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1.
Int J Biol Macromol ; 185: 592-603, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34216661

RESUMO

This paper presents a new thermal sensitive hydrogel system based on cystamine-functionalised sodium alginate-g-pluronic F127 (ACP). The introduction of cystamine to the alginate backbone not only creates a covalent bond with pluronic F127 but also provides intrinsic anti-bacterial activity for the resultant hydrogel. The amount of water uptake inside the hydrogel remained ~200% for 6 days and the degradation was completed in 12 days in physiological media. The ACP copolymer solution could form a hydrogel at body temperature (~37 °C) and could return to the solution phase if the temperature decreased below 25o °C. Fibroblast encapsulated in situ in the ACP hydrogel maintained their viability (≥90% based on the live/dead assay) for 7 days, demonstrating the good biocompatibility of the ACP hydrogel for long-term cell cultivation. In addition, three-dimensional (3D) culture showed that fibroblast attached to the hydrogels and successfully mimicked the porous structure of the ACP hydrogel after 5 days of culture. Fibroblast cells could migrate from the cell-ACP clusters and form a confluent cell layer on the surface of the culture dish. Altogether, the obtained results indicate that the thermal-responsive ACP hydrogel synthesised in this study may serve as a cellular delivery platform for diverse tissue engineering applications.


Assuntos
Alginatos/farmacologia , Antibacterianos/farmacologia , Cistamina/química , Poloxâmero/química , Alginatos/química , Antibacterianos/química , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Hidrogéis/química , Injeções , Termodinâmica , Engenharia Tecidual
2.
J Chromatogr A ; 1652: 462353, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34237484

RESUMO

Poloxamer 188 (P188) is formulated in proteinaceous therapeutics as an alternative surfactant to polysorbate because of its good chemical stability and surfactant properties, which enable interfacial protection, preventing visible and sub-visible particle formation. However, due to the nature of polymer heterogeneity and limited analytical approaches to resolve the superimposed components of P188, the impact of its quality variance on protein stability is still not well understood. In this study, we developed an analytical method to evaluate the components of P188 as a function of the length of polypropylene oxide (PPO), by maintaining polyethylene oxide (PEO) at the critical point of adsorption (CPA) to eliminate its chromatographic interference. The effectiveness of the separation was confirmed by nuclear magnetic resonance (NMR) spectroscopy and mass spectroscopy (MS) of the individual fractions corresponding to each peak. Additionally, a design of experiments (DoE) and method qualification were carried out to identify and optimize the key operation parameters, including column temperature and evaporative light scattering detector (ELSD) settings that need to be strictly controlled for reliable analytical results. In conclusion, this method is sensitive and reliable to compare the quality variance of commercial P188 and is suitable for routine quality control purposes. The application of this method could help in further understanding the Critical Material Attributes (CMA) that may affect the quality attributes of proteins in formulations.


Assuntos
Cromatografia Líquida/métodos , Poloxâmero/química , Tensoativos/química , Adsorção , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Poloxâmero/isolamento & purificação , Polietilenoglicóis/química , Polímeros/química , Propilenoglicóis/química , Proteínas/uso terapêutico , Tensoativos/isolamento & purificação
3.
Molecules ; 26(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200887

RESUMO

Royal jelly is a natural substance produced by worker bees that possesses a variety of biological activities, including antioxidant, anti-inflammatory, antibacterial, and protective. Although fresh royal jelly is kept at low temperatures, to increase its stability, it needs to be incorporated into pharmaceutical formulations, such as in situ gels. The aim of this study was to formulate in situ ocular gels containing Lithuanian royal jelly for topical corneal use in order to increase the retention time of the formulation on the ocular surface and bioavailability. Gels were evaluated for physicochemical characteristics (pH, rheological properties, refractive index) and in vitro drug release measuring the amount of 10-hydroxy-2-decenoic acid (10-HDA). An ocular irritation test and cell viability tests were performed using the SIRC (Statens Seruminstitut Rabbit Cornea) cell culture line. Results indicated that all the in situ gels were within an acceptable pH and refractive index range close to corneal properties. Rheology studies have shown that the gelation temperature varies between 25 and 32 °C, depending on the amount of poloxamers. The release studies have shown that the release of 10-HDA from in situ gels is more sustained than royal jelly suspension. All gel formulations were non-irritant according to the short-time exposure test (STE) using the SIRC cell culture line, and long-term cell viability studies indicated that the formulations used in small concentrations did not induce cell death. Prepared in situ gels containing royal jelly have potential for ocular drug delivery, and they may improve the bioavailability, stability of royal jelly, and formation of non-irritant ocular formulations.


Assuntos
Córnea/efeitos dos fármacos , Ácidos Graxos/química , Ácidos Graxos/farmacologia , Géis/química , Géis/farmacologia , Animais , Abelhas/metabolismo , Disponibilidade Biológica , Produtos Biológicos/química , Produtos Biológicos/farmacocinética , Produtos Biológicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica/métodos , Córnea/metabolismo , Ácidos Decanoicos/química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Excipientes/química , Géis/farmacocinética , Poloxâmero/química , Coelhos , Reologia , Temperatura
4.
Int J Nanomedicine ; 16: 4239-4250, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34194227

RESUMO

Purpose: Pore-forming toxins (PFTs) perform important functions during bacterial infections. Among various virulence-targeting therapies, nanosponges (NSs) have excellent neutralization effects on multiple PFTs. To enhance treatment efficacy, NSs tend to be incorporated into other biomaterials, such as hydrogels. Methods: In the present work, red blood cell (RBC) vesicles were harvested to wrap polymer nanoparticles, leading to the formation of NSs, and the optimal Pluronic F127 hydrogel concentration was determined for gelation. Then, a novel detoxification system was constructed by incorporating NSs into an optimized Pluronic F127 hydrogel (NS-pGel). Next, the system was characterized by rheological and sustained release behavior as well as micromorphology. Then, the in vitro neutralization effect of NS-pGel on various PFTs was examined by a hemolysis protocol. Finally, therapeutic and prophylactic detoxification efficiency was evaluated in a mouse subcutaneous infection model in vivo. Results: A thermosensitive, injectable detoxification system was successfully constructed by loading NSs into a 30% Pluronic F127 hydrogel. Characterization results demonstrated that the NS-pGel hybrid system sustained an ideal fluidity and viscosity at lower temperatures but exhibited a quick sol-gel transition capacity near body temperature. In addition, this hybrid system had a sustained release behavior accompanied by good biocompatibility and biodegradability. Finally, the NS-pGel system showed neutralization effects similar to those of NSs both in vitro and in vivo, indicating a good preservation of NS functionality. Conclusion: In conclusion, we constructed a novel temperature-sensitive detoxification system with good biocompatibility and biodegradability, which may be applied to the clinical treatment of PFT-induced local lesions and infections.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/química , Hidrogéis/administração & dosagem , Hidrogéis/química , Poloxâmero/química , Animais , Proteínas de Bactérias , Materiais Biocompatíveis , Eritrócitos/química , Proteínas Hemolisinas , Hemólise/efeitos dos fármacos , Masculino , Teste de Materiais , Camundongos Endogâmicos ICR , Nanopartículas/química , Testes de Neutralização , Reologia , Staphylococcus aureus/patogenicidade , Temperatura , Vibrio vulnificus/patogenicidade , Viscosidade
5.
Molecules ; 26(11)2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204150

RESUMO

The purpose of this study was to develop mixed polymeric micelles with high drug loading capacity to improve the oral bioavailability of icaritin with Soluplus® and Poloxamer 407 using a creative acid-base shift (ABS) method, which exhibits the advantages of exclusion of organic solvents, high drug loading and ease of scaling-up. The feasibility of the ABS method was successfully demonstrated by studies of icaritin-loaded polymeric micelles (IPMs). The prepared IPMs were characterized to have a spherical shape with a size of 72.74 ± 0.51 nm, and 13.18% drug loading content. In vitro release tests confirmed the faster release of icaritin from IPMs compared to an oil suspension. Furthermore, bioavailability of icaritin in IPMs in beagle dogs displayed a 14.9-fold increase when compared with the oil suspension. Transcellular transport studies of IPMs across Caco-2 cell monolayers confirmed that the IPMs were endocytosed in their intact forms through macropinocytosis, clathrin-, and caveolae-mediated pathways. In conclusion, the results suggested that the mixed micelles of Soluplus® and Poloxamer 407 could be a feasible drug delivery system to enhance oral bioavailability of icaritin, and the ABS method might be a promising technology for the preparation of polymeric micelles to encapsulate poorly water-soluble weakly acidic and alkaline drugs.


Assuntos
Flavonoides/administração & dosagem , Poloxâmero/química , Polietilenoglicóis/química , Polivinil/química , Transdução de Sinais/efeitos dos fármacos , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Cavéolas/metabolismo , Clatrina/metabolismo , Cães , Estudos de Viabilidade , Flavonoides/síntese química , Flavonoides/farmacocinética , Humanos , Masculino , Micelas , Nanopartículas , Tamanho da Partícula
6.
Molecules ; 26(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204668

RESUMO

Pluronic polymers (pluronics) are a unique class of synthetic triblock copolymers containing hydrophobic polypropylene oxide (PPO) and hydrophilic polyethylene oxide (PEO) arranged in the PEO-PPO-PEO manner. Due to their excellent biocompatibility and amphiphilic properties, pluronics are an ideal and promising biological material, which is widely used in drug delivery, disease diagnosis, and treatment, among other applications. Through self-assembly or in combination with other materials, pluronics can form nano carriers with different morphologies, representing a kind of multifunctional pharmaceutical excipients. In recent years, the utilization of pluronic-based multi-functional drug carriers in tumor treatment has become widespread, and various responsive drug carriers are designed according to the characteristics of the tumor microenvironment, resulting in major progress in tumor therapy. This review introduces the specific role of pluronic-based polymer drug delivery systems in tumor therapy, focusing on their physical and chemical properties as well as the design aspects of pluronic polymers. Finally, using newer literature reports, this review provides insights into the future potential and challenges posed by different pluronic-based polymer drug delivery systems in tumor therapy.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Propilenoglicóis/química , Propilenoglicóis/farmacologia , Portadores de Fármacos/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Neoplasias/tratamento farmacológico , Poloxâmero/química , Poloxâmero/metabolismo , Poloxâmero/farmacologia , Polietilenoglicóis/metabolismo , Polímeros/química , Polipropilenos/química , Polipropilenos/farmacologia , Propilenoglicóis/metabolismo , Microambiente Tumoral/efeitos dos fármacos
7.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070506

RESUMO

Concentration of hyaluronic acid (HA) in the lungs increases in idiopathic pulmonary fibrosis (IPF). HA is involved in the organization of fibrin, fibronectin, and collagen. HA has been proposed to be a biomarker of fibrosis and a potential target for antifibrotic therapy. Hyaluronidase (HD) breaks down HA into fragments, but is a subject of rapid hydrolysis. A conjugate of poloxamer hyaluronidase (pHD) was prepared using protein immobilization with ionizing radiation. In a model of bleomycin-induced pulmonary fibrosis, pHD decreased the level of tissue IL-1ß and TGF-ß, prevented the infiltration of the lung parenchyma by CD16+ cells, and reduced perivascular and peribronchial inflammation. Simultaneously, a decrease in the concentrations of HA, hydroxyproline, collagen 1, total soluble collagen, and the area of connective tissue in the lungs was observed. The effects of pHD were significantly stronger compared to native HD which can be attributed to the higher stability of pHD. Additional spiperone administration increased the anti-inflammatory and antifibrotic effects of pHD and accelerated the regeneration of the damaged lung. The potentiating effects of spiperone can be explained by the disruption of the dopamine-induced mobilization and migration of fibroblast progenitor cells into the lungs and differentiation of lung mesenchymal stem cells (MSC) into cells of stromal lines. Thus, a combination of pHD and spiperone may represent a promising approach for the treatment of IPF and lung regeneration.


Assuntos
Ácido Hialurônico/metabolismo , Hialuronoglucosaminidase/farmacologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/efeitos dos fármacos , Espiperona/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Hialuronoglucosaminidase/administração & dosagem , Hialuronoglucosaminidase/farmacocinética , Hidroxiprolina/metabolismo , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/enzimologia , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Queratinas/metabolismo , Pulmão/enzimologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Poloxâmero/química , Receptores de IgG/metabolismo , Espiperona/administração & dosagem , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
8.
Int J Nanomedicine ; 16: 4073-4085, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34163160

RESUMO

Background: The efficacy of systemic chemotherapy for hepatocellular carcinoma (HCC) is predominantly hampered by low accumulation in tumor tissue and the high systemic toxicity of anticancer drugs. In this study, we designed an in situ drug-loaded injectable thermosensitive hydrogel system for the simultaneous delivery of norcantharidin-loaded nanoparticles (NCTD-NPs) and doxorubicin (Dox) via intratumoral administration to HCC tumors. Methods: NCTD-NPs were prepared by the thin film dispersion method using PCEC polymers as the carrier. Then, NCTD-NPs and Dox were co-encapsulated in a thermosensitive hydrogel based on Pluronic F127 (PF127) to construct a dual drug-loaded hydrogel system. The rheological properties of the drug-loaded hydrogel were studied using a rheometer. Drug release of the drug-loaded hydrogel and cytotoxicity in HepG2 cells were evaluated in vitro. An H22 tumor-bearing mice model was used to assess the in vivo antitumor activity of the drug-loaded hydrogel via intratumoral administration. Results: The prepared drug-loaded hydrogel exhibited good thermal-sensitive properties, which remained liquid at room temperature and rapidly transformed into a non-flowing gel at body temperature, and released the drugs in a sustained manner. In vitro studies revealed that the drug-loaded hydrogel exhibited remarkable antiproliferative activity in HepG2 cells compared to free drugs. In vivo antitumor efficacy experiments showed that the drug-loaded hydrogel significantly suppressed tumor growth, alleviated side effects, and prolonged the survival time of mice bearing H22 tumors compared to the other groups. Moreover, immunohistochemical staining revealed that the expression of Ki-67 and CD31 in the drug-loaded hydrogel group was significantly lower than that in the other groups (P < 0.05), indicating that the drug-loaded hydrogel effectively inhibited tumor proliferation and angiogenesis. Conclusion: The formulated hybrid thermosensitive hydrogel system with sustained drug release and enhanced therapeutic efficacy was demonstrated to be a promising strategy for the local-regional treatment of HCC via intratumoral administration.


Assuntos
Antineoplásicos/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Doxorrubicina/administração & dosagem , Hidrogéis/química , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/química , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Temperatura Corporal , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Preparações de Ação Retardada , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Poloxâmero/química
9.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069278

RESUMO

Clinical outcomes of conventional drug combinations are not ideal due to high toxicity to healthy tissues. Cisplatin (CDDP) is the standard component for many cancer treatments, yet its principal dose-limiting side effect is nephrotoxicity. Thus, CDDP is commonly used in combination with other drugs, such as the autophagy inhibitor chloroquine (CQ), to enhance tumor cell killing efficacy and prevent the development of chemoresistance. In addition, nanocarrier-based drug delivery systems can overcome chemotherapy limitations, decreasing side effects and increasing tumor accumulation. The aim of this study was to evaluate the toxicity of CQ and CDDP against tumor and non-tumor cells when used in a combined treatment. For this purpose, two types of micelles based on Pluronic® F127 hybrid dendritic-linear-dendritic block copolymers (HDLDBCs) modified with polyester or poly(esteramide) dendrons derived from 2,2'-bis(hydroxymethyl)propionic acid (HDLDBC-bMPA) or 2,2'-bis(glycyloxymethyl)propionic acid (HDLDBC-bGMPA) were explored as delivery nanocarriers. Our results indicated that the combined treatment with HDLDBC-bMPA(CQ) or HDLDBC-bGMPA(CQ) and CDDP increased cytotoxicity in tumor cells compared to the single treatment with CDDP. Encapsulations demonstrated less short-term cytotoxicity individually or when used in combination compared to the free drugs. However, and more importantly, a low degree of cytotoxicity against non-tumor cells was maintained, even when drugs were given simultaneously.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Portadores de Fármacos/química , Micelas , Polímeros/química , Células A549 , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cloroquina/administração & dosagem , Cloroquina/farmacocinética , Cisplatino/administração & dosagem , Cisplatino/farmacocinética , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Fibroblastos/efeitos dos fármacos , Células HeLa , Humanos , Poloxâmero/química , Polímeros/síntese química
10.
Int J Nanomedicine ; 16: 3581-3598, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079251

RESUMO

Background: BF211, a derivative of bufalin (BF), shows significantly improved solubility and potent antitumor efficiency compared to BF. Unfortunately, the unwanted toxicity such as cardiotoxicity caused by unspecific distribution has hindered its clinical use. Methods: PEGylated BF211 liposomes (BF211@Lipo) were designed and optimizely prepared based on the pre-prescription research. In vitro and in vivo cardiotoxicity was evaluated. In vivo pharmacokinetics and biodistribution of BF211@Lipo were investigated. In vivo antitumor activity and toxicity were evaluated in HepG2 cell xenograft models. The rapid-release triggered by Poloxamer 188 (P188) was assessed in vitro and in vivo. Results: The optimized BF211@Lipo displayed a spherical morphology with a size of (164.6 ± 10.3) nm and a high encapsulation efficiency of (93.24 ± 2.15) %. The in vivo concentration-time curves of BF211 loaded in liposomes showed a prolonged half-life in plasma and increased tumor accumulation. No obvious abnormality in electrocardiograms was observed in guinea pigs even at 9 mg/kg. Moreover, to improve the efficient release of BF211@Lipo, a surfactant-assisted rapid-release strategy was developed, and the release-promoting mechanism was revealed by the fluorescence resonance energy transfer (FRET) and fluorescence nanoparticle tracking analysis (fl-NTA) technology. Sequential injection of BF211@Lipo and P188 could ignite the "cold" liposomes locally in tumor regions, facilitating the burst release of BF211 and enhancing the therapeutic index. Conclusion: Our progressive efforts that begin with preparation technology and dosage regimen enable BF211 to like a drug, providing a promising nano platform to deliver the cardiac glycosides and alleviate the side effects by decreasing unspecific biodistribution.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Bufanolídeos/administração & dosagem , Bufanolídeos/farmacologia , Coração/efeitos dos fármacos , Tensoativos/química , Animais , Antineoplásicos/química , Antineoplásicos/toxicidade , Bufanolídeos/química , Bufanolídeos/toxicidade , Cobaias , Células Hep G2 , Humanos , Lipossomos , Nanopartículas/química , Poloxâmero/química , Solubilidade , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Int J Nanomedicine ; 16: 3707-3724, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34103912

RESUMO

Introduction: Intracellular delivery of molecules is central to applications in biotechnology, medicine, and basic research. Nanoparticle-mediated photoporation using carbon black nanoparticles exposed to pulsed, near-infrared laser irradiation offers a physical route to create transient cell membrane pores, enabling intracellular delivery. However, nanoparticle-mediated photoporation, like other physical intracellular delivery technologies, necessitates a trade-off between achieving efficient uptake of exogenous molecules and maintaining high cell viability. Methods: In this study, we sought to shift this balance by adding serum to cells during nanoparticle-mediated photoporation as a viability protectant. DU-145 prostate cancer cells and human dermal fibroblasts were exposed to laser irradiation in the presence of carbon black (CB) nanoparticles and other formulation additives, including fetal bovine serum (FBS) and polymers. Results: Our studies showed that FBS can protect cells from viability loss, even at high-fluence laser irradiation conditions that lead to high levels of intracellular delivery in two different mammalian cell types. Further studies revealed that full FBS was not needed: viability protection was achieved with denatured FBS, with just the high molecular weight fraction of FBS (>30 kDa), or even with individual proteins like albumin or hemoglobin. Finally, we found that viability protection was also obtained using certain neutral water-soluble polymers, including Pluronic F127, polyvinylpyrrolidone, poly(2-ethyl-2-oxazoline), and polyethylene glycol, which were more effective at increased concentration, molecular weight, or hydrophobicity. Conclusion: Altogether, these findings suggest an interaction between amphiphilic domains of polymers with the cell membrane to help cells maintain viability, possibly by facilitating transmembrane pore closure. In this way, serum components or synthetic polymers can be used to increase intracellular delivery by nanoparticle-mediated photoporation while maintaining high cell viability.


Assuntos
Citoproteção , Sistemas de Liberação de Medicamentos , Espaço Intracelular/química , Luz , Nanopartículas/química , Soro/química , Carboximetilcelulose Sódica/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Citoproteção/efeitos da radiação , Fibroblastos/efeitos da radiação , Humanos , Lasers , Peso Molecular , Poloxâmero/química , Polietilenoglicóis/química , Fuligem/química , Viscosidade
12.
Int J Mol Sci ; 22(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071110

RESUMO

Rectal drug delivery is an effective alternative to oral and parenteral treatments. This route allows for both local and systemic drug therapy. Traditional rectal dosage formulations have historically been used for localised treatments, including laxatives, hemorrhoid therapy and antipyretics. However, this form of drug dosage often feels alien and uncomfortable to a patient, encouraging refusal. The limitations of conventional solid suppositories can be overcome by creating a thermosensitive liquid suppository. Unfortunately, there are currently only a few studies describing their use in therapy. However, recent trends indicate an increase in the development of this modern therapeutic system. This review introduces a novel rectal drug delivery system with the goal of summarising recent developments in thermosensitive liquid suppositories for analgesic, anticancer, antiemetic, antihypertensive, psychiatric, antiallergic, anaesthetic, antimalarial drugs and insulin. The report also presents the impact of various types of components and their concentration on the properties of this rectal dosage form. Further research into such formulations is certainly needed in order to meet the high demand for modern, efficient rectal gelling systems. Continued research and development in this field would undoubtedly further reveal the hidden potential of rectal drug delivery systems.


Assuntos
Administração Retal , Géis/administração & dosagem , Preparações Farmacêuticas/administração & dosagem , Supositórios/administração & dosagem , Resinas Acrílicas/química , Alginatos/química , Temperatura Corporal , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Previsões , Géis/química , Temperatura Alta , Humanos , Absorção Intestinal , Metilcelulose/química , Poloxâmero/química , Povidona/química , Supositórios/química
13.
Int J Biol Macromol ; 183: 1596-1606, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34022312

RESUMO

Tumor intrinsic or acquired multidrug resistance (MDR) is still one of the major obstacles to the success of nanomedicine. To address this, the pH-sensitive nanoparticles (L61-OE-CS) with MDR-reversal ability were prepared by the crosslinking between acid-labile ortho-ester-modified pluronic (L61-OE) and chitosan (CS) for efficient doxorubicin (DOX) delivery. The size and micromorphology of the prepared nanoparticles were observed by dynamic light scanning and scanning electron microscopy and the nanoparticles displayed a uniform spherical shape with a diameter around 200 nm. The pH-triggered morphology change of the nanoparticles was also observed by scanning electron microscope. Drug release profiles under different pH values showed that DOX release amount within 72 h reached 16% (pH 7.4) and 76.5% (pH 5.0), respectively. In vitro cellular uptake and MTT assay demonstrated that the ortho ester and pluronic-based nanoparticles had higher cytotoxicity than non-sensitive nanoparticles. In vivo antitumor experiments also proved the superiority of the dual-functional nanoparticles, and the tumor growth inhibition rate (TGI) on day 14 was higher than 80%. Therefore, L61-OE-CS nanoparticles have great potential to be used as drug carriers in anticancer therapy.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Quitosana/química , Doxorrubicina/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Poloxâmero/química , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos , Difusão Dinâmica da Luz , Ésteres , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Microscopia Eletrônica de Varredura , Nanopartículas , Tamanho da Partícula , Ensaios Antitumorais Modelo de Xenoenxerto
14.
ACS Appl Mater Interfaces ; 13(14): 15992-16006, 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33797224

RESUMO

Pharmacological-based treatment approaches have been used over time to prevent postlaparotomy adhesion. However, the rapid elimination of therapeutics from the peritoneum, and their unwanted side effects, easy flow from the wound site by gravity, and low therapeutic efficacy increase the urgent need for the next generation of antiadhesion agents. This article represents the development of biocompatible and biodegradable antiadhesion agents that consist of carboxymethyl cellulose (CMC) and pullulan with three different types of physical characteristics such as the solution type (ST), film type (FT), and thermosensitive type (TST). These antiadhesion agents that contain no drugs exhibit excellent physical characteristics and superior stability over 30 days in the operative sites without any toxicity and side effects that make the compositions strong candidates as novel antiadhesion agents. Also, the proposed samples reveal superior antiadhesion and tissue regeneration properties in Sprague-Dawley (SD) rats after surgery over Medicurtain. Medicurtain effectively prevented postlaparotomy adhesion in ∼42% of experimental animals, whereas ST 2.25-10, ST 2.5-5, ST 2.5-10, FT 20, and TST 1.5 were effective in 100% of animals. Thus, we believe these antiadhesion agents could be promising to reduce adhesion-related complications during and post-surgical operations and deserve consideration for further study for clinical purposes.


Assuntos
Carboximetilcelulose Sódica/química , Glucanos/química , Poloxâmero/química , Regeneração , Aderências Teciduais/prevenção & controle , Animais , Feminino , Complicações Pós-Operatórias , Ratos , Ratos Sprague-Dawley , Aderências Teciduais/etiologia
15.
Int J Nanomedicine ; 16: 2917-2931, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33911861

RESUMO

Purpose: Ivabradine hydrochloride is selective pacemaker current (If) ion channel inhibitor used in case of chronic heart failure (CHF) with superior efficacy and lower side effects than most ß-blockers. However, the drug suffers from low bioavailability (≈40%) due to extensive first-pass metabolism. Hence, this work aims to formulate nanovesicular platforms to enhance their bioavailability both orally and transdermally. Materials and Methods: A central composite face-centered design was employed to formulate the nanovesicles, both phosphatidylcholine: drug ratio and percentage of pluronic F68 were used as independent variables. The nine developed formulae were characterized in terms of vesicle size (nm), polydispersity index, zeta potential (mV), entrapment efficiency (%). Decreasing vesicle size, increasing negative value of the zeta potential, and increasing entrapment efficiency were the chosen constraints to optimize the engineered nanovesicles. The candidate formula was subjected to further investigation including lyophilization, loading into carbopol gel, in vitro release, imaging with a transmission electron microscope, histopathological examination, in vitro cytotoxicity study and in vivo pharmacokinetics. Results: The optimized nanovesicular formula was composed of lipid: drug ratio of 3.91:1 and 100% pluronic as a stabilizer. It has particle size, zeta potential and entrapment efficiency of 337.6 nm, -40.5 mV and 30.5, respectively. It was then lyophilized in the presence of 5% trehalose as a cryoprotectant, dispersed in 0.5% carbopol to develop the transdermal gel. The two different forms of the candidate formula (lyophilized and gel form) displayed sustained drug release in comparison to drug solution. The histopathological and cytotoxicity studies showed that the optimized formula was safe and highly biocompatible. The pharmacokinetics parameters measured declared a higher Cmax and half-life of both formulae in comparison to market product (Procoralan®) with a 2.54- and 1.85-folds increase in bioavailability, respectively. Conclusion: Hence, the developed nanovesicles can be reported as the first nanoplatforms to be used for simultaneous ivabradine delivery by both oral and topical routes with enhanced oral and transdermal drug delivery. The developed nanoplatforms hence can be further used to formulate other drugs that suffer from low bioavailability due to extensive first-pass metabolism.


Assuntos
Portadores de Fármacos/administração & dosagem , Ivabradina/administração & dosagem , Ivabradina/farmacologia , Nanoestruturas/química , Administração Cutânea , Administração Oral , Animais , Disponibilidade Biológica , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Excipientes/química , Liofilização , Géis/química , Células Hep G2 , Hexoses/química , Humanos , Ivabradina/sangue , Masculino , Nanoestruturas/administração & dosagem , Tamanho da Partícula , Fosfatidilcolinas/química , Poloxâmero/química , Coelhos
16.
Int J Nanomedicine ; 16: 2667-2687, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33854314

RESUMO

Purpose: The goal was to directly deliver curcumin, a natural polyphenolic anticancer and anti-inflammatory compound, to the lung tissues with minimal systemic exposure through the fabrication of proliposomes, overcoming its poor aqueous solubility and oral bioavailability. Methods: Nano-spray drying was employed to prepare proliposomes using hydroxypropyl beta-cyclodextrin as a carrier. Lecithin and cholesterol were used as lipids, stearylamine and Poloxamer 188 were added as positive charge inducer and a surfactant, respectively. Different characterization parameters were evaluated like percentage yield, entrapment efficiency, drug loading, aerodynamic particle size, in vitro release besides morphological examination. Cytotoxicity studies on cell line A549 lung tumor cells as well as in vivo lung pharmacokinetic studies were also carried. Results: The optimized formulations showed superior aerosolization properties coupled their enhanced ability to reach deep lung tissues with a high % of fine particle fraction. Cytotoxicity studies using MTT assay demonstrated enhanced growth inhibitory effect on lung tumor cells A549 and significant reduction of proinflammatory cytokines such as tumor necrosis factor-α, interleukin-6 and interleukin-10 compared to the pure drug. Results of lung pharmacokinetic tests confirmed the superiority of proliposomal curcumin over curcumin powder in both, the rate and extent of lung tissue absorption, as well as the mean residence time within the lung tissues. Conclusion: The pulmonary delivery of curcumin-loaded proliposomes as dry powder provides a direct approach to lung tissues targeting while avoiding the limitations of the oral route and offering a non-invasive alternative to the parenteral one.


Assuntos
Curcumina/administração & dosagem , Curcumina/farmacologia , Sistemas de Liberação de Medicamentos , Pulmão/efeitos dos fármacos , Secagem por Atomização , Células A549 , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Morte Celular/efeitos dos fármacos , Curcumina/farmacocinética , Liberação Controlada de Fármacos , Humanos , Lipossomos , Masculino , Tamanho da Partícula , Poloxâmero/química , Pós , Ratos , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática
17.
Int J Biol Macromol ; 180: 418-431, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33737187

RESUMO

Hydrogel-based wound dressings have been intensively studied as promising materials for wound healing and care. The mixed-mode thiol-acrylate photopolymerization is used in this paper for alginate/poloxamer hydrogels formation. First, the alginate was modified with thiol groups using the esterification reaction with cysteamine, and second, the terminal hydroxyl groups of poloxamer were esterified with acryloyl chloride to introduce polymerizable acrylate groups. Finally, the cross-linking reaction between the two macromers was performed to produce degradable alginate/poloxamer hydrogels. The optimum conditions for the photo-initiated reaction were studied in order to obtain high gel fractions. The resulting hydrogels have high swelling capacity in simulated physiological conditions, good elasticity and strength, and appropriate porosity, some of the physico-chemical properties required for their applications as wound dressings/patches. The biological assays show that the alginate/poloxamer hydrogels induce proliferation of human keratinocyte and have an anti-inflammatory effect on lipopolysaccharides (LPS)-activated keratinocytes by inhibiting the extracellular signal-regulated kinases (ERK)/ nuclear factor (NF)-kB/ tumor necrosis factor (TNF)-α signalling pathway. Taken together, the results showed that the chemical cross-linked alginate/poloxamer hydrogels may function as a dressing/patch applied directly on the skin lesion to heal the wound by reducing the exacerbated inflammation, the main cause of wound healing delay and local infection.


Assuntos
Acrilatos/química , Alginatos/química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Hidrogéis/química , Hidrogéis/farmacologia , Queratinócitos/efeitos dos fármacos , Poloxâmero/química , Compostos de Sulfidrila/química , Curativos Hidrocoloides , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Reagentes para Ligações Cruzadas/química , Elasticidade , Células HaCaT , Humanos , Concentração de Íons de Hidrogênio , Luz , Polimerização , Porosidade , Cicatrização/efeitos dos fármacos
18.
AAPS PharmSciTech ; 22(3): 77, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33595740

RESUMO

Currently, periodontitis is treated by oral dosage forms (antibiotics) which shows systemic side effects and failed to reach the therapeutic concentration (above minimum inhibitory concentration, MIC) in the periodontal pocket. The present study aimed to overcome the above issues, by designing tailored doxycycline hyclate laden in situ gel by Poloxamer 407, chitosan, and polyethylene glycol 600. The in situ gel-forming system has attracted attention owing to its ability of sustained drug release above MIC, easy administration (syringeability), and high drug retention (localization) in the periodontal cavity. The Box-Behnken design (BBD) was used to tailor and optimize the concentration of Poloxamer 407 (X1 = 14.3%), chitosan (X2 = 0.58%), and polyethylene glycol 600 (X3 = 1.14%) to achieve sufficient syringeability (149 N), t90% (1105 min), and viscosity at non-physiological condition (512 cps) and physiological condition (5415 cps). The optimized in situ gel was clear and isotonic (RBCs test). The gelation temperature of the optimized in situ was 34 ± 1°C with sufficient mucoadhesive strength (26 ± 2 dyn/cm2), gel strength (29 ± 2 sec), and texture profile for periodontal application. The in vitro drug release studies showed sustain release from optimized in situ gel (24h) in comparison to marketed gel (7h). The antimicrobial activity (cup plate technique) of the in situ gel was equivalent to the marketed doxycycline gel, which suggests that the doxycycline hyclate retained its antimicrobial efficacy when formulated as in situ gelling system. In conclusion, BBD was effectively utilized to optimize in situ gel with minimum level of polymers to achieve the required characteristics of the in situ gel for sustaining drug delivery to treat periodontitis.


Assuntos
Antibacterianos/administração & dosagem , Doxiciclina/administração & dosagem , Sistemas de Liberação de Medicamentos , Periodontite/tratamento farmacológico , Quitosana/química , Doxiciclina/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Géis/administração & dosagem , Humanos , Poloxâmero/química , Polímeros/química
19.
ACS Appl Mater Interfaces ; 13(8): 9630-9642, 2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33616382

RESUMO

One potential approach to address the rising threat of antibiotic resistance is through novel formulations of established drugs. We designed antibiotic cross-linked micelles (ABC-micelles) by cross-linking the Pluronic F127 block copolymers with an antibiotic itself, via a novel one-pot synthesis in aqueous solution. ABC-micelles enhanced antibiotic encapsulation while also reducing systemic toxicity in mice. Using colistin, a hydrophilic, potent ″last-resort" antibiotic, ABC-micelle encapsulation yield was 80%, with good storage stability. ABC-micelles exhibited an improved safety profile, with a maximum tolerated dose of over 100 mg/kg colistin in mice, at least 16 times higher than the free drug. Colistin-induced nephrotoxicity and neurotoxicity were reduced in ABC-micelles by 10-50-fold. Despite reduced toxicity, ABC-micelles preserved bactericidal activity, and the clinically relevant combination of colistin and rifampicin (co-loaded in the micelles) showed a synergistic antimicrobial effect against antibiotic-resistant strains of Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii. In a mouse model of sepsis, colistin ABC-micelles showed equivalent efficacy as free colistin but with a substantially higher therapeutic index. Microscopic single-cell imaging of bacteria revealed that ABC-micelles could kill bacteria in a more rapid manner with distinct cell membrane disruption, possibly reflecting a different antimicrobial mechanism from free colistin. This work shows the potential of drug cross-linked micelles as a new class of biomaterials formed from existing antibiotics and represents a new and generalized approach for formulating amine-containing drugs.


Assuntos
Antibacterianos/uso terapêutico , Colistina/uso terapêutico , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Micelas , Sepse/tratamento farmacológico , Animais , Antibacterianos/síntese química , Antibacterianos/toxicidade , Bactérias/efeitos dos fármacos , Colistina/síntese química , Colistina/toxicidade , Ciclofosfamida , Feminino , Camundongos , Testes de Sensibilidade Microbiana , Síndromes Neurotóxicas/prevenção & controle , Poloxâmero/síntese química , Poloxâmero/química , Poloxâmero/toxicidade , Sepse/induzido quimicamente
20.
Theranostics ; 11(5): 2137-2148, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33500716

RESUMO

Aggregation induced emission (AIE)-active bright two-photon fluorescent probes with second near-infrared (NIR-II) light excitability can be used for efficient brain bioimaging studies, wherein the fabrication of water-dispersible nanoparticles by encapsulating the hydrophobic probes with amphiphilic polymer holds the key to ensuring biocompatibility and in vivo adaptability. However, barely any study has evaluated the structural requirements that can substantially affect the water-dispersible nanoparticle formation ability of an organic AIE-active dye with amphiphilic polymers. The present study systematically assessed the structural dependency of a well-known acrylonitrile based AIE system/fluorogenic core upon the formation of water-dispersible nanoparticles and elucidated how the structural modifications can impact the in vivo two-photon imaging. Methods: A total of four acrylonitrile-based aggregation induced emission (AIE)-active two-photon (TP) fluorescent probes (AIETP, AIETP C1, AIETP C2 and AIETP C3) have been judiciously designed and synthesized with structural variations to realize how the structural alterations could substantially influence the water-dispersible nanoparticle formation ability (with amphiphilic polymers) and photo-stability to impact the in vivo imaging. Results: It has been found that the incorporation of the phenyl-thiazole unit in AIETP, AIETP C2 and AIETP C3 facilitated the formation of water-dispersible nanoparticles (NPs) with amphiphilic polymers (Pluronic F127) whereas the presence of only phenyl moiety instead in AIETP C1 could not meet the suitable condition to form the NPs with good aqueous dispersibility. Rationally designed AIETP NPs that exhibited higher brightness, improved photostability and good two-photon absorption cross section was successfully employed for in vivo brain vasculature imaging. Conclusions: Robust noninvasive 2D and 3D two-photon (NIR-II light, 1040 nm) brain vasculature imaging with beneficial attributes such as outstanding penetration depth (800 µm) and exceptional spatial resolution (1.92 µm), were achieved by utilizing AIETP NPs in this study.


Assuntos
Encéfalo/irrigação sanguínea , Corantes Fluorescentes/química , Nanopartículas/química , Imagem Óptica/métodos , Fótons , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Animais , Apoptose , Encéfalo/patologia , Proliferação de Células , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Poloxâmero/química , Polímeros/química
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