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1.
AAPS PharmSciTech ; 21(1): 11, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31808011

RESUMO

The main aim of the research was to synthesize amphiphilic cyclodextrin (AMCD) by substituting C12 alkyl chain to a ß-cyclodextrin (ßCD) in a single step and to study its self-assembly in an aqueous medium. The drug delivery application of the AMCD was also evaluated by encapsulating tamoxifen citrate as a model hydrophobic drug. AMCD was able to self-assemble in aqueous media, forming nanovesicles of size < 200 nm, capable of encapsulating tamoxifen citrate (TMX). Molecular docking and MD simulation studies revealed the interaction between TMX and AMCD which formed a stable complex. TEM and AFM studies showed that nanovesicles were perfectly spherical having a smooth surface and a theoretical AMCD bilayer thickness of ~ 7.2 nm as observed from SANS studies. XRD and DSC studies revealed that TMX was amorphized and molecularly dispersed in AMCD bilayer which was released slowly following Fickian diffusion. AMCD has excellent hemocompatibility as opposed to ßCD and no genotoxicity. IC50 of TMX against MCF-7 cell lines was significantly reduced from 11.43 to 7.96 µg/ml after encapsulation in nanovesicle because of nanovesicles being endocytosed by the MCF-7 cells. AMCD was well tolerated by IV route at a dose of > 2000 mg/kg in rats. Pharmacokinetic profile of TMX after encapsulation was improved giving 3-fold higher AUC; extended mean residence time is improving chances of nanovesicle to extravasate in tumor via EPR effect.


Assuntos
Ciclodextrinas/administração & dosagem , Ciclodextrinas/síntese química , Sistemas de Liberação de Medicamentos/métodos , Tamoxifeno/administração & dosagem , Tamoxifeno/síntese química , Administração Oral , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Masculino , Camundongos , Simulação de Acoplamento Molecular/métodos , Ratos , Ratos Wistar
2.
J Biomed Sci ; 26(1): 85, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31647037

RESUMO

INTRODUCTION: Efficacy and safety are critical concerns when designing drug carriers. Nanoparticles are a particular type of carrier that has gained recent attention in cancer therapeutics. METHODS: In this study, we assess the safety profile of IT-101, a nanoparticle formed by self-assembly of camptothecin (CPT) conjugated cyclodextrin-based polymers. IT-101 delivers CPT to target cancer cells in animal models of numerous human cancers and in humans. Previous data from preclinical and clinical trials indicate that IT-101 has no notable immunological side effects. However, there have been no published studies focused on evaluating the effects of IT-101 on host immune systems. RESULTS: In this work, we demonstrate that IT-101 diminished initial host immune response following first injection of the nanopharmaceutical and induced NK cell activation and T cell proliferation upon further IT-101 exposure. Additionally, IT-101 could attenuate tumor growth more efficiently than CPT treatment only. CONCLUSIONS: Drugs administration in whole-body circulation may lead to poorly bioavailable in central nervous system and often has toxic effects on peripheral tissues. Conjugated with cyclodextrin-based polymers not only reduce adverse effects but also modulate the immune responses to elevate drug efficacy. These immune responses may potentially facilitate actions of immune blockage, such as PD1/PDL1 in cancer treatment.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Antineoplásicos/administração & dosagem , Camptotecina/administração & dosagem , Celulose/administração & dosagem , Ciclodextrinas/administração & dosagem , Imunidade Inata/efeitos dos fármacos , Nanopartículas/administração & dosagem , Animais , Camundongos , Organismos Livres de Patógenos Específicos
3.
Exp Eye Res ; 189: 107829, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31605685

RESUMO

Approximately 30-70% of the existing and new chemical entities exhibit poor aqueous solubility. For topical ocular delivery, drug molecules need to possess both hydrophilic and lipophilic nature to enable absorption through the aqueous tear layer and permeation through the corneal lipophilic barrier. To overcome the aqueous solubility related issues, various techniques such as solid dispersion, particle size reduction, cyclodextrin complexation, co-solvency, prodrug, derivatization, and salt formation are being explored in the healthcare sector. Cyclodextrin inclusion complexation techniques have been established by several pharmaceutical industries for systemic administration allowing a transition from the lab to the clinics. Though cyclodextrins are exploited in ocular drug delivery, there are prevailing concerns regarding its absorption enhancing capacity and mechanism, retention at the ocular surfaces and, irritation and toxicity profiles. In the present review, the efforts taken by various research groups to address the concerns of using cyclodextrin and its derivatives in ocular therapeutics are summarized. Also, considerations and utility of cyclodextrin systems in fabricating newer formulations such as contact lens, inserts, and implants have been discussed in the review.


Assuntos
Ciclodextrinas/administração & dosagem , Oftalmopatias/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Humanos , Soluções Oftálmicas/administração & dosagem , Resultado do Tratamento
4.
Biol Pharm Bull ; 42(10): 1679-1688, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582656

RESUMO

Targeted drug delivery system (DDS) is required for RNA interference (RNAi) therapy to increase the therapeutic effect and to reduce the adverse effect. Especially in transthyretin (TTR)-related amyloidosis, hepatocyte specific delivery is desired because TTR mainly expresses in hepatocyte. Herein, we report on a hepatocyte-specific small interfering RNA (siRNA) delivery system using polyethylene glycol (PEG)-modified lactosylated dendrimer (generation 3; G3) conjugates with α-cyclodextrin (PEG-LαCs (G3)) for TTR-related amyloidosis therapy, and investigated the in vitro and in vivo gene silencing effect of PEG-LαCs (G3)/siRNA polyplexes. PEG-LαC (G3, average degree of substitution of PEG (DSP) 2)/TTR siRNA (siTTR) polyplex exhibited the asialoglycoprotein receptor (ASGPR)-mediated cellular uptake, high endosomal escaping ability and localization of the siRNA in cytoplasm, resulting in significant TTR silencing in HepG2 cells. In vivo studies showed that PEG-LαC (G3, DSP2)/siTTR polyplex led to a significant TTR silencing effect in liver after systemic administration to mice. Furthermore, safety evaluation revealed that PEG-LαC (G3, DSP2)/siTTR polyplex had no significant toxicity both in vitro and in vivo. These findings suggest the utility of PEG-LαC (G3, DSP2) as a promising hepatocyte-specific siRNA delivery system both in vitro and in vivo, and as a therapeutic approach for TTR-related amyloidosis.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Ciclodextrinas/administração & dosagem , Dendrímeros/administração & dosagem , Hepatócitos/metabolismo , Polietilenoglicóis/administração & dosagem , Pré-Albumina/genética , RNA Interferente Pequeno/administração & dosagem , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/metabolismo , Animais , Dendrímeros/farmacocinética , Células Hep G2 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Polietilenoglicóis/farmacocinética , Pré-Albumina/metabolismo , RNA Interferente Pequeno/farmacocinética
5.
Colloids Surf B Biointerfaces ; 182: 110382, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31352250

RESUMO

Solid inclusion complexes with cyclodextrins (CD) may be used to overcome volatility and solubility problems of essential oils of pharmacological interest. However, they lack the many dermatological advantages of lipid nanoparticles. This study intends to evaluate the ability of nanostructured lipid carriers (NLC) to encapsulate hydroxypropyl-ß-cyclodextrin inclusion complexes of Lippia origanoides essential oil (EO) and to maintain the desirable aspects of lipid colloids interaction with the skin, specifically follicular accumulation and controlled delivery. CD and NLC were also evaluated separately. Thymol (TML) was used as the essential oil marker and to produce control formulations. As expected, CD alone, though effective in overcoming volatility and low aqueous solubility of TML, were ineffective in controlling marker release (˜50% of EO released after 3 h, Hixson-Crowell kinetics). Even though NLC controlled drug release (˜20% EO released after 12 h, zero-order kinetics) enabling TML penetration into the skin (> 40 µg/cm2after 12 h), NLC alone were not efficient in preventing TML volatility, especially at higher temperatures (calculated shelf-life of 2 days at 35 °C). The combined approach resulted in a synergistic effect (˜20% EO released after 12 h; shelf life of 6 days). The lack of statistical difference of TML skin penetration from NLC and NLC-CD suggests the developed system maintained all skin interaction aspects of lipid colloids, including follicular accumulation forming a depot for controlled delivery. In conclusion, lipid nanoparticles demonstrated to be promising carriers for inclusion complexes of this particular volatile essential oil.


Assuntos
Ciclodextrinas/administração & dosagem , Portadores de Fármacos/química , Lipídeos/química , Nanopartículas/química , Óleos Voláteis/administração & dosagem , Administração Cutânea , Animais , Ciclodextrinas/química , Ciclodextrinas/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Nanopartículas/ultraestrutura , Óleos Voláteis/química , Óleos Voláteis/farmacocinética , Pele/metabolismo , Solubilidade , Suínos , Temperatura , Timol/administração & dosagem , Timol/química , Timol/farmacocinética , Volatilização
6.
Int J Pharm ; 566: 391-399, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31158453

RESUMO

Chronic pain represents one of the most important public health problems, with a great prevalence of comorbidity with depression and cognitive decline. Antidepressants such as duloxetine, a serotonin-norepinephrine reuptake inhibitor, represent an essential part of the therapeutic strategy for chronic pain management in addition to classical analgesics. Duloxetine is endowed with good efficacy and a good profile of safety and tolerability. Yet, duloxetine is metabolized by the cytochrome P450 system 2D6 and 1A2 (CYP2D6 and CYP1A2) and it exhibits moderate inhibitory activity on CYP2D6, resulting in side effects and metabolic interactions that may occur on a long term therapeutic schedule. Cyclodextrins (CyDs) are used in pharmaceutical applications for numerous purposes, including the improvement of drug bioavailability. In order to evaluate their effects on the activity of duloxetine, we first spectrophotometrically studied the host-guest complexes obtained combining duloxetine and different ß-CyD derivatives (ß-CyD, ß-CyDen-c-(Glu-Glu), and succinyl-ß-CyD) and then performed in vivo and in vitro studies. Among duloxetine/CyDs complexes, succinyl-ß-CyD ameliorated the analgesic activity of duloxetine in the tail flick test and in the formalin test in mice and significantly protected the drug from CYP2D6 metabolism.


Assuntos
Analgésicos/administração & dosagem , Ciclodextrinas/administração & dosagem , Cloridrato de Duloxetina/administração & dosagem , Dor/tratamento farmacológico , Analgésicos/química , Animais , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Ciclodextrinas/química , Citocromo P-450 CYP2D6/metabolismo , Cloridrato de Duloxetina/química , Humanos , Masculino , Camundongos
7.
Theranostics ; 9(9): 2489-2504, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31131049

RESUMO

Rationale: Targeted delivery of therapeutic drugs or imaging agents to injured blood vessels via nanocarriers is likely to be dependent on the particle shape, yet cubic nanoparticle carriers have not been reported for vascular targeting. Here, we demonstrate that cuboidal cyclodextrin frameworks possess superior hemostasis effect and injured vessels targeting compared with spherical counterpart. Methods: Cuboidal and biocompatible γ-cyclodextrin metal-organic frameworks (CD-MOFs) are synthesized, tethered via crosslinking and surface modification with GRGDS peptide (GS5-MOFs). The specific interactions of cubic GS5-MOF nanoparticles with activated platelets were investigated by in vitro platelet aggregation assay and atomic force microscopy measurements (AFM). The hemostatic capacity and injured vessel targeting efficacy were evaluated in vivo. Results: Cuboidal GS5-MOF nanoparticles exhibit enhanced adhesion and aggregation with activated platelets in vitro under static condition and a physiologically relevant flow environment. The cubic GS5-MOF nanoparticles show efficient hemostatic effects with bleeding time and blood loss decrease of 90% and strong injured vessel targeting in vivo, markedly superior to spherical γ-CD nanosponges with the same chemical composition. Conclusions: These results clearly highlight the contribution of the cuboidal shape of GS5-MOFs to the enhanced aggregation of activated platelets and high targeting to damaged vessels. The cuboidal nanoparticle system provides an innovative delivery platform for the treatment and diagnosis of vascular diseases.


Assuntos
Plaquetas/metabolismo , Ciclodextrinas/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Hemorragia/terapia , Compostos Organometálicos/farmacologia , Agregação Plaquetária , Nanomedicina Teranóstica/métodos , Animais , Adesão Celular , Ciclodextrinas/administração & dosagem , Ciclodextrinas/síntese química , Modelos Animais de Doenças , Hemostasia , Camundongos , Oligopeptídeos/administração & dosagem , Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/síntese química , Ratos Sprague-Dawley , Resultado do Tratamento , Doenças Vasculares/diagnóstico
8.
Int J Mol Sci ; 20(9)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31071925

RESUMO

Current organ shortages have led centers to extend the acceptance criteria for organs, increasing the risk for adverse outcomes. Current preservation protocols have not been adapted so as to efficiently protect these organs. Herein, we target oxidative stress, the key mechanism of ischemia reperfusion injury. Vectisol® is a novel antioxidant strategy based on the encapsulation of resveratrol into a cyclodextrin, increasing its bioavailability. We tested this compound as an additive to the most popular static preservation solutions and machine perfusion (LifePort) in a preclinical pig model of kidney autotransplantation. In regard to static preservation, supplementation improved glomerular filtration and proximal tubular function early recovery. Extended follow-up confirmed the higher level of protection, slowing chronic loss of function (creatininemia and proteinuria) and the onset of histological lesions. Regarding machine perfusion, the use of Vectisol® decreased oxidative stress and apoptosis at the onset of reperfusion (30 min post declamping). Improved quality was confirmed with decreased early levels of circulating SOD (Superoxide Dismutase) and ASAT (asparagine amino transferase). Supplementation slowed the onset of chronic loss of function, as well as interstitial fibrosis and tubular atrophy. The simple addition of Vectisol® to the preservation solution significantly improved the performance of organ preservation, with long-term effects on the outcome. This strategy is thus a key player for future multi-drug therapy aimed at ischemia reperfusion in transplantation.


Assuntos
Antioxidantes/administração & dosagem , Transplante de Rim/efeitos adversos , Rim/fisiopatologia , Resveratrol/química , Transplante Autólogo , Animais , Antioxidantes/química , Ciclodextrinas/administração & dosagem , Ciclodextrinas/química , Modelos Animais de Doenças , Composição de Medicamentos , Humanos , Rim/efeitos dos fármacos , Preservação de Órgãos/métodos , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/fisiopatologia , Resveratrol/administração & dosagem , Solubilidade , Suínos
9.
Int J Pharm ; 564: 153-161, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-30981874

RESUMO

It is essential to optimize a carrier of dry powder inhalation (DPI) for the aerodynamic deposition in vitro to achieve pulmonary delivery of drug molecules in vivo. In this study, neutralized nanoporous γ-cyclodextrin metal-organic framework (CD-MOF) crystals with cubic morphology and uniform inhalation size were developed and modified as a DPI carrier for budesonide (BUD). Cholesterol (CHO) and leucine (LEU)-poloxamer were used to modify the CD-MOF powder for the improvement of flowability and particle aerodynamic behaviour, for which the particle size distribution, Carr's index and in vitro pulmonary deposition were assessed. Compared to CD-MOF or LEU-CD-MOF-BUD, CHO-CD-MOF had a superior mass median aerodynamic diameter (4.35 ±â€¯0.04 µm) and inhalable performance (fine particle fraction of 30.60 ±â€¯0.76%), which were maintained after budesonide loading (4.47 ±â€¯0.30 µm, 24.95 ±â€¯4.33%). The crystallinity, cytotoxicity and in vivo deposition of drug loaded samples (CHO-CD-MOF-BUD) were then investigated by powder X-ray diffraction (PXRD), cell viability study, in vivo fluorescence imaging and pharmacokinetic studies in rats. The characteristic PXRD crystallinity peaks of budesonide disappeared after being loaded into CHO-CD-MOF, potentially indicating the molecular incorporation of budesonide into the pores of CD-MOF. The cell viability of A549 cell was more than 90% for CHO-CD-MOF-BUD as a result of the good biocompatibility of CD-MOF. When Rhodamine B was carried by the DPI particles, the fluorescence signal at the lung tissue was markedly improved after cholesterol modification compared with CD-MOF, whilst the bioavailability of CHO-CD-MOF-BUD in rat was equivalent with that of the commercial product of Pulmicort Turbuhaler. Therefore, the CD-MOF powders modified by cholesterol can be used as a promising inhalable carrier for pulmonary delivery of drugs with small dose.


Assuntos
Broncodilatadores/administração & dosagem , Budesonida/administração & dosagem , Colesterol/administração & dosagem , Ciclodextrinas/administração & dosagem , Hidróxidos/administração & dosagem , Leucina/administração & dosagem , Compostos de Potássio/administração & dosagem , Administração por Inalação , Animais , Broncodilatadores/química , Broncodilatadores/farmacocinética , Budesonida/química , Budesonida/farmacocinética , Colesterol/química , Colesterol/farmacocinética , Ciclodextrinas/química , Ciclodextrinas/farmacocinética , Hidróxidos/química , Hidróxidos/farmacocinética , Leucina/química , Leucina/farmacocinética , Masculino , Nanoporos , Compostos de Potássio/química , Compostos de Potássio/farmacocinética , Ratos Sprague-Dawley
10.
Int J Pharm ; 564: 59-76, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-30959238

RESUMO

Cyclodextrins (CDs) are cyclic oligosaccharides able to improve drug water solubility and stability by forming CD/drug inclusion complexes. To further increase drug entrapment and delay its release, the CD/drug inclusion complex can be embedded in the aqueous phase of a liposome, a lipid vesicle composed of phospholipid bilayer surrounding an aqueous compartment. The resulting carrier is known as drug-in-cyclodextrin-in-liposome (DCL) system. CDs and DCLs are recognized as effective drug delivery systems; therefore, understanding the interaction of CDs with liposomal and biological membranes is of great importance. CDs are able to extract phospholipids, cholesterol, and proteins from membranes; the effect depends on the membrane structure and composition as well as on the CD type and concentration. Under definite conditions, CDs can affect the membrane fluidity, permeability, and stability of liposomes and cells, leading to the leakage of some of their internal constituents. On the other side, CDs demonstrated their beneficial effects on the membrane structure, including preservation of the membrane integrity during freeze-drying. In this paper, we review the literature concerning the interaction of CDs with biomimetic and biological membranes. Moreover, the impact of CDs on the membrane properties, mainly fluidity, stability, and permeability, is highlighted.


Assuntos
Ciclodextrinas/administração & dosagem , Sistemas de Liberação de Medicamentos , Animais , Materiais Biomiméticos , Membrana Celular , Humanos , Membranas Artificiais
11.
Biol Pharm Bull ; 42(1): 116-122, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30369530

RESUMO

The emulsion prepared with ß-cyclodextrin as an emulsifier (ßCDE) is considered to be a Pickering emulsion. We examined the characteristics of ßCDEs using captopril (CP) as a model drug, and studied the in vitro skin permeation of CP from ßCDEs through hairless mouse skin. The stability of ßCDE was increased with increasing ßCD concentration and conversely decreased with increasing CP concentration. The yield stress value from the rheological measurement results was suggested to be one of the factors determining the stability of the ßCDE, and ßCDEs with higher yield stress values were more stable. We found that the skin permeability of CP could be improved by using ßCDE with isopropyl myristate as the oil phase and that the flux of CP depended on the free CP concentration in the water phase of ßCDE.


Assuntos
Ciclodextrinas/administração & dosagem , Ciclodextrinas/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Emulsificantes/administração & dosagem , Emulsificantes/metabolismo , Absorção Cutânea/efeitos dos fármacos , Administração Cutânea , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Captopril/administração & dosagem , Captopril/metabolismo , Camundongos , Camundongos Pelados , Técnicas de Cultura de Órgãos , Absorção Cutânea/fisiologia
12.
Invest New Drugs ; 37(4): 771-778, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30556100

RESUMO

Polymeric cyclodextrin-based nanoparticles are currently undergoing clinical trials as nanotherapeutics. Using a non-covalent approach, we decorated two cross-linked cyclodextrin polymers of different molecular weights with an RGD peptide derivative to construct a novel carrier for the targeted delivery of doxorubicin. RGD is the binding sequence for the integrin receptor family that is highly expressed in tumour tissues. The assembled host-guest systems were investigated using NMR and DLS techniques. We found that, in comparison with free doxorubicin or the binary complex doxorubicin/cyclodextrin polymer, the RGD units decorating the cyclodextrin-based nanosystems improved the selectivity and cytotoxicity of the complexed doxorubicin towards cultured human tumour cell lines. Our results suggest that the nanocarriers under study may contribute to the development of new platforms for cancer therapy.


Assuntos
Antineoplásicos/administração & dosagem , Celulose/administração & dosagem , Ciclodextrinas/administração & dosagem , Doxorrubicina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Oligopeptídeos/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos
13.
Pak J Pharm Sci ; 31(5(Supplementary)): 2069-2076, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30393214

RESUMO

Ellagic acid (EA) is a polyphenolic compound, naturally occurring in various fruits. It has antioxidant, anticancer and antimutagenic properties. Its low aqueous solubility and permeability in GIT, permanent binding to DNA and proteins of cells and first pass metabolism are considered as the reasons for its low oral bioavailability and consequently its low therapeutic potential. Cyclodextrin-based nanosponges (NS) have been utilized to improve the solubilization efficiency of Ellagic acid and to control its release. The scope of the work was to prepare EA nanosponges (EA-NS) using cyclodextrin (ß-CD) and cross-linked by dimethyl carbonate (DMC). It was found that the particle size of the prepared EA-NS was 423.2 nm with low polydispersity index (0.409) and high zeta potential (-34 mV) which manifests the construction of a stabilized colloidal nanoformulation. Moreover, high solubilization efficiency of the loaded EA-NS (49.79µg/ml) compared with the free EA (9.73µg/ml) was spotted. The prepared EA-NS was characterized by XRD, FTIR, and DSC studies and it elucidated a definite interaction of EA with NS. EA-NS successively improved its solubility and provided a controlled in vitro release for 24 hours. EA-NS produced about 69.17% drug content which indicates a good drug loading of the prepared nanosponges. Dissolution of EA-NS was higher than the drug alone. Animal study displayed an improvement in the oral bioavailability of EA indicated by an increase in AUC (1345.49 ng.hr.ml-1) of the EA -NS compared with (598.94 ng.hr.ml-1) for EA.


Assuntos
Ciclodextrinas/química , Sistemas de Liberação de Medicamentos/métodos , Ácido Elágico/química , Lythraceae , Nanoestruturas/química , Administração Oral , Animais , Disponibilidade Biológica , Ciclodextrinas/administração & dosagem , Ciclodextrinas/metabolismo , Ácido Elágico/administração & dosagem , Ácido Elágico/isolamento & purificação , Ácido Elágico/metabolismo , Masculino , Nanoestruturas/administração & dosagem , Coelhos , Solubilidade , Difração de Raios X/métodos
14.
Drug Des Devel Ther ; 12: 3491-3499, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30425452

RESUMO

Background: In this study, fluvastatin (FVT) nanosuspensions containing cyclodextrin were developed to improve oral bioavailability. Methods: FVT nanosuspensions containing cyclodextrin were prepared by a high pressure homogenization technique. The nanosuspensions system was then characterized by transmission electron microscopy (TEM), particle size, differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD). In addition, in vitro drug release properties, pharmacokinetics and pharmacodynamics were also investigated in detail. Results: After lyophilization, the nanosuspensions could be redispersed gently and with a narrow particle size distribution, but the particle size has no obvious change. The powder X-ray diffraction and differential scanning calorimetry of FVT nanosuspensions showed that FVT existed in amorphous form in nanosuspensions. In vitro release, FVT nanosuspensions have sustained-release properties. Meanwhile, FVT nanosuspensions could significantly modify the pharmacokinetic profile and increase the bioavailability of FVT by more than 2.4-fold in comparison with the FVT capsules group. In vivo irritation test showed that there was almost no evidence of hemorrhagic mucosal erosion and intestinal villus destruction in rat gastric mucosa. Conclusion: The combination of nanocrystallization and cyclodextrin complexation techniques is a new attempt to formulate poorly water-soluble FVT.


Assuntos
Ciclodextrinas/farmacocinética , Fluvastatina/farmacocinética , Nanopartículas/química , Animais , Disponibilidade Biológica , Ciclodextrinas/administração & dosagem , Ciclodextrinas/química , Estabilidade de Medicamentos , Tolerância a Medicamentos , Fluvastatina/administração & dosagem , Fluvastatina/química , Concentração de Íons de Hidrogênio , Nanopartículas/administração & dosagem , Ratos , Ratos Wistar , Suspensões/administração & dosagem , Suspensões/química , Suspensões/farmacocinética
15.
J Control Release ; 290: 75-87, 2018 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-30290244

RESUMO

Activation of the Wnt signaling pathway promotes lung cancer progression and contributes to poor patient prognosis. The porcupine inhibitor LGK974, a novel orally bioavailable cancer therapeutic in Phase I clinical trials, induces potent Wnt signaling inhibition and leads to suppressed growth and progression of multiple types of cancers. The clinical use of LGK974, however, is limited in part due to its low solubility and high toxicity in tissues that rely on Wnt signaling for normal homeostasis. Here, we report the use of host-guest chemistry to enhance the solubility and bioavailability of LGK974 in mice through complexation with cyclodextrins (CD). We assessed the effects of these complexes to inhibit Wnt signaling in lung adenocarcinomas that are typically driven by overactive Wnt signaling. 2D 1H NMR confirmed host-guest complexation of CDs with LGK974. CD:LGK974 complexes significantly decreased the expression of Wnt target genes in lung cancer organoids and in lung cancer allografts in mice. Further, CD:LGK974 complexes increased the bioavailability upon oral administration in mice compared to free LGK974. In a mouse lung cancer allograft model, CD:LGK974 complexes induced potent Wnt signaling inhibition with reduced intestinal toxicity compared to treatment with free drug. Collectively, the development of these complexes enables safer and repeated oral or parenteral administration of Wnt signaling inhibitors, which hold promise for the treatment of multiple types of malignancies.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos/administração & dosagem , Ciclodextrinas/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Pirazinas/administração & dosagem , Piridinas/administração & dosagem , Proteínas Wnt/antagonistas & inibidores , Via de Sinalização Wnt/efeitos dos fármacos , Adenocarcinoma de Pulmão/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Ciclodextrinas/química , Ciclodextrinas/farmacocinética , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos Nus , Pirazinas/química , Pirazinas/farmacocinética , Piridinas/química , Piridinas/farmacocinética
16.
Free Radic Res ; 52(9): 988-999, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30203709

RESUMO

Oxidative stress alters signalling pathways for survival and cell death favouring the adverse remodelling of postmyocardial remnant cardiomyocytes, promoting functional impairment. The administration of pterostilbene (PTS), a phytophenol with antioxidant potential, can promote cardioprotection and represents a therapeutic alternative in acute myocardial infarction (AMI). The present study aims to explore the effects of oral administration of PTS complexed with hydroxypropyl-ß-cyclodextrin HPßCD (PTS:HPßCD complex) on the glutathione cycle, thiol protein activities and signalling pathways involving the protein kinase B (AKT) and glycogen synthase kinase-3ß (GSK-3ß) proteins in the left ventricle (LV) of infarcted rats. Animals were submitted to acute myocardial infarction through surgical ligation of the descending anterior branch of the left coronary artery and received over 8 days, by gavage, PTS:HPßCD complex at dose of 100 mg kg-1 day-1 (AMI + PTS group) or vehicle (aqueous solution with HPßCD) divided into Sham-operated (SHAM) and infarcted (AMI) groups. The results showed that the PBS: HPßCD complex decreased lipid peroxidation, prevented the decrease in thioredoxin reductase (TRxR) activity, and increased the activity of glutathione-S-transferase (GST) and glutaredoxin (GRx). Additionally, the expression of nuclear factor-erythroid two (Nrf2) and p-GSK-3ß was increased, whereas the p-GSK-3ß/GSK-3ß ratio was reduced in the LV of the infarcted animals. Overall, the PTS:HPßCD complex modulates activity of thiol-dependent enzymes and induces to the expression of antioxidant proteins, improving systolic function and mitigating the adverse cardiac remodelling post infarction.


Assuntos
Glicogênio Sintase Quinase 3 beta/genética , Infarto do Miocárdio/tratamento farmacológico , Fator 2 Relacionado a NF-E2/genética , Estilbenos/administração & dosagem , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Apoptose/efeitos dos fármacos , Cardiotônicos/administração & dosagem , Cardiotônicos/química , Ciclodextrinas/administração & dosagem , Ciclodextrinas/química , Modelos Animais de Doenças , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos , Estilbenos/química , Função Ventricular Esquerda/genética , Função Ventricular Esquerda/fisiologia
17.
AAPS PharmSciTech ; 19(8): 3734-3741, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30255471

RESUMO

Drug repositioning refers to the identification of new therapeutic indications for drugs already approved. Albendazole and ricobendazole have been used as anti-parasitic drugs for many years; their therapeutic action is based on the inhibition of microtubule formation. Therefore, the study of their properties as antitumor compounds and the design of an appropriate formulation for cancer therapy is an interesting issue to investigate. The selected compounds are poorly soluble in water, and consequently, they have low and erratic bioavailability. In order to improve their biopharmaceutics properties, several formulations employing cyclodextrin inclusion complexes were developed. To carefully evaluate the in vitro and in vivo antitumor activity of these drugs and their complexes, several studies were performed on a breast cancer cell line (4T1) and BALB/c mice. In vitro studies showed that albendazole presented improved antitumor activity compared with ricobendazole. Furthermore, albendazole:citrate-ß-cyclodextrin complex decreased significantly 4T1 cell growth both in in vitro and in vivo experiments. Thus, new formulations for anti-parasitic drugs could help to reposition them for new therapeutic indications, offering safer and more effective treatments by using a well-known drug.


Assuntos
Antiparasitários/administração & dosagem , Ciclodextrinas/administração & dosagem , Reposicionamento de Medicamentos/métodos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Albendazol/administração & dosagem , Albendazol/análogos & derivados , Albendazol/química , Animais , Antiparasitários/química , Disponibilidade Biológica , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Ciclodextrinas/química , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Aleatória , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/patologia , Difração de Raios X , beta-Ciclodextrinas/administração & dosagem , beta-Ciclodextrinas/química
18.
Int J Pharm ; 548(1): 649-658, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-29981896

RESUMO

Injection of insulin is an effective therapy to treat most patients with the type I diabetes and some with type II diabetes. Additionally, the release of insulin under specific conditions has attracted widespread interest. In this study, a smart drug carrier that can release insulin depending on the changes in blood glucose levels was designed. Combining two popular molecules through facile synthetic processes, a drug carrier of reversible phenylboronate group modified cyclodextrin (ß-CD-EPDME) was fabricated. The drug carrier is composed of cyclodextrin, which can encapsulate insulin, and phenylboronate, which is sensitive to the cis-diols in some saccharides. Moreover, ß-CD-EPDME can successfully encapsulate insulin and almost completely release insulin in the presence of glucose. The detached phenylboronic acid moiety triggered by glucose can attack the ß-CD cavity and form a host-guest complex, which can force out the encapsulated insulin within the cavity. In addition, the insulin released from the ß-CD-EPDME@Insulin complex retains its secondary structure, and the drug carrier has been proven to have low cytotoxicity. Thus, this safe and glucose-responsive drug carrier shows the potential for use in the therapy of diabetes.


Assuntos
Ácidos Borônicos , Ciclodextrinas , Sistemas de Liberação de Medicamentos , Glucose/química , Hipoglicemiantes , Insulina , Animais , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclodextrinas/administração & dosagem , Ciclodextrinas/química , Liberação Controlada de Fármacos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Insulina/administração & dosagem , Insulina/química , Camundongos
19.
J Control Release ; 284: 112-121, 2018 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-29906555

RESUMO

Drug delivery strategies generally use inert materials, such as high molecular weight polymers, to encapsulate and control the release rate of therapeutic drugs. Diffusion governs release and depends on the ease of permeation of the polymer alongside the device thickness. Yet in applications such as osteoarthritis, the physiological constraints and limited intra-articular joint space prevent the use of large, solid drug delivery implants. Other investigators have explored the use of micro- and nanoparticle drug delivery systems. However, the small size of the systems limits the total drug that may be encapsulated and its short diffusion distance causes rapid release. Ordinarily, the extremely low diffusivity of a polymer fluid would make this an unsuitable delivery system. Our technology takes advantage of specific molecular interactions between drug and polymer, which can control the rate of release beyond diffusion. With this "affinity-based drug delivery", we have shown that delivery rates from solid polymer can be prolonged from hours and days, to weeks and months. In this paper, we demonstrate that this affinity-based mechanism also applies to low diffusivity fluid-phase polymers. They show release rates that are substantially slower than chemically similar polymers incapable of forming those inclusion complexes. The similarity of this study's liquid polymers to the viscoelastic fluids used in current clinical practice makes it an ample delivery system for osteoarthritic application. We confirmed the capacity of anti-inflammatory delivery of corticosteroids: hydrocortisone, triamcinolone, and dexamethasone; from both solid implants and polymer fluids. Further, we demonstrated that viscoelastic properties are widely tunable, and within the range of native synovial fluid. Lastly, we determined these polymer fluids have no impact on the differentiation of mesenchymal stem cells to cartilage and are not cytotoxic to a common cell line.


Assuntos
Corticosteroides/administração & dosagem , Ciclodextrinas/química , Preparações de Ação Retardada/química , Osteoartrite/tratamento farmacológico , Polímeros/química , Viscossuplementos/química , Corticosteroides/farmacocinética , Linhagem Celular , Ciclodextrinas/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Difusão , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Injeções , Polímeros/administração & dosagem , Viscossuplementos/administração & dosagem
20.
AAPS PharmSciTech ; 19(5): 2358-2369, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29869305

RESUMO

Rilpivrine is BCS class II drug used for treatment of HIV infection. The drug has low aqueous solubility (0.0166 mg/ml) and dissolution rate leading to low bioavailability (32%). Aim of this work was to enhance solubility and dissolution of rilpivirine using beta-cyclodextrin-based nanosponges. These nanosponges are biocompatible nanoporous particles having high loading capacity to form supramolecular inclusion and non-inclusion complexes with hydrophilic and lipophilic drugs for solubility enhancement. Beta-cyclodextrin was crosslinked with carbonyl diimidazole and pyromellitic dianhydride to prepare nanosponges. The nanosponges were loaded with rilpivirine by solvent evaporation method. Binary and ternary complexes of drug with ß-CD, HP-ß-CD, nanosponges, and tocopherol polyethylene glycol succinate were prepared and characterized by phase solubility, saturation solubility in different media, in vitro dissolution, and in vivo pharmacokinetics. Spectral analysis by Fourier transform infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry was performed. Results obtained from spectral characterization confirmed inclusion complexation. Phase solubility studies indicated stable complex formation. Saturation solubility was found to be 10-13-folds higher with ternary complexes in distilled water and 12-14-fold higher in 0.1 N HCl. Solubility enhancement was evident in biorelevant media. Molecular modeling studies revealed possible mode of entrapment of rilpivirine within ß-CD cavities. A 3-fold increase in dissolution with ternary complexes was observed. Animal studies revealed nearly 2-fold increase in oral bioavailability of rilpivirine. It was inferred that electronic interactions, hydrogen bonding, and van der Waals forces are involved in the supramolecular interactions.


Assuntos
Fármacos Anti-HIV/metabolismo , Ciclodextrinas/metabolismo , Nanoestruturas , Rilpivirina/metabolismo , Animais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/química , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Ciclodextrinas/administração & dosagem , Ciclodextrinas/química , Sinergismo Farmacológico , Interações Hidrofóbicas e Hidrofílicas , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Ratos , Ratos Wistar , Rilpivirina/administração & dosagem , Rilpivirina/química , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Difração de Raios X
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