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1.
Chemistry ; 26(11): 2456-2463, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-31889346

RESUMO

Polyamine-salt aggregates (PSA) are biomimetic soft materials that have attracted great attention due to their straightforward fabrication methods, high drug-loading efficiencies, and attractive properties for pH-triggered release. Herein, a simple and fast multicomponent self-assembly process was used to construct cross-linked poly(allylamine hydrochloride)/phosphate PSAs (hydrodynamic diameter of 360 nm) containing glucose oxidase enzyme, as a glucose-responsive element, and human recombinant insulin, as a therapeutic agent for the treatment of diabetes mellitus (GI-PSA). The addition of increasing glucose concentrations promotes the release of insulin due to the disassembly of the GI-PSAs triggered by the catalytic in situ formation of gluconic acid. Under normoglycemia, the GI-PSA integrity remained intact for at least 24 h, whereas hyperglycemic conditions resulted in 100 % cargo release after 4 h of glucose addition. This entirely supramolecular strategy presents great potential for the construction of smart glucose-responsive delivery nanocarriers.


Assuntos
Sistemas de Liberação de Medicamentos , Glucose/química , Insulina/administração & dosagem , Insulina/química , Nanocápsulas/química , Poliaminas/química , Reagentes para Ligações Cruzadas/química , Diabetes Mellitus/tratamento farmacológico , Gluconatos/química , Humanos , Insulina/farmacologia
2.
Chemistry ; 26(11): 2470-2477, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-31912555

RESUMO

Multidrug resistance (MDR) is regarded as a main obstacle for effective chemotherapy, and P-glycoprotein (P-gp)-mediated drug efflux has been demonstrated to be the key factor responsible for MDR. In this study, a novel pH-responsive hybrid drug delivery system was developed by conjugating d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), a kind of P-gp inhibitor, on the surface of laponite nanodisks to overcome MDR. The prepared LM-TPGS display excellent colloidal stability, a high encapsulation efficiency of doxorubicin (DOX), and a pH-responsive drug release profile. In vitro experiments verified that LM-TPGS/DOX could exhibit significantly enhanced therapeutic efficacy in treating DOX-resistant breast cancer cells (MCF-7/ADR) through inhibiting the activity of P-gp-mediated drug efflux and effectively accumulating DOX within cancer cells. In vivo results revealed that LM-TPGS/DOX outstandingly suppressed MCF-7/ADR tumors with low side effects. Therefore, the high drug payload, enhanced inhibition efficacy to drug-resistant cells, and low side effects make the LM-TPGS/DOX a promising nanoplatform to reverse MDR for effective chemotherapy.


Assuntos
Antibióticos Antineoplásicos/química , Doxorrubicina/química , Nanocápsulas/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Composição de Medicamentos/métodos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Polietilenoglicóis/química , Polietilenoglicóis/metabolismo , Vitamina E/química , Vitamina E/metabolismo
3.
Pharm Res ; 37(3): 39, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31965330

RESUMO

PURPOSE: The intratumoral heterogeneity observed in breast cancer (BC), in particular with regard to cell surface receptor expression, can hinder the success of many targeted cancer therapies. The development of novel therapeutic agents that target more than one receptor can overcome this inherent property of tumors and can facilitate their selective internalization in cancer cells. The goal of this study is to develop a drug combination-loaded nanoparticle (NP) formulation that is actively-targeted to HER2 and EGFR receptors on BC cells. METHODS: A polymeric NP formulation was prepared which co-encapsulated a synergistic combination of the chemotherapeutic agent, paclitaxel (PTX), and the mTOR inhibitor, everolimus (EVER), and is targeted to HER2 and EGFR receptors on BC cells using antibody Fab fragments as the targeting moieties. The physicochemical characteristics of the dual-targeted formulation (Dual-NP) were evaluated, along with its cytotoxic profile (in both, monolayer and 3D BC models), as well as the degree of cellular uptake in HER2high/EGFRmod and HER2neg/EGFRlow BC cells. RESULTS: Dual-NPs were found to have significantly higher cytotoxicity relative to HER2 mono-targeted (T-NPs) and untargeted NPs (UT-NPs) in HER2high/EGFRmod monolayer BC cells after 72 h exposure, while no significant difference was observed in HER2neg/EGFRlow cells. However, in the HER2high/EGFRmod spheroids, the cytotoxicity of Dual-NPs was comparable to that of T-NPs. This was thought to be attributed to the previously reported downregulation of EGFR in 3D in comparison to 2D BC models. Dual-NPs had significantly higher cellular uptake relative to UT-NPs and T-NPs in HER2high/EGFRmod BC cells after 24 h exposure, whereas in the HER2neg/EGFRlow cells, the increase in cellular uptake of the Dual-NPs was not as high as the level achieved in the HER2high/EGFRmod cells. Blocking HER2 and EGFR significantly reduced the uptake of T-NPs and Dual-NPs in the HER2high/EGFRmod BC cells, demonstrating specific binding to both EGFR and HER2. CONCLUSIONS: The dual-targeting strategy developed in this study in conjunction with a potentially promising delivery vector for a synergistic combination therapy can overcome receptor heterogeneity, yielding significant improvements in the cytotoxicity and cellular uptake in BC cells.


Assuntos
Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Everolimo/química , Nanocápsulas/química , Paclitaxel/química , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Receptores ErbB/metabolismo , Everolimo/farmacologia , Feminino , Humanos , Terapia de Alvo Molecular/métodos , Paclitaxel/farmacologia , Panitumumabe/química , Panitumumabe/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Receptor ErbB-2/metabolismo , Propriedades de Superfície , Trastuzumab/química , Trastuzumab/metabolismo
4.
Pharm Res ; 37(3): 43, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31989336

RESUMO

PURPOSE: Pyrvinium pamoate (PP) is an anthelmintic drug that has been found to have anti-cancer activity in several cancer types. In the present study, we evaluated PP for potential anti-leukemic activity in B cell acute lymphoblastic leukemia (ALL) cell lines, in an effort to evaluate the repurposing potential of this drug in leukemia. METHODS: ALL cells were treated with PP at various concentrations to determine its effect on cell proliferation. Metabolic function was tested by evaluating Extracellular Acidification Rate (ECAR) and Oxygen Consumption Rate (OCR). Lastly, 3D spheroids were grown, and PP was reformulated into nanoparticles to evaluate distribution effectiveness. RESULTS: PP was found to inhibit ALL proliferation, with varied selectivity to different ALL cell subtypes. We also found that PP's cell death activity was specific for leukemic cells, as primary normal immune cells were resistant to PP-mediated cell death. Metabolic studies indicated that PP, in part, inhibits mitochondrial oxidative phosphorylation. To increase the targeting of PP to a hypoxic bone tumor microenvironment (BTME) niche, we successfully encapsulated PP in a nanoparticle drug delivery system and demonstrated that it retained its anti-leukemic activity in a hemosphere assay. CONCLUSION: We have demonstrated that PP is a novel therapeutic lead compound that counteracts the respiratory reprogramming found in refractory ALL cells and can be effectively formulated into a nanoparticle delivery system to target the BTME.


Assuntos
Antineoplásicos/farmacologia , Osso e Ossos/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Compostos de Pirvínio/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Morte Celular , Linhagem Celular Tumoral , Proliferação de Células , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Nanocápsulas/química , Fosforilação , Transdução de Sinais
5.
Food Chem Toxicol ; 135: 110958, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31715307

RESUMO

Nerolidol is naturally occurring sesquiterpene has wide range of biological properties including anti-inflammatory activity. However, it has high volatility with low solubility in nature. The present study aimed to develop and characterized nano-encapsulated nerolidol and evaluated its activity on zymosan-induced arthritis model. Nano-capsules were produced by interfacial deposition of preformed polymer method and characterized by particle size, pH, polydispersity index (PDI), zeta potential, drug content and transmission electron microscopy (TEM). In vitro cytotoxicity of formulations was evaluated by alamar blue and MTT assays. In vivo neutrophils migration assay was performed on intra-articular zymosan-induced arthritis model in mice. Nano-encapsulated nerolidol suspensions presented adequate properties: mean diameter of particles 219.5 ±â€¯8.4 nm, pH: 6.84 ±â€¯0.5, PDI≤0.2, the zeta potential was -20.3 ±â€¯3.6 mV and drug content 71,2 ±â€¯1.3%. The formulations did not demonstrated cytotoxicity under the conditions assessed. Nerolidol 300 mg/kg inhibited neutrophils migration into joint cavity by 18.8% remains compared with control group, and nano-encapsulated nerolidol 3 mg/kg inhibited (26.7% remains) similar to free nerolidol 10 mg/kg (27.4% remains). Histological, quantification of pro-inflammatory and anti-inflammatory cytokines proves the same results. In conclusion the data suggests that nanoencapsulation of nerolidol improved its anti-inflammatory effect on arthritis in mice.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Portadores de Fármacos/química , Nanocápsulas/química , Sesquiterpenos/uso terapêutico , Animais , Articulação do Tornozelo/efeitos dos fármacos , Articulação do Tornozelo/patologia , Artrite Experimental/induzido quimicamente , Artrite Reumatoide/induzido quimicamente , Linhagem Celular Tumoral , Feminino , Camundongos , Tamanho da Partícula , Zimosan
6.
Int J Nanomedicine ; 14: 9587-9602, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824153

RESUMO

Background: The functionalization of a nanoparticle surface with PEG (polyethylene glycol) is an approach most often used for extending nanomaterial circulation time, enhancing its delivery and retention in the target tissues, and decreasing systemic toxicity of nanocarriers and their cargos. However, because PEGylated nanomedicines were reported to induce immune response including production of anti-PEG antibodies, activation of the complement system as well as hypersensitivity reactions, hydrophilic polymers other than PEG are gaining interest as its replacement in nanomaterial functionalization. Here, we present the results of in vivo evaluation of polyelectrolyte nanocapsules with biodegradable, polyelectrolyte multilayer shells consisting of poly-l-lysine (PLL) and poly-l-glutamic (PGA) acid as a potential drug delivery system. We compared the effects of nanocapsules functionalized with two different "stealth" polymers as the external layer of tested nanocapsules was composed of PGA (PGA-terminated nanocapsules, NC-PGA) or the copolymer of poly-l-lysine and polyethylene glycol (PEG-terminated nanocapsules, NC-PEG). Methods: Nanocapsules pharmacokinetics, biodistribution and routes of eliminations were analysed postmortem by fluorescence intensity measurement. Toxicity of intravenously injected nanocapsules was evaluated with analyses of blood morphology and biochemistry and by histological tissue analysis. DNA integrity was determined by comet assay, cytokine profiling was performed using flow cytometer and detection of antibodies specific to PEG was performed by ELISA assay. Results: We found that NC-PGA and NC-PEG had similar pharmacokinetic and biodistribution profiles and both were eliminated by hepatobiliary and renal clearance. Biochemical and histopathological evaluation of long-term toxicity performed after a single as well as repeated intravenous injections of nanomaterials demonstrated that neither NC-PGA nor NC-PEG had any acute or chronic hemato-, hepato- or nephrotoxic effects. In contrast to NC-PGA, repeated administration of NC-PEG resulted in prolonged increased serum levels of a number of cytokines. Conclusion: Our results indicate that NC-PEG may cause undesirable activation of the immune system. Therefore, PGA compares favorably with PEG in equipping nanomaterials with stealth properties. Our research points to the importance of a thorough assessment of the potential influence of nanomaterials on the immune system.


Assuntos
Nanocápsulas/toxicidade , Polieletrólitos/farmacocinética , Polieletrólitos/toxicidade , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/toxicidade , Ácido Poliglutâmico/farmacocinética , Ácido Poliglutâmico/toxicidade , Animais , Citocinas/sangue , Sistemas de Liberação de Medicamentos , Feminino , Fluorescência , Camundongos Endogâmicos BALB C , Nanocápsulas/química , Especificidade de Órgãos/efeitos dos fármacos , Polieletrólitos/química , Polietilenoglicóis/química , Ácido Poliglutâmico/química , Rodaminas/química , Distribuição Tecidual , Regulação para Cima/efeitos dos fármacos
7.
J Nanobiotechnology ; 17(1): 123, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847857

RESUMO

BACKGROUND: Nanomedicine is a promising new approach to cancer treatment that avoids the disadvantages of traditional chemotherapy and improves therapeutic indices. However, the lack of a real-time visualization imaging technology to monitor drug distribution greatly limits its clinical application. Image-tracked drug delivery is of great clinical interest; it is useful for identifying those patients for whom the therapy is more likely to be beneficial. This paper discusses a novel nanomedicine that displays features of nanoparticles and facilitates functional magnetic resonance imaging but is challenging to prepare. RESULTS: To achieve this goal, we synthesized an acylamino-containing amphiphilic block copolymer (polyethylene glycol-polyacrylamide-polyacetonitrile, PEG-b-P(AM-co-AN)) by reversible addition-fragmentation chain transfer (RAFT) polymerization. The PEG-b-P(AM-co-AN) has chemical exchange saturation transfer (CEST) effects, which enable the use of CEST imaging for monitoring nanocarrier accumulation and providing molecular information of pathological tissues. Based on PEG-b-P(AM-co-AN), a new nanomedicine PEG-PAM-PAN@DOX was constructed by nano-precipitation. The self-assembling nature of PEG-PAM-PAN@DOX made the synthesis effective, straightforward, and biocompatible. In vitro studies demonstrate decreased cytotoxicity of PEG-PAM-PAN@DOX compared to free doxorubicin (half-maximal inhibitory concentration (IC50), mean ~ 0.62 µg/mL vs. ~ 5 µg/mL), and the nanomedicine more efficiently entered the cytoplasm and nucleus of cancer cells to kill them. Further, in vivo animal experiments showed that the nanomedicine developed was not only effective against breast cancer, but also displayed an excellent sensitive CEST effect for monitoring drug accumulation (at about 0.5 ppm) in tumor areas. The CEST signal of post-injection 2 h was significantly higher than that of pre-injection (2.17 ± 0.88% vs. 0. 09 ± 0.75%, p < 0.01). CONCLUSIONS: The nanomedicine with CEST imaging reflects the characterization of tumors and therapeutic functions has great potential medical applications.


Assuntos
Acrilamidas/síntese química , Antineoplásicos/química , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/química , Nanocápsulas/química , Polímeros/síntese química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Corantes Fluorescentes/química , Humanos , Imagem por Ressonância Magnética/métodos , Camundongos , Camundongos Nus , Imagem Óptica/métodos , Distribuição Tecidual
8.
J Nanobiotechnology ; 17(1): 125, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31870362

RESUMO

BACKGROUND: Multidrug resistance (MDR) is a pressing obstacle in clinical chemotherapy for breast cancer. Based on the fact that the drug efflux is an important factor in MDR, we designed a codelivery system to guide the drug efflux inhibitor verapamil (VRP) and the chemotherapeutic agent novantrone (NVT) synergistically into breast cancer cells to reverse MDR. RESULTS: This co-delivery system consists of following components: the active targeting peptide RGD, an inorganic calcium phosphate (CaP) shell and an organic inner core. VRP and NVT were loaded into CaP shell and phosphatidylserine polyethylene glycol (PS-PEG) core of nanoparticles (NPs) separately to obtain NVT- and VRP-loaded NPs (NV@CaP-RGD). These codelivered NPs allowed VRP to prevent the efflux of NVT from breast cancer cells by competitively combining with drug efflux pumps. Additionally, NV@CaP-RGD was effectively internalized into breast cancer cells by precise delivery through the effects of the active targeting peptides RGD and EPR. The pH-triggered profile of CaP was also able to assist the NPs to successfully escape from lysosomes, leading to a greatly increased effective intracellular drug concentration. CONCLUSION: The concurrent administration of VRP and NVT by organic/inorganic NPs is a promising therapeutic approach to reverse MDR in breast cancer.


Assuntos
Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Mitoxantrona/química , Nanocápsulas/química , Verapamil/química , Animais , Fosfatos de Cálcio/química , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Sobrevivência Celular , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Quimioterapia Combinada/métodos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitoxantrona/farmacologia , Terapia de Alvo Molecular , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Fosfatidilserinas/química , Polietilenoglicóis/química , Verapamil/metabolismo
9.
Chem Commun (Camb) ; 55(92): 13820-13823, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31664274

RESUMO

A supramolecular nanocapsule was constructed by the ternary host-guest complexation of azobenzene (Azo) and methylviologen (MV) to cucurbit[8]uril (CB[8]) and the subsequent self-assembly. The supramolecular nanocapsule with both glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities can mimic the intracellular enzymatic reactive oxygen species (ROS) defense system.


Assuntos
Antioxidantes/química , Hidrocarbonetos Aromáticos com Pontes/química , Imidazóis/química , Nanocápsulas/química , Células 3T3 , Animais , Compostos Azo/química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Glutationa Peroxidase/química , Glutationa Peroxidase/metabolismo , Camundongos , Microscopia Confocal , Nanocápsulas/toxicidade , Paraquat/química , Espécies Reativas de Oxigênio/química , Superóxido Dismutase/química , Superóxido Dismutase/metabolismo
10.
Int J Nanomedicine ; 14: 7017-7038, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564863

RESUMO

Background: Fabrication of a smart drug delivery system that could dramatically increase the efficiency of chemotherapeutic drugs and reduce the side effects is still a challenge for pharmaceutical researchers. By the emergence of nanotechnology, a huge window was opened towards this goal, and a wide type of nanocarriers were introduced for delivering the chemotherapeutic to the cancer cells, among them are cyclodextrins with the ability to host different types of hydrophobic bioactive molecules through inclusion complexation process. Aim: The aim of this study is to design and fabricate a pH-responsive theranostic nanocapsule based on cyclodextrin supramolecular nano-structure. Materials and methods: This nanostructure contains iron oxide nanoparticles in the core surrounded with three polymeric layers including polymeric ß-cyclodextrin, polyacrylic acid conjugated to sulfadiazine, and polyethylenimine functionalized with ß-cyclodextrin. Sulfadiazine is a pH-responsive hydrophobic component capable of making inclusion complex with ß-cyclodextrin available in the first and third layers. Doxorubicin, as an anti-cancer drug model, was chosen and the drug loading and release pattern were determined at normal and acidic pH. Moreover, the biocompatibility of the nanocapsule (with/without drug component) was examined using different techniques such as MTT assay, complement activation, coagulation assay, and hemolysis. Results: The results revealed the successful preparation of a spherical nanocapsule with mean size 43±1.5 nm and negatively charge of -43 mV that show 160% loading efficacy. Moreover, the nanocapsule has an on/off switching release pattern in response to pH that leads to drug released in low acidic pH. The results of the biocompatibility tests indicated that this nano drug delivery system had no effect on blood and immune components while it could affect cancer cells even at very low concentrations (0.3 µg mL-1). Conclusion: The obtained results suggest that this is a "switchable" theranostic nanocapsule with potential application as an ideal delivery system for simultaneous cancer diagnosis and therapy.


Assuntos
Nanocápsulas/química , Polietilenoimina/química , Nanomedicina Teranóstica , beta-Ciclodextrinas/química , Animais , Doxorrubicina/química , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Compostos Férricos/química , Hemólise/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Camundongos , Nanocápsulas/ultraestrutura , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Eletricidade Estática , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química , Difração de Raios X , beta-Ciclodextrinas/síntese química
11.
J Photochem Photobiol B ; 199: 111619, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31622787

RESUMO

Curcumin, a naturally derived polyphenolic compound has potent activities against cardiac disease like reducing hypertrophy, increasing antioxidant activity, maintaining hormone levels and blood pressure etc. Polymeric curcumin nanoparticles is a solemn concern nowadays in accordance to improve the beneficial properties of curcumin by diminishing its disadvantages like hydrophobic nature thereby results in maximum delivery of drug curcumin at the target. This study demonstrated the application of curcumin capped gold loaded poly (lactic-co-glycolic acid) nanoparticles (CAu-PLGA Nps) for the inhibition of cardiac hypertrophy by preserving myocardial functions of Wister rat model. Rat models were arbitrarily divided into five groups and observation period was 10 weeks; 1. Control 2. Enalopril (EP), an hypertropic agent induced group 3. EP and Curcumin (C) 4. EP and Curcumin capped gold (CAu) Nps and 5. EP and CAu-PLGA Nps injected group. CAu-PLGA Nps was first synthesized from double emulsion-solvent evaporation method and were characterized by its adoptable techniques such as FT-IR, XRD, SEM and TEM analysis. These analyses demonstrate the encapsulation of curcumin capped gold nanoparticles into PLGA there confirms the successful synthesis of CAu-PLGA Nps. Animals studies illustrates that the CAu-PLGA Nps has significantly produced cardiac anti-hypertrophy and drug delivery when compared to the other groups. CAu-PLGA Nps exhibit increased survival rate, improved cardiac functions like cardiac systolic and diastolic function, maintaining heart weight and left ventricle pressure at the controlled level. Beneficiary activities of CAu-PLGA Nps were associated with its cardiovascular functions like anti-inflammatory, antioxidant, controls cardiomycete growth, increased drug delivery, prevents accumulation of cholesterol and prevents myocardial infarction.


Assuntos
Anti-Inflamatórios não Esteroides/química , Cardiomegalia/tratamento farmacológico , Curcumina/química , Nanopartículas Metálicas/química , Nanocápsulas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Antioxidantes , Terapia Combinada/métodos , Curcumina/farmacocinética , Liberação Controlada de Fármacos , Emulsões/química , Ouro/química , Humanos , Masculino , Tamanho da Partícula , Fototerapia/métodos , Polimerização , Ratos , Solventes/química
12.
Eur J Pharm Sci ; 140: 105070, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31518679

RESUMO

Homogeneous PEGylated lipid bilayer coated highly ordered MSNs (PLMSNs) which were systematically optimized and characterized to co-encapsulate paclitaxel (Tax) and curcumin (Cur) were verified to manifest prolonged and enhanced cytotoxic effect against canine breast cancer cells in our previous study. In this article, we took further study of the pharmacokinetic property, cellular uptake, subcellular localization, in vivo distribution and tumor accumulation ability, and treatment efficacy of the drug delivery system. The results revealed that the delivery system could significantly increase the AUC of two drugs, and the anti-tumor effect showed that both intravenous and intratumoral administration group better controlled the tumor weight than that of other groups (P < .05), and the anti-tumor rates were 58.4% and 58.3% respectively. Cell uptake and localization study showed that PLMSNs could effectively carry drugs into cancer cells with sustained release characteristics. The subcellular localization of PLMSNs was mainly in lysosomes and mitochondria. In vivo fluorescence tracing results showed that PLMSNs could be effectively accumulated in the tumor site. The results revealed that the delivery system could effectively reduce the clinical dosage of drugs and reduce its toxic side effects, effectively carry drugs into cancer cells, and exhibit good targeting characteristics for breast cancer.


Assuntos
Antineoplásicos/farmacocinética , Curcumina/farmacocinética , Bicamadas Lipídicas/química , Nanocápsulas/química , Paclitaxel/farmacocinética , Polietilenoglicóis/química , Dióxido de Silício/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Transporte Biológico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Curcumina/administração & dosagem , Curcumina/efeitos adversos , Cães , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Quimioterapia Combinada/métodos , Feminino , Humanos , Lisossomos/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Porosidade , Ratos Sprague-Dawley , Propriedades de Superfície , Carga Tumoral/efeitos dos fármacos
13.
Chem Commun (Camb) ; 55(79): 11860-11863, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31528890

RESUMO

An easy to synthesize azobenzene based amphiphile spontaneously self-assembles into monodisperse nanoaggregates in water. The large difference in the critical aggregation concentration between the E and Z stereoisomeric forms enables photocontrol of its aggregation state over a wide concentration range: light-triggered release and uptake of lipophilic molecules is achieved in aqueous solution.


Assuntos
Compostos Azo/química , Nanocápsulas/química , Corantes Fluorescentes/química , Interações Hidrofóbicas e Hidrofílicas , Luz , Tamanho da Partícula , Processos Fotoquímicos , Polietilenoglicóis/química , Estereoisomerismo , Água/química
14.
Nat Commun ; 10(1): 4418, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562357

RESUMO

Smart drug delivery systems (SDDSs) for cancer treatment are of considerable interest in the field of theranostics. However, developing SDDSs with early diagnostic capability, enhanced drug delivery and efficient biodegradability still remains a scientific challenge. Herein, we report near-infrared light and tumor microenvironment (TME), dual responsive as well as size-switchable nanocapsules. These nanocapsules are made of a PLGA-polymer matrix coated with Fe/FeO core-shell nanocrystals and co-loaded with chemotherapy drug and photothermal agent. Smartly engineered nanocapsules can not only shrink and decompose into small-sized nanodrugs upon drug release but also can regulate the TME to overproduce reactive oxygen species for enhanced synergistic therapy in tumors. In vivo experiments demonstrate that these nanocapsules can target to tumor sites through fluorescence/magnetic resonance imaging and offer remarkable therapeutic results. Our synthetic strategy provides a platform for next generation smart nanocapsules with enhanced permeability and retention effect, multimodal anticancer theranostics, and biodegradability.


Assuntos
Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Raios Infravermelhos/uso terapêutico , Nanocápsulas/química , Neoplasias/terapia , Nanomedicina Teranóstica/métodos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacocinética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células NIH 3T3 , Nanopartículas/química , Neoplasias/metabolismo , Neoplasias/patologia , Polímeros/química , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
15.
Pharm Res ; 36(11): 160, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31520196

RESUMO

PURPOSE: Bortezomib (BTZ) is a proteasome inhibitor used for multiple myeloma and mantle cell lymphoma treatment. BTZ's aqueous in solubility is the main hindrance in its successful development as a commercial formulation. The main objective of the present study is to develop and characterize folic acid-glycine-poly-L-lactic acid (FA-Gly4-PLA) based nanoformulation (NPs) to improve solubility and efficacy of BTZ. METHODS: BTZ loaded FA-Gly4-PLA NPs were prepared and characterized for size, zeta potential, in vitro studies such as release, kinetics modeling, hemolytic toxicity, and cell line-based studies (Reactive Oxygen Species: ROS and cytotoxicity). RESULTS: BTZ loaded NPs (BTZ-loaded FA-Gly4-PLA) and blank NPs (FA-Gly4-PLA) size, zeta, and PDI were found to be 110 ± 8.1 nm, 13.7 ± 1.01 mV, 0.19 ± 0.03 and 198 ± 9.01 nm, 8.63 ± 0.21 mV, 0.21 ± 0.08 respectively. The percent encapsulation efficiency (% EE) and percent drug loading (% DL) of BTZ loaded FA-Gly4-PLA NPs was calculated to be 78.3 ± 4.1 and 12.38 ± 2.1. The Scanning Electron Microscopy (SEM) showed that NPs were slightly biconcave in shape. The in vitro release of BTZ from FA-Gly4-PLA NPs resulted in the sustained manner. The prepared NPs were less hemolytic than BTZ. CONCLUSIONS: BTZ loaded Gly4-PLA NPs apoptotic index was found to be much higher than BTZ but lesser than BTZ loaded FA-Gly4-PLA against breast cancer cell lines (MDA-MB-231). ROS intracellular assessment assay indicated that BTZ and BTZ loaded FA-Gly4-PLA NPs exhibited higher ROS production. Conclusively, the BTZ loaded FA-Gly4-PLA NPs were able to encapsulate more BTZ than BTZ loaded Gly4-PLA NPs and were found to be more effective as per as in vitro anti-cancer effect is concerned.


Assuntos
Antineoplásicos/administração & dosagem , Bortezomib/administração & dosagem , Sistemas de Liberação de Medicamentos , Ácido Fólico/química , Glicina/química , Nanocápsulas/química , Poliésteres/química , Antineoplásicos/química , Bortezomib/química , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Composição de Medicamentos/métodos , Feminino , Humanos
16.
J Photochem Photobiol B ; 199: 111606, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31522112

RESUMO

This study aimed to develop Eudragit® RL 100 nanocapsules loaded with desonide (DES) using açai oil (AO) or medium chain triglycerides (MCT) as oil core. Pre-formulation study showed that AO and MCT are suitable for nanocapsules preparation. The nanocapsules prepared with AO and MCT presented mean particle size around 165 and 131 nm, respectively; polydispersity index values <0.20, positive zeta potential values, drug content close to the theoretical value (0.25 mg mL-1), and DES encapsulation efficiency around 81%, regardless of the oil core (AO or MCT). Considering the photoinstability reported to DES, photodegradation studies were performed. The UV-A (365 nm) and UV-C (254 nm) photodegradation studies revealed less DES degradation when associated to the nanocapsules containing AO in comparison to those with MCT. The in vitro release study showed a biphasic release profile for both nanocapsule suspensions: an initial burst effect followed by a prolonged DES release. In addition, the formulations were considered non-phototoxic at 0.5 mg mL-1 when tested on 3 T3 murine fibroblasts and HaCaT human keratinocytes using the MTT and NRU viability assays. The irritant potential of the prepared nanocapsules and DES in free form were evaluated by HET-CAM method. All formulations were classified as slightly irritant, including the non-associate DES. In conclusion, the nanocapsule formulations developed in this study may be promising for therapeutic applications.


Assuntos
Anti-Inflamatórios/química , Desonida/química , Euterpe/química , Nanocápsulas/química , Óleos Vegetais/química , Ácidos Polimetacrílicos/química , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Desonida/farmacologia , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Humanos , Luz , Camundongos , Tamanho da Partícula , Fotólise , Óleos Vegetais/farmacologia , Suspensões/química , Triglicerídeos/química
17.
J Photochem Photobiol B ; 199: 111620, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31522113

RESUMO

Current scenario of bio-nanotechnology, successfully fabrication of ultrafine titanium dioxide nanoparticles (TiO2NPs) using various biological protein sources for the multipurpose targets. The present research report involves synthesis of TiO2NPs using antimicrobial peptide (AMP) crustin (Cr). Crustin previously purified from the blue crab, Portunus pelagicus haemolymph, by blue Sepharose CL-6B matrix assisted affinity column chromatography. Synthesized Cr-TiO2NPs was physico-chemically characterized by UV-Visible spectroscopy (UV-Visible), X-ray Diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), High-resolution transmission electron microscopy (HR-TEM) and zeta potential examination. X-ray diffraction analysis for crystalline nature and phase identification of titanium dioxide nanoparticles was absorbed. Functional groups were found through FTIR ranges between 1620 and 1700 cm-1. HR-TEM analysis showed that the synthesized Cr-TiO2NPs tetragonal shape and sizes ranging from 10 to 50 nm. Finally, the surface charge of the Cr-TiO2NPs was confirmed through zeta potential analysis. Furthermore, the characterized Cr-TiO2NPs exhibited good biofilm inhibition against GPB - S. mutans (Gram Positive Bacteria- Streptococcus mutans), GNB - P. vulgaris (Gram Negative Bacteria- Proteus vulgaris) and fungal Candida albicans. Moreover, photocatalysis demonstrated that the Cr-TiO2NPs was effectively explored the degradation of dyes. The results suggest that Cr-TiO2NPs is an excellent bactericidal, fungicidal and photocatalytic agent that can be supportively used for biomedical and industrial applications.


Assuntos
Anti-Infecciosos/química , Peptídeos Catiônicos Antimicrobianos/química , Inseticidas/química , Nanocápsulas/química , Processos Fotoquímicos , Titânio/química , Animais , Anti-Infecciosos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Biofilmes , Braquiúros/química , Candida albicans/efeitos dos fármacos , Catálise , Sobrevivência Celular/efeitos dos fármacos , Culicidae , Liberação Controlada de Fármacos , Humanos , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Luz , Estrutura Molecular , Proteus vulgaris/efeitos dos fármacos , Streptococcus mutans/efeitos dos fármacos
18.
Mater Sci Eng C Mater Biol Appl ; 105: 110099, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546395

RESUMO

Multi-modality strategies of albumin-mediated drug accumulation in tumor, boronate-based active tumor targeting and synergistic cancer therapy were combined together for effective treatment of breast cancer. Herein we report the development of albumin-shell oily-core nanocapsules (NCs), loaded with novel combination of hydrophobic drugs, exemestane (EXE) and hesperetin (HES), for targeted breast cancer therapy. This protein-lipid nanohybrid carrier was successfully fabricated using a simple protein-coating method based on the electrostatic adsorption of negatively charged albumin shell onto the oily core containing cationic surfactant. While EXE was directly encapsulated into the oily core, HES was pre-formulated in the form of phospholipid complex before solubilization in oily phase. In addition to albumin-mediated binding to albondin and SPARC, phenylboronic acid was chemically coupled to the albumin shell to confer additional tumor targeting. The targeted nanocarrier (TNC) demonstrated enhanced internalization into MCF-7 breast cancer cells resulting in synergistic cytotoxic activity with a combination index (CI) of 0.662 and dose reduction index (DRI) of 8.22 and 1.84 for EXE and HES, respectively. In vivo, TNC displayed superior anti-cancer activity in tumor-bearing mice compared to their non-targeted counterparts and the free drug combination. A significant reduction of both tumor volume (7-folds) and Ki67 expression (3-folds) was obtained by the targeted nanocarriers compared to positive control. Overall, the boronic-targeted albumin NCs offer a promising platform for hydrophobic drug combination against cancer therapy.


Assuntos
Androstadienos , Antineoplásicos Fitogênicos , Inibidores da Aromatase , Neoplasias da Mama , Hesperidina , Nanocápsulas , Albuminas/química , Albuminas/farmacocinética , Albuminas/farmacologia , Androstadienos/química , Androstadienos/farmacocinética , Androstadienos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Inibidores da Aromatase/química , Inibidores da Aromatase/farmacocinética , Inibidores da Aromatase/farmacologia , Boro/química , Boro/farmacocinética , Boro/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Hesperidina/química , Hesperidina/farmacocinética , Hesperidina/farmacologia , Humanos , Células MCF-7 , Nanocápsulas/química , Nanocápsulas/uso terapêutico , Fosfolipídeos/química , Fosfolipídeos/farmacocinética , Fosfolipídeos/farmacologia
19.
Mater Sci Eng C Mater Biol Appl ; 104: 110006, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499941

RESUMO

The present work shows the development and evaluation of the veterinary antibiotic cloxacillin benzathine (CLOXB) loaded into poly-ε-caprolactone (PCL) nanocapsules (NC), as a potential new treatment strategy to manage bovine intramammary infections, such as mastitis. Staphylococcus aureus-induced mastitis is often a recurrent disease due to the persistence of bacteria within infected cells. CLOXB-PCL NC were prepared by interfacial deposition of preformed biodegradable polymer followed by solvent displacement method. The mean diameter of NC varied from 241 to 428 nm and from 326 to 375 nm, when determined by dynamic light scattering and by atomic force microscopy, respectively. The zeta potential of NC was negative and varied from -28 to -51 mV. In vitro release studies from the NC were performed in two media under sink conditions: PBS with 1% polyethylene glycol or milk. A reversed-phase HPLC method was developed to determine the NC entrapment efficiency and kinetics of CLOXB release from the NC. Free CLOXB dissolution occurred very fast in both media, while drug release from the NC was slower and incomplete (below 50%) after 9 h. CLOXB release kinetics from polymeric NC was fitted with the Korsmeyer-Peppas model indicating that CLOXB release is governed by diffusion following Fick's law. The fluorescence confocal microscopy images of macrophage-like J774A.1 cells reveal NC uptake and internalization in vitro. In addition, antimicrobial effect of the intramammary administration of CLOXB-PCL NC in cows with mastitis resulted in no clinical signs of toxicity and allowed complete pathogen elimination after treatment. The in vivo results obtained in this work suggest that CLOXB-PCL NC could be a promising formulation for the treatment of intramammary infections in cattle, considering their physicochemical properties, release profiles and effects on bovine mastitis control.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Cloxacilina/análogos & derivados , Cloxacilina/química , Etilenodiaminas/química , Nanocápsulas/química , Polímeros/química , Animais , Caproatos/química , Bovinos , Linhagem Celular , Difusão , Feminino , Lactonas/química , Mastite Bovina , Camundongos , Leite/microbiologia , Polietilenoglicóis/química , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos
20.
Pharm Res ; 36(11): 153, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31482243

RESUMO

The purpose of this review is to discuss the challenges associated with the development of nanoparticle-based quality drug products in adhering to the principles of quality by design (QbD) and defining appropriate quality parameters towards successful product development. With the advent of nanotechnology into the pharmaceutical field, the novel field of nanomedicine was born. Due to their unique properties in terms of size, conformation and targeted delivery, nanomedicines are able to overcome many drawbacks of conventional medicine. As nano-sized formulations have made their way into more and more therapies, it has became clear that these very unique properties create hurdles for nanomedicines in successfully traversing the regulatory pathways and there is a need to develop nanomedicines in a more controlled and consistent fashion. The elements of a QbD methodology explained in this review enable the development of nano-based formulations in a way that maximizes the possibility of success. The identification of critical quality attributes (CQA) of the drug product and its intermediates are discussed in detail with a focus on nanomaterial-based formulations. In conclusion, QbD and the identification and specification of CQAs at its core are critical to the design, development and growth of nanomaterials in pharmaceuticals.


Assuntos
Desenvolvimento de Medicamentos/métodos , Nanocápsulas/química , Nanotecnologia/métodos , Animais , Preparações de Ação Retardada/química , Composição de Medicamentos , Estabilidade de Medicamentos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Nanomedicina , Resultado do Tratamento
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