm in diameter crossing intestinal epithelial monolayer were carefully studied using a simulative intestinal epithelial monolayer formed by Madin-Darby canine kidney (MDCK) epithelial cells. The results demonstrated that SLNs transportation did not induce a significant change on tight junction structure. We found that the endocytosis of SLNs into the epithelial cells was energy-dependent and was significantly greater than nanoparticle exocytosis. The endocytosis of SLNs was found to be rarely mediated via macropinocytosis, as confirmed by the addition of 5-(N-ethyl-N-isopropyl)amiloride (EIPA) as an inhibitory agent, and mainly depended on lipid raft/caveolae- and clathrin-mediated pathways. After SLNs was internalized into MDCK cells, lysosome was one of the main destinations for these nanoparticles. The exocytosis study indicated that the endoplasmic reticulum, Golgi complex, and microtubules played important roles in the transport of SLNs out of MDCK cells. The transcytosis study indicated that only approximately 2.5% of the total SLNs was transported from the apical side to the basolateral side. For SLNs transportation in MDCK cell monolayer, greater transport (approximately 4-fold) was observed to the apical side than to the basolateral side. Our findings may present a more comprehensive understanding on the transport of SLNs across epithelial cell monolayer.


Assuntos
Nanopartículas/química , Nanopartículas/metabolismo , Amilorida/análogos & derivados , Amilorida/farmacologia , Animais , Transporte Biológico , Linhagem Celular , Cães , Endocitose/fisiologia , Exocitose/fisiologia , Células Madin Darby de Rim Canino
19.
Int J Nanomedicine ; 9: 2993-3003, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24971010

RESUMO

Cis-aconitate-modified chitosan-g-stearic acid (CA-CSO-SA) micelles were synthesized in this study to improve the gene transfection efficiency of chitosan-g-stearic acid (CSO-SA). The CA-CSO-SA micelles had a similar size, critical micelle concentration, and morphology, but their zeta potential and cytotoxicity were reduced compared with CSO-SA micelles. After modification with cis-aconitate, the CA-CSO-SA micelles could also compact plasmid DNA (pDNA) to form nanocomplexes. However, the DNA binding ability of CA-CSO-SA was slightly reduced compared with that of CSO-SA. The transfection efficiency mediated by CA-CSO-SA/pDNA against HEK-293 cells reached up to 37%, and was much higher than that of CSO-SA/pDNA (16%). Although the cis-aconitate modification reduced cellular uptake kinetics in the initial stages, the total amount of cellular uptake tended to be the same after 24 hours of incubation. An endocytosis inhibition experiment showed that the internalization mechanism of CA-CSO-SA/pDNA in HEK-293 cells was mainly via clathrin-mediated endocytosis, as well as caveolae-mediated endocytosis and macropinocytosis. Observation of intracellular trafficking indicated that the CSO-SA/pDNA complexes were trapped in endolysosomes, but CA-CSO-SA/pDNA was more widely distributed in the cytosol. This study suggests that modification with cis-aconitate improves the transfection efficiency of CSO-SA/pDNA.


Assuntos
Ácido Aconítico/química , Quitosana/química , DNA/administração & dosagem , DNA/genética , Nanocompostos/química , Ácidos Esteáricos/química , Transfecção/métodos , Células HEK293 , Humanos , Micelas , Nanocápsulas/administração & dosagem , Nanocápsulas/química , Nanocompostos/administração & dosagem , Nanocompostos/ultraestrutura
20.
Dalton Trans ; 43(21): 8062-71, 2014 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-24718303

RESUMO

As biomimetic models for [Fe]-hydrogenase, the 2-acylmethyl-6-ester group-difunctionalized pyridine-containing iron(II) complexes 1-4 have been successfully prepared via the following three separate steps. In the first step, the acylation or esterification of difunctionalized pyridine 2-(p-MeC6H4SO3CH2)-6-HOCH2C5H3N with acetyl chloride or benzoic acid gives the corresponding pyridine derivatives 2-(p-MeC6H4SO3CH2)-6-RCO2CH2C5H3N (A, R = Me; B, R = Ph). The second step involves reaction of A or B with Na2Fe(CO)4 followed by treatment of the intermediate Fe(0) complexes [Na(2-CH2-6-RCO2CH2C5H3N)Fe(CO)4] (M1, R = Me; M2, R = Ph) with iodine to afford 2-acylmethyl-6-acetoxymethyl or 6-benzoyloxymethyl-difunctionalized pyridine-containing Fe(II) iodide complexes [2-C(O)CH2-6-RCO2CH2C5H3N]Fe(CO)2I (1, R = Me; 3, R = Ph). Finally, when 1 or 3 is treated with sodium 2-mercaptopyridinate, the corresponding difunctionalized pyridine-containing Fe(ii) mercaptopyridinate complexes [2-C(O)CH2-6-RCO2C5H3N]Fe(CO)2(2-SC5H4N) (2, R = Me; 4, R = Ph) are produced. While the structures of model complexes 1-4 are confirmed by X-ray crystallography, the electrochemical properties of 2 and 4 are compared with those of the two previously reported models. In addition, complexes 2 and 4 have been found to be catalysts for H2 production in the presence of TFA under CV conditions.


Assuntos
Materiais Biomiméticos/química , Complexos de Coordenação/química , Hidrogenase/química , Proteínas Ferro-Enxofre/química , Ferro/química , Piridinas/química , Acilação , Materiais Biomiméticos/síntese química , Catálise , Domínio Catalítico , Complexos de Coordenação/síntese química , Cristalografia por Raios X , Metilação , Modelos Moleculares , Piridinas/síntese química
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