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1.
Nat Commun ; 11(1): 4929, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004789

RESUMO

Non-invasive, molecularly-specific, focal modulation of brain circuits with low off-target effects can lead to breakthroughs in treatments of brain disorders. We systemically inject engineered ultrasound-controllable drug carriers and subsequently apply a novel two-component Aggregation and Uncaging Focused Ultrasound Sequence (AU-FUS) at the desired targets inside the brain. The first sequence aggregates drug carriers with millimeter-precision by orders of magnitude. The second sequence uncages the carrier's cargo locally to achieve high target specificity without compromising the blood-brain barrier (BBB). Upon release from the carriers, drugs locally cross the intact BBB. We show circuit-specific manipulation of sensory signaling in motor cortex in rats by locally concentrating and releasing a GABAA receptor agonist from ultrasound-controlled carriers. Our approach uses orders of magnitude (1300x) less drug than is otherwise required by systemic injection and requires very low ultrasound pressures (20-fold below FDA safety limits for diagnostic imaging). We show that the BBB remains intact using passive cavitation detection (PCD), MRI-contrast agents and, importantly, also by sensitive fluorescent dye extravasation and immunohistochemistry.


Assuntos
Barreira Hematoencefálica/metabolismo , Encefalopatias/tratamento farmacológico , Portadores de Fármacos/efeitos da radiação , Agonistas de Receptores de GABA-A/administração & dosagem , Ultrassonografia de Intervenção/métodos , Animais , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/efeitos da radiação , Relação Dose-Resposta à Radiação , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Feminino , Agonistas de Receptores de GABA-A/farmacocinética , Humanos , Imagem por Ressonância Magnética , Modelos Animais , Muscimol/administração & dosagem , Muscimol/farmacocinética , Ratos , Técnicas Estereotáxicas , Ondas Ultrassônicas
2.
Int J Nanomedicine ; 15: 6069-6084, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32884263

RESUMO

Introduction: Adoptive T-cell immunotherapy emerged as a powerful and promising cancer therapy, as the problem regarding the immuno-reaction between different donors and recipients can be avoided. However, this approach is challenging. After long cultivation and expansion under laboratory media conditions, T-cells are losing their viability and function due to immune checkpoint proteins, leading to decreased efficiency in killing cancer cells. Therefore, a new strategy to improve T-cell survival and function is needed. With the advantages of nanotechnology and the biocompatibility of silica-based material, silica nanocapsules (SiNCs) provide an ideal delivery system to transport therapeutic biomolecules to T-cells. Up to now, there is a lack of cellular uptake studies of nanocarriers towards T-cells. Methods: We systematically studied the influence of various physicochemical properties such as sizes, core hydrophobicities, surface charges, and surface functionalities of SiNC for their impact on cellular uptake and toxicity in CD8+ T-cells by flow cytometry and confocal laser scanning microscopy. Cytokine secretion assay was performed using the enzyme-linked immunosorbent assay. To identify suitable uptake conditions for SiNCs into CD8+ T-cells, the impact of human serum in cell culture medium was also investigated. Results: The major impact on cellular uptake and toxicity was found to be size- and dose-dependent. Smaller sizes of SiNCs than 100 nm caused significant toxicity to the cells. It was found that the formed protein corona reduced the toxicity of the SiNCs. However, it also inhibited their uptake. Conclusion: Overall, we present a set of different criteria for a suitable design of nanocarriers and cell culture conditions, which need to be carefully considered for T-cell immunotherapy in vitro to facilitate uptake while avoiding toxicity.


Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Nanocápsulas/administração & dosagem , Nanocápsulas/química , Portadores de Fármacos/administração & dosagem , Eletroforese em Gel de Poliacrilamida , Citometria de Fluxo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Microscopia Confocal , Coroa de Proteína/química , Dióxido de Silício/química
3.
J Vis Exp ; (162)2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32831304

RESUMO

Several negatively charged tissues in the body, like cartilage, present a barrier to the targeted drug delivery due to their high density of negatively charged aggrecans and, therefore, require improved targeting methods to increase their therapeutic response. Because cartilage has a high negative fixed charge density, drugs can be modified with positively charged drug carriers to take advantage of electrostatic interactions, allowing for enhanced intra-cartilage drug transport. Studying the transport of drug carriers is, therefore, crucial towards predicting the efficacy of drugs in inducing a biological response. We show the design of three experiments which can quantify the equilibrium uptake, depth of penetration and non-equilibrium diffusion rate of cationic peptide carriers in cartilage explants. Equilibrium uptake experiments provide a measure of the solute concentration within the cartilage compared to its surrounding bath, which is useful for predicting the potential of a drug carrier in enhancing therapeutic concentration of drugs in cartilage. Depth of penetration studies using confocal microscopy allow for the visual representation of 1D solute diffusion from the superficial to deep zone of cartilage, which is important for assessing whether solutes reach their matrix and cellular target sites. Non-equilibrium diffusion rate studies using a custom-designed transport chamber enables the measurement of the strength of binding interactions with the tissue matrix by characterizing the diffusion rates of fluorescently labeled solutes across the tissue; this is beneficial for designing carriers of optimal binding strength with cartilage. Together, the results obtained from the three transport experiments provide a guideline for designing optimally charged drug carriers which take advantage of weak and reversible charge interactions for drug delivery applications. These experimental methods can also be applied to evaluate the transport of drugs and drug-drug carrier conjugates. Further, these methods can be adapted for the use in targeting other negatively charged tissues such as meniscus, cornea and the vitreous humor.


Assuntos
Cartilagem/metabolismo , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Peptídeos/farmacocinética , Animais , Cartilagem/efeitos dos fármacos , Cátions/química , Difusão , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Peptídeos/administração & dosagem , Peptídeos/química , Eletricidade Estática
4.
Int J Nanomedicine ; 15: 5389-5403, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801695

RESUMO

Hypothesis: Developing oral formulations to enable effective release of poorly water-soluble drugs like progesterone is a major challenge in pharmaceutics. Coaxial electrospray can generate drug-loaded nanoparticles of strategic compositions and configurations to enhance physiological dissolution and bioavailability of poorly water-soluble drug progesterone. Experiments: Six formulations comprising nanoparticles encapsulating progesterone in different poly(lactide-co-glycolide) (PLGA) matrix configurations and compositions were fabricated and characterized in terms of morphology, molecular crystallinity, drug encapsulation efficiency and release behavior. Findings: A protocol of fabrication conditions to achieve 100% drug encapsulation efficiency in nanoparticles was developed. Scanning electron microscopy shows smooth and spherical morphology of 472.1±54.8 to 588.0±92.1 nm in diameter. Multiphoton Airyscan super-resolution confocal microscopy revealed core-shell nanoparticle configuration. Fourier transform infrared spectroscopy confirmed presence of PLGA and progesterone in all formulations. Diffractometry indicated amorphous state of the encapsulated drug. UV-vis spectroscopy showed drug release increased with hydrophilic copolymer glycolide ratio while core-shell formulations with progesterone co-dissolved in PLGA core exhibited enhanced release over five hours at 79.9±1.4% and 70.7±3.5% for LA:GA 50:50 and 75:25 in comparison with pure progesterone without polymer matrix in the core at 67.0±1.7% and 57.5±2.8%, respectively. Computational modeling showed good agreement with the experimental drug release behavior in vitro.


Assuntos
Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Progesterona/administração & dosagem , Progesterona/farmacocinética , Disponibilidade Biológica , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Microscopia Eletrônica de Varredura , Nanopartículas/administração & dosagem , Tamanho da Partícula , Solubilidade , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Água/química , Difração de Raios X
5.
Int J Nanomedicine ; 15: 5417-5432, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801697

RESUMO

Introduction: Green-based materials have been increasingly studied to circumvent off-target cytotoxicity and other side-effects from conventional chemotherapy. Materials and Methods: Here, cellulose fibers (CF) were isolated from rice straw (RS) waste by using an eco-friendly alkali treatment. The CF network served as an anticancer drug carrier for 5-fluorouracil (5-FU). The physicochemical and thermal properties of CF, pure 5-FU drug, and the 5-FU-loaded CF (CF/5-FU) samples were evaluated. The samples were assessed for in vitro cytotoxicity assays using human colorectal cancer (HCT116) and normal (CCD112) cell lines, along with human nasopharyngeal cancer (HONE-1) and normal (NP 460) cell lines after 72-hours of treatment. Results: XRD and FTIR revealed the successful alkali treatment of RS to isolate CF with high purity and crystallinity. Compared to RS, the alkali-treated CF showed an almost fourfold increase in surface area and zeta potential of up to -33.61 mV. SEM images illustrated the CF network with a rod-shaped structure and comprised of ordered aggregated cellulose. TGA results proved that the thermal stability of 5-FU increased within the drug carrier. Based on UV-spectroscopy measurements for 5-FU loading into CF, drug loading encapsulation efficiency was estimated to be 83 ±0.8%. The release media at pH 7.4 and pH 1.2 showed a maximum drug release of 79% and 46%, respectively, over 24 hours. In cytotoxicity assays, CF showed almost no damage, while pure 5-FU killed most of the both normal and cancer cells. Impressively, the drug-loaded sample of CF/5-FU at a 250 µg/mL concentration demonstrated a 58% inhibition against colorectal cancer cells, but only a 23% inhibition against normal colorectal cells. Further, a 62.50 µg/mL concentration of CF/5FU eliminated 71% and 39% of nasopharyngeal carcinoma and normal nasopharyngeal cells, respectively. Discussion: This study, therefore, showed the strong potential anticancer activity of the novel CF/5-FU formulations, warranting their further investigation.


Assuntos
Celulose/química , Portadores de Fármacos/química , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Fluoruracila/farmacocinética , Células HCT116 , Humanos , Neoplasias Nasofaríngeas/tratamento farmacológico , Oryza/química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria , Difração de Raios X
6.
Int J Nanomedicine ; 15: 5253-5264, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801690

RESUMO

Background and Aim: Flibanserin (FLB) is a multifunctional serotonergic agent used for treating hypoactive sexual desire disorder in premenopausal women via oral administration. FLB has a reported limited oral bioavailability of 33% that could be attributed to the drug's first-pass metabolism. In addition, FLB has a pH-dependent solubility that could be a challenging factor for drug dissolution in the body neutral fluid, and consequently, absorption via mucosal barriers. Thus, this work aims at investigating the potential of utilizing nanostructured lipid carriers (NLCs) to overcome the aforementioned drawbacks and to enhance nose-to-brain drug delivery. Methods: Box-Behnken design was applied to explore the impact of solid lipid % (SL%, X 1), liquid lipid % (LL%, X 2), and sonication time (ST, X 3) on particle size. The optimized NLC formulation was characterized and incorporated into gellan gum in situ gel. The prepared gel was subjected to in vitro drug release, in vivo pharmacokinetic performance, and histopathological assessment in rats. Results: Statistical analysis revealed a significant negative effect for both SL% and ST on NLCs size. In contrast, a significant positive effect was observed for the LL%. The optimized formulation showed spherical shape with vesicular size of 114.63 nm. The optimized FLB-NLC in situ gel exhibited adequate stability and enhanced in vitro release compared to raw FLB control gel. The plasma and brain concentrations of the drug after nasal administration in rats increased by more than 3-6-fold, respectively, compared to raw FLB in situ gel. In addition, the histopathological studies revealed the absence of any pathological signs. Conclusion: The aforementioned results highlight the safety of FLB-NLC in situ nasal gel and its potential to improve the drug bioavailability and brain delivery.


Assuntos
Benzimidazóis/administração & dosagem , Encéfalo/efeitos dos fármacos , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Nanoestruturas/administração & dosagem , Administração Intranasal , Animais , Benzimidazóis/farmacocinética , Disponibilidade Biológica , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Géis , Lipídeos/administração & dosagem , Lipídeos/química , Masculino , Nanoestruturas/química , Tamanho da Partícula , Polissacarídeos Bacterianos/química , Ratos Wistar , Solubilidade
7.
Int J Nanomedicine ; 15: 5333-5344, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801692

RESUMO

Purpose: Cabazitaxel (CBZ) is a new taxane-based antitumor drug approved by the FDA for the treatment of prostate cancer, especially for patients with advanced prostate cancer for whom docetaxel is ineffective or causes aggravation. However, Tween 80 injection can cause serious allergic reactions, and CBZ itself has strong toxicity, adverse reactions, and poor tumor selectivity, which greatly limits its clinical applications. Therefore, the CBZ-loaded bovine serum albumin nanoparticles (CBZ-BSA-Gd-NPs) were developed to overcome the allergenic response of Tween 80 and realize the integration of diagnosis and treatment. Methods: CBZ-BSA-Gd-NPs were prepared by the biomineralization method. The characterization, magnetic resonance imaging (MRI), safety, and antitumor activity of the nanoparticles were evaluated in vitro and in vivo. Results: The prepared nanoparticles were uniform in size (166 nm), with good MRI performance and stability over 24 h. Compared with CBZ-Tween 80 injection, CBZ-BSA-Gd-NPs showed much lower hemolysis, similar tumor inhibition, and enhanced cellular uptake in vitro. The pharmacokinetic behavior of CBZ-BSA-Gd-NPs in rats showed that the retention time of the nanoparticles was prolonged, the clearance rate decreased, and the area under the drug-time curve increased. The distribution of CBZ-BSA-Gd-NPs in nude mice was characterized by UPLC-MS/MS and MRI, and the results showed that CBZ-BSA-Gd-NPs could effectively target tumor tissues with reduced distribution in the heart, liver, spleen, lungs, and kidneys compared with CBZ-Tween 80, which indicated that CBZ-BSA-Gd-NPs not only had a passive targeting effect on tumor tissue but also achieved the integration of diagnosis and treatment. In vivo, CBZ-BSA-Gd-NPs showed improved tumor inhibitory effect with a safer profile. Conclusion: In summary, CBZ-BSA-Gd-NPs can serve as an effective therapeutic drug carrier to deliver CBZ into prostate cancer, and realize the integration of diagnosis and therapy.


Assuntos
Antineoplásicos/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Soroalbumina Bovina/administração & dosagem , Taxoides/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Cromatografia Líquida , Meios de Contraste/administração & dosagem , Meios de Contraste/farmacocinética , Docetaxel , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Humanos , Imagem por Ressonância Magnética , Masculino , Camundongos Endogâmicos BALB C , Nanopartículas/química , Neoplasias da Próstata/diagnóstico por imagem , Ratos Sprague-Dawley , Soroalbumina Bovina/farmacocinética , Espectrometria de Massas em Tandem , Taxoides/farmacocinética , Distribuição Tecidual
8.
Int J Nanomedicine ; 15: 5603-5612, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848390

RESUMO

Introduction: Organ transplantation is a critically important procedure, which requires immune modulation by using immunosuppressants. Development of nanoparticles is an emerging and beneficial engineering process to increase the dissolution rate of poorly soluble immunosuppressants as well as to provide controlled release for better therapeutic outcomes. Method: Currently, the nanoprecipitation method was employed to fabricate ß-cyclodextrin (ßCD) facilitated mycophenolate mofetil (MMF)-loaded solid lipid nanoparticles (SLNPs). The prime objectives of the study included, improvement of the dissolution profile of poorly aqueous soluble drug and controlled release from the SLNs to provide steady state drug concentration. Drug release from the prepared SLNs was assessed in two different media, ie, acidic buffer at pH 1.2 and phosphate buffer at pH 7.2 using USP dissolution apparatus for 12 h, followed by the evaluation of drug release mechanism and pattern by applying kinetic models. Results: Justifiably, in acidic medium, the release was found to be 12% more (68%) in comparison to that in basic medium (56%). However, in both dissolution media, drug release was independent of initial concentration (R2>0.95) with non-Fickian type of diffusion mechanism. The outcomes of the study have exhibited that prepared formulations were in nanosized range (80-170 nm) with a net charge of ±23 charge on their surface. They possessed fairly uniform surface with acceptable polydispersity index (0.23±0.09). Scanning electron microscopy (SEM) analysis illustrated that the nanoparticles had uniform particle size and shape. Discussion: The findings show potential applications of the nanoparticles and the method for the development of SLNPs in controlled release of MMF for better therapeutic outcomes. Conclusively, the prepared SLNPs were well designed in nanosized ranges and justifying the once daily controlled release formulation dose of MMF to enhance patient compliance.


Assuntos
Portadores de Fármacos/química , Imunossupressores/farmacocinética , Ácido Micofenólico/farmacocinética , Nanopartículas/química , Disponibilidade Biológica , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Difusão , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Imunossupressores/química , Lipídeos/química , Microscopia Eletrônica de Varredura , Ácido Micofenólico/química , Nanopartículas/administração & dosagem , Tamanho da Partícula , Solubilidade , beta-Ciclodextrinas/química
9.
AAPS PharmSciTech ; 21(5): 170, 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32529303

RESUMO

Felodipine (FLD), a dihydropyridine calcium channel blocker with excellent antihypertensive effect, is poorly soluble and undergoes extensive hepatic metabolism, which lead to poor oral bioavailability (about 15%) and limit its clinic application. The goal of this study was to develop solid lipid nanoparticles (SLNs) loading FLD to improve the oral bioavailability. The FLD loaded solid lipid nanoparticles (FLD-SLNs) were prepared by the effervescent dispersion technique developed by our laboratory, which might have some advantages over traditional methods. The FLD-SLNs showed desired particle characteristics with particle size (198.15 ± 1.82 nm), poly dispersity index (0.26 ± 0.02), zeta-potential (- 25.53 ± 0.60 mV), entrapment efficiency (95.65 ± 0.70%), drug loading (2.33 ± 0.10%), and a spherical appearance. Pharmacokinetic results showed that the FLD-SLNs presented 3.17-fold increase in area under the curve (AUC(0-t)) compared with free FLD after oral administration in beagle dogs, which indicated that SLNs prepared using the effervescent dispersion technique can improve the bioavailability of lipophilic drugs like felodipine by enhancement of absorption and reduction first-pass metabolism.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacocinética , Química Farmacêutica/métodos , Felodipino/farmacocinética , Nanopartículas/metabolismo , Administração Oral , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Disponibilidade Biológica , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/síntese química , Estudos Cross-Over , Cães , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Portadores de Fármacos/farmacocinética , Felodipino/administração & dosagem , Felodipino/síntese química , Lipídeos , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/química , Tamanho da Partícula , Distribuição Aleatória
10.
J Mycol Med ; 30(3): 101003, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32586733

RESUMO

OBJECTIVE: In order to improve the effect of ketoconazole, poly-lactic acid (PLA) nanoparticles containing ketoconazole were prepared, characterized and tested against dermatophytes and Candida spp planktonic and biofilm cells. METHODS: The ketoconazole-PLA nanoparticles obtained by nanoprecipitation were characterized using dynamic light scattering, scanning electron microscopy, transmission electron microscopy, and differential scanning calorimetry. In addition, quantification of encapsulated ketoconazole and the in vitro release profile were determined. Antifungal susceptibility tests against dermatophytes Trichophyton rubrum, Trichophyton mentagrophytes, and Microsporum gypseum and yeasts Candida albicans, C. dubliniensis, C. krusei, C. parapsilosis, and C. tropicalis were performed. RESULTS: Spherical nanoparticles, with a mean diameter of 188.5nm and an encapsulation efficiency of 45% ketoconazole, were obtained. The nanoparticles containing ketoconazole had superior antifungal activity against all tested fungi strains than free ketoconazole. Inhibition of yeast biofilm formation was also achieved. CONCLUSION: Ketoconazole-PLA nanoparticles resulted in better antifungal activity of ketoconazole nanoparticles than free drug against dermatophytes and Candida species, indicating a promising tool for the development of therapeutic strategies.


Assuntos
Antifúngicos/administração & dosagem , Arthrodermataceae/efeitos dos fármacos , Candida/efeitos dos fármacos , Portadores de Fármacos , Cetoconazol/administração & dosagem , Nanopartículas/química , Poliésteres/química , Antifúngicos/farmacocinética , Arthrodermataceae/fisiologia , Biofilmes/efeitos dos fármacos , Candida/fisiologia , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Cetoconazol/farmacocinética , Teste de Materiais , Testes de Sensibilidade Microbiana , Resultado do Tratamento
11.
Proc Natl Acad Sci U S A ; 117(22): 11987-11994, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32424082

RESUMO

Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis worldwide and kills more Americans than 59 other infections, including HIV and tuberculosis, combined. While direct-acting antiviral (DAA) treatments are effective, limited uptake of therapy, particularly in high-risk groups, remains a substantial barrier to eliminating HCV. We developed a long-acting DAA system (LA-DAAS) capable of prolonged dosing and explored its cost-effectiveness. We designed a retrievable coil-shaped LA-DAAS compatible with nasogastric tube administration and the capacity to encapsulate and release gram levels of drugs while resident in the stomach. We formulated DAAs in drug-polymer pills and studied the release kinetics for 1 mo in vitro and in vivo in a swine model. The LA-DAAS was equipped with ethanol and temperature sensors linked via Bluetooth to a phone application to provide patient engagement. We then performed a cost-effectiveness analysis comparing LA-DAAS to DAA alone in various patient groups, including people who inject drugs. Tunable release kinetics of DAAs was enabled for 1 mo with drug-polymer pills in vitro, and the LA-DAAS safely and successfully provided at least month-long release of sofosbuvir in vivo. Temperature and alcohol sensors could interface with external sources for at least 1 mo. The LA-DAAS was cost-effective compared to DAA therapy alone in all groups considered (base case incremental cost-effectiveness ratio $39,800). We believe that the LA-DAA system can provide a cost-effective and patient-centric method for HCV treatment, including in high-risk populations who are currently undertreated.


Assuntos
Antivirais/administração & dosagem , Sistemas de Liberação de Medicamentos , Hepatite C Crônica/tratamento farmacológico , Animais , Antivirais/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Análise Custo-Benefício , Modelos Animais de Doenças , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/economia , Sistemas de Liberação de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/métodos , Fluorenos/administração & dosagem , Fluorenos/farmacocinética , Hepacivirus/efeitos dos fármacos , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Cirrose Hepática/tratamento farmacológico , Modelos Animais , Ribavirina/administração & dosagem , Ribavirina/farmacocinética , Sofosbuvir/administração & dosagem , Sofosbuvir/farmacocinética , Suínos
12.
AAPS PharmSciTech ; 21(4): 125, 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350635

RESUMO

Sunlight is important to health, but higher exposure to radiation causes early aging of the skin and skin damage that can lead to skin cancers. This study aimed at producing a stable octyl p-methoxycinnamate (OMC)-loaded nanostructured lipid carrier (NLC) sunscreen, which can help in the photoprotective effect. NLC was produced by emulsification-sonication method and these systems were composed of myristyl myristate (MM), caprylic capric triglyceride (CCT), Tween® 80 (TW), and soybean phosphatidylcholine (SP) and characterized by dynamic light scattering (DLS), zeta potential (ZP) measurement, atomic force microscopy (AFM), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and in vitro release studies. Pre-formulation studies were performed changing TW concentrations and no differences were found at concentrations of 1.0 and 2.0%. Two selected formulations were designed and showed an average size of 91.5-131.7, polydispersity index > 0.2, and a negative value of ZP. AFM presented a sphere-like morphology and SEM showed ability to form a thin film. DSC exhibited that the incorporation of OMC promoted reduction of enthalpy due to formation of a more amorphous structure. Drug release shows up to 55.74% and 30.57%, and this difference could be related to the presence of SP in this formulation that promoted a more amorphous structure; the release mechanism study indicated Fickian diffusion and relaxation. Sun protection factor (SPF) evaluation was performed using NLC and presented values around 40, considerably higher than those observed in the literature. The developed formulations provide a beneficial alternative to conventional sunscreen formulations.


Assuntos
Cinamatos/síntese química , Portadores de Fármacos/síntese química , Lipídeos/síntese química , Nanoestruturas/química , Fator de Proteção Solar/métodos , Protetores Solares/síntese química , Varredura Diferencial de Calorimetria/métodos , Cinamatos/farmacocinética , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Lipídeos/farmacocinética , Microscopia de Força Atômica/métodos , Microscopia Eletrônica de Varredura/métodos , Tamanho da Partícula , Protetores Solares/farmacocinética
13.
J Nanobiotechnology ; 18(1): 67, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32345323

RESUMO

BACKGROUND: Exenatide is an insulinotropic peptide drug for type 2 diabetes treatment with low risk of hypoglycemia, and is administrated by subcutaneous injection. Oral administration is the most preferred route for lifelong treatment of diabetes, but oral delivery of peptide drug remains a significant challenge due to the absorption obstacles in gastrointestinal tract. We aimed to produce exenatide-loaded nanoparticles containing absorption enhancer, protectant and stabilizer using FDA approved inactive ingredients and easy to scale-up method, and to evaluate their long-term oral therapeutic effect in type 2 diabetes db/db mice. RESULTS: Two types of nanoparticles, named COM NPs and DIS NPs, were fabricated using anti-solvent precipitation method. In COM NPs, the exenatide was complexed with cholic acid and phosphatidylcholine to increase the exenatide loading efficiency. In both nanoparticles, zein acted as the cement and the other ingredients were embedded in zein nanoparticles by hydrophobic interaction. Casein acted as the stabilizer. The nanoparticles had excellent lyophilization, storage and re-dispersion stability. Hypromellose phthalate protected the loaded exenatide from degradation in simulated gastric fluid. Cholic acid promoted the intestinal absorption of the loaded exenatide via bile acid transporters. The exenatide loading efficiencies of COM NPs and DIS NPs were 79.7% and 53.6%, respectively. The exenatide oral pharmacological availability of COM NPs was 18.6% and DIS NPs was 13.1%. COM NPs controlled the blood glucose level of the db/db mice well and the HbA1c concentration significantly decreased to 6.8% during and after 7 weeks of once daily oral administration consecutively. Both DIS NPs and COM NPs oral groups substantially increased the insulin secretion by more than 60% and promoted the ß-cell proliferation by more than 120% after the 7-week administration. CONCLUSIONS: Both COM NPs and DIS NPs are promising systems for oral delivery of exenatide, and COM NPs are better in blood glucose level control than DIS NPs. Using prolamin to produce multifunctional nanoparticles for oral delivery of peptide drug by hydrophobic interaction is a simple and effective strategy.


Assuntos
Exenatida/farmacologia , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Nanopartículas/química , Zeína/química , Administração Oral , Animais , Glicemia/análise , Ácido Cólico/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Exenatida/administração & dosagem , Exenatida/química , Trato Gastrointestinal/química , Trato Gastrointestinal/patologia , Hemoglobina A Glicada/análise , Meia-Vida , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Células Secretoras de Insulina/classificação , Células Secretoras de Insulina/metabolismo , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Nanopartículas/metabolismo , Permeabilidade/efeitos dos fármacos , Fosfatidilcolinas/química
14.
Curr Pharm Biotechnol ; 21(11): 1016-1027, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32188383

RESUMO

Graphene Derivatives (GDs) have captured the interest and imagination of pharmaceutical scientists. This review exclusively provides pharmacokinetics and pharmacodynamics information with a particular focus on biopharmaceuticals. GDs can be used as multipurpose pharmaceutical delivery systems due to their ultra-high surface area, flexibility, and fast mobility of charge carriers. Improved effects, targeted delivery to tissues, controlled release profiles, visualization of biodistribution and clearance, and overcoming drug resistance are examples of the benefits of GDs. This review focuses on the application of GDs for the delivery of biopharmaceuticals. Also, the pharmacokinetic properties and the advantage of using GDs in pharmaceutics will be reviewed to achieve a comprehensive understanding about the GDs in pharmaceutical sciences.


Assuntos
Portadores de Fármacos/farmacologia , Grafite/farmacologia , Preparações Farmacêuticas/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/tendências , Liberação Controlada de Fármacos , Grafite/química , Grafite/farmacocinética , Humanos , Cinética , Nanomedicina Teranóstica , Distribuição Tecidual
15.
Sci Rep ; 10(1): 3651, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32107425

RESUMO

Phenylketonuria is a genetic disorder affecting the metabolism of phenylalanine (phe) due to a deficiency in the enzyme phenylalanine hydroxylase. This disorder is characterized by an elevated phe blood level, which can lead to severe intellectual disabilities in newborns. The current strategy to prevent these devastating consequences is limited to a life-long phe-free diet, which implies major lifestyle changes and restrictions. Recently, an injectable enzyme replacement therapy, Pegvaliase, has been approved for treating phenylketonuria, but is associated with significant side-effects. In this study a phe-metabolizing system suitable for oral delivery is designed to overcome the need for daily injections. Active phenylalanine ammonia-lyase (PAL), an enzyme that catalyses phe metabolism, is loaded into mesoporous silica microparticles (MSP) with pore sizes ranging from 10 to 35 nm. The surface of the MSP is lined with a semipermeable barrier to allow permeation of phe while blocking digestive enzymes that degrade PAL. The enzymatic activity can be partially preserved in vitro by coating the MSP with poly(allylamine) and poly(acrylic acid)-bowman birk (protease inhibitor) conjugate. The carrier system presented herein may provide a general approach to overcome gastro-intestinal proteolytic digestion and to deliver active enzymes to the intestinal lumen for prolonged local action.


Assuntos
Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Fenilalanina Amônia-Liase/química , Fenilalanina Amônia-Liase/farmacocinética , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacocinética , Portadores de Fármacos/uso terapêutico , Terapia de Reposição de Enzimas , Humanos , Fenilalanina Amônia-Liase/uso terapêutico , Fenilcetonúrias/tratamento farmacológico , Fenilcetonúrias/enzimologia , Porosidade , Proteínas Recombinantes/uso terapêutico , Dióxido de Silício/química , Dióxido de Silício/farmacocinética , Dióxido de Silício/uso terapêutico
16.
Nanoscale ; 12(7): 4676-4685, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32048702

RESUMO

Platelets play an important role in the early stage of arterial remodeling after injury. Integrin GPIIb/IIIα (αIIbß3) regulates platelet activation in the inside-out and outside-in signaling pathways. The use of tirofiban, an integrin αIIbß3 inhibitor, in clinical therapy is limited by its short in vivo circulation time. Herein, a controlled drug-release system was formulated using CuS@mSiO2-PEG core-shell nanoparticles as near-infrared-triggered nanocarriers to release tirofiban on demand. The nanocarriers possessed good colloidal stability and very high loading efficiency for the integrin αIIbß3 inhibitor (14.5 wt% for tirofiban). Local application of αIIbß3 antagonist-tirofiban on an injured arterial wall inhibited platelet activation, which was accelerated by laser irradiation. Ex vivo platelet-promoted monocyte transmigration trans-well assays revealed decreased monocyte transmigration after platelet activation was inhibited by tirofiban. Two weeks after the wire-induced injury, the intimal area and cellular content were analyzed. The neointimal area was decreased in ApoE-/- mice with CuS@mSiO2-PEG/tirofiban and laser irradiation-promoted tirofiban release, which had limited the neointima formation. The lesions showed a decreased content of macrophages and smooth muscle cells compared with ApoE-/- mice without tirofiban inhibition. Therefore, the action of platelet-integrin αIIbß3 in neointima formation after vascular injury was successfully inhibited in vivo through the controlled release of tirofiban using a near-infrared-triggered nanocarrier, leading to the decrease of early-stage neointima formation. This study also emphasizes the role of platelets in vascular remodeling and provides a new target, namely integrin αIIbß3, for the inhibition of neointimal hyperplasia during vascular inflammation.


Assuntos
Plaquetas/metabolismo , Portadores de Fármacos , Raios Infravermelhos , Nanopartículas , Neointima/tratamento farmacológico , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Tirofibana , Animais , Plaquetas/patologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Camundongos , Camundongos Knockout para ApoE , Nanopartículas/química , Nanopartículas/uso terapêutico , Neointima/metabolismo , Neointima/patologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Células RAW 264.7 , Tirofibana/química , Tirofibana/farmacocinética , Tirofibana/farmacologia
17.
Molecules ; 25(4)2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32092877

RESUMO

The intestinal epithelium is a major barrier that limits the absorption of oral drugs. The integrity of the epithelial tissue is a very important factor for preventing intestinal diseases. However, destabilization of the epithelium can promote the transportation of nanocarriers and increase the absorption of oral drugs. In our research, three different gold nanoparticles (GNPs) of the same size but with differing negative surface charge were designed and constructed as a model to determine the surface properties crucial for promoting absorptivity and bioavailability of the nanocarriers. The higher the ratio of surface carboxyl groups on GNPs, the higher capacity to induce transepithelial electrical resistance change and cell monolayer tight junction opening with higher permeability. The half carboxyl and half methyl surfaced GNPs displayed unique zonal surface patterns exhibited the greater ability to pass through intestinal epithelial cell layer but had a relatively small influence on tight junction distribution.


Assuntos
Portadores de Fármacos , Enterócitos/metabolismo , Ouro , Nanopartículas Metálicas/química , Células CACO-2 , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Enterócitos/citologia , Ouro/química , Ouro/farmacocinética , Ouro/farmacologia , Humanos , Permeabilidade
18.
Int J Nanomedicine ; 15: 301-313, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021181

RESUMO

Purpose: Multifunctional drug delivery systems (DDS) are emerging as a new strategy to highly treat malignant tumors. The aim of this study is to develop a drug dual-carriers delivery system (DDDS) using the natural protein ferritin (FRT) and a nanoscale graphene oxide (NGO) as dual-carriers. Methods: The FRT is a pH-sensitive hollow cage protein with disassembly and reassembly properties and the NGO has a large surface area and a photothermal effect by which it can load and release drugs under near-infrared irradiation (NIR). Due to these unique features, the NGO loaded the anticancer drug resveratrol (RSV) and the conjugated mitochondrion targeted molecule IR780 as IR780-NGO-RSV (INR), the first drug delivery platform. Next, the INR was capsulated by FRT to form the DDDS INR@FRT which was applied for synergistic photothermal-chemotherapy of ovarian cancer. Results: Through a series of characterizations, INR@FRT showed a uniform nanosphere structure and remarkable stability in physiological condition. Heat/pH 5.0 was confirmed to trigger RSV release from the INR@FRT. After taken up by cells, INR@FRT located to the lysosomes where the acidic environment triggered INR release. INR targeted the mitochondrion and released RSV to directly react with organelles, which in turn decreased the mitochondrion membrane potential and caused cell apoptosis. In-vivo experiments showed that INR@FRT combined with NIR irradiation displayed remarkable tumor suppression with a high survival rate after 60 days of treatment. Finally, the biocompatibility of INR@FRT was demonstrated in vitro and in vivo. Conclusion: These results highlight the immense potential of INR@FRT as a type of DDDS for the treatment of tumors.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Indóis/farmacologia , Mitocôndrias/efeitos dos fármacos , Nanoestruturas/química , Neoplasias Ovarianas/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Feminino , Ferritinas/química , Grafite/química , Temperatura Alta , Humanos , Concentração de Íons de Hidrogênio , Indóis/administração & dosagem , Indóis/química , Raios Infravermelhos , Camundongos Nus , Nanoestruturas/administração & dosagem , Resveratrol/administração & dosagem , Resveratrol/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Int J Nanomedicine ; 15: 601-618, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32099354

RESUMO

Purpose: The purpose of this research was to study the basic physicochemical and biological properties regarding the application of L-tartaric acid modified chiral mesoporous silica nanoparticle (CMSN) as a drug carrier, and to explore the structure-property relationship of silica-based materials. Methods: CMSN with functions of carboxyl modification and chirality was successfully synthesized through co-condensation method, and the basic characteristics of CMSN, including morphology, structure, wettability, degradation, bio-adhesion and retention ability in gastrointestinal tract (GI tract) were estimated by comparing with non-functionalized mesoporous silica nanoparticles (MSN). Meanwhile, the biocompatibility and toxicity of L-tartaric modification were systematically evaluated both in vitro and in vivo through MTT cell viability assay, cell cycle and apoptosis assay, hemolysis assay, histopathology examination, hematology analysis, and clinical chemistry examination. Results: CMSN and MSN were spherical nanoparticles with uniform mesoporous structure. CMSN with smaller pore size and carboxyl functional groups exhibited better wettability. Besides, CMSN and MSN could dissolve thoroughly in simulated physiological fluids during a degradation period of 1-12 weeks. Interestingly, the in vitro and in vivo behaviors of carriers, including degradation, bio-adhesion and retention ability in the GI tract were closely related to wettability. As expected, CMSN had faster degradation rate, higher mucosa-adhesion ability, and longer retention time. Particularly, CMSN improved the bio-adhesion property in both gastric mucosa and small intestinal mucosa, and prolonged the GI tract retention time to at least 12 h, which meant higher probability for absorption. The biocompatibility and toxicity examination indicated that CMSN was a kind of biocompatible bio-material with good blood compatibility and negligible toxicity, which is required for further applications in biological fields. Conclusion: CMSN with functions of carboxyl modification and chirality had superiority in terms of both physicochemical and biological properties. The in vitro and in vivo behaviors of carriers, including degradation, bio-adhesion, and retention were closely related to wettability.


Assuntos
Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Nanopartículas/química , Tartaratos/química , Animais , Apoptose/efeitos dos fármacos , Materiais Biocompatíveis , Linhagem Celular , Sobrevivência Celular , Dicroísmo Circular , Suco Gástrico/efeitos dos fármacos , Suco Gástrico/metabolismo , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Teste de Materiais , Microscopia Eletrônica de Transmissão , Nanopartículas/metabolismo , Coelhos , Ratos Sprague-Dawley , Dióxido de Silício/química , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-Atividade , Molhabilidade
20.
Int J Nanomedicine ; 15: 779-793, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32099365

RESUMO

Purpose: Cancer chemotherapy effect has been largely limited by cell autophagy and little drug accumulation at the action sites. Herein, we designed an intelligent strategy involving paclitaxel (PTX) polymer micelles in response to biological functions of ambroxol (Ax). The amphiphilic polymers polyethyleneglycol-polylactic acid (PEG-PLA) and Pluronic P105 were selected as nanocarriers to encapsulate PTX to form into lung affinity PEG-PLA/P105/PTX micelles. Ax which can up-regulate the secretion of pulmonary surfactant (PS) and inhibit autophagy was hired to change the microenvironment of the lung, thereby promoting the lung accumulation and increasing cell-killing sensitivity of the micelles. Methods: The physical and chemical properties of the micelles were characterized including size, morphology, critical micellar concentration (CMC) and in vitro drug release behavior. The therapeutic effects of the combination regimen were characterized both in vitro and in vivo including study on Ax in promoting the secretion of pulmonary surfactant, in vitro cytotoxicity, cellular uptake, Western blotting, in vivo biodistribution, in vivo pharmacokinetics and in vivo antitumor efficacy. Results: The PEG-PLA/P105/PTX micelles showed a particle size of 16.7 ± 0.5 nm, a nearly round shape, small CMC and sustained drug release property. Moreover, the in vitro results indicated that Ax could increase PS and LC3 protein secretion and enhance the cytotoxicity of PEG-PLA/P105/PTX micelles toward A549 cells. The in vivo results indicated that the combination therapeutic regimen could promote the micelles to distribute in lung and enhance the therapeutic effect on lung cancer. Conclusion: This multifunctional approach of modulating the tumor microenvironment to enhance drug transportation and cell-killing sensitivity in the action sites might offer a new avenue for effective lung cancer treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Portadores de Fármacos/química , Neoplasias Pulmonares/tratamento farmacológico , Ambroxol/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Micelas , Paclitaxel/administração & dosagem , Paclitaxel/farmacologia , Tamanho da Partícula , Poloxâmero/química , Polietilenoglicóis/química , Polímeros/química , Ratos Sprague-Dawley , Distribuição Tecidual
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