Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 8.066
Filtrar
1.
Pharm Res ; 37(3): 34, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31942651

RESUMO

PURPOSE: Alzheimer's disease is a neurodegenerative disorder, and most common form of dementia afflicting over 35 million people worldwide. Rivastigmine is a widely used therapeutic for ameliorating clinical manifestations of Alzheimer's disease. However, current treatments require frequent dosing either orally or via transdermal patch that lead to compliance issues and administration errors risking serious adverse effects. Our objective was to develop a smart polymer based delivery system for controlled release of rivastigmine over an extended period following a single subcutaneous injection. METHODS: Rivastigmine release was optimized by tailoring critical factors including polymer concentration, polymer composition, drug concentration, solvent composition, and drug hydrophobicity (rivastigmine tartrate vs base). Optimized in vitro formulation was evaluated in vivo for safety and efficacy. RESULTS: Formulation prepared using PLGA (50:50) at 5% w/v in 95:5 benzyl benzoate: benzoic acid demonstrated desirable controlled drug release characteristics in vitro. The formulation demonstrated sustained release of rivastigmine tartrate for 7 days in vivo with promising biocompatibility and acetylcholinesterase inhibition efficacy for 14 days. CONCLUSION: The results exemplify an easily injectable controlled release formulation of rivastigmine prepared using phase-sensitive smart polymer. The optimized formulation significantly increases the dosing interval, and can potentially improve patient compliance as well as quality of life of patients living with Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/química , Portadores de Fármacos/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Rivastigmina/química , /química , Inibidores da Colinesterase/administração & dosagem , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Cinética , Transição de Fase , Rivastigmina/administração & dosagem , Solventes/química
2.
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
3.
Pharm Res ; 37(3): 36, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31965346

RESUMO

PURPOSE: We describe the preparation of injectable polymeric paste (IPP) formulations for local and sustained release of drugs. Furthermore, we include the characterization and possible applications of such pastes. Particular attention is paid to characteristics relevant to the successful clinical formulation development, such as viscosity, injectability, degradation, drug release, sterilization, stability performance and pharmacokinetics. METHODS: Paste injectability was characterized using measured viscosity and the Hagen-Poiseuille equation to determine injection forces. Drug degradation, release and formulation stability experiments were performed in vitro and drug levels were quantified using HPLC-UV methods. Pharmacokinetic evaluation of sustained-release lidocaine IPPs used five groups of six rats receiving increasing doses subcutaneously. An anti-cancer formulation was evaluated in a subcutaneous tumor xenograft mouse model. RESULTS: The viscosity and injectability of IPPs could be controlled by changing the polymeric composition. IPPs demonstrated good long-term stability and tunable drug-release with low systemic exposure in vivo in rats. Preliminary data in a subcutaneous tumor model points to a sustained anticancer effect. CONCLUSIONS: These IPPs are tunable platforms for local and sustained delivery of drugs and have potential for further clinical development to treat a number of diseases.


Assuntos
Portadores de Fármacos/química , Composição de Medicamentos/métodos , Pomadas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Anilidas/química , Anilidas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Docetaxel/química , Docetaxel/farmacologia , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Humanos , Injeções , Lidocaína/química , Lidocaína/farmacocinética , Masculino , Camundongos , Camundongos Nus , Neoplasias Experimentais , Nitrilos/química , Nitrilos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Ratos , Compostos de Tosil/química , Compostos de Tosil/farmacologia , Viscosidade
4.
J Nanobiotechnology ; 18(1): 16, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959180

RESUMO

BACKGROUND: The clustered regularly interspaced short palindromic repeats (CRISPR) and Cas9 protein system is a revolutionary tool for gene therapy. Despite promising reports of the utility of CRISPR-Cas9 for in vivo gene editing, a principal problem in implementing this new process is delivery of high molecular weight DNA into cells. RESULTS: Using poly(lactic-co-glycolic acid) (PLGA), a nanoparticle carrier was designed to deliver a model CRISPR-Cas9 plasmid into primary bone marrow derived macrophages. The engineered PLGA-based carriers were approximately 160 nm and fluorescently labeled by encapsulation of the fluorophore 6,13-bis(triisopropylsilylethynyl) pentacene (TIPS pentacene). An amine-end capped PLGA encapsulated 1.6 wt% DNA, with an encapsulation efficiency of 80%. Release studies revealed that most of the DNA was released within the first 24 h and corresponded to ~ 2-3 plasmid copies released per nanoparticle. In vitro experiments conducted with murine bone marrow derived macrophages demonstrated that after 24 h of treatment with the PLGA-encapsulated CRISPR plasmids, the majority of cells were positive for TIPS pentacene and the protein Cas9 was detectable within the cells. CONCLUSIONS: In this work, plasmids for the CRISPR-Cas9 system were encapsulated in nanoparticles comprised of PLGA and were shown to induce expression of bacterial Cas9 in murine bone marrow derived macrophages in vitro. These results suggest that this nanoparticle-based plasmid delivery method can be effective for future in vivo applications of the CRISPR-Cas9 system.


