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1.
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
2.
Int J Nanomedicine ; 16: 4351-4369, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34234430

RESUMO

Purpose: Multifunctional nanoparticles with targeted therapeutic function and diagnostic-imaging are of great interest in the domain of precision therapy. NIR laser responsive nanoparticles (PLGA-PEG-FA encapsulating Bi2S3, PFP, and Dox (designed as FBPD NPs)) are synthesized for ovarian cancer targeted combination therapy with CT/PA dual-modal imaging guidance (PA: photoacoustic; CT: X-ray computed tomography). Methods and Results: The FBPD NPS prepared by the double emulsification method revealed excellent dispersity, great stability, outstanding optical properties. The temperature of FBPD NPs increased rapidly after laser irradiation, inducing liquid-to-gas conversion of perfluoropentane (PFP), and promoting the release of Dox up to 86.7%. These FBPD NPs demonstrated their outstanding imaging capability for both PA and CT imaging both in vitro and in vivo, providing the potential for therapeutic guidance and monitoring. Assisted by folic acid, these nanoparticles could highly enrich in ovarian tumor tissue and the accumulation peaked at 3 h after intravenous administration. The desirable photothermal-conversion efficiency of the nanoparticles combined with chemotherapy achieved highly efficient therapy, which was demonstrated both in vitro and in vivo. Conclusion: We successfully constructed multifunctional theranostic FBPD NPs for highly efficient PTT/chemotherapy combined therapy with dual CT/PA imaging guidance/monitoring. The unique nanoparticles with multiple abilities pave an emerging way toward precise treatment of ovarian cancer.


Assuntos
Raios Infravermelhos , Lasers , Nanopartículas/uso terapêutico , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/terapia , Técnicas Fotoacústicas , Tomografia Computadorizada por Raios X , Animais , Terapia Combinada , Feminino , Ácido Fólico/química , Humanos , Nanopartículas/química , Poliésteres/química , Polietilenoglicóis/química
3.
Int J Nanomedicine ; 16: 4391-4407, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34234433

RESUMO

Background: Gold nanocages have been widely used as multifunctional platforms for drug and gene delivery, as well as photothermal agents for cancer therapy. However, their potential as gene delivery systems for cancer treatment has been reported in combination with chemotherapeutics and photothermal therapy, but not in isolation so far. The purpose of this work was to investigate whether the conjugation of gold nanocages with the cancer targeting ligand lactoferrin, polyethylene glycol and polyethylenimine could lead to enhanced transfection efficiency on prostate cancer cells in vitro, without assistance of external stimulation. Methods: Novel lactoferrin-bearing gold nanocages conjugated to polyethylenimine and polyethylene glycol have been synthesized and characterized. Their transfection efficacy and cytotoxicity were assessed on PC-3 prostate cancer cell line following complexation with a plasmid DNA. Results: Lactoferrin-bearing gold nanocages, alone or conjugated with polyethylenimine and polyethylene glycol, were able to condense DNA at conjugate:DNA weight ratios 5:1 and higher. Among all gold conjugates, the highest gene expression was obtained following treatment with gold complex conjugated with polyethylenimine and lactoferrin, at weight ratio 40:1, which was 1.71-fold higher than with polyethylenimine. This might be due to the increased DNA cellular uptake observed with this conjugate, by up to 8.65-fold in comparison with naked DNA. Conclusion: Lactoferrin-bearing gold nanocages conjugates are highly promising gene delivery systems to prostate cancer cells.


Assuntos
Portadores de Fármacos/química , Técnicas de Transferência de Genes , Ouro/química , Lactoferrina/química , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , DNA/administração & dosagem , DNA/química , DNA/genética , Terapia Genética , Humanos , Masculino , Plasmídeos/genética , Polietilenoglicóis/química , Polietilenoimina/química , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/terapia , Transfecção
4.
Molecules ; 26(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34063773

RESUMO

Flaky graphene oxide (GO) nanoparticles (NPs) were synthesized using Hummer's method and then capped with polyethylene glycol (PEG) by an esterification reaction, then loaded with Nigella sativa (N. sativa) seed extract. Aiming to investigate their potential use as a smart drug delivery system against Staphylococcus aureus and Escherichia coli, the spectral and structural characteristics of GO-PEG NPs were comprehensively analyzed by XRD, AFM, TEM, FTIR, and UV- Vis. XRD patterns revealed that GO-PEG had different crystalline structures and defects, as well as a higher interlayer spacing. AFM results showed GONPs with the main grain size of 24.41 nm, while GONPs-PEG revealed graphene oxide aggregation with the main grain size of 287.04 nm after loading N. sativa seed extract, which was verified by TEM examination. A strong OH bond appeared in FTIR spectra. Furthermore, UV- Vis absorbance peaks at (275, 284, 324, and 327) nm seemed to be correlated with GONPs, GO-PEG, N. sativa seed extract, and GO -PEG- N. sativa extract. The drug delivery system was observed to destroy the bacteria by permeating the bacterial nucleic acid and cytoplasmic membrane, resulting in the loss of cell wall integrity, nucleic acid damage, and increased cell-wall permeability.


Assuntos
Antibacterianos/farmacologia , Sistemas de Liberação de Medicamentos , Grafite/química , Nanopartículas/química , Nigella sativa/química , Extratos Vegetais/farmacologia , Polietilenoglicóis/química , Antibacterianos/administração & dosagem , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Transmissão , Extratos Vegetais/administração & dosagem , Análise Espectral/métodos , Staphylococcus aureus/efeitos dos fármacos , Difração de Raios X
5.
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
6.
Nat Commun ; 12(1): 3764, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145265

RESUMO

Post-surgical cardiac adhesions represent a significant problem during routine cardiothoracic procedures. This fibrous tissue can impair heart function and inhibit surgical access in reoperation procedures. Here, we propose a hydrogel barrier composed of oxime crosslinked poly(ethylene glycol) (PEG) with the inclusion of a catechol (Cat) group to improve retention on the heart for pericardial adhesion prevention. This three component system is comprised of aldehyde (Ald), aminooxy (AO), and Cat functionalized PEG mixed to form the final gel (Ald-AO-Cat). Ald-AO-Cat has favorable mechanical properties, degradation kinetics, and minimal swelling, as well as superior tissue retention compared to an initial Ald-AO gel formulation. We show that the material is cytocompatible, resists cell adhesion, and led to a reduction in the severity of adhesions in an in vivo rat model. We further show feasibility in a pilot porcine study. The Ald-AO-Cat hydrogel barrier may therefore serve as a promising solution for preventing post-surgical cardiac adhesions.


Assuntos
Materiais Biocompatíveis/uso terapêutico , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Hidrogéis/química , Hidrogéis/uso terapêutico , Aderências Teciduais/prevenção & controle , Aldeídos/química , Animais , Materiais Biocompatíveis/química , Catecóis/química , Linhagem Celular , Masculino , Camundongos , Oximas/química , Oximas/uso terapêutico , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley , Suínos
7.
Int J Nanomedicine ; 16: 4017-4030, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34140769

RESUMO

Purpose: This study was aimed at developing the trispecific antibodies (anti-EGFR/anti-FAP/anti-mPEG, TsAb) or dual bispecific antibodies (anti-EGFR/anti-mPEG and anti-FAP/anti-mPEG) docetaxel (DTX)-loaded mPEGylated lecithin-stabilized micelles (mPEG-lsbPMs) for improving the targeting efficiency and therapeutic efficacy. Methods: mPEG-lsbPMs were simply prepared via thin film method. The trispecific antibodies or bispecific antibodies bound the mPEG-lsbPMs by anti-mPEG Fab fragment. The formulations were characterized by DLS and TEM; in vitro and in vivo studies were also conducted to evaluate the cellular uptake, cell cytotoxicity and therapeutic efficacy. Results: The particle sizes of mPEG-lsbPMs with or without the antibodies were around 100 nm; the formulations showed high encapsulation efficiencies of 97.12%. The TsAb and dual bispecific antibodies were fabricated and demonstrated their targeting ability. Two EGFR-overexpressed cell lines (HT-29 and MIA PaCa-2) were co-cultured with FAP-overexpressed WS1 cells (HT-29/WS1; MIA PaCa-2/WS1) to mimic a tumor coexisting in the tumor microenvironment. Cellular binding study revealed that the binding of anti-FAP micelles to three co-culture ratios (4:1, 1:1, and 1:4) of HT-29/EGFR to WS1/FAP was significantly higher than that for TsAb micelles and dual (1:1) micelles, and the binding of those targeting antibodies to WS1/FAP and MIA PaCa-2/EGFR was equally efficacious resulting in a similar binding amount of the TsAb and dual BsAbs (1:1) with the co-culture of MIA PaCa-2/EGFR and WS1/FAP at a 1:1 ratio. Antitumor efficacy study showed that treatment with DTX-loaded mPEG-lsbPMs modified with or without BsAbs, dual BsAbs (1:1), and TsAbs was enhanced in inhibiting tumor growth compared with that for Tynen® while showing fewer signs of adverse effects. Conclusion: Active targeting of both tumors and TAF-specific antigens was able to increase the affinity of DTX-loaded mPEG-lsbPMs toward tumor cells and TAFs leading to successive uptake by tumor cells or TAFs which enhanced their chemotherapeutic efficacy against antigen-positive cancer cells.


Assuntos
Anticorpos Biespecíficos/farmacologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/farmacologia , Docetaxel/administração & dosagem , Portadores de Fármacos/química , Animais , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/química , Antineoplásicos Imunológicos/farmacocinética , Fibroblastos Associados a Câncer/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Cocultura , Docetaxel/farmacocinética , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/imunologia , Humanos , Injeções Intradérmicas , Lecitinas/química , Masculino , Camundongos Nus , Micelas , Tamanho da Partícula , Polietilenoglicóis/química , Ratos Sprague-Dawley , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Int J Nanomedicine ; 16: 4209-4224, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34188470

RESUMO

Background and Purpose: Strontium ranelate (SrR) is an oral pharmaceutical agent for osteoporosis. In recent years, numerous unwanted side effects of oral SrR have been revealed. Therefore, its clinical administration and applications are limited. Hereby, this study aims to develop, formulate, and characterize an effective SrR carrier system for spinal bone regeneration. Methods: Herein, glycol chitosan with hyaluronic acid (HA)-based nanoformulation was used to encapsulate SrR nanoparticles (SrRNPs) through electrostatic interaction. Afterward, the poly(ethylene glycol) diacrylate (PEGDA)-based hydrogels were used to encapsulate pre-synthesized SrRNPs (SrRNPs-H). The scanning electron microscope (SEM), TEM, rheometer, Fourier-transform infrared spectroscopy (FTIR), and dynamic light scattering (DLS) were used to characterize prepared formulations. The rabbit osteoblast and a rat spinal decortication models were used to evaluate and assess the developed formulation biocompatibility and therapeutic efficacy. Results: In vitro and in vivo studies for cytotoxicity and bone regeneration were conducted. The cell viability test showed that SrRNPs exerted no cytotoxic effects in osteoblast in vitro. Furthermore, in vivo analysis for new bone regeneration mechanism was carried out on rat decortication models. Radiographical and histological analysis suggested a higher level of bone regeneration in the SrRNPs-H-implanted groups than in the other experimental groups. Conclusion: Local administration of the newly developed formulated SrR could be a promising alternative therapy to enhance bone regeneration in bone-defect sites in future clinical applications.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Portadores de Fármacos/química , Ácido Hialurônico/química , Nanopartículas/química , Polietilenoglicóis/química , Coluna Vertebral/fisiologia , Tiofenos/administração & dosagem , Tiofenos/farmacologia , Animais , Comunicação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacologia , Hidrogéis/química , Masculino , Nanopartículas/ultraestrutura , Tamanho da Partícula , Coelhos , Ratos Wistar , Coluna Vertebral/efeitos dos fármacos
9.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34063962

RESUMO

Drug-eluting stents have been widely implanted to prevent neointimal hyperplasia associated with bare metal stents. Conventional polymers and anti-proliferative drugs suffer from stent thrombosis due to the non-selective nature of the drugs and hypersensitivity to polymer degradation products. Alternatively, various herbal anti-proliferative agents are sought, of which biochanin A (an isoflavone phytoestrogen) was known to have anti-proliferative and vasculoprotective action. PLA-PEG diblock copolymer was tagged with heparin, whose degradation releases heparin locally and prevents thrombosis. To get a controlled drug release, biochanin A was loaded in layered double hydroxide nanoparticles (LDH), which are further encapsulated in a heparin-tagged PLA-PEG copolymer. LDH nanoparticles are synthesized by a co-precipitation process; in situ as well as ex situ loading of biochanin A were done. PLA-PEG-heparin copolymer was synthesized by esterification reaction, and the drug-loaded nanoparticles are coated. The formulation was characterized by FTIR, XRD, DSC, DLS, and TEM. In vitro drug release studies, protein adhesion, wettability, hemocompatibility, and degradation studies were performed. The drug release was modeled by mathematical models to further emphasize the mechanism of drug release. The developed drug-eluting stent coating is non-thrombogenic, and it offers close to zero-order release for 40 days, with complete polymer degradation in 14 weeks.


Assuntos
Genisteína/química , Heparina/química , Hidróxidos/química , Lactatos/química , Nanopartículas/química , Polietilenoglicóis/química , Polímeros/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/fisiologia , Stents Farmacológicos , Humanos , Modelos Teóricos , Trombose/tratamento farmacológico
10.
Molecules ; 26(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068693

RESUMO

The intracellular environment is overcrowded with a range of molecules (small and large), all of which influence protein conformation. As a result, understanding how proteins fold and stay functional in such crowded conditions is essential. Several in vitro experiments have looked into the effects of macromolecular crowding on different proteins. However, there are hardly any reports regarding small molecular crowders used alone and in mixtures to observe their effects on the structure and stability of the proteins, which mimics of the cellular conditions. Here we investigate the effect of different mixtures of crowders, ethylene glycol (EG) and its polymer polyethylene glycol (PEG 400 Da) on the structural and thermal stability of myoglobin (Mb). Our results show that monomer (EG) has no significant effect on the structure of Mb, while the polymer disrupts its structure and decreases its stability. Conversely, the additive effect of crowders showed structural refolding of the protein to some extent. Moreover, the calorimetric binding studies of the protein showed very weak interactions with the mixture of crowders. Usually, we can assume that soft interactions induce structural perturbations while exclusion volume effects stabilize the protein structure; therefore, we hypothesize that under in vivo crowded conditions, both phenomena occur and maintain the stability and function of proteins.


Assuntos
Substâncias Macromoleculares/química , Mioglobina/química , Redobramento de Proteína , Temperatura , Animais , Difusão Dinâmica da Luz , Etilenoglicol/química , Fluorescência , Guanidina/farmacologia , Cavalos , Hidrodinâmica , Simulação de Acoplamento Molecular , Polietilenoglicóis/química , Conformação Proteica , Desnaturação Proteica/efeitos dos fármacos , Redobramento de Proteína/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos
11.
Molecules ; 26(9)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066875

RESUMO

The main core of wound treatment is cell growth and anti-infection. To accelerate the proliferation of fibroblasts in the wound and prevent wound infections, various strategies have been tried. It remains a challenge to obtain good cell proliferation and antibacterial effects. Here, human hair kerateine (HHK)/poly(ethylene oxide) (PEO)/poly(vinyl alcohol) (PVA) nanofibers were prepared using cysteine-rich HHK, and then, silver nanoparticles (AgNPs) were in situ anchored in the sulfur-containing amino acid residues of HHK. After the ultrasonic degradation test, HHK/PEO/PVA nanofibrous mats treated with 0.005-M silver nitrate were selected due to their relatively complete structures. It was observed by TEM-EDS that the sulfur-containing amino acids in HHK were the main anchor points of AgNPs. The results of FTIR, XRD and the thermal analysis suggested that the hydrogen bonds between PEO and PVA were broken by HHK and, further, by AgNPs. AgNPs could act as a catalyst to promote the thermal degradation reaction of PVA, PEO and HHK, which was beneficial for silver recycling and medical waste treatment. The antibacterial properties of AgNP-HHK/PEO/PVA nanofibers were examined by the disk diffusion method, and it was observed that they had potential antibacterial capability against Gram-positive bacteria, Gram-negative bacteria and fungi. In addition, HHK in the nanofibrous mats significantly improved the cell proliferation of NIH3T3 cells. These results illustrated that the AgNP-HHK/PEO/PVA nanofibrous mats exhibited excellent antibacterial activity and the ability to promote the proliferation of fibroblasts, reaching our target applications.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Proliferação de Células/efeitos dos fármacos , Queratinas Específicas do Cabelo/química , Nanopartículas Metálicas/química , Nanofibras/química , Polietilenoglicóis/química , Álcool de Polivinil/química , Prata/química , Animais , Candida albicans/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Cabelo/química , Humanos , Ligação de Hidrogênio , Camundongos , Testes de Sensibilidade Microbiana , Células NIH 3T3 , Nitrato de Prata/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
12.
Int J Nanomedicine ; 16: 4147-4159, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34168445

RESUMO

Purpose: To develop microchannel-based preparation of curcumin (Cur)-loaded hybrid nanoparticles using enzyme-targeted peptides and star-shaped polycyclic lipids as carriers, and to accomplish a desirable targeted drug delivery via these nanoparticles, which could improve the bioavailability and antitumor effects of Cur. Methods: The amphiphilic tri-chaintricarballylic acid-poly (ε-caprolactone)-methoxypolyethylene glycol (Tri-CL-mPEG) and the enzyme-targeted tetra-chain pentaerythritol-poly (ε-caprolactone)-polypeptide (PET-CL-P) were synthesized. The Cur-loaded enzyme-targeted hybrid nano-delivery systems (Cur-P-NPs) were prepared by using the microfluidic continuous granulation technology. The physicochemical properties, release behavior in vitro, and stability of these Cur-P-NPs were investigated. Their cytotoxicity, cellular uptake, anti-proliferative efficacy in vitro, biodistribution, and antitumor effects in vivo were also studied. Results: The particle size of the prepared Cur-P-NPs was 146.1 ± 1.940 nm, polydispersity index was 0.175 ± 0.014, zeta potential was 10.1 ± 0.300 mV, encapsulation rate was 74.66 ± 0.671%, and drug loading capacity was 5.38 ± 0.316%. The stability of Cur-P-NPs was adequate, and the in vitro release rate increased with the decrease of the environmental pH. Seven days post incubation, the cumulative release values of Cur were 52.78%, 67.39%, and 98.12% at pH 7.4, pH 6.8 and pH 5.0, respectively. Cur-P-NPs exhibited better cell entry and antiproliferation efficacy against U251 cells than the Cur-solution and Cur-NPs and were safe for use. Cur-P-NPs specifically targeted tumor tissues and inhibited their growth (78.63% tumor growth inhibition rate) with low toxic effects on normal tissues. Conclusion: The enzyme-targeted hybrid nanoparticles prepared in the study clearly have the tumor-targeting ability. Cur-P-NPs can effectively improve the bioavailability of Cur and have potential applications in drug delivery and tumor management.


Assuntos
Curcumina/química , Curcumina/farmacologia , Dispositivos Lab-On-A-Chip , Nanopartículas/química , Nanotecnologia/instrumentação , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Caproatos/química , Linhagem Celular Tumoral , Curcumina/farmacocinética , Portadores de Fármacos/química , Humanos , Lactonas/química , Camundongos , Tamanho da Partícula , Polietilenoglicóis/química , Distribuição Tecidual
13.
Int J Nanomedicine ; 16: 4045-4061, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34163158

RESUMO

Purpose: Previous studies demonstrated the possibility of targeting tumor-angiogenic endothelial cells with positively charged nanocarriers, such as cationic liposomes. We investigated the active targeting potential of positively charged nanoparticles in combination with the heat-induced drug release function of thermosensitive liposomes (TSL). This novel dual-targeted approach via cationic TSL (CTSL) was thoroughly explored using either a novel synthetic phospholipid 1,2-dipalmitoyl-sn-glycero-3-phosphodiglycerol (DPPG2) or a conventional polyethylene glycol (PEG) surface modification. Anionic particles containing either DPPG2 or PEG were also included in the study to highlight difference in tumor enrichment driven by surface charge. With this study, we aim to provide a deep insight into the main differences between DPPG2- and PEG-functionalized liposomes, focusing on the delivery of a well-known cytotoxic drug (doxorubicin; DOX) in combination with local hyperthermia (HT, 41-43°C). Materials and Methods: DPPG2- and PEG-based cationic TSLs (PG2-CTSL/PEG-CTSL) were thoroughly analyzed for size, surface charge, and heat-triggered DOX release. Cancer cell targeting and DOX delivery was evaluated by FACS, fluorescence imaging, and HPLC. In vivo particle behavior was analyzed by assessing DOX biodistribution with local HT application in tumor-bearing animals. Results: The absence of PEG in PG2-CTSL promoted more efficient liposome-cell interactions, resulting in a higher DOX delivery and cancer cell toxicity compared with PEG-CTSL. By exploiting the dual-targeting function of CTSLs, we were able to selectively trigger DOX release in the intracellular compartment by HT. When tested in vivo, local HT promoted an increase in intratumoral DOX levels for all (C)TSLs tested, with DOX enrichment factors ranging from 3 to 14-fold depending on the type of formulation. Conclusion: Cationic particles showed lower hemocompatibility than their anionic counterparts, which was partially mitigated when PEG was grafted on the liposome surface. DPPG2-based anionic TSL showed optimal local drug delivery compared to all other formulations tested, demonstrating the potential advantages of using DPPG2 lipid in designing liposomes for tumor-targeted applications.


Assuntos
Comunicação Celular , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Fosfatidilgliceróis/química , Polietilenoglicóis/química , Temperatura , Animais , Comunicação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Concentração Inibidora 50 , Espaço Intracelular/metabolismo , Lipossomos , Polietilenoglicóis/administração & dosagem , Ratos , Propriedades de Superfície , Distribuição Tecidual/efeitos dos fármacos
14.
AAPS PharmSciTech ; 22(5): 189, 2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34159457

RESUMO

Phospholipid complexation, despite being a successful, versatile, and burgeoning strategy, stickiness of phospholipids leads to suboptimal dissolution rate of drugs. This work was undertaken to fabricate simvastatin-phospholipid complex (SIM-PLC)-loaded matrix dispersion (SIM-PLC-MD) using Soluplus® as carrier material, to augment dispersibility and dissolution of SIM-PLC without altering complexation between simvastatin (SIM) and phospholipid. SIM-PLC and SIM-PLC-MD were prepared using solvent evaporation and discontinuous solvent evaporation techniques, respectively. The successful complexation was substantiated by FTIR method. Besides, PXRD and SEM studies disclosed the absence of crystallinity of SIM in both SIM-PLC and SIM-PLC-MD. The TEM analysis monitored the self-assembly of SIM-PLC and SIM-PLC-MD into colloidal structures, which could be correlated with redispersion in GIT fluids upon oral administration. The considerable increase in hydrophilicity of SIM-PLC-MD and SIM-PLC as evident from partition coefficient experiment can further be correlated with their remarkably improved solubility profiles in the following pattern: SIM-PLC-MD˃SIM-PLC˃SIM. Correspondingly, improved dispersibility of SIM-PLC-MD in comparison to SIM-PLC can be accountable for accelerated dissolution rate by 2.53-fold and 1.5-fold in pH 1.2 and 6.8 conditions, respectively. The oral pharmacokinetic evaluation in Sprague Dawley (SD) rats revealed 3.19-fold enhancement in oral bioavailability of SIM through SIM-PLC-MD when compared with plain SIM, whereas 1.83-fold increment was observed in the case of SIM-PLC. Finally, the efficacy experimentation in SD rats revealed that SIM-PLC-MD significantly reduced triglycerides and cholesterol levels in comparison to SIM and SIM-PLC. These outcomes suggest that a matrix dispersion strategy improves oral bioavailability and hypolipidemic activity of SIM.


Assuntos
Fosfolipídeos/química , Fosfolipídeos/farmacocinética , Sinvastatina/química , Sinvastatina/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Feminino , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polivinil/administração & dosagem , Polivinil/química , Polivinil/farmacocinética , Ratos , Ratos Sprague-Dawley , Sinvastatina/administração & dosagem , Solubilidade , Solventes/administração & dosagem , Solventes/química , Solventes/farmacocinética
15.
Artigo em Inglês | MEDLINE | ID: mdl-33989987

RESUMO

OBJECTIVE: To optimize a screening method for macroprolactinemia and improve the accuracy of free prolactin (freePRL) detection. METHOD: Overall efficiency, calculated as the product of the immunoglobulin G (IgG) precipitation rate and the freePRL recovery rate were employed to determine the concentration of the precipitant polyethylene glycol (PEG). Then, an optimized screening method for macroprolactinemia was established. The concentrations of freePRL, obtained by gel filtration chromatography (GFC), from 66 cases were used as the gold standard, and the sensitivity, specificity, accuracy and precision of the optimized and traditional methods for detecting macroprolactinemia were compared. RESULTS: (1) The IgG precipitation rate increased with increasing PEG6000 concentration, and the freePRL recovery rate decreased with increasing PEG6000 concentration; the overall efficiency first increased and then decreased. When the IgG concentrations in the mixture were 10 g/L, 25 g/L and 40 g/L, the concentrations of PEG6000 with the highest overall efficiency were 24%, 20% and 18%, respectively. (2) The effect of high and low IgG on the overall efficiency was 4.7% when using 20% PEG6000, which was lower than the effects when using 18% or 24% PEG6000 (9.2% and 13.2%). (3) In the optimized method established using 20% PEG6000, the macroprolactin (macroPRL) chromatographic peak disappeared, but the freePRL chromatographic peak was retained. The sensitivity of this macroprolactinemia screening method was 96.7%, and the specificity was 100%. (4) The freePRL concentrations obtained by the optimized method for samples from 30 macroprolactinemia cases and 36 true hyperprolactinemia cases were 15.8 (10.2-21.4) ng/mL and 60.2 (51.8-79.9) ng/mL; the concentrations were similar to those obtained using the GFC method (16.3 (11.9-27.2) ng/mL and 68.1 (49.5-92.9) ng/mL, respectively (p > 0.05)) and higher than those obtained using the traditional method (9.1 (6.1-17.6) ng/mL and 51.4 (43.7-71.9) ng/mL), respectively, p < 0.05)). (5) The relative deviation between the optimized and GFC methods was -7.0%, which was significantly lower than the relative deviation between the traditional and GFC methods (-21.4%, p < 0.01). (6) The in-batch coefficients of variation (CVs) for the dual-level quality control materials measured by the optimized method were 1.88% and 1.87%, and the within-laboratory CVs were 2.55% and 2.29%, which were slightly lower than the in-batch CVs (1.93% and 2.81%) and within-laboratory CVs (2.75% and 2.81%) measured by the traditional method. CONCLUSION: The established optimized method for screening macroprolactinemia using 20% PEG6000 as a precipitant can completely precipitate macroPRL components and effectively retain freePRL components. Compared with traditional methods, the optimized method is simpler, more accurate and more stable for the quantitative detection of freePRL.


Assuntos
Cromatografia em Gel/métodos , Hiperprolactinemia/diagnóstico , Prolactina/sangue , Precipitação Química , Humanos , Imunoglobulina G/química , Polietilenoglicóis/química , Sensibilidade e Especificidade
16.
J Allergy Clin Immunol ; 148(1): 91-95, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33991580

RESUMO

BACKGROUND: The mechanisms underpinning allergic reactions to the BNT162b2 (Pfizer) COVID-19 vaccine remain unknown, with polyethylene glycol (PEG) contained in the lipid nanoparticle suspected as being the cause. OBJECTIVE: Our aim was to evaluate the performance of skin testing and basophil activation testing to PEG, polysorbate 80, and the BNT162b2 (Pfizer) and AZD1222 (AstraZeneca) COVID-19 vaccines in patients with a history of PEG allergy. METHODS: Three known individuals with PEG allergy and 3 healthy controls were recruited and evaluated for hypersensitivity to the BNT162b2 and AZD1222 vaccines, and to related compounds by skin testing and basophil activation, as measured by CD63 upregulation using flow cytometry. RESULTS: We found that the BNT162b2 vaccine induced positive skin test results in patients with PEG allergy, whereas the result of traditional PEG skin testing was negative in 2 of 3 patients. One patient was found to be cosensitized to both the BNT162b2 and AZD1222 vaccines because of cross-reactive PEG and polysorbate allergy. The BNT162b2 vaccine, but not PEG alone, induced dose-dependent activation of all patients' basophils ex vivo. Similar basophil activation could be induced by PEGylated liposomal doxorubicin, suggesting that PEGylated lipids within nanoparticles, but not PEG in its native state, are able to efficiently induce degranulation. CONCLUSIONS: Our findings implicate PEG, as covalently modified and arranged on the vaccine lipid nanoparticle, as a potential trigger of anaphylaxis in response to BNT162b2, and highlight shortcomings of current skin testing protocols for allergy to PEGylated liposomal drugs.


Assuntos
Anafilaxia/imunologia , Basófilos/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Doxorrubicina/análogos & derivados , Hipersensibilidade a Drogas/imunologia , Nanopartículas/efeitos adversos , Polietilenoglicóis/efeitos adversos , SARS-CoV-2/fisiologia , Adulto , Degranulação Celular , Células Cultivadas , Doxorrubicina/efeitos adversos , Doxorrubicina/química , Feminino , Humanos , Lipídeos/química , Masculino , Pessoa de Meia-Idade , Nanopartículas/química , Polietilenoglicóis/química , Testes Cutâneos , Adulto Jovem
17.
Nat Commun ; 12(1): 3192, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34045434

RESUMO

Tissues achieve their complex spatial organization through an interplay between gene regulatory networks, cell-cell communication, and physical interactions mediated by mechanical forces. Current strategies to generate in-vitro tissues have largely failed to implement such active, dynamically coordinated mechanical manipulations, relying instead on extracellular matrices which respond to, rather than impose mechanical forces. Here, we develop devices that enable the actuation of organoids. We show that active mechanical forces increase growth and lead to enhanced patterning in an organoid model of the neural tube derived from single human pluripotent stem cells (hPSC). Using a combination of single-cell transcriptomics and immunohistochemistry, we demonstrate that organoid mechanoregulation due to actuation operates in a temