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1.
AAPS PharmSciTech ; 20(8): 317, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31605252

RESUMO

The present work aims to develop folate-targeted paclitaxel liposome (F-PTX-LIP), which will selectively target tumor cells overexpressing folate receptor (FR) and leave normal cells. Liposomes were prepared by thin-film hydration method followed by post-insertion of synthesized ligand 1,2-distearoyl-sn-glycero-phosphoethanolamine-polyethyleneglycol 2000-folic acid (DSPE-PEG2000-FA) on the outer surface of the liposome. The synthesized ligand was evaluated for in vivo acute toxicity in Balb/c mice. Developed liposomal formulations were characterized using transmission electron microscopy (TEM) and small-angle neutron scattering (SANS). We have investigated the effect of ligand number on cell uptake and cytotoxicity by confocal laser scanning microscopy (CLSM), competitive inhibition and 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay. Compared to lung adenocarcinoma cells (A549), uptake in human ovarian carcinoma cells (SKOV3) was 2.2- and 1.2-fold higher for liposome with 480 and 240 ligand number respectively. Competitive inhibition experiment shows that prior incubation of SKOV3 cells with free folic acid significantly reduced the cell uptake of F-PTX-LIP with 480 ligand number (480 F-PTX-LIP) by 2.6-fold. 480 F-PTX-LIP displays higher cytotoxicity than free drug and PTX liposome. Moreover, it specifically targets the cells with higher folate receptor expression. Optimized 480 F-PTX-LIP formulation can be potentially useful for the treatment of folate receptor-positive tumors.


Assuntos
Ácido Fólico/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/administração & dosagem , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Ligantes , Lipossomos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Ovarianas/química , Fosfatidiletanolaminas/administração & dosagem , Polietilenoglicóis/administração & dosagem
2.
Drug Des Devel Ther ; 13: 3307-3319, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571832

RESUMO

Purpose: Hyaluronic acid-poly(ethylene glycol)-distearoyl phosphoethanolamine (HA-PEG-DSPE) modified and tocopheryl polyethylene glycol 1000 succinate (TPGS) contained nanostructured lipid carriers (NLCs) were prepared loading ropivacaine and dexmedetomidine to improve the topical anesthetic analgesic anesthesia efficiency. Methods: NLCs were prepared by the solvent diffusion method. The average particle size, zeta potential, release behavior, and cytotoxicity of the NLCs were tested. Ex vivo skin permeation was studied using a Franz diffusion cell mounted with depilated rat skin. Local anesthesia antinociceptive efficiency was evaluated by rat tail flick latency study in vivo. Results: NLCs have sizes of about 100 nm, with negative zeta potentials. All the NLCs formulations were found to be significantly less cytotoxic than free drugs at equivalent concentrations. The cumulative amount of drugs penetrated through rat skin from NLCs was 2.0-4.7 folds higher than that of the drugs solution. The in vivo anesthesia antinociception study displayed that NLCs showed stronger and longer anesthesia antinociceptive effect when compared with single drugs loaded NLCs and drugs solution even at a lower dosage of drugs. Conclusion: The results demonstrated that the HA modified, TPGS contained, dual drugs loaded NLCs could perform a synergistic effect and may reduce the amount of drugs, which can lower the toxicity of the system and at the meanwhile, increase the anesthesia antinociceptive efficiency.


Assuntos
Analgésicos/administração & dosagem , Anestésicos Locais/administração & dosagem , Dexmedetomidina/administração & dosagem , Portadores de Fármacos/química , Ropivacaina/administração & dosagem , Administração Cutânea , Analgésicos/farmacologia , Anestésicos Locais/farmacologia , Animais , Células 3T3 BALB , Dexmedetomidina/farmacologia , Liberação Controlada de Fármacos , Ácido Hialurônico , Lipídeos , Camundongos , Nanopartículas , Nanoestruturas/administração & dosagem , Tamanho da Partícula , Fosfatidiletanolaminas/administração & dosagem , Fosfatidiletanolaminas/farmacologia , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacologia , Ratos , Ratos Sprague-Dawley , Ropivacaina/farmacologia , Absorção Cutânea , Vitamina E/administração & dosagem
3.
Biol Pharm Bull ; 42(7): 1216-1225, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257297

RESUMO

Small interfering RNA (siRNA) has been proposed as a novel treatment for atopic dermatitis (AD) because it suppresses sequence-specific mRNA expression. Indeed siRNA-based therapy achieves an almost complete cure with fewer side effects than currently available treatments. However, the tight junctions in the granular layer of the epidermis in the atopic skin are barriers to siRNA delivery. We previously reported the potential clinical utility of AT1002, a peptide that opens tight junctions. In the present study, we evaluated a topical siRNA-based therapy for AD using AT1002 in combination with a flexible liposome. The 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)/cholesteryl hemisuccinate (CHEMS) liposome was chosen as a carrier for siRNA because of its highly flexible structure and permeability. We prepared siRNA-encapsulated DOPE/CHEMS liposomes and examined their physical properties, safety, uptake into RAW264.7 cells, and topical application in healthy and AD-affected skin. We then assessed the efficacy of anti-nuclear factor-kappa B (NF-κB) (RelA) siRNA (siRelA)-encapsulated DOPE/CHEMS liposomes with AT1002 in AD model mice. The siRNA-DOPE/CHEMS liposomes were absorbed significantly better than siRNA alone and they enhanced siRNA skin penetration without toxicity. Moreover, siRelA-DOPE/CHEMS liposomes with AT1002 alleviated AD symptoms and reduced the levels of inflammatory cytokines in AD model mice. Therefore, the combination of AT1002 and DOPE/CHEMS liposomes could be a dermally applied RNA interference therapeutic system for effective RNA delivery and AD treatment.


Assuntos
Dermatite Atópica/terapia , Oligopeptídeos/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Fator de Transcrição RelA/genética , Administração Tópica , Animais , Sobrevivência Celular , Ésteres do Colesterol/administração & dosagem , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidiletanolaminas/administração & dosagem , Células RAW 264.7 , Interferência de RNA , Pele/metabolismo , Junções Íntimas/metabolismo
4.
Int J Pharm ; 567: 118492, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31271815

RESUMO

Liposome is one of the promising technologies for antigen delivery in cancer immunotherapies. It seems that the phospholipid content of liposomes can act as immunostimulatory molecules in cancer immunotherapy. In the present study, the immunological properties of different phospholipid content of liposomal antigen delivery platforms were investigated. To this aim, F1 to F4 naïve liposomes (without tumor-specific loaded antigens) of positively charged DOTAP/Cholesterol/DOPE (4/4/4 mol ratio), negatively charged DMPC/DMPG/Cholesterol/DOPE (15/2/3/5), negatively charged DSPC/DSPG/Cholesterol/DOPE (15/2/3/5) and PEGylated HSPC/mPEG2000-DSPE/Cholesterol (13/110) liposomal compositions were administered in mice bearing C26 colon carcinoma to assess tumor therapy. Moreover, In-vitro studies were conducted, including cytotoxicity assay, serum cytokines measurements, IFN-γ and IL-4 ELISpot assay, T cells subpopulation frequencies assay. The liposomes containing DOTAP and DOPE (F1 liposomes) were able to stimulate cytotoxic T lymphocytes signals such as IFN-γ secretions. In parallel, the aforementioned phospholipids stimulated secretion of IL-4 and IL-17 cytokines from T helper cells. However, these liposomes did not improve survival indices in mice. As conclusion, DOTAP and DOPE contained liposomes (F1 liposomes) stimulate a mixture of Th1 and Th2 immune responses in a tumor-specific antigens-free manner in mice bearing C26 colon carcinoma. Therefore, phospholipid composition of liposomes merits consideration in designing antigen-containing liposomes for cancer immunotherapy.


Assuntos
Ácidos Graxos Monoinsaturados/administração & dosagem , Imunoterapia , Neoplasias/terapia , Fosfatidiletanolaminas/administração & dosagem , Compostos de Amônio Quaternário/administração & dosagem , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocinas/sangue , Citocinas/imunologia , Lipossomos , Camundongos Endogâmicos BALB C , Neoplasias/imunologia , Neoplasias/patologia , Carga Tumoral
5.
Biol Pharm Bull ; 42(6): 996-1003, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155597

RESUMO

A small interfering RNA (siRNA) delivery system using dioleylphosphate-diethylenetriamine conjugate (DOP-DETA)-based liposomes (DL) was assessed for systemic delivery of siRNA to tumors. DL carrying siRNA capable of inducing efficient gene silencing with low doses of siRNA were modified with polyethylene glycol (PEG-DL/siRNA) for systemic injection of siRNA. The biodistribution of DL and siRNA in the PEG-DL/siRNA was studied by using radiolabeled DL and fluorescence-labeled siRNA, respectively. DL in the PEG-DL/siRNA showed a high retention in the plasma, accumulation in the tumor, and low accumulation in the liver and spleen after intravenous injection. The in vivo effects of PEGylation were observed only when distearoylphosphatidylethanolamine (DSPE)-PEG but not distearoylglycerol (DSG)-PEG were used. This result suggests that the electrostatic interaction between lipid molecules on the surface of PEG-DL/siRNA was a critical determinant for the in vivo effect of PEGylation. When PEG-DL/siRNA (0.1 mg/kg siRNA) was intravenously injected into tumor-bearing mice, in vivo gene silencing was observed in subcutaneous tumors. These results indicate that PEG-DL/siRNA designed in this study is a promising formulation for systemic use of siRNA.


Assuntos
Neoplasias/genética , Fosfatidiletanolaminas/administração & dosagem , Polietilenoglicóis/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Animais , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Inativação Gênica , Vetores Genéticos , Humanos , Lipossomos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/metabolismo , Fosfatidiletanolaminas/química , Fosfatidiletanolaminas/farmacocinética , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/sangue , RNA Interferente Pequeno/química , RNA Interferente Pequeno/farmacocinética , Baço/metabolismo , Distribuição Tecidual
6.
Drug Deliv ; 26(1): 70-77, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30744424

RESUMO

Gout is a kind of joint disease characterized by the accumulation of monosodium urate (MSU) crystals in the joint and its surrounding tissue, causing persistent hyperuricemia. Colchicine is the first choice of treatment for acute gout attacks. Due to strong toxicity of colchicines oral tablets, there are high fluctuations of blood drug concentration and serious irritation of gastrointestinal tract, and hence a transdermal preparation can help to slow down the blood drug concentration, reduce the frequency of drug taking, and improve the patients' compliance of the drug. The ethosome is a lipid carrier with high concentration of ethanol and has been proved to promote the penetration of drugs into the skin. Borneol (BO) is an excellent penetration enhancer in Chinese medicine, which can promote the entry of drugs into the skin. This paper prepared the borneol-physically-modified colchicine ethosome (COL-bpES) and used the prepared borneol-dioleoyl phosphoethanloamine (BO-DOPE) to prepare borneol-chemically-modified colchicine ethosome (COL-bcES). Compared to the free colchicine aqueous solution (free COL) and normal colchicine ethosome (COL-ES), the borneol-modified colchicine ethosome (COL-bES) demonstrated better drug penetration effect, while the particle size of the COL-bcES was lower than that of the COL-bpES. Toxicity, in vitro diffusion, pharmacokinetics and pharmacodynamics are superior to those of COL-bpES, providing a better delivery system for the treatment of small molecule inflammatory drugs.


Assuntos
Artrite Gotosa/tratamento farmacológico , Colchicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Fosfatidiletanolaminas/administração & dosagem , Absorção Cutânea/efeitos dos fármacos , Administração Cutânea , Animais , Artrite Gotosa/metabolismo , Artrite Gotosa/patologia , /metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Colchicina/química , Colchicina/metabolismo , Desenho de Fármacos , Humanos , Masculino , Camundongos , Técnicas de Cultura de Órgãos , Fosfatidiletanolaminas/química , Fosfatidiletanolaminas/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Absorção Cutânea/fisiologia
7.
Curr Drug Deliv ; 16(2): 111-122, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30360740

RESUMO

BACKGROUND: Gemcitabine (GEM) is found effective in the treatment of many solid tumors. However, its use is restricted due to its small circulation half-life, fast metabolism and low capacity for selective tumor uptake. Folate receptors (FRs) have been recognized as cellular surface markers, which can be used for cancer targeting. PEGylated liposomes decorated with folic acid have been investigated for several anticancer agents not only to extend plasma half-life but also for tumor targeting via folic acid receptors which overexpressed on tumor cell surface. OBJECTIVE: Therefore, the objective of the present study was to prepare GEM-loaded folic acid tagged liposomes to improve the pharmacokinetics and tumor distribution of GEM. METHODS: The blank folate-targeted liposomes composed of HSPC/DSPE-mPEG2000/DSPE-mPEG-Folic acid were prepared first by thin film hydration technique. GEM was then loaded into liposomes by remote loading technique. The optimized liposomal formulations were evaluated in vitro for GEM release using dialysis technique, HeLa cell uptake using FACS technique, and cytotoxicity using MTT dye reduction assay. The comparative in vivo pharmacokinetic and biodistribution characteristics of radiolabeled (99mTc-labeled) plain GEM solution, and all liposomal formulations (conventional:CLs; stealth: SLs; folate targeted: FTLs) were evaluated in mice model. RESULTS: GEM-loaded FTLs showed sustained release profile, efficient uptake by HeLa cells and greater cytotoxicity. Further, FTLs displayed significantly improved pharmacokinetics, and biodistribution profile of loaded GEM. CONCLUSION: In conclusion, the developed GEM-loaded folic acid receptor-targeted liposomal formulation could be a promising and potential alternative formulation for further development.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Desoxicitidina/análogos & derivados , Ácido Fólico/administração & dosagem , Fosfatidiletanolaminas/administração & dosagem , Polietilenoglicóis/administração & dosagem , Animais , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/administração & dosagem , Desoxicitidina/química , Desoxicitidina/farmacocinética , Liberação Controlada de Fármacos , Feminino , Ácido Fólico/química , Ácido Fólico/farmacocinética , Células HeLa , Humanos , Lipossomos , Camundongos , Fosfatidiletanolaminas/química , Fosfatidiletanolaminas/farmacocinética , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Distribuição Tecidual
8.
Pharm Nanotechnol ; 6(2): 116-123, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30207210

RESUMO

BACKGROUND: Patients undergoing chemotherapy can develop resistance not only to the administered drug, but also to many other unrelated types of drugs, a phenomenon known as multidrug resistance. One of the most common mechanisms of multidrug resistance is an elevated expression of drug efflux pumps. Codelivery of an efflux pump inhibitor with a chemotherapeutic can increase the killing of multidrug-resistant cancer cells. OBJECTIVE: Our hypothesis was that delivering doxorubicin directly to the cytosol of multidrug resistant cancer cells via a folate-targeted liposome loaded with a perfluoropentane emulsion droplet and doxorubicin (folated eLipoDox), along with the delivery of verapamil to block the efflux pumps will prove to be more effective in killing multidrug resistant cancer cells compared to conventional drug delivery. METHOD: Multidrug-resistant KB-V1 cells and doxorubicin-sensitive KB-3-1 cells were treated with 500 µM verapamil and 6.5 µM doxorubicin for 2 hours. Cell viability was measured 48 hours later via an MTT assay. RESULTS: Doxorubicin-sensitive KB-3-1 cells had a cell viability of 29% when treated with verapamil and folated eLipoDox, whereas multidrug-resistant KB-V1 cells had a cell viability of 25% (p=0.38). The co-delivery of verapamil and folated eLipoDox produced the greatest toxicity to KB-V1 and KB- 3-1 cells. CONCLUSION: We conclude that the cytosolic delivery of doxorubicin via folated eLipoDox combined with the blocking of export pumps via verapamil can overcome the multidrug resistance of KB-V1 cells and even significantly reduce the viability of doxorubicin-sensitive KB-3-1 cells.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Bloqueadores dos Canais de Cálcio/administração & dosagem , Doxorrubicina/administração & dosagem , Ácido Fólico/administração & dosagem , Verapamil/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Combinação de Medicamentos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Células KB , Lipossomos , Fosfatidiletanolaminas/administração & dosagem , Polietilenoglicóis/administração & dosagem
9.
Eur J Pharm Sci ; 125: 11-22, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30219410

RESUMO

Drug-fortified cationic liposomes of 6­methoxy­2­naphthylacetic acid (6­MNA) were prepared and characterized by various techniques. The residence time of drug-fortified liposomes in joint cavity was evaluated by intra-articular (IA) administration of the radio-labeled (99mTc) liposomal formulation in the inflamed joints in rats. The cationic liposomal formulation composed of 6­MNA (3) as an active agent, its double salt (4) with the lipid 1,2­distearoyl­sn­glycero­3­phosphoethanolamine (DSPE), and pharmaceutically acceptable excipients such as hydrogenated soyabean phospatidylcholine (HSPC) and 1,2­dioleyloxy­3­trimethylammoniumpropane chloride (DOTAP) were developed using thin film hydration technique. The cryo-TEM analysis confirmed that the prepared optimized liposomal formulation (DFL-2) was a mixture of small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs) and multilamellar vesicles (MLVs). In addition, the TEM analysis confirmed that the prepared liposomes were of spherical in shape having liposome size in the range of 500-900 nm and zeta potential of about +30 mV. The developed cationic liposomes exhibited sustained release profile of payload of 6­MNA for over >12 h and about five times higher retention in the inflamed animal joints after 24 h (by scintigraphy of the joints) as compared to the plain 6­MNA solution when administered by IA route. The anti-inflammatory activity of prepared liposomal composition is evaluated by Freund's adjuvant induced arthritic model in rats. The liposomal formulation was well tolerated by all animals indicating good biocompatibility. Further, the cationic liposomal formulation treated group showed decreased erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level in comparison to the control and the standard groups in the in vivo study. The improved efficacy of the drug-fortified liposomal formulation was due to the coupled effect of longer retention and sustained release of the active drug 6­MNA in the joints. From the obtained results it could be concluded that the combined effect of the cationic charge on the drug-fortified liposomes and the inherent affinity of the active agent towards the synovial joint tissues, coupled with slow release of the active drug due to double salt approach at the site of administration could potentially decrease the frequency of IA drug administration. Hence such a formulation could prove to be a therapeutic boon for the management of late stage arthritis.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Artrite Experimental/tratamento farmacológico , Ácidos Naftalenoacéticos/administração & dosagem , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Ácidos Graxos Monoinsaturados/administração & dosagem , Ácidos Graxos Monoinsaturados/farmacocinética , Lipossomos , Masculino , Camundongos , Células NIH 3T3 , Ácidos Naftalenoacéticos/farmacocinética , Fosfatidilcolinas/administração & dosagem , Fosfatidilcolinas/farmacocinética , Fosfatidiletanolaminas/administração & dosagem , Fosfatidiletanolaminas/farmacocinética , Compostos de Amônio Quaternário/administração & dosagem , Compostos de Amônio Quaternário/farmacocinética , Ratos Sprague-Dawley
10.
Eur J Pharm Sci ; 124: 240-248, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30071282

RESUMO

Effective chemotherapy for clinical glioma treatment is still lacking due to the poor penetration of blood-brain barrier (BBB) and the poor internalization into tumor cells. To facilitate the transmigration across the BBB as well as the glioma targeting of chemotherapeutics, we constructed cell penetrating peptide dNP2 and tumor microenvironment-cleavable folic acid (FA) dual modified, paclitaxel (PTX) loaded liposome for the targeted delivery of glioma. The modification of dNP2 significantly enhanced the transmigration across the BBB in an in vitro BBB model. The acid-cleavable cFd-Lip/PTX exhibited sensitive cleavage of FA at pH 6.8, which led to enhanced cellular uptake mediated by both cell penetrating peptide dNP2 and the interaction between FA and folate receptor (FR) on the glioma cells. After intravenous injection, compared with non-cleavable Fd-Lip and single modified liposomes, cFd-Lip enhanced the accumulation in orthotropic glioma and improved the anti-tumor effect of glioma-bearing mice. The dual modified liposomes also facilitated deep penetration into tumor cells and consequently enhanced the cytotoxicity of PTX-loaded liposomes. The acid-cleavable dual modified strategy retained the BBB penetrating and tumor targeting ability, meanwhile, the cleavage of FA further maximized the cell permeability of dNP2, exhibiting enhanced tumor targeting effect. The multi-targeting strategy provides a promising approach towards targeted chemotherapy for glioma.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Peptídeos Penetradores de Células/administração & dosagem , Ácido Fólico/administração & dosagem , Glioma/tratamento farmacológico , Paclitaxel/administração & dosagem , Animais , Antineoplásicos Fitogênicos/química , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Peptídeos Penetradores de Células/química , Feminino , Receptores de Folato com Âncoras de GPI/metabolismo , Ácido Fólico/química , Glioma/metabolismo , Concentração de Íons de Hidrogênio , Lipossomos , Camundongos Endogâmicos BALB C , Terapia de Alvo Molecular , Paclitaxel/química , Fosfatidiletanolaminas/administração & dosagem , Fosfatidiletanolaminas/química , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química
11.
J Control Release ; 288: 148-160, 2018 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-30099017

RESUMO

Autophagy acts as a cytoprotective mechanism for malignant tumors, thus maintaining the survival and promoting proliferation and metastasis of malignant tumors. Recent studies have showed that autophagy inhibitors can enhance the chemotherapeutic efficacy of anti-tumor growth. However, the antimetastasis effects and the possible mechanisms of chemotherapeutics combined with autophagy inhibitors have not been thoroughly explored. Here, we prepared R8-dGR peptide modified paclitaxel (PTX) and hydroxychloroquine (HCQ) co-loaded liposomes (PTX/HCQ-R8-dGR-Lip) for enhanced delivery by recognizing integrin αvß3 receptors and neuropilin-1 receptors on B16F10 melanoma cells. Our results showed that R8-dGR modified liposomes (R8-dGR-Lip) enhanced tumor-targeting delivery in vitro and in vivo. Besides, PTX/HCQ-R8-dGR-Lip exhibited the optimum inhibitory effects on migration, invasion and anoikis resistance of B16F10 cells in vitro, and showed enhanced efficiency on inhibiting primary tumor growth and reducing lung metastasis in vivo. Meanwhile, the antimetastasis mechanism studies confirmed that the combination of the chemotherapeutic PTX and the autophagy inhibitor HCQ further suppressed the degradation of paxillin, the expression of MMP9 and MMP2. Moreover, HCQ disturbed the CXCR4/CXCL12 axis which could induce invasion and metastasis of malignant melanoma in an autophagy-independent way.


Assuntos
Antineoplásicos/administração & dosagem , Hidroxicloroquina/administração & dosagem , Melanoma/tratamento farmacológico , Oligopeptídeos/administração & dosagem , Paclitaxel/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Autofagia/efeitos dos fármacos , Linhagem Celular , Humanos , Integrina alfaVbeta3/metabolismo , Lipossomos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Melanoma/metabolismo , Melanoma/patologia , Camundongos Endogâmicos C57BL , Neuropilina-1/metabolismo , Paxilina/metabolismo , Fosfatidiletanolaminas/administração & dosagem , Polietilenoglicóis/administração & dosagem , Receptores CXCR4/metabolismo
12.
Biomater Sci ; 6(9): 2360-2374, 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30019051

RESUMO

Prodrug self-nanoassemblies have many advantages for anticancer drug delivery, including high drug loading rate, resistance to recrystallization, and on-demand drug release. However, few studies have focused on their protein corona, which is inevitably formed after entering the blood and determines their subsequent fates in vivo. To actively tune the protein corona of prodrug nanoassemblies, three maleimide-paclitaxel prodrugs were synthesized via different redox-sensitive linkers (ester bond, thioether bond and disulfide bond). After incubation with rat plasma, the surface maleimide groups effectively captured albumins, resulting in albumin-enriched protein corona. The recruited albumin corona enabled enhanced tumor accumulation and facilitated cellular uptake, ensuring the high-efficiency delivery of nanoassemblies to tumor cells. Surprisingly, we found that the traditionally reduction-sensitive disulfide bond could also be triggered by reactive oxygen species (ROS). Such a redox dual-responsive drug release property of the disulfide bond-containing prodrug nanoassemblies further increased the selectivity in cytotoxicity between normal and tumor cells. Moreover, the disulfide bond-containing prodrug nanoassemblies exhibited the highest antitumor efficacy in vivo compared to marketed Abraxane® and other prodrug nanoassemblies. Thus, the fabrication of the maleimide-decorated disulfide bond bridged prodrug nanoassembly, integrating a tunable protein corona and on-demand drug release, is a promising strategy for improved cancer chemotherapy.


Assuntos
Antineoplásicos Fitogênicos/química , Nanoestruturas/química , Paclitaxel/química , Pró-Fármacos/química , Coroa de Proteína/química , Soroalbumina Bovina/química , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dissulfetos/química , Liberação Controlada de Fármacos , Endocitose , Feminino , Humanos , Maleimidas/administração & dosagem , Maleimidas/química , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Nanoestruturas/administração & dosagem , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Fosfatidiletanolaminas/administração & dosagem , Fosfatidiletanolaminas/química , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
13.
J Pediatr Hematol Oncol ; 40(6): e373-e376, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29889801

RESUMO

The aim of the present study was to evaluate the efficiency and side effects of mifamurtide in childhood osteosarcoma (OS). In total, 477 doses of 2 mg/m intravenous (IV) mifamurtide, along with paracetamol as a premedication, were given to 15 patients with primary nonmetastatic OS after complete surgical resection and to 3 patients with progressive OS. The most common side effects encountered in the patients were chills and fever (17/18). These reactions were observed in 4 patients during the administration of each dose, in a single patient during the last administration, and in the remaining 12 patients during the first or initial 2 administrations. Headache, myalgia, and arthralgia were observed in 2 patients during each infusion. Headache was observed in 1 patient with additional hearing loss during the first 2 infusions. One patient had back pain occuring within the first infusion. Of the 15 patients with primary nonmetastatic OS and treated with the addition of mifamurtide to chemotherapy, 13 showed a complete remission, and 2 patients were still under treatment with a complete remission. Of 3 patients with progressive disease, 2 died while the disease progressed further in the third case over a 51-month period. The 3-year overall survival and event-free survival distributions were 87.5% (mean follow-up time, 46.12; 95% confidence interval, 37.79-52.45 mo) and 75.6% (mean follow-up time, 31.30; 95% confidence interval, 26.54-36.06 mo), respectively. We consider that mifamurtide therapy is a safe and well-tolerated agent in childhood OS.


Assuntos
Acetilmuramil-Alanil-Isoglutamina/análogos & derivados , Neoplasias Ósseas , Osteossarcoma , Fosfatidiletanolaminas , Acetaminofen/administração & dosagem , Acetaminofen/efeitos adversos , Acetilmuramil-Alanil-Isoglutamina/administração & dosagem , Acetilmuramil-Alanil-Isoglutamina/efeitos adversos , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Criança , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/mortalidade , Fosfatidiletanolaminas/administração & dosagem , Fosfatidiletanolaminas/efeitos adversos , Estudos Retrospectivos , Taxa de Sobrevida , Turquia/epidemiologia
14.
J Control Release ; 283: 241-260, 2018 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-29885417

RESUMO

Aberrant lipid accumulation in both endothelial cells and macrophage foam cells as well as atherogenic inflammation in the atherosclerotic lesions, if left untreated, eventually lead to plaque rupture and arterial damage, causing devastating consequences. In this report, we explore a dual cell therapy modality by designing a dual-targeting core-shell nanoplatform to deliver siRNA against lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1 siRNA) and atorvastatin (AT) to control lipid trafficking to and from endothelial cells and macrophages in the atherosclerotic lesions selectively and sequentially. The core-shell nanoparticles are composed of a poly(D,L-lactide-co-glycolide) (PLGA) core for AT encapsulation and siRNA complexation and three external layers: a lipid bilayer as the inner layer for cholesterol receiving, apolipoprotein A-I (apoA-I) as the intermediate layer for macrophage targeting, and hyaluronic acid (HA)-DOPE as the outermost layer for endothelial cell targeting. The nanoplatform is designed such that it can shed the HA-DOPE layer extracellularly upon encountering HAase type II (Hyal-2) to expose the intermediate apoA-I layer for enhanced entry into macrophages. We thoroughly characterized dual-targeting bifunctional core-shell nanoparticles and studied the dual-targeting mechanism and biofunctions of the nanoplatform both in vitro and in vivo. Following a 12-week biweekly dosing regimen, the core-shell nanoparticles coated with high molecular weight HA (200 kDa) exhibited the most potent anti-atherosclerotic activities as evidenced by 39% plaque size reduction, 63% decrease in lipid accumulation, 68% reduction in CD68+ macrophage content and 74% reduction in monocyte chemoattractant protein 1 (MCP-1) content compared with the baseline group. Taken together, the dual-targeting bifunctional core-shell nanoparticles exert a synergistic therapeutic effect on both endothelial cells and macrophages as a dual cell therapy modality to regress atherosclerotic plaques.


Assuntos
Atorvastatina/administração & dosagem , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Placa Aterosclerótica/terapia , RNA Interferente Pequeno/administração & dosagem , Receptores Depuradores Classe E/genética , Animais , Colesterol/administração & dosagem , Endocitose , Humanos , Ácido Hialurônico/administração & dosagem , Masculino , Camundongos Knockout para ApoE , Nanopartículas/administração & dosagem , Fosfatidiletanolaminas/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Células THP-1
15.
J Control Release ; 292: 67-77, 2018 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-29723611

RESUMO

Nanoparticles (NPs) offer new solutions for the diagnosis and treatment of tumors. However, the anti-tumor effect has not been greatly improved. Tumors are easily spread through the lymphatic system while the traditional NPs (~100 nm) can hardly reach lymph nodes for the treatment of metastasis. In addition, the NPs with fixed particle size cannot achieve efficient "penetration" and long-term "retention" simultaneously. Herein, we established "transformable" micelles modified with azide/alkyne groups for click chemical reaction. Not surprisingly, the small micelles (~25 nm) could effectively target lymph nodes, limiting the growth of the metastases associated with their size-regulated abilities to extravasate from the vasculature. Tumor lymph node metastasis dropped by 66.7%. After reaching primary tumors, cycloaddition reaction occurred between groups on micelles, resulting in the formation of aggregates. The strategy resulted in improved retention of the micelles in 4 T1 cells both in vitro and in vivo owing to the decreasing of nanoparticle exocytosis and minimizing the backflow to the bloodstream. Enhanced cytotoxicity on 4 T1 cells and improved antitumor efficacy were also observed. S-PTX (+) exhibited 76.23% tumor suppression, and tumor mass at the end of the treatment also showed the best tumor inhibitory effect. In conclusion, this drug delivery system provides a strategy for effective treatment of the primary tumor and lymphatic metastasis.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Metástase Linfática/prevenção & controle , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Fosfatidiletanolaminas/administração & dosagem , Polietilenoglicóis/administração & dosagem , Animais , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Micelas , Tamanho da Partícula
16.
Food Funct ; 9(5): 3008-3017, 2018 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-29774334

RESUMO

Ethanolamine plasmalogen (pPE), a major phospholipid in neuronal membranes, is specifically reduced in postmortem brains from patients with Alzheimer's disease (AD). The purpose of the present study was to compare the effects of EPA-enriched ethanolamine plasmalogen (EPA-pPE) and EPA-enriched phosphatidylethanolamine (EPA-PE) on cognitive deficiency and illustrate the possible underlying mechanisms. SD rats were divided into four groups including the sham group injected with 0.9% saline and three amyloid-ß (Aß) infusion groups, Aß42 group, EPA-pPE group and EPA-PE group. EPA-pPE and EPA-PE were administered by gavage (150 mg kg-1 day-1), respectively, once a day for 26 days. Administration of EPA-pPE exerted better effects than EPA-PE in improving Aß-induced cognitive deficiency in a rat model of Alzheimer's disease. Further mechanical research indicated that EPA-pPE was superior to EPA-PE in regulating oxidative stress via increasing SOD activity and decreasing MDA level, as well as reducing GSK-3ß and tau phosphorylation. Moreover, EPA-PE was more effective than EPA-pPE at inhibiting the protein expressions of Bax and caspase 9. The results of neuro-inflammation and inflammasome activation showed that EPA-pPE exerted more significant effects than EPA-PE in inhibiting the expressions of TNF-α and IL-1ß, and decreasing NLRP3, pro-caspase 1 and caspase 1 levels. EPA-pPE alleviated Aß-induced neurotoxicity by inhibiting oxidative stress, neuronal injury, apoptosis and neuro-inflammation, which might depend on the vinyl ether linkage at the sn-1 position.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Ácido Eicosapentaenoico/administração & dosagem , Fosfatidiletanolaminas/administração & dosagem , Plasmalogênios/administração & dosagem , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/toxicidade , Animais , Apoptose/efeitos dos fármacos , Cognição/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
17.
Eur J Pharm Biopharm ; 128: 188-199, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29678733

RESUMO

Drugs that are neither lipophilic nor suitable for encapsulation via remote loading procedures are generally characterized by low entrapment efficiencies and poor retention in liposomes. One approach to circumvent this problem consists in covalently linking a lipid to the drug molecule in order to permit its insertion into the vesicle membrane. The nature of the conjugated lipid and linker, as well as the composition of the liposomal bilayer were found to have a profound impact on the pharmacokinetic properties and biodistribution of the encapsulated drugs as well as on their biological activity. This contribution reviews the past and recent developments on liposomal lipid-drug conjugates, and discusses important issues related to their stability and in vivo performance. It also provides an overview of the data that were generated during the clinical assessment of these formulations. The marketing authorization of the immunomodulating compound mifamurtide in several countries as well as the promising results obtained with the lipid prodrug of mitomycin C suggest that carefully designed liposomal formulations of lipid-drug conjugates is a valid strategy to improve a drug's pharmacokinetic profile and with that its therapeutic index and/or efficacy.


Assuntos
Acetilmuramil-Alanil-Isoglutamina/análogos & derivados , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Lipídeos/farmacocinética , Mitomicina/farmacocinética , Fosfatidiletanolaminas/farmacocinética , Acetilmuramil-Alanil-Isoglutamina/administração & dosagem , Acetilmuramil-Alanil-Isoglutamina/química , Acetilmuramil-Alanil-Isoglutamina/farmacocinética , Animais , Humanos , Lipídeos/administração & dosagem , Lipídeos/química , Lipossomos , Taxa de Depuração Metabólica , Mitomicina/administração & dosagem , Mitomicina/química , Fosfatidiletanolaminas/administração & dosagem , Fosfatidiletanolaminas/química , Solubilidade , Distribuição Tecidual
18.
Drug Deliv Transl Res ; 8(3): 602-616, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29536348

RESUMO

Polysialic acid (PSA) is a nonimmunogenic and biodegradable polysaccharide. In recent years, PSA has shown its potential applications to cancer treatment. In this study, PSA-polyethylene glycol (PEG) conjugate was synthesized for the decoration of epirubicin (EPI)-loaded liposomes. The study aimed to evaluate the PSA-PEG conjugated modified liposomes (EPI-PSL) in vitro and in vivo to investigate the role of PSA on physicochemical characteristics and antitumor activity in PEGylated liposomes. EPI-PSL showed a particle size of 116.9 ± 5.2 nm, zeta potential of - 40.3 ± 3.5 mV, and encapsulation efficiency of 99.1 ± 1.5%. The results of in vitro release experiments showed a delayed release of EPI from EPI-PSL. Greater cellular uptake of EPI-PSL was observed compared with PEGylated liposomes (EPI-PL) in B16 cells. Cytotoxicity studies suggested that EPI-PSL exhibited stronger cytotoxic activity than EPI-PL. Though EPI-PSL exhibited comparable blood plasma profiles with EPI-PL, biodistribution studies proved that the distribution of EPI-PSL in tumors was more than that of EPI-PL. The superior antitumor efficacy of EPI-PSL was also verified in the B16 xenograft mouse model with a reduction in systemic toxicity. In conclusion, these results therefore indicated that PSA-modified PEGylated liposomes may represent an excellent anticancer drug delivery system for targeted cancer therapy.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Epirubicina/administração & dosagem , Polietilenoglicóis/administração & dosagem , Ácidos Siálicos/administração & dosagem , Animais , Antibióticos Antineoplásicos/sangue , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Transporte Biológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Epirubicina/sangue , Epirubicina/química , Epirubicina/farmacocinética , Lipossomos , Masculino , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Fosfatidiletanolaminas/administração & dosagem , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Ratos Wistar , Ácidos Siálicos/química , Carga Tumoral/efeitos dos fármacos
19.
Am J Trop Med Hyg ; 98(3): 849-856, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29363446

RESUMO

We conducted an open label, dose escalation Phase 1 clinical trial of a tetravalent dengue DNA vaccine (TVDV) formulated in Vaxfectin® to assess safety and immunogenicity. A total of 40 dengue- and flavivirus-naive volunteers received either low-dose (1 mg) TVDV alone (N = 10, group 1), low-dose TVDV (1 mg) formulated in Vaxfectin (N = 10, group 2), or high-dose TVDV (2 mg, group 3) formulated in Vaxfectin® (N = 20). Subjects were immunized intramuscularly with three doses on a 0-, 30-, 90-day schedule and monitored. Blood samples were obtained after each immunization and various time points thereafter to assess anti-dengue antibody and interferon gamma (IFNγ) T-cell immune responses. The most common adverse events (AEs) across all groups included mild to moderate pain and tenderness at the injection site, which typically resolved within 7 days. Common solicited signs and symptoms included fatigue (42.5%), headache (45%), and myalgias (47.5%). There were no serious AEs related to the vaccine or study procedures. No anti-dengue antibody responses were detected in group 1 subjects who received all three immunizations. There were minimal enzyme-linked immunosorbent assay and neutralizing antibody responses among groups 2 and 3 subjects who completed the immunization schedule. By contrast, IFNγ T-cell responses, regardless of serotype specificity, occurred in 70%, 50%, and 79% of subjects in groups 1, 2, and 3, respectively. The largest IFNγ T-cell responses were among group 3 subjects. We conclude that TVDV was safe and well-tolerated and elicited predominately anti-dengue T-cell IFNγ responses in a dose-related fashion.


Assuntos
Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/biossíntese , Vacinas contra Dengue/administração & dosagem , Vírus da Dengue/imunologia , Dengue/prevenção & controle , Imunidade Celular/efeitos dos fármacos , Vacinas de DNA/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/química , Adulto , Dengue/imunologia , Dengue/virologia , Vacinas contra Dengue/efeitos adversos , Fadiga/etiologia , Fadiga/fisiopatologia , Feminino , Cefaleia/etiologia , Cefaleia/fisiopatologia , Humanos , Esquemas de Imunização , Imunogenicidade da Vacina , Injeções Intramusculares , Interferon gama/biossíntese , Interferon gama/imunologia , Masculino , Mialgia/etiologia , Mialgia/fisiopatologia , Segurança do Paciente , Fosfatidiletanolaminas/administração & dosagem , Fosfatidiletanolaminas/química , Vacinação , Vacinas de DNA/efeitos adversos
20.
Int J Pharm ; 535(1-2): 333-339, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-29146539

RESUMO

The work aimed to evaluate the feasibility to design hyaluronic acid (HA) decorated flexible liposomes to enhance the skin penetration of nifedipine. Egg phosphatidylcholine (e-PC) based transfersomes (Tween 80) and transethosomes (ethanol) were prepared. HA was reacted with 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (HA-DPPE) and two molar ratios (0.5 and 3%) of conjugate with respect to e-PC were tested. The presence of HA significantly increased the packing order of the bilayer (as verified by differential scanning calorimetry), reducing both the encapsulation efficiency and the flexibility of the decorated liposomes in a dose-dependent manner. In fact, at the highest HA content the constant of deformability (K, N/mm) increased and the carriers remained on the skin surface after topical application. The stiffening effect of HA was counterbalanced by the addition of ethanol as fluidizing agent that allowed to maintain the highest HA concentration, meanwhile reducing the K value of the vesicles. HA-transethosomes allowed a suitable nifedipine permeation (J ∼ 30 ng/cm2/h) and significantly improved the drug penetration, favouring the formation of a drug depot in the epidermis. These data suggest the potentialities of HA-transethosomes as drug delivery systems intended for the treatment of cutaneous pathologies and underline the importance of studying the effect of surface functionalization on carrier deformability to rationalize the design of such systems.


Assuntos
Sistemas de Liberação de Medicamentos , Ácido Hialurônico/administração & dosagem , Nifedipino/administração & dosagem , Administração Cutânea , Bloqueadores dos Canais de Cálcio/administração & dosagem , Humanos , Ácido Hialurônico/química , Lipossomos , Fosfatidilcolinas/administração & dosagem , Fosfatidilcolinas/química , Fosfatidiletanolaminas/administração & dosagem , Fosfatidiletanolaminas/química , Pele/metabolismo , Absorção Cutânea
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