Assuntos
Proteína 9 Associada à CRISPR/genética , Sistemas CRISPR-Cas , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Proteína 9 Associada à CRISPR/metabolismo , DNA/química , Corantes Fluorescentes/química , Técnicas de Transferência de Genes , Macrófagos/metabolismo , Camundongos , Compostos de Organossilício/química , Plasmídeos , Transfecção
5.
J Shoulder Elbow Surg ; 29(1): 157-166, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31401128

RESUMO

BACKGROUND: The purpose of this study was to evaluate the biomechanical and histologic properties of rotator cuff repairs using a vented anchor attached to a bioresorbable interpositional scaffold composed of aligned PLGA (poly(l-lactide-co-glycoside)) microfibers in an animal model compared to standard anchors in an ovine model. METHODS: Fifty-six (n = 56) skeletally mature sheep were randomly assigned to a repair of an acute infraspinatus tendon detachment using a innovative anchor-PLGA scaffold device (Treatment) or a similar anchor without the scaffold (Control). Animals were humanely euthanized at 7 and 12 weeks post repair. Histologic and biomechanical properties of the repairs were evaluated and compared. RESULTS: The Treatment group had a significantly higher fibroblast count at 7 weeks compared to the Control group. The tendon bone repair distance, percentage perpendicular fibers, new bone formation at the tendon-bone interface, and collagen type III deposition was significantly greater for the Treatment group compared with the Control group at 12 weeks (P ≤ .05). A positive correlation was identified in the Treatment group between increased failure loads at 12 weeks and the following parameters: tendon-bone integration, new bone formation, and collagen type III. No statistically significant differences in biomechanical properties were identified between Treatment and Control Groups (P > .05). CONCLUSIONS: Use of a vented anchor attached to a bioresorbable interpositional scaffold composed of aligned PLGA microfibers improves the histologic properties of rotator cuff repairs in a sheep model. Improved histology was correlated with improved final construct strength at the 12-week time point.


Assuntos
Osso e Ossos/fisiologia , Lesões do Manguito Rotador/cirurgia , Tendões/fisiologia , Tecidos Suporte , Cicatrização , Implantes Absorvíveis , Animais , Materiais Biocompatíveis/uso terapêutico , Fenômenos Biomecânicos , Osso e Ossos/cirurgia , Contagem de Células , Colágeno Tipo III/metabolismo , Modelos Animais de Doenças , Feminino , Fibroblastos , Osteogênese , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/uso terapêutico , Estudos Prospectivos , Lesões do Manguito Rotador/patologia , Ovinos , Técnicas de Sutura , Tendões/cirurgia
6.
Int J Nanomedicine ; 14: 8543-8560, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31802868

RESUMO

Background: Nanoparticles exhibit great promise for improving the solubility and tissue-specific distribution of chemotherapeutic agents; however, the passive and highly variable enhanced permeability and retention (EPR) effects observed in tumors frequently leads to insufficient delivery of nanodrugs into tumors. The tumor-penetrating peptide iRGD can actively enhance tumor-selective delivery of nanoparticles into tumors by binding to integrin and interacting with tissue-penetrating receptor neuropilin-1. Materials and methods: To improve colorectal cancer treatment, in this study, we prepared a paclitaxel (PTX)-loaded PLGA nanoparticle (PLGA-PTX) and evaluated its tumor-targeting and antitumor activity by co-administration with iRGD. Results: Compared to free PTX, encapsulated PTX retained preferential cytotoxicity toward various colorectal cancer cells while effectively sparing healthy cells. PLGA-PTX treatment resulted in cell cycle arrest at the G2/M phase and apoptosis, leading to inhibition of cancer cell migration and invasion. PLGA-PTX combined with iRGD displayed little enhancement of cytotoxicity in vitro. Despite this, iRGD receptors integrin and neuropilin-1 were found to be primarily overexpressed on abundant tumor vessels in mice bearing colorectal tumors. Consequently, co-administration of nanoparticles with iRGD promoted the selective delivery of nanoparticles into tumor tissues in vivo. Additionally, the combined regimen enhanced the antitumor effects compared to those of each individual reagent. Conclusion: Our findings suggest that PLGA nanoparticles combined with the iRGD peptide provide a promising drug delivery strategy for facilitating active drug accumulation into tumors, given that iRGD receptors are overexpressed on tumor vessels. This co-administration system lacking covalent conjugation provides a more convenient means to combine various therapeutic agents with iRGD to achieve personalized nanotherapy.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Oligopeptídeos/administração & dosagem , Paclitaxel/uso terapêutico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/patologia , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/administração & dosagem , Invasividade Neoplásica , Oligopeptídeos/química , Paclitaxel/farmacologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Distribuição Tecidual
7.
Int J Nanomedicine ; 14: 8819-8834, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819410

RESUMO

Purpose: Age-related macular degeneration is a multifactorial disease involving inflammation and choroidal neovascularization. Vascular endothelial growth factor (VEGF) has been regarded as a potential therapeutic target to treat choroidal neovascularization. Dexamethasone can interfere with the expression or action of VEGF while bevacizumab targets and combines with VEGF. We propose electrostatically-conjugated bevacizumab-bearing dexamethasone-loaded poly (D,L-lactide-co-glycolide)/polyethylenimine nanoparticles (eBev-DPPNs) for angiogenic combination treatment of ocular diseases. Methods: We prepared a novel nanoparticle composed of poly (D, L-lactide-co-glycolide) and polyethylenimine and loaded the nanoparticles with dexamethasone. Bevacizumab was adsorbed onto the surfaces of the nanoparticles by electrostatic interactions. The eBev-DPPNs were evaluated according to their size, polydispersity index, zeta potential, morphology, drug loading, release behavior, and stability. The structural stability of bevacizumab on the surface of the nanoparticles was also analyzed. Subsequently, angiogenesis was investigated in the presence of the eBev-DPPNs using cell apoptosis, wound healing, Transwell invasion, and tube formation assays on the human umbilical vein endothelial cells (HUVECs) in vitro and chick embryo chorioallantoic membrane assay in vivo. The eBev-DPPNs intravitreal injection was applied in the laser-induced rabbit choroidal neovascularization (CNV) model to confirm the role for potential intravitreal applications. Results: The eBev-DPPNs was about 200 nm in diameter, with a narrow diameter distribution, and the surface charge was neutral (0.85 ± 0.37mV), which made the eBev-DPPNs stable under physiological conditions. The apoptosis, migration, invasion, and tube formation assays showed that the eBev-DPPNs had a good anti-angiogenic effect on HUVECs. The eBev-DPPNs also provided a strong inhibitory effect on VEGF secretion from HUVECs. Moreover, in vivo chick embryo chorioallantoic membrane assay showed eBev-DPPNs greatly reduced the amount of blood vessels. The leakage area of CNV decreased in the eBev-DPPNs group on rabbit CNV model. Conclusion: The eBev-DPPNs are a promising novel anti-angiogenesis therapeutic for potential intravitreal applications such as age-related macular degeneration.


Assuntos
Inibidores da Angiogênese/farmacologia , Bevacizumab/farmacologia , Dexametasona/farmacologia , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Inibidores da Angiogênese/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Bevacizumab/administração & dosagem , Embrião de Galinha , Membrana Corioalantoide/efeitos dos fármacos , Dexametasona/administração & dosagem , Liberação Controlada de Fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Injeções Intravítreas , Masculino , Nanopartículas/ultraestrutura , Coelhos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Cicatrização/efeitos dos fármacos
8.
J Biomed Nanotechnol ; 15(11): 2271-2280, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31847941

RESUMO

Stem-cell-based therapy has attracted considerable attention due to the significant benefits to patients experiencing a wide range of diseases and injuries. However, their underlying mechanism of action is not completely understood. One main reason is the lack of imaging tools for real-time tracking of deep-seated transplanted stem cells. For the present study, we exploited a lipid poly(lactic-co-glycolic acid) nanobubble (LPN) probe with nanoscale size, good compatibility, and strong contrast-enhanced ultrasound signals. Due to the nanoscale particle size, cellular labeling of mesenchymal stem cells can be achieved via incubation with LPNs. Significantly enhanced ultrasound images of these labeled stem cells were obtained in vitro and in vivo. More importantly, the labeled stem cells could be tracked by ultrasound imaging for up to 5 days. Additional evaluation found that the in vivo detection limit achieved 2,000 labeled stem cells in the subcutaneous tissues of living mice. Our study presents a strategy to achieve real-time ultrasound imaging tracking, paving the way for an investigation on the underlying mechanism and future clinical application of stem cell therapy.


Assuntos
Células-Tronco Mesenquimais , Animais , Rastreamento de Células , Glicóis , Lipídeos , Camundongos , Nanotubos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Células-Tronco
9.
Drug Deliv ; 26(1): 1049-1057, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31691602

RESUMO

Doxorubicin (DOX) is widely used in the chemotherapy of a wide range of cancers. However, intravenous administration of DOX causes toxicity to most major organs which limits its clinical application. DOX-loaded drug delivery system could provide a continuous sustained-release of drugs and enables high drug concentrations at the target site, while reducing systemic toxicity. Additionally, local chemotherapy with DOX may be a promising approach for lowering post-surgical recurrence of cancer. In this study, the sustained-release DOX-loaded implants were prepared by melt-molding method. The implants were characterized with regards to drug content uniformity, micromorphology and drug release profiles. Furthermore, differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) analyses were carried out to investigate the drug-excipient compatibility. To determine the local penetration of DOX in liver, the minipigs received intrahepatic implantation of DOX-loaded implants by abdominal surgery. UPLC-MS/MS method was used to detect the concentration of DOX in liver tissues. Our results suggested that DOX-loaded implants delivered high doses of drug at the implantation site for a prolonged period and provided valuable information for the future clinical applications of the DOX-loaded implants.


Assuntos
Doxorrubicina/administração & dosagem , Doxorrubicina/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Varredura Diferencial de Calorimetria/métodos , Cromatografia Líquida de Alta Pressão/métodos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Excipientes/química , Feminino , Fígado/efeitos dos fármacos , Masculino , Próteses e Implantes , Ratos , Ratos Wistar , Suínos , Porco Miniatura , Espectrometria de Massas em Tandem/métodos
10.
Pharm Res ; 36(12): 182, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31741089

RESUMO

PURPOSE: Combination chemotherapy is gradually receiving more attention because of its potential synergistic effect and reduced drug doses in clinical application. However, how to precisely control drug release dose and time using vehicles remains a challenge. This work developed an efficient drug delivery system to combat breast cancer, which can enhance drug effects despite reducing its concentration. METHODS: Controlled-release poly-lactic-co-glycolic acid (PLGA) scaffolds were fabricated by E-jet 3D printing to deliver doxorubicin (DOX) and cisplatin (CDDP) simultaneously. RESULTS: This drug delivery system allowed the use of a reduced drug dosage resulting in a better effect on the human breast cancer cell apoptosis and inhibiting tumor growth, compared with the effect of each drug and the two drugs administrated without PLGA scaffolds. Our study suggested that DOX-CDDP-PLGA scaffolds could efficiently destroy MDA-MB-231 cells and restrain tumor growth. CONCLUSIONS: The 3D printed PLGA scaffolds with their time-programmed drug release might be useful as a new multi-drug delivery vehicle in cancer therapy, which has a potential advantage in a long term tumor cure and prevention of tumor recurrence.


Assuntos
Antineoplásicos/química , Cisplatino/química , Doxorrubicina/química , Portadores de Fármacos/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/farmacologia , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Quimioterapia Combinada/métodos , Excipientes/química , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Impressão Tridimensional
11.
Int J Nanomedicine ; 14: 7039-7052, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564864

RESUMO

Purpose: In this study, we fabricated multifunctional, electrically conductive composites by incorporating graphene oxide (GO) into a poly (lactic-co-glycolic acid) (PLGA) copolymer for wound repair. Furthermore, the resultant composites were coupled with electrical stimulation to further improve the therapeutic effect of wound repair. Methods: We evaluated the surface morphology of the composites, as well as their physical properties, cytotoxicity, and antibacterial activity, along with the combined effects of composites and electrical stimulation (ES) in a rat model of wound healing. Results: Application of the PLGA/GO composites to full-thickness wounds confirmed their advantageous biological properties, as evident from the observed improvements in wound-specific mechanical properties, biocompatibility, and antibacterial activity. Additionally, we found that the combination of composites and ES improved composite-mediated cell survival and accelerated wound healing in vivo by promoting neovascularization and the formation of type I collagen. Conclusion: These results demonstrated that combined treatment with the PLGA/GO composite and ES promoted vascularization and epidermal remodeling and accelerated wound healing in rats, thereby suggesting the efficacy of PLGA/GO+ES for broad applications associated with wound repair.


Assuntos
Grafite/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Cicatrização , Animais , Antibacterianos/farmacologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Forma Celular/efeitos dos fármacos , Forma Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Estimulação Elétrica , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Neovascularização Fisiológica/efeitos dos fármacos , Ratos Sprague-Dawley , Propriedades de Superfície , Cicatrização/efeitos dos fármacos , Cicatrização/genética
12.
Int J Nanomedicine ; 14: 7107-7121, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564868

RESUMO

Background: Cervical cancer (CxCa) ranks as the fourth most prevalent women-related cancer worldwide. Therefore, there is a crucial need to develop newer treatment modalities. Ormeloxifene (ORM) is a non-steroidal, selective estrogen receptor modulator (SERM) that is used as an oral contraceptive in humans. Recent investigations suggest that ORM exhibits potent anti-cancer activity against various types of cancers. Nanoparticulates offer targeted delivery of anti-cancer drugs with minimal toxicity and promise newer approaches for cancer diagnosis and treatment. Therefore, the nanotherapy approach is superior compared to traditional chemotherapy, which is not site-specific and is often associated with various side effects. Methods: Pursuing this novel nanotherapy approach, our lab has recently developed ORM-loaded poly [lactic-co-glycolic acid] (PLGA), an FDA-approved biodegradable polymer, nanoparticles to achieve targeted drug delivery and improved bioavailability. Our optimized PLGA-ORM nanoformulation showed improved internalization in both dose- and energy-dependent manners, through endocytosis-mediated pathways in both Caski and SiHa cell lines. Additionally, we employed MTS and colony forming assays to determine the short- and long-term effects of PLGA-ORM on these cells. Results: Our results showed that this formulation demonstrated improved inhibition of cellular proliferation and clonogenic potential compared to free ORM. Furthermore, the PLGA-ORM nanoformulation exhibited superior anti-tumor activities in an orthotopic cervical cancer mouse model than free ORM. Conclusion: Collectively, our findings suggest that our novel nanoformulation has great potential for repurposing the drug and becoming a novel modality for CxCa management.


Assuntos
Benzopiranos/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Benzopiranos/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Clonais , Modelos Animais de Doenças , Endocitose/efeitos dos fármacos , Eritrócitos/metabolismo , Feminino , Hemólise/efeitos dos fármacos , Humanos , Teste de Materiais , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Nus , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Soro/química , Neoplasias do Colo do Útero/patologia
13.
Int J Nanomedicine ; 14: 7191-7213, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564873

RESUMO

Background: Diosmin showed poor water solubility and low bioavailability. Poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles were successfully used to improve the drugs solubility and bioavailability. Coating of PLGA nanoparticles with chitosan can ameliorate their gastric retention and cellular uptake. Methodology: PLGA nanoparticles of diosmin were prepared using different drug and polymer amounts. Nanoparticles were selected based on entrapment efficiency% (EE%) and particle size measurements to be coated with chitosan. The selected nanoparticles either uncoated or coated were evaluated regarding morphology, ζ-potential, solid-state characterization, in vitro release, storage stability, and mucoadhesion. The anti-ulcer activity (AA) against ethanol-induced ulcer in rats was assessed through macroscopical evaluation, histopathological examination, immunohistochemical localization of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and transmission electron microscopic examination of gastric tissues compared to free diosmin (100 mg/kg) and positive control. Results: Based on EE% and particle size measurements, the selected nanoparticles, either uncoated or coated with 0.1% w/v chitosan, were based on 1:15 drug-PLGA weight ratio and 20 mg diosmin employing methylene chloride as an organic phase. Examination by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed nanoscopic spherical particles. Drug encapsulation within the selected nanoparticles was suggested by Fourier transform-infrared, differential scanning calorimetry (DSC) and X-ray diffractometry results. Chitosan-coated nanoparticles were more stable against size enlargement probably due to the higher ζ-potential. Only coated nanoparticles showed gastric retention as revealed by SEM examination of stomach and duodenum. The superior AA of coated nanoparticles was confirmed by significant reduction in average mucosal damage, the majority of histopathological changes and NF-κB expression in gastric tissue when compared to positive control, diosmin and uncoated nanoparticles as well as insignificant difference relative to normal control. Coated nanoparticles preserved the normal ultrastructure of the gastric mucosa as revealed by TEM examination. Conclusion: The optimized chitosan-coated PLGA nanoparticles can be represented as a potential oral drug delivery system of diosmin.


Assuntos
Antiulcerosos/uso terapêutico , Quitosana/química , Diosmina/uso terapêutico , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Estômago/patologia , Úlcera/tratamento farmacológico , Adesividade , Animais , Antiulcerosos/farmacologia , Varredura Diferencial de Calorimetria , Diosmina/farmacologia , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Duodeno/efeitos dos fármacos , Duodeno/patologia , Duodeno/ultraestrutura , Mucosa Gástrica/patologia , Mucosa Gástrica/ultraestrutura , Cinética , Masculino , Muco/química , NF-kappa B/metabolismo , Nanopartículas/ultraestrutura , Tamanho da Partícula , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier , Estômago/efeitos dos fármacos , Estômago/ultraestrutura , Úlcera/patologia , Difração de Raios X
14.
Int J Nanomedicine ; 14: 7627-7642, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571868

