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1.
Int J Nanomedicine ; 14: 8345-8360, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695371

RESUMO

Background: The protective role of puerarin (PUE) against myocardial infarction is closely related to its regulation on mitochondria. However, free PUE can hardly reach the mitochondria of ischemic cardiomyocytes due to the lack of mitochondrial targeting of PUE. Here PUE was loaded into mitochondria-targeted micelles (PUE@TPP/PEG-PE) for precisely delivering PUE into mitochondria with the aim of enhancing the anti-apoptosis effect. Methods: The mitochondriotropic polymer TPP-PEG-PE was synthesized for the preparation of PUE@TPP/PEG-PE micelles modified with triphenylphosphonium (TPP) cation. The physicochemical properties and anti-apoptosis effect of PUE@TPP/PEG-PE micelles were investigated. The coumarin 6 (C6)-labeled TPP/PEG-PE (C6@TPP/PEG-PE) micelles were used to observe the enhanced cellular uptake, mitochondrial targeting and lysosomes escape. Moreover, in vivo and ex vivo biodistribution of lipophilic near-infrared dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR)-labeled PUE@TPP/PEG-PE (DiR@TPP/PEG-PE) micelles were detected through fluorescence imaging. Results: The successful synthesis of TPP-PEG-PE conjugate was confirmed. PUE@TPP/PEG-PE micelles had a particle size of 17.1 nm, a zeta potential of -6.2 mV, and a sustained-release behavior. The in vitro results showed that the intracellular uptake of C6@TPP/PEG-PE micelles was significantly enhanced in H9c2 cells. C6@TPP/PEG-PE micelles could deliver C6 to mitochondria and reduce the capture of lysosomes. In addition, compared with the PUE@PEG-PE micelles and free PUE, the PUE@TPP/PEG-PE micelles exerted an enhanced protective effect against isoprenaline-induced H9c2 cell apoptosis, as evident by the decreased percentage of apoptotic cells, Caspase-3 activity, ROS level, Bax expression, and increased Bcl-2 expression. The in vivo detecting results of the targeting effect using DiR probe also indicated that TPP/PEG-PE micelles could accumulate and retain in the ischemic myocardium. Conclusion: The results of this study demonstrate the promising potential of applying PUE@TPP/PEG-PE micelles in mitochondria-targeted drug delivery to achieve maximum therapeutic effects of PUE.

2.
Acta Biomater ; 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31629893

RESUMO

Pancreatic cancer remains one of the most highly lethal diseases with very poor prognosis. Gemcitabine (GEM) is the first-line chemotherapeutic drug for pancreatic cancer treatment but is associated with significant side effects when administered systemically. Exosomes have emerged as attractive candidates for drug delivery for their high delivery efficiency and biocompatibility. Here, GEM was loaded into autologous exosomes to formulate ExoGEM for targeted chemotherapy of pancreatic cancer. Autologous exosomes facilitate cellular uptake of GEM and contributed to significantly increased cytotoxic effect of GEM, while heterologous cellular uptake showed less efficiency. Autologous exosomes showed targeting ability to pancreatic cancer in biodistribution study, and GEM concentration in tumor site was increased via ExoGEM delivery. ExoGEM treatment, in tumor-bearing mice, significantly suppressed tumor growth, with prolonged survival in a dose-response manner, but caused minimal damage to normal tissues. More importantly, tumors in several mice treated with ExoGEM were disappeared without recurrence. Autologous exosomes are safe and effective vehicles for targeted delivery of GEM against pancreatic cancer. This delivery strategy may have implications for personalized chemotherapy of pancreatic cancer. STATEMENT OF SIGNIFICANCE: Exosomes are efficient delivery vehicles in intracellular communication. Moreover, potential tropism of autologous exosomes to the tumor microenvironment make them competitive delivery vehicles. The use of cancer-derived exosomes for drug delivery and superior targeting efficacy and enhanced anticancer efficacy of therapeutics have been evidenced. Gemcitabine is a mainstay for pancreatic treatment. However, poor cellular uptake and low targeting effects of gemcitabine often lead to severe systemic toxicity. Therefore, to overcome this limitation, we herein loaded gemcitabine into autologous pancreatic cancer-derived exosomes for the targeted chemotherapy of pancreatic cancer.

3.
Int J Nanomedicine ; 14: 7489-7502, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571860

RESUMO

Background: 3,5,4'-trimethoxy-trans-stilbene (BTM) is a methylated derivative of resveratrol. To improve the pharmaceutical properties of BTM, BTM loaded PEG-PE micelles (BTM@PEG-PE) were fabricated and its anti-cancer efficacy against colon cancer was evaluated. Methods: BTM@PEG-PE micelles were prepared by the solvent evaporation method and were characterized by nuclear magnetic resonance (NMR), size, zeta potential, polymer disperse index (PDI) and transmission electron microscopy (TEM). Cellular uptake, cell viability assay, caspase-3 activity assay and flow cytometry were performed to evaluate the cell internalization and anti-cancer efficacy of BTM@PEG-PE micelles in vitro. Pharmacokinetic profiles of BTM and BTM@PEG-PE micelles were compared and in vivo anti-cancer therapeutic efficacy and safety of BTM@PEG-PE micelles on CT26 xenograft mice were evaluated. Results: BTM was successfully embedded in the core of PEG-PE micelles, with a drug loading capacity of 5.62±0.80%. PEG-PE micelles facilitated BTM entering to the CT26 cells and BTM@PEG-PE micelles exerted enhanced anti-cancer efficacy against CT26 cells. BTM@PEG-PE micelles showed prolonged half-life and increased bioavailability. More importantly, BTM@PEG-PE micelles treatment suppressed tumor growth in tumor-bearing mice and prolonged survival with minimal damage to normal tissues. Conclusion: Altogether, the BTM@PEG-PE micelles might be a promising strategy to enhance the pharmacokinetic and pharmacodynamic potentials of BTM for colon cancer therapy.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Micelas , Fosfatidiletanolaminas/uso terapêutico , Polietilenoglicóis/uso terapêutico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Disponibilidade Biológica , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular , Neoplasias do Colo/patologia , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Endocitose , Feminino , Humanos , Camundongos Endogâmicos BALB C , Fosfatidiletanolaminas/efeitos adversos , Fosfatidiletanolaminas/farmacocinética , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinética , Polímeros/química , Ratos Sprague-Dawley , Resultado do Tratamento
4.
Int J Nanomedicine ; 14: 3055-3067, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118622

RESUMO

Purpose: The aim of this research was to develop a phospholipid complex based nanoemulsion system for oral insulin delivery. Methods: Insulin-phospholipid complex (IPC) was firstly prepared by an anhydrous co-solvent lyophilization method, and then encapsulated into the oil phase of nanoemulsion to obtain the IPC-based nanoemulsion (IPC-NE). Both water-in-oil (W/O) IPC-NE and oil-in-water (O/W) IPC-NE were formulated and evaluated for comparison. Results: The obtained W/O IPC-NE and O/W IPC-NE were both spherical in shape with a mean particle size of 18.6±0.79 nm and 27.3±1.25 nm, respectively. While both IPC-NEs exhibited enhanced Caco-2 cell monolayers permeability than IPC and insulin solution, W/O IPC-NE showed relatively greater protective effects against enzymatic degradation than O/W IPC-NE. Moreover, oral administration of W/O IPC-NE exhibited significant hypoglycemic effects, with 12.4-fold and 1.5-fold higher oral bioavailability compared with insulin solution and O/W IPC-NE, respectively. Conclusion: IPC-NEs, especially the W/O IPC-NE showed promising efficiency in vitro and in vivo, thus could be a potential strategy for oral insulin delivery.


Assuntos
Sistemas de Liberação de Medicamentos , Emulsões/química , Insulina/administração & dosagem , Nanopartículas/química , Fosfolipídeos/química , Administração Oral , Animais , Transporte Biológico/efeitos dos fármacos , Glicemia/metabolismo , Células CACO-2 , Morte Celular/efeitos dos fármacos , Portadores de Fármacos , Liberação Controlada de Fármacos , Emulsões/administração & dosagem , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/farmacocinética , Insulina/farmacologia , Masculino , Nanopartículas/ultraestrutura , Tamanho da Partícula , Permeabilidade , Ratos Sprague-Dawley , Suínos , Difração de Raios X
5.
Int J Nanomedicine ; 14: 2327-2340, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31015760

RESUMO

Background: 8-methoxypsoralen (8-MOP) is one of the most commonly utilized drugs in psoralen-ultraviolet A therapy for treatment of vitiligo. However, poor skin retention and systemic side effects limit the clinical application of 8-MOP. Methods: Microemulsions (MEs) and chitosan derivative-coated 8-MOP MEs were developed and compared for dermal delivery of 8-MOP. Ex vivo skin retention/permeation study was performed to select the ME formulation with the highest retention:permeation ratio. Four different chitosan-coated MEs were prepared and compared with the ME formulation for their ability to distribute 8-MOP in the skin. Results: Among various ME formulations developed, a formulation containing 2.9% ethyl oleate, 17.2% Cromophor EL35, 8.6% ethanol and 71.3% water showed the highest ex vivo skin retention:permeation ratio (1.98). Of four chitosan-coated MEs prepared, carboxymethyl chitosan-coated MEs (CC-MEs) and hydroxypropyl chitosan-coated MEs (HC-MEs) showed higher ex vivo skin retention:permeation ratio (1.46 and 1.84). and were selected for in vivo pharmacokinetic study. AUCskin (0-12 h) for 8-MOP MEs (4578.56 h·ng·mL-1) was higher than HC-MEs (3422.47 h·ng·mL-1), CC-MEs (2808.51 h·ng·mL-1) and tincture (1500.16 h·ng·mL-1). Also, AUCplasma (0-12 h) for MEs (39.35±13.90 h·ng·mL-1) was significantly lower than HC-MEs (66.32 h·ng·mL-1), CC-MEs (59.70 h·ng·mL-1) and tincture (73.02 h·ng·mL-1). Conclusion: These combined results suggested that the MEs developed could be a promising and safe alternative for targeted skin delivery of 8-MOP.


Assuntos
Quitosana/química , Sistemas de Liberação de Medicamentos , Emulsões/química , Metoxaleno/administração & dosagem , Administração Cutânea , Animais , Quitosana/análogos & derivados , Humanos , Masculino , Microdiálise , Permeabilidade , Ratos Sprague-Dawley , Pele/metabolismo , Absorção Cutânea , Suínos
6.
Nanomedicine (Lond) ; 14(4): 493-509, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30694095

RESUMO

Extracellular vesicles (EVs) are nanoscale natural membrane vesicles released by cells and are involved in intercellular communication. A number of studies have used autologous cancer cell-derived EVs (ACCD-EVs) as nanocarriers for delivery of therapeutics as they may be more efficiently uptaken by the cancer cells themselves. However, they also have been suggested to promote proliferation, survival and metastasis of cancers. Here, we evaluated the targeting efficacy, therapeutic outcome and safety of ACCD-EVs. Overall, superior targeting efficacy and enhanced anticancer efficacy of ACCD-EV-mediated delivery of therapeutics are evidenced. But existing data are insufficient to allow any conclusion about the safety of therapeutic-loaded EVs. A more profound elucidation of the specificity, efficacy and safety will contribute to future translational research of ACCD-EVs.


Assuntos
Vesículas Extracelulares/química , Nanomedicina/métodos , Sistemas de Liberação de Medicamentos/métodos , Exossomos/química , Humanos , Processamento de Proteína Pós-Traducional
7.
Drug Deliv Transl Res ; 9(1): 357-365, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30430453

RESUMO

The aim of this study was to develop a microemulsion-based hydrogel (MBH) formulation of 3,5,4'-trimethoxy-trans-stilbene (BTM) as topical delivery system for the treatment of osteoarthritis (OA). The pseudo-ternary phase diagrams were constructed to optimize the microemulsion (ME) formulation. The ME formulation containing 18.8% Cremopher EL35 (surfactant), 9.4% Transcutol HP (co-surfactant), 3.1% LABRAFIL M 1944 CS (oil), and 68.7% water was selected. The obtained BTM-loaded ME (BTM-ME) had a spherical morphology (17.5 ± 1.4 nm), with polydispersity index (PDI) value of 0.068 ± 0.016 and zeta potential of - 11.8 ± 0.5 mV, and was converted into BTM-loaded MBH (BTM-MBH) using Carbopol 940. Ex vivo skin permeation study showed that both ME and MBH formulations significantly enhanced the amount of BTM permeated. The cumulative amount of BTM permeated after 12 h (Q12) for ME, and MBH formulations were 3.25- and 1.96-fold higher than that for emulsion gel (EG). Pharmacokinetic study showed that the AUC of BTM suspension (oral) was three times higher than that of BTM-MBH (topical). Topical delivery of BTM-MBH demonstrated remarkable anti-OA effect in a rabbit model of OA induced by papain, with decreased levels of pro-inflammatory cytokines. The developed MBH formulation might be a promising strategy for topical delivery of BTM for treatment of OA.


Assuntos
Resinas Acrílicas/química , Hidrogéis/química , Osteoartrite/tratamento farmacológico , Papaína/efeitos adversos , Estilbenos/administração & dosagem , Administração Cutânea , Administração Oral , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Emulsões , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Osteoartrite/induzido quimicamente , Osteoartrite/metabolismo , Coelhos , Estilbenos/química , Estilbenos/farmacocinética
8.
Drug Deliv ; 25(1): 1858-1864, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30338713

RESUMO

Puerarin (PUE) and tetramethylpyrazine (TMP) are central nervous system (CNS) drugs used in cerebrovascular diseases. Poor brain-blood barrier (BBB) permeability limited their clinical application. Borneol and α-asarone have been proposed as an oral brain-targeting enhancer. In this study, we aimed to first evaluate the 'orifice-opening' effect of borneol and α-asarone, both aromatic resuscitation drugs, on improvement of brain delivery of PUE and TMP and second to investigate whether the enhancing effects were associated with adenosine receptors (ARs)-mediated trans-BBB pathway. In vitro BBB model was established and borneol and α-asarone significantly increased the cumulative amount of permeated PUE and TMP and the enhancing effects could be counteracted by AR inhibitors. Borneol and α-asarone could decrease expression of ZO-1, an important BBB junction protein, but inversely increase the expression of A1AR and A2AAR. In vivo pharmacokinetic study also confirmed that oral co-administration of borneol or α-asarone significantly increased AUCbrain for PUE and TMP. These results suggested that borneol and α-asarone are both effective adjuvant agents for delivery of PUE and TMP to the brain.


Assuntos
Adjuvantes Farmacêuticos , Anisóis/química , Barreira Hematoencefálica , /química , Receptores Purinérgicos P1/metabolismo , Adjuvantes Farmacêuticos/metabolismo , Adjuvantes Farmacêuticos/farmacologia , Animais , Transporte Biológico , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Humanos , Isoflavonas/farmacologia , Masculino , Camundongos , Permeabilidade , Pirazinas/farmacologia , Ratos Sprague-Dawley
9.
Drug Dev Ind Pharm ; 44(8): 1336-1341, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29513046

RESUMO

Puerarin is a phytochemical with various pharmacological effects, but poor water solubility and low oral bioavailability limited usage of puerarin. The purpose of this study was to develop a new microemulsion (ME) based on phospholipid complex technique to improve the oral bioavailability of puerarin. Puerarin phospholipid complex (PPC) was prepared by a solvent evaporation method and was characterized by X-ray diffraction and infrared spectroscopy. Pseudo-ternary phase diagrams were constructed to investigate the effects of different oil on the emulsifying performance of the blank ME. Intestinal mucosal injury test was conducted to evaluate safety of PPC-ME, and no sign of damage on duodenum, jejunum and ileum of rats was observed using hematoxylin-eosin staining. In pharmacokinetic study of PPC-ME, a significantly greater Cmax (1.33 µg/mL) was observed when compared to puerarin (Cmax 0.55 µg/mL) or PPC (Cmax 0.70 µg/mL); the relative oral bioavailability of PPC-ME was 3.16-fold higher than puerarin. In conclusion, the ME combined with the phospholipid complex technique was a promising strategy to enhance the oral bioavailability of puerarin.


Assuntos
Portadores de Fármacos/química , Composição de Medicamentos/métodos , Isoflavonas/farmacocinética , Fosfolipídeos/química , Vasodilatadores/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Portadores de Fármacos/efeitos adversos , Emulsões , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/patologia , Isoflavonas/efeitos adversos , Masculino , Modelos Animais , Pueraria/química , Ratos , Ratos Sprague-Dawley , Solubilidade , Vasodilatadores/efeitos adversos
10.
Drug Deliv ; 24(1): 1868-1873, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29191058

RESUMO

Berberine hydrochloride (BBH) has a variety of pharmacological activities such as antitumor, antimicrobial, anti-inflammation, and reduce irritable bowel syndrome. However, poor stability and low oral bioavailability limited its usage. Herein, an oil-in-water nanoemulsion system of BBH was developed to improve its stability and oral bioavailability. The pseudoternary phase diagrams were constructed for the determination of composition of various nanoemulsions. The nanoemulsions of BBH composed of Labrafil M 1944 CS (oil phase), RH-40 (surfactant), glycerin (co-surfactant), and water (aqueous phase). The O/W nanoemulsion of BBH showed a relative bioavailability of 440.40% compared with unencapsulated BBH and was stable in our 6-month stability study. Further, there was a significant increase in intestinal permeability of BBH as assessed by Caco-2 cell monolayers and a significant reduction in efflux of BBH by the multidrug efflux pump P-glycoprotein. This study confirmed that the nanoemulsion formulation could be used as an alternative oral formulation of BBH to improve its stability, oral bioavailability and permeability.


Assuntos
Berberina/química , Emulsões/química , Administração Oral , Berberina/administração & dosagem , Disponibilidade Biológica , Células CACO-2 , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Glicerídeos/química , Humanos , Absorção Intestinal/efeitos dos fármacos , Nanopartículas/química , Permeabilidade/efeitos dos fármacos , Polietilenoglicóis/química , Solubilidade , Tensoativos/química , Água/química
11.
ACS Appl Mater Interfaces ; 6(9): 6765-75, 2014 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-24720695

RESUMO

In this report, an atom efficient and facile synthetic strategy for accessing multi-diketopyrrolopyrrole (DPP)-based oligomers used in solution-processed organic field effect transistors (OFETs) and organic solar cells (OSCs) has been developed. The DPP units were successfully installed onto benzene and pyrene cores via palladium-catalyzed dehydrohalogenative coupling of mono-capped DPPs with multi-bromo-benzene or -pyrene (direct arylation), affording four oligomer small molecules (SMs 1-4) containing bis-, tri-, tri-, and tetra-DPP, respectively, in high yields of 78-96%. All the designed linear or branched DPP-based oligomers exhibit broad light absorptions, narrow band-gaps (1.60-1.73 eV), deep highest occupied molecular orbital (HOMO) levels (-5.26∼-5.18 eV), and good thermal stability (Td=390-401 °C). OFETs based on SMs 1-4 showed hole mobilities of 0.0033, 0.0056, 0.0005, and 0.0026 cm2 V(-1) s(-1), respectively. OSCs based on SMs 1-4 under one sun achieved power conversion efficiencies of 3.00%, 3.71%, 2.47%, and 1.86% accordingly, along with high open-circuit voltages of 0.86-0.94 V. For OSC devices of SM 1, SM 3, and SM 4, the solvent CHCl3 was solely employed to the formation of active layers; neither high boiling point additives nor annealing post-treatment was needed. Such a simple process benefits the large-scale production of OSCs via roll to roll technology.

12.
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 1): o123, 2009 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-21580013

RESUMO

The mol-ecule of the title compound, C(12)H(11)N(3)O(2), is approximately planar with an r.m.s. deviation of 0.0814 Šfrom the plane through all the non-H atoms. The dihedral angle formed by the benzene and isoxazole rings is 6.88 (16)°. The mol-ecular conformation is stabilized by an intra-molecular C-H⋯N hydrogen bond, forming an S(6) ring, and the mol-ecule displays an E configuration with respect to the C=N double bond. In the crystal structure, inter-molecular N-H⋯O hydrogen bonds form centrosymmetric dimers which are further linked by weak C-H⋯N inter-actions augmented by very weak C-H⋯π contacts, forming layers parallel to (120).

13.
J Chem Phys ; 127(17): 175102, 2007 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-17994852

RESUMO

The nature of interactions of furan with various hydrides (Y) (Y=HF,HCl,H2O,H2S,NH3,PH3) is investigated using ab initio calculations. The contribution of attractive (electrostatic, inductive, and dispersive) and repulsive (exchange) components to the interactions energy is analyzed. HF, H2O, and NH3 favor sigma o-type H bonding, while HCl, H2S, and PH3 favor pi-type H bonding. Interaction energy decomposition reveals that sigma o-type complexes interactions are predominantly electrostatic in nature, while the dispersion and electrostatic interactions dominate the pi-type complexes.

14.
J Chem Phys ; 126(13): 134301, 2007 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-17430026

RESUMO

Equilibrium geometries, interaction energies, atomic charge, and charge transfer for the intermolecular interactions between furan and dihalogen molecules XY(X; Y=F,Cl,Br) were studied at the MP2aug-cc-pVDZ level. Three types of geometry are observed in these interactions: the pi-type geometry (I), in which the XY lies above the furan ring and almost perpendicularly to the C4-C5 bond of furan; the sigma-type geometry (II), where the X atom is pointed toward the nonbonding electron pair (n pair) of oxygen atom in furan; and the chi-type geometry (III), describing a blueshift hydrogen bond formed between the hydrogen atom of furan and dihalogen molecules XY. The calculated interaction energies show that the pi-type structures are more stable than the corresponding sigma-type and chi-type structures. To study the nature of the intermolecular interactions, an energy decomposition analysis was carried out and the results indicate that both the pi-type and sigma-type interactions are dominantly inductive energy in nature, while dispersion energy governs the chi-type interactions.

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