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1.
Mater Sci Eng C Mater Biol Appl ; 106: 110159, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31753404

RESUMO

Stimuli-triggered drug delivery systems have been recognized as a crucial strategy to achieve on-demand drug release at the tumor for improving therapeutic efficacy. In this work, novel biocompatible and biodegradable reactive oxygen species (ROS)-responsive amino acid- based polymeric micelles were developed for tumor-specific drug release triggered by high ROS levels in cancer cells, which were composed of amphiphilic poly(aspartic acid) (PASP) derivatives (PASP-BSer) with phenylborate serine (BSer) side groups as the ROS-responsive unit. A series of PASP-BSer conjugates with different degree of substitution (DS) were synthesized, and their self-assembly and H2O2-responsive behaviors were investigated to optimize the structure of PASP-BSer. In vitro drug loading and release studies confirmed that the optimized PASP-BSer micelles could effectively encapsulate the model anticancer drug doxorubicin (Dox) and exhibit desirable H2O2-triggered release behaviors. More importantly, Dox-loaded PASP-BSer micelles showed high selective cytotoxicity against A549 cancer cells than L929 normal cells. Accordingly, PASP-BSer micelles have significant potential as on-demand drug carriers for anticancer therapy.


Assuntos
Aminoácidos/química , Portadores de Fármacos/química , Nanoestruturas/química , Polímeros/química , Espécies Reativas de Oxigênio/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/farmacologia , Concentração de Íons de Hidrogênio , Camundongos , Tamanho da Partícula
2.
Drug Deliv ; 26(1): 1125-1139, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31736389

RESUMO

Stability in systemic circulation, effective tumor accumulation, and the subsequent crucial subcellular targeting are significant elements that maximize the therapeutic efficacy of a drug. Accordingly, novel nanoparticles based on polysaccharides that simultaneously presented prolonged systemic circulation and mitochondrial-targeted drug release were synthesized. First, the mitochondrial-targeted polymer, 3,4-dihydroxyphenyl propionic acid-chitosan oligosaccharide-dithiodipropionic acid-berberine (DHPA-CDB), was synthesized, which was used to form self-assembled curcumin (Cur)-encapsulated cationic micelles (DHPA-CDB/Cur). Negatively charged oligomeric hyaluronic acid-3-carboxyphenylboronic acid (oHA-PBA), a ligand to sialic acid and CD44, was further added to the surface of the preformed DHPA-CDB/Cur core to shield the positive charges and to prolong blood persistence. oHA-PBA@DHPA-CDB/Cur formed a covalent polyplex of oHA-PBA and DHPA-CDB/Cur via the pH-responsive borate ester bond between PBA and DHPA. The mildly acidic tumor environment led to the degradation of borate ester bonds, thereby realizing the exposure of the cationic micelles and causing a charge reversal from -19.47 to +12.01 mV, to promote cell internalization and mitochondrial localization. Compared with micelles without the oHA-PBA modification, the prepared oHA-PBA@DHPA-CDB/Cur showed enhanced cytotoxicity to PANC-1 cells and greater cellular uptake via receptor-mediated endocytosis. oHA-PBA@DHPA-CDB/Cur was effectively targeted to the mitochondria, which triggered mitochondrial membrane depolarization. In mice xenografted with PANC-1 cells, compared with control mice, oHA-PBA@DHPA-CDB/Cur resulted in more effective tumor suppression and greater biosafety with preferential accumulation in the tumor tissue. Thus, the long-circulating oHA-PBA@DHPA-CDB/Cur, with mitochondrial targeting and tumor environment charge-reversal capabilities, was shown to be an excellent candidate for subcellular-specific drug delivery.


Assuntos
Antineoplásicos/química , Preparações de Ação Retardada/química , Mitocôndrias/efeitos dos fármacos , Nanopartículas/química , Polissacarídeos/química , Adenina/análogos & derivados , Adenina/química , Animais , Antineoplásicos/farmacologia , Berberina/química , Linhagem Celular , Quitosana/química , Curcumina/química , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/química , Camundongos , Camundongos Nus , Micelas , Polímeros/química , Polissacarídeos/farmacologia
3.
Drug Deliv ; 26(1): 1049-1057, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31691602

RESUMO

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


Assuntos
Doxorrubicina/administração & dosagem , Doxorrubicina/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Varredura Diferencial de Calorimetria/métodos , Cromatografia Líquida de Alta Pressão/métodos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Excipientes/química , Feminino , Fígado/efeitos dos fármacos , Masculino , Próteses e Implantes , Ratos , Ratos Wistar , Suínos , Porco Miniatura , Espectrometria de Massas em Tandem/métodos
4.
Eur J Pharm Biopharm ; 145: 12-26, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31622652

RESUMO

A major shortcoming of drug nanocomposites as compared with amorphous solid dispersions (ASDs) is their limited supersaturation capability in dissolution media. Here, we prepared drug hybrid nanocrystal-amorphous solid dispersions (HyNASDs) and compare their performance to ASDs. A wet-milled griseofulvin (GF, BCS II drug) nanosuspension and a GF solution, both containing the same dissolved polymer-surfactant (SDS: sodium dodecyl sulfate) with 1:1 and 1:3 GF:polymer mass ratios, were spray-dried. Hydroxypropyl cellulose (HPC) and Soluplus (Sol) were used as matrix-forming polymers. XRPD, DSC, and Raman spectroscopy reveal that ASDs were formed upon spray-drying the solution-based feed, whereas nanocomposites and nanocomposites with >10% amorphous content, HyNASDs, were formed with the nanosuspension-based feed. Sol provided higher GF relative supersaturation, up to 180% and 360% for HyNASDs and ASDs, respectively, in the dissolution tests than HPC (up to 50% for both) owing to Sol's stronger intermolecular interactions and miscibility with GF and its recrystallization inhibition. Besides the higher kinetic solubility of GF in Sol, presence of GF nanoparticles vs. micron-sized particles in the nanocomposites enabled fast supersaturation. This study demonstrates successful preparation of fast supersaturating (190% within 20 min) HyNASDs, which renders nanoparticle formulations competitive to ASDs in bioavailability enhancement of poorly soluble drugs.


Assuntos
Liberação Controlada de Fármacos/efeitos dos fármacos , Griseofulvina/química , Nanopartículas/química , Celulose/análogos & derivados , Celulose/química , Cristalização/métodos , Composição de Medicamentos/métodos , Nanocompostos/química , Tamanho da Partícula , Polietilenoglicóis/química , Polímeros/química , Polivinil/química , Dodecilsulfato de Sódio/química , Solubilidade , Tensoativos/química , Suspensões/química
5.
Mar Drugs ; 17(10)2019 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-31614820

RESUMO

Marine ecosystems are the most prevalent ecosystems on the planet, providing a diversity of living organisms and resources. The development of nanotechnology may provide solutions for utilizing these thousands of potential compounds as marine pharmaceuticals. Here, we designed a liposomal glycol chitosan formulation to load both doxorubicin (DOX) and rapamycin (RAPA), and then evaluated its therapeutic potential in a prepared drug-resistant cell model. We explored the stability of the drug delivery system by changing the physiological conditions and characterized its physicochemical properties. The electrostatic complexation between DOX-glycol chitosan and docosahexaenoic acid RAPA-liposomes (GC-DOX/RAPA ω-liposomes) was precisely regulated, resulting in particle size of 131.3 nm and zeta potential of -14.5 mV. The well-characterized structure of GC-DOX/RAPA ω-liposomes led to high loading efficiencies of 4.1% for DOX and 6.2% for RAPA. Also, GC-DOX/RAPA ω-liposomes exhibited high colloidal stability under physiological conditions and synergistic anti-cancer effects on DOX-resistant MDA-MB-231 cells, while showing pH-sensitive drug release behavior. Our results provided a viable example of marine pharmaceuticals with therapeutic potential for treating drug-resistant tumors using an efficient and safe drug delivery system.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quitosana/química , Ácidos Docosa-Hexaenoicos/química , Doxorrubicina/química , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Lipossomos/química , Sirolimo/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Ecossistema , Feminino , Humanos , Nanopartículas/química , Tamanho da Partícula
6.
Eur J Pharm Biopharm ; 144: 180-192, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31550525

RESUMO

Oromucosal delivery of active pharmaceutical ingredients provides an attractive alternative route of administration, due to avoidance of the first pass effect and improved patient compliance. In the current work, fused deposition modelling (FDM) 3D printing was investigated as an additive manufacturing approach for poly(vinyl alcohol)-based mucoadhesive films, enabling unidirectional drug release. For this purpose, chitosan was incorporated as a permeation and mucoadhesion enhancer whereas ethylcellulose and commercial wafer sheets were evaluated as backing layers. The formulated films were initially assessed for structural integrity and dose uniformity. Solid-state characterization of the films, including thermal methods (DSC, TGA), diffraction (XRPD) and Raman spectroscopy, was implemented to characterize the physicochemical properties of the produced polymeric filaments and buccal films. The mechanical properties of the products were investigated by instrumented indentation and tensile tests. Evaluation of buccal films was assessed in vitro, to study the effect of backing-layer type on hydration capacity of the films, diffusion of the drug throughout the restricting layer and release profiles in simulated saliva. The ex vivo performance of the manufactured products, associated with the presence of chitosan, was investigated by textural analysis for mucoadhesion properties, whereas permeation studies and histological studies were performed across porcine buccal epithelium. The results demonstrated that FDM printing is a timesaving and versatile approach in the context of manufacturing multi-layered mucoadhesive buccal films, providing unidirectional release properties.


Assuntos
Adesivos/química , Preparações Farmacêuticas/química , Administração Bucal , Animais , Celulose/análogos & derivados , Celulose/química , Quitosana/química , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Mucosa Bucal/metabolismo , Polímeros/química , Álcool de Polivinil/química , Impressão Tridimensional , Suínos
7.
Eur J Pharm Biopharm ; 144: 217-229, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31563632

RESUMO

Poor encapsulation and high initial burst were two major obstacles for the water-soluble peptide drug loaded microspheres preparation using the industrial emulsification method. In the present study, we hypothesized that the hydrophobic ion-pairing (HIP) complex strategy with a further healing of the pores within the microspheres may improve drug encapsulation and initial burst release. DSS was chosen as the most suitable one among the three test ion-pairing agents (SDS, DSS and STC) due to its high binding efficiency with drug and reversible dissociation capacity in presence of counter ions. The formation of HIP complex between octreotide acetate and DSS successfully reversed the highly water-soluble nature of the drug. A specific S/O/W method was adopted to encapsulate such drug containing HIP complex. The encapsulation efficiency of the drug was greatly improved compared with the conventional W1/O/W2 method (from 44% to 90%). Under the optimal healing conditions (the healing time 6 h, temperature 40 °C and 4% DEP content), the pores within the microspheres were effectively healed. Initial burst amount of octreotide acetate in S/O/W microspheres decreased to 3.56%. The pore healing effect was further confirmed by the scanning electron microscopy and fluorescence microscopy results. In the process of testing the drug release performance of such new strategy in vitro and in vivo, a more satisfactory single phase release profile with sustained and steady drug release was observed. These results suggested that the modified HIP strategy could be a promising platform for water-soluble peptide encapsulation with high encapsulation efficiency, low initial burst and stable drug release mechanism.


Assuntos
Liberação Controlada de Fármacos/efeitos dos fármacos , Íons/química , Peptídeos/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Composição de Medicamentos/métodos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Microscopia Eletrônica de Varredura/métodos , Microesferas , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Solventes/química , Temperatura , Água/química
8.
Eur J Pharm Biopharm ; 144: 193-206, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31560954

RESUMO

To achieve redox-controlled and tumor active targeting synergistic self-delivery of camptothecin and gemcitabine, redox-sensitive rod-shaped nano-micelles are fabricated through co-assembling between camptothecin-disulfide bond-PEG2000-4-carboxyphenylboronic acid and camptothecin-disulfide bond-gemcitabine conjugate. Most of all, for multidrug resistant cancer cell line MCF-7/ADR which is more resistant against CPT, increasing content of CPT in the formulation is favorable for synergistic effect of CPT and GEM drug combination. Benefiting from simple co-assembling strategy, it is easy and convenient to adjust drug ratio of CPT/GEM to optimize the synergism of drug combination. In addition, nano-micelles fabricated from co-assembling are endowed with both high absolute drug concentration and enhanced colloidal stability, which is helpful to in vivo studies. Transmission electron microscopy observation confirmed the rod-shaped morphology, which is beneficial to cellular internalization, of co-assembled nano-micelles resulting from π-π stacking interactions of CPT moieties and appropriate hydrophilic and hydrophobic interactions during co-assembling. Taking advantages of the specific interactions between 4-carboxyphenylboronic acid and sialic acid, co-assembled nano-micelles exerted enhanced cellular internalization. Noteworthy, compared with cocktail mixture of free CPT and GEM, nano-micelles greatly alleviated drug reflux against MCF-7/ADR and 4T1 cells. The nano-micelles realized redox-controlled ratio-metric and synchronous delivery of CPT and GEM, thereby pronounced in vitro synergistic antiproliferative effect against MCF-7/ADR and 4T1cells. Furthermore, in vivo bio-distribution analysis indicated the preferential accumulation of nano-micelles at tumor site, which could increase therapeutic efficacy and decrease side effects of non-selective anticancer drugs. Taken together, the redox-sensitive CPBA decorated co-assembled nano-micelles provided a promising strategy for tumor active targeting and redox-controlled intracellular synergistic combinational delivery of chemotherapeutics.


Assuntos
Ácidos Borônicos/química , Camptotecina/química , Desoxicitidina/análogos & derivados , Nanopartículas/química , Oxirredução/efeitos dos fármacos , Antineoplásicos/química , Linhagem Celular Tumoral , Desoxicitidina/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Células MCF-7 , Micelas , Polietilenoglicóis/química
9.
Int J Pharm ; 570: 118651, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31493496

RESUMO

The focus of the study was to understand the effects of formulation and process variables on the printlets quality manufactured by selective laser sintering (SLS) 3D printing. The Box-Behnken response surface methodology was used to evaluate effects of individual variables and combinations thereof. The formulation and process variables studied were printing chamber temperature (°C, X1), laser scanning speed (mm/sec, X2) and lactose monohydrate concentration (%, X3). The responses studied were weight of printlets (mg, Y1), hardness (N, Y2), disintegration time (sec, Y3) and dissolved drug fraction in 15 min (%, Y4). The values of Y1, Y2, Y3 and Y4 varied from 170.2-257.0 mg, 5.5-32.0 N, 20-120 s and 64.4-97.5%, respectively. The studied factors showed statistically significant effects on the dependent variables (p < 0.04). The correlation coefficient between empirical and model predicted values for Y1, Y2, Y3 and Y4 were 0.999, 0.992, 0.998 and 0.983, respectively. The model was validated by an independent experiment and actual values of the responses were in close agreement with model predicted values. Fourier transformed infrared spectroscopy indicated no chemical interactions between the components of the formulation during printing process. X-ray powder diffractograms suggested a decrease in crystallinity of the drug and lactose in the printlets. Chemical images indicated uniform distribution of the drug. Scanning electron microscopy and X-ray micro-CT scanning showed a very porous microstructure of the printlets with a porosity of about 37.89%. In conclusion, the SLS method of manufacturing provides a feasible and flexible avenue for fabricating dosage forms with tailored characteristics.


Assuntos
Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Excipientes/química , Dureza , Lasers , Tamanho da Partícula , Porosidade , Pós/química , Impressão Tridimensional , Solubilidade/efeitos dos fármacos
10.
Int J Pharm ; 570: 118667, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31494238

RESUMO

Diabetic patients suffer from impaired wound healing. In this study, the anti-diabetic drug, Pioglitazone hydrochloride (PG), was loaded in three-dimensional (3D) composite scaffolds (SC) designed to be applied topically for the management of diabetic wounds. Hydroxypropyl methyl cellulose (HPMC) of different molecular weight (E5, K4M or K15M) were used, in different ratios, with chitosan (CS) for the preparation of the 3D-SC. Investigations to examine the prepared SCs revealed that SC-F3 composed of CS /HPMC E5 (2:1) attained the highest porosity (99.12 ±â€¯5.01), highest water absorption capacity % (300.09 ±â€¯20.20), and attained the fastest drug release profile (p < 0.05), with release kinetics following the diffusion model. SEM microphotographs showed the highly porous structure of SC-F3. According to the modified Draize test, the selected 3D-SC (the medicated as well as the unmedicated) showed to be safe for skin application (PII = 0). During the in-vivo studies, both the selected PG-loaded SC and the unmedicated SC showed a significant improvement in the healing process compared to the untreated group, this was evidenced by the measurement of wound contraction % [627% and 467%, respectively, p < 0.05], as well as the level of some biomarkers (TNF-α, VEGF and MMP-9). PG-loaded SC had a significantly better effect than the unmedicated SC (p < 0.05). Histopathological studies confirmed the complete tissue regeneration and healing process after the use of the selected PG-loaded scaffolds. The current study presents a feasible approach to support diabetic wound healing using a simple and safe formulation.


Assuntos
Diabetes Mellitus Experimental/complicações , Pioglitazona/química , Pioglitazona/farmacologia , Polímeros/química , Tecidos Suporte/química , Cicatrização/efeitos dos fármacos , Animais , Bandagens , Quitosana/química , Liberação Controlada de Fármacos/efeitos dos fármacos , Derivados da Hipromelose/química , Masculino , Porosidade , Estudo de Prova de Conceito , Ratos , Ratos Wistar , Pele/efeitos dos fármacos
11.
J Nanobiotechnology ; 17(1): 95, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506085

RESUMO

BACKGROUND: It is extremely difficult to develop targeted treatments for triple-negative breast (TNB) cancer, because these cells do not express any of the key biomarkers usually exploited for this goal. RESULTS: In this work, we develop a solution in the form of a cascade responsive nanoplatform based on thermo-sensitive poly(N-vinylcaprolactam) (PNVCL)-chitosan (CS) nanoparticles (NPs). These are further modified with the cell penetrating peptide (CPP) and loaded with the chemotherapeutic drug doxorubicin (DOX). The base copolymer was optimized to undergo a phase change at the elevated temperatures of the tumor microenvironment. The acid-responsive properties of CS provide a second trigger for drug release, and the inclusion of CPP should ensure the formulations accumulate in cancerous tissue. The resultant CPP-CS-co-PNVCL NPs could self-assemble in aqueous media into spherical NPs of size < 200 nm and with low polydispersity. They are able to accommodate a high DOX loading (14.8% w/w). The NPs are found to be selectively taken up by cancerous cells both in vitro and in vivo, and result in less off-target cytotoxicity than treatment with DOX alone. In vivo experiments employing a TNB xenograft mouse model demonstrated a significant reduction in tumor volume and prolonging of life span, with no obvious systemic toxicity. CONCLUSIONS: The system developed in this work has the potential to provide new therapies for hard-to-treat cancers.


Assuntos
Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Quitosana/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Linhagem Celular , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Camundongos , Nanopartículas/química , Ratos , Ratos Wistar , Microambiente Tumoral/efeitos dos fármacos
12.
Int J Pharm ; 570: 118658, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31491485

RESUMO

Micro fabricated delivery systems have shown promise in increasing oral bioavailability of drugs. Micrometer-sized polymeric devices (microcontainers) have the potential to facilitate unidirectional drug release directly into the intestinal mucosa whereby, drug absorption can be enhanced. The aim of this study was to develop an ex vivo model to investigate mucosal adhesion and orientation of microcontainers. Furthermore, to investigate how microcontainers with varying height, shape and material behave in regards to mucoadhesion and orientation. Microcontainers were placed at the top of an inclined piece of porcine small intestine. The tissue was perfused with biorelevant medium followed by microscopic examination to observe the orientation and amount of microcontainers on the tissue. The mucoadhesion of the microcontainers were evaluated based on the observed position on the tissue after being exposed to flow. When comparing the varying types of microcontainers, good adhesion was in general observed since most of the microcontainers were located in the beginning of the intestine. Microcontainers fabricated from the epoxy-based photoresist SU-8 had a slightly better adherence than those fabricated from poly-ɛ-caprolactone (PCL). The orientation of the microcontainers appeare to be dictated mainly by the height. In general, the model showed promising results in evaluating mucoadhesion and orientation.


Assuntos
Mucosa Intestinal/metabolismo , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Caproatos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Lactonas/química , Polímeros/química , Suínos
13.
Int J Pharm ; 570: 118655, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31479731

RESUMO

New approaches integrating stimuli-responsive linkers into prodrugs are currently emerging. These "smart" prodrugs can enhance the effectivity of conventional prodrugs with promising clinical applicability. Oxidative stress is central to several diseases, including cancer. Therefore, the design of prodrugs that respond to ROS stimulus, allowing a selective drug release in this condition, is fairly encouraging. Aiming to investigate the ROS-responsiveness of prodrugs containing the ROS-cleavable moiety, Thioketal (TK), we performed proof-of-concept studies by synthesizing ROS-responsive conjugate, namely mPEG-TK-Cy5, through exploiting Cy5 fluorescent dye. We demonstrated that, differently to non-ROS-responsive control conjugate (mPEG-Cy5), mPEG-TK-Cy5 shows a selective release of Cy5 in response to ROS in both, ROS-simulated conditions and in vitro on glioblastoma cells. Our results confirm the applicability of TK-technology in the design of ROS-responsive prodrugs, which constitutes a promising approach in cancer treatment. The translatability of this technology for other diseases treatment makes this a highly relevant and promising approach.


Assuntos
Polímeros/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular Tumoral , Liberação Controlada de Fármacos/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Humanos , Polietilenoglicóis/química , Ratos
14.
AAPS PharmSciTech ; 20(7): 300, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31482251

RESUMO

Implantable drug delivery systems, such as drug pumps and polymeric drug depots, have emerged as means of providing predetermined drug release profiles at the desired site of action. While initial implants aimed at providing an enduring drug supply, developments in polymer chemistry and pharmaceutical technology and the growing need for refined drug delivery patterns have prompted the design of sophisticated drug delivery implants such as on-demand drug-eluting implants and personalized 3D printed implants. The types of cargo loaded into these implants range from small drug molecules to hormones and even therapeutic cells. This review will shed light upon recent advances in materials and composites used for polymeric implant fabrication, highlight select approaches employed in polymeric implant fabrication, feature medical applications where polymeric implants have a significant impact, and report recent advances made in these areas.


Assuntos
Implantes de Medicamento/química , Polímeros/química , Impressão Tridimensional , Animais , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/tendências , Implantes de Medicamento/administração & dosagem , Implantes de Medicamento/farmacocinética , Liberação Controlada de Fármacos/efeitos dos fármacos , Liberação Controlada de Fármacos/fisiologia , Humanos , Bombas de Infusão Implantáveis/tendências , Polímeros/administração & dosagem , Polímeros/farmacocinética , Impressão Tridimensional/tendências , Tecnologia Farmacêutica/métodos , Tecnologia Farmacêutica/tendências
15.
Eur J Pharm Biopharm ; 144: 79-90, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499162

RESUMO

Despite the fact that solid dispersions are gaining momentum, the number of polymers that have been used as a carrier during the past 50 years is rather limited. Recently, the poly(2-alkyl-2-oxazoline) (PAOx) polymer class profiled itself as a versatile platform for a wide variety of applications in drug delivery, including their use as amorphous solid dispersion (ASD) carrier. The aim of this study was to investigate the potential of poly(2-ethyl-2-oxazoline) (PEtOx) by applying a benchmark approach with well-known, commercially available carriers (i.e. polyvinylpyrrolidone (PVP) K30, poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA) 64 and hydroxypropylmethylcellulose (HPMC)). For this purpose, itraconazole (ITC) and fenofibrate (FFB) were selected as poorly water-soluble model drugs. The four polymers were compared by establishing their supersaturation maintaining potential and by investigating their capability as carrier for ASDs with high drug loadings. Spray drying, as well as hot melt extrusion and cryo-milling were implemented as ASD manufacturing technologies for comparative evaluation. For each manufacturing technique, the formulations with the highest possible drug loadings were tested with respect to in vitro drug release kinetics. This study indicates that PEtOx is able to maintain supersaturation of the drugs to a similar extent as the commercially available polymers and that ASDs with comparable drug loadings can be manufactured. The results of the in vitro dissolution tests reveal that high drug release can be obtained for PEtOx formulations. Overall, proof-of-concept is provided for the potential of PEtOx for drug formulation purposes.


Assuntos
Portadores de Fármacos/química , Poliaminas/química , Solubilidade/efeitos dos fármacos , Química Farmacêutica/métodos , Cristalização/métodos , Dessecação/métodos , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Derivados da Hipromelose/química , Polímeros/química , Povidona/química , Pirrolidinas/química , Compostos de Vinila/química
16.
Mater Sci Eng C Mater Biol Appl ; 104: 109889, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499943

RESUMO

In this paper, near infrared (NIR)-responsive core-shell gold nanorods/mesoporous silica nanoparticles capped with PEGylated graphene oxide (GNRs/SiO2/GO-PEG) were prepared via electrostatic and physical absorption interactions. Hybrid nanoparticles display distinct photothermal stability in physiological environment and acidic media because of the introduction of biocompatible GO-PEG. In addition, due to the high specific surface area of GO-PEG and synergistically enhanced photothermal effect between GO-PEG and GNRs, GNRs/SiO2/GO-PEG nanoparticles exhibit excellent drug loading efficiency and superior photothermal conversion efficiency (39.53%). More importantly, significant pH-/NIR- dual responsive drug release upon NIR irradiation could be observed from GNRs/SiO2/GO-PEG nanoparticles due to the π-π cooperative interaction between GO-PEG and doxorubicin hydrochloride (DOX), and synergistically enhanced NIR-responsiveness derived from GNRs/GO-PEG. The present paper furnishes a green and feasible method to prepare smart core/shell hybrid nanoparticles with high drug loading efficiency and excellent photothermal conversion efficiency, which possess great perspectives as a multifunctional platform for remotely controllable drug delivery.


Assuntos
Ouro/química , Grafite/química , Nanopartículas Metálicas/química , Nanotubos/química , Polietilenoglicóis/química , Dióxido de Silício/química , Linhagem Celular Tumoral , Doxorrubicina/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Humanos , Células MCF-7 , Fototerapia/métodos
17.
Mater Sci Eng C Mater Biol Appl ; 104: 109967, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499981

RESUMO

The statistical proof that most forms of cancer metastasize to bone tissue has redirected research focus to the development of efficient secondary bone cancer treatment regimens. Bisphosphonates (BPs) have been earmarked as a drug of choice for bone metastasis. However, they have a shortcoming of being released before reaching targeted sites due to their low molecular weight. In haste to attain increased efficacy, there is a tendency for drug overdose to occur, resulting in systemic toxicity. One way to curb this is by employing drug delivery systems for targeted and controlled release of the drugs. Having been explored as versatile and innovative drug carriers, multi-walled carbon nanotubes (MWCNTs) have emerged as potential drug delivery systems. Hence, in the present study, alendronate, neridronate and pamidronate are three classes of bisphosphonates that were conjugated onto multi-walled carbon nanotubes. Conjugation was confirmed by characterization techniques including SEM, TEM, EDX, FTIR, Raman and TGA. Drug release studies were also conducted at pH 1.2, 5.5 and 7.4 to study the mechanism of release for neridronate. Results obtained were fitted into Zero order (42.6%), Higuchi (26%) and Korsmeyer-Peppas (22%). The best models describing the release of neridronate from MWCNTs were Zero order, Higuchi and Korsmeyer-Peppas at pH 1.2, 5.5 and 7.4, respectively. A tetrazolium cell viability assay was performed to assess the anticancer activity of the MWCNTs conjugated BPs.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Difosfonatos/química , Difosfonatos/farmacologia , Nanotubos de Carbono/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Humanos , Cinética , Células MCF-7
18.
Drug Deliv ; 26(1): 918-927, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31526064

RESUMO

Protein-based nanocarriers with inherent biocompatibility have been widely served as building blocks to construct versatile therapeutic nanoplatforms. Herein, bovine serum albumin-iridium oxide nanoparticles (denoted BSA-IrO2 NPs) are successfully synthesized via one-step biomineralization approach. The BSA-IrO2 NPs exhibits uniform size (40 nm), superb biocompatibility and high drug loading capacity for doxorubicin (27.4 wt%). Under near-infrared (NIR) laser irradiation, the as-prepared BSA-IrO2 NPs exhibited high photothermal conversion ability (54.3%) and good photostability. The in vitro drug release experiments displayed pH and NIR laser -triggered DOX release profiles, which could enhance the therapeutic anticancer effect. By utilizing this DOX loaded nanoplatform, effective synergistic chemo-photothermal therapy against human osteosarcoma can be realized, which has been systematically verified both in vitro and in vivo. Notably, in vivo pharmacokinetics studies showed that BSA-IrO2@DOX had prolonged blood circulation time due to the BSA component can improve the stealthiness of the nanoparticles during the blood circulation. Meanwhile, in vitro and in vivo toxicity studies demonstrated that the BSA-IrO2 NPs can act as biocompatible agents for drug delivery and cancer therapy. Therefore, this work presents a biomineralized iridium-based NPs with remarkable features and be used as a very potential therapeutic nanoplatform for cancer treatment.


Assuntos
Doxorrubicina/química , Doxorrubicina/farmacologia , Irídio/química , Irídio/farmacologia , Nanopartículas/química , Osteossarcoma/tratamento farmacológico , Soroalbumina Bovina/química , Células A549 , Animais , Neoplasias Ósseas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fototerapia/métodos , Dióxido de Silício/química
19.
J Nanobiotechnology ; 17(1): 97, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31526377

RESUMO

BACKGROUND: Externally triggered drug delivery systems hold considerable promise for improving the treatment of many diseases, in particular, diseases where the spatial-temporal release of the drug is critical to maximize their biological effect whilst minimizing undesirable, off-target, side effects. RESULTS: Herein, we developed a light-triggerable formulation that takes advantage of host-guest chemistry to complex drugs functionalized with a guest molecule and release it after exposure to near infrared (NIR) light due to the disruption of the non-covalent host-guest interactions. The system is composed by a gold nanorod (AuNR), which generates plasmonic heat after exposure to NIR, a thin layer of hyaluronic acid immobilized to the AuNR upon functionalization with a macrocycle, cucurbit[6]uril (CB[6]), and a drug functionalized with a guest molecule that interacts with the macrocycle. For proof of concept, we have used this formulation for the intracellular release of a derivative of retinoic acid (RA), a molecule known to play a key role in tissue development and homeostasis as well as during cancer treatment. We showed that the formulation was able to conjugate approximately 65 µg of RA derivative per mg of CB[6] @AuNR and released it within a few minutes after exposure to a NIR laser. Importantly, the bioactivity of RA released from the formulation was demonstrated in a reporter cell line expressing luciferase under the control of the RA receptor. CONCLUSIONS: This NIR light-triggered supramolecular-based modular platform holds great promise for theranostic applications.


Assuntos
Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos/métodos , Bibliotecas de Moléculas Pequenas/química , Linhagem Celular Tumoral , Células Cultivadas , Liberação Controlada de Fármacos/efeitos dos fármacos , Ouro/química , Humanos , Ácido Hialurônico/química , Raios Infravermelhos , Nanotubos/química , Bibliotecas de Moléculas Pequenas/administração & dosagem , Tretinoína/química
20.
Int J Pharm ; 570: 118688, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31513870

RESUMO

In the present study, we developed and evaluated an in situ gelling system based on hexanoyl glycol chitosan (H-GCS) for enhanced ocular bioavailability. An aqueous solution of H-GCS exhibited a typical sol-gel transition at 32 °C. The formed H-GCS hydrogel was characterized by rheology and scanning electron microscopy (SEM). H-GCS had minimal in vitro cytotoxicity against L-929 and HCEC cells over a concentration range of 0-0.8 mg/mL. Additionally, the H-GCS hydrogel exhibited good ocular tolerance and biocompatibility after a single instillation. Moreover, H-GCS hydrogel significantly prolonged the precorneal retention of fluorescein sodium compared with its aqueous solution. An in vivo pharmacokinetic study demonstrated that the levofloxacin-loaded H-GCS hydrogel could provide a significantly higher Cmax and AUC0-12h compared with the levofloxacin aqueous solution, thus increasing ocular bioavailability. Overall, the proposed H-GCS hydrogel acts as an in situ gelling system that might represent a promising vehicle for topical ocular drug delivery.


Assuntos
Quitosana/química , Olho/efeitos dos fármacos , Olho/metabolismo , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Soluções Oftálmicas/química , Soluções Oftálmicas/metabolismo , Animais , Disponibilidade Biológica , Linhagem Celular , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Humanos , Hidrogel de Polietilenoglicol-Dimetacrilato/metabolismo , Levofloxacino/química , Levofloxacino/metabolismo , Coelhos , Temperatura
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