RESUMO

Purpose: Focused ultrasound-mediated chemotherapy, as a non-invasive therapeutic modality, has been extensively explored in combating deep tumors for predominant penetration performance. However, the generally used high-intensity focused ultrasound (HIFU) inevitably jeopardizes normal tissue around the lesion for hyperthermal energy. To overcome this crucial issue, low-intensity focused ultrasound (LIFU) was introduced to fulfill precisely controlled imaging and therapy in lieu of HIFU. The objective of this study was to develop a facile and versatile nanoplatform (DPP-R) in response to LIFU and provide targeted drug delivery concurrently. Methods: Multifunctional DPP-R was fabricated by double emulsion method and carbodiimide method. Physicochemical properties of DPP-R were detected respectively and the bio-compatibility and bio-safety were evaluated by CCK-8 assay, blood analysis, and histologic section. The targeted ability, imaging function, and anti-tumor effect were demonstrated in vitro and vivo. Results: The synthetic DPP-R showed an average particle size at 367 nm, stable physical-chemical properties in different media, and high bio-compatibility and bio-safety. DPP-R was demonstrated to accumulate at the tumor site by active receptor/ligand reaction and passive EPR effect with intravenous administration. Stimulated by LIFU at the tumor site, phase-transformable PFH was vaporized in the core of the integration offering contrast-enhanced ultrasound imaging. The stimuli led to encapsulated DOX's initial burst release and subsequent sustained release for anti-tumor therapy which was verified to be more effective and have less adverse effects than free DOX. Conclusion: DPP-R combined with LIFU provides a novel theranostic modality for GC treatment with potent therapeutic effect, including prominent performance of targeting, ultrasound imaging, and accurate drug release.


Assuntos
Doxorrubicina/uso terapêutico , Composição de Medicamentos , Nanopartículas/química , Transição de Fase , Neoplasias Gástricas/terapia , Nanomedicina Teranóstica , Ultrassonografia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Feminino , Fluorcarbonetos/química , Humanos , Concentração de Íons de Hidrogênio , Camundongos Nus , Oligopeptídeos/química , Imagem Óptica , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Neoplasias Gástricas/tratamento farmacológico , Distribuição Tecidual/efeitos dos fármacos
15.
Zhonghua Fu Chan Ke Za Zhi ; 54(10): 680-686, 2019 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-31648444

RESUMO

Objective: To investigate whether poly (lactic-co-glycolic acid) (PLGA) as protein delivery vehicles that encapsulate CC chemokine receptor 5 antibody (anti-CCR5) has more suppressive function on macrophages than single anti-CCR5 in mouse endometriosis model. Methods: The PLGA/anti-CCR5 nanoparticles were synthesized. The cumulative release of anti-CCR5 from PLGA/anti-CCR5 nanoparticles was evaluated. The mouse endometriosis model was established and divided into control group, anti-CCR5 group and PLGA/anti-CCR5 group. Meanwhile, ectopic endometrial cells (EEC) and macrophages isolated from peritoneal fluid were cultured in vitro. Flow cytometry was used to detect the proportion of macrophages in the peritoneal fluid of each group. The secretion of interleukin 10 (IL-10) and transforming growth factor ß (TGF-ß) in each group were determined by ELISA. The proliferation and infiltration of EEC were detected by 5-bromodeoxyuridine proliferation kit and matrigel invasion kit. Results: The PLGA/anti-CCR5 nanoparticles were successfully synthesized. The mouse endometriosis model was established and the EEC and macrophages were cultured. Compared with the anti-CCR5 without nanoparticles, the bioconjugate PLGA/anti-CCR5 nanoparticles could control the release of anti-CCR5 from day 3 to day 24. The proportion of macrophages in PLGA/anti-CCR5 group were gradually reduced compared with those in anti-CCR5 group (P<0.01), the ratios of day 7 [(4.5±1.5)%] and day 3 [(6.3±0.6)%], day 14 [(2.6±0.7)%] and day 7 were significantly different (P<0.01 and P<0.05). PLGA/anti-CCR5 reduced IL-10 and TGF-ß levels relative to anti-CCR5 (P<0.01),and decreased gradually on day 3, day 7, and day 14 (P<0.01). Anti-IL-10+anti-TGF-ß could reduce the proliferation [(70.8±7.6)%] and invasion ability [(50.2±9.1)%] of EEC (P<0.05). Conclusions: In mouse endometriosis model, PLGA/anti-CCR5 may inhibit the proliferation and invasion of EEC by inhibiting the secretion of IL-10 and TGF-ß by macrophages, suggesting that it provide a new idea for the treatment of clinical endometriosis.


Assuntos
Endometriose/tratamento farmacológico , Ácido Láctico/química , Nanopartículas/uso terapêutico , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/uso terapêutico , Receptores CCR5/uso terapêutico , Animais , Endometriose/imunologia , Feminino , Humanos , Camundongos , Nanopartículas/química , Resultado do Tratamento
16.
Eur J Pharm Biopharm ; 145: 65-75, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31628997

RESUMO

With a very poor prognosis and no clear etiology, glioma is the most aggressive cancer in the brain. Thanks to its versatility, nanomedicine is a promising option to overcome the limitations on chemotherapy imposed by the blood brain barrier (BBB). The objective of this paper was to obtain monitored tumor-targeted therapeutic nanoparticles (NPs). To that end, theranostic surfactant-coated polymer poly-Lactic-co-Glycolic Acid (PLGA) nanoplatform encapsulating doxorubicin hydrochloride (DOX) and superparamagnetic iron oxide NPs (SPIONs) were developed. Different non-ionic surfactants known as BBB crossing enhancers (Tween 80, Brij-35, Pluronic F68 or Vitamin E-TPGS) were used to develop 4 types of theranostic nanoplatforms, which were characterized in terms of size and morphology by DLS, TEM and STEM-HAADF analyses. Moreover, the 3-month stability test, the therapeutic efficacy against different glioma cell lines (U87-MG, 9L/LacZ and patient derived-neuronal stem cells) and the Magnetic Resonance Imaging (MRI) relaxivity were studied. Results showed that the synthesised nanoplatforms were stable at 4 °C after their lyophilization, being that of paramount importance to ensure a long-term stability in a future in vivo application. Furthermore, the theranostic nanoplatforms were efficient in the in vitro treatment of glioma cells, proving to have imaging efficacy as MRI contrast agents. Our results show an efficient loading of drugs and good value of the relaxivity. Therefore, the efficient theranostic hybrid nanoplatform developed here could be used to perform MRI-guided delivery of hydrophobic drugs.


Assuntos
Antineoplásicos/química , Doxorrubicina/química , Portadores de Fármacos/química , Glioma/tratamento farmacológico , Nanopartículas de Magnetita/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Humanos , Tamanho da Partícula , Ratos , Tensoativos/química
17.
Int J Nanomedicine ; 14: 8073-8094, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632019

RESUMO

Background and objective: Targeted drug delivery of nanoparticles decorated with site-specific recognition ligands is of considerable interest to minimize cytotoxicity of chemotherapeutics in the normal cells. The study was designed to develop CD-340 antibody-conjugated polylactic-co-glycolic acid (PLGA) nanoparticles loaded with a highly water-soluble potent anticancer drug, doxorubicin (DOX), to specifically deliver entrapped DOX to breast cancer cells. Methods: The study showed how to incorporate water-soluble drug in a hydrophobic PLGA (85:15) based matrix which otherwise shows poor drug loading due to leaching effect. The optimized formulation was covalently conjugated to anti-human epidermal growth factor receptor-2 (HER2) antibody (CD-340). Surface conjugation of the ligand was assessed by flow cytometry, confocal microscopy, and gel electrophoresis. Selectivity and cytotoxicity of the experimental nanoparticles were tested on human breast cancer cells SKBR-3, MCF-7, and MDA-MB-231. Both CD-340-conjugated and unconjugated nanoparticles were undergone in vitro and in vivo characterization. Result: Higher level of incorporation of DOX (8.5% W/W), which otherwise shows poor drug loading due to leaching effect of the highly water-soluble drug, was seen in this method. In HER2-overexpressing tumor xenograft model, radiolabeled antibody-conjugated nanoparticles showed preferentially more of the formulation accumulation in the tumor area when compared to the treatments with the unconjugated one or with the other control groups of mice. The ligand conjugated nanoparticles showed considerable potential in reduction of tumor growth and cardiac toxicity of DOX in mice, a prominent side-effect of the drug. Conclusion: In conclusion, CD-340-conjugated PLGA nanoparticles containing DOX preferentially delivered encapsulated drug to the breast cancer cells and in breast tumor and reduced the breast tumor cells by apoptosis. Site-specific delivery of the formulation to neoplastic cells did not affect normal cells and showed a drastic reduction of DOX-related cardiotoxicity.


Assuntos
Apoptose/efeitos dos fármacos , Cardiotoxicidade/tratamento farmacológico , Doxorrubicina/uso terapêutico , Nanopartículas/química , Receptor ErbB-2/metabolismo , Carga Tumoral/efeitos dos fármacos , Animais , Anticorpos/metabolismo , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Doxorrubicina/sangue , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Feminino , Humanos , Cinética , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Distribuição Tecidual/efeitos dos fármacos
18.
Int J Nanomedicine ; 14: 8095-8104, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632020

RESUMO

Introduction: Nimbolide (Nim), a limonoid obtained from the neem tree, Azadirachta indica, has several pharmacological properties, including anticancer effects in different type of cancers. No drug-delivery system has been reported for enhancing the therapeutic application of this novel hydrophobic molecule. Methods: In the present research, poly(lactic-co-glycolic acid) (PLGA) nanoparticles of Nim (Nim-nano) were formulated by nanoprecipitation, characterized for physicochemical properties, and screened for anticancer potential in breast (MCF-7 and MDA-MB-231) and pancreatic (AsPC-1) cancer cell lines. Results: The Nim-nano had a particle size of 183.73±2.22 nm and 221.20±11.03 nm before and after lyophilization, respectively. Cryoprotectants (mannitol and sucrose) significantly inhibited growth in particle size due to lyophilization. The ζ-potential of the Nim-nano was -22.40±4.40 mV. Drug loading and encapsulation efficiency of Nim-nano were 5.25%±1.12% and 55.67%±12.42%, respectively. The Nim-nano exhibited sustained release of Nim for more than 6 days in PBS (pH 7.4) and showed two- to three-fold enhanced cytotoxicity in breast and pancreatic cancer cell lines compared with free Nim. Conclusion: The Nim-nano formulation has great potential for treatment of cancers, such as pancreatic and breast cancer. Further, the PLGA-polymer surface can be modified by conjugation with polyethylene glycol, receptor-binding ligands (eg, folic acid), and other that which may lead to targeted delivery of Nim in the treatment of cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Limoninas/administração & dosagem , Limoninas/uso terapêutico , Nanopartículas/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias da Mama/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Crioprotetores/farmacologia , Liberação Controlada de Fármacos , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Limoninas/química , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Eletricidade Estática
19.
Beijing Da Xue Xue Bao Yi Xue Ban ; 51(5): 907-912, 2019 Oct 18.
Artigo em Chinês | MEDLINE | ID: mdl-31624397

RESUMO

OBJECTIVE: It has been proven that acetylsalicylic acid (aspirin), as a kind of classical non-steroidal anti-inflammatory drug, not only has the effect of anti-inflammatory, but also has the function of immunity regulation and mineralization. However, it needs further investigation to study how to delay release of aspirin for a long time and enable to promote bone regeneration. Herein, we demonstrated that the longterm delayed release pattern of aspirin through the construction of microsphere scaffolds is promising to achieve the excellent bone regeneration. METHODS: Here we synthesized three kinds of scaffolds as follows: (1) aspirin loaded calcium silicate (CaSiO3) microsphere (CaSiO3-aspirin) via simple immersion; (2) aspirin loaded polylactic-co-glycolic acid (PLGA) microsphere (PLGA-aspirin) via oil/water (O/W) emulsion; (3) aspirin loaded PLGA-CaSiO3 scaffold (PLGA-CaSiO3-aspirin) via O/W emulsion, optimal morphology and structure of PLGA-CaSiO3-aspirin scaffold was acquired through modulating the ratio between PLGA and CaSiO3. Furthermore, spectrophotometer was used to monitor the concentration of the extract of the three scaffolds for different releasing time, including 1, 2, 4, 6, 9, 13, 17, 21, 24, 30, 36, and 45 days, aspirin loading efficiency and its accumulation releasing curves were both achieved according to the concentration of aspirin. Their sustained release effects of aspirin were evaluated eventually. RESULTS: Environmental scanning electron microscope (ESEM) results showed that the surface structure of the three kinds of scaffolds were smooth and had uniform size distribution. In addition, a small amount of PLGA-aspirin microspheres occurred to aggregation, while a small amount of CaSiO3-aspirin microspheres were broken. Moreover, the PLGA-aspirin microspheres in the PLGA-CaSiO3-aspirin scaffolds were uniformly adhered to the surface of CaSiO3 microspheres. The aspirin loadings of CaSiO3-aspirin, PLGA-aspirin, and PLGA-CaSiO3-aspirin were (1.06±0.04)%, (7.05±0.06)%, and (6.75±0.18)%, respectively. In addition, their corresponding time for releasing 95% of aspirin was 3, 24, and 36 days, respectively. The releasing time of PLGA-CaSiO3-aspirin was longer than that of the others and the releasing rate was more stable. CONCLUSION: The microsphere scaffold of PLGA-CaSiO3-aspirin composites has excellent delayedrelease effect on aspirin, which is promising for using as osteogenic materials.


Assuntos
Aspirina , Preparações de Ação Retardada , Microesferas , Ácido Láctico , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico
20.
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
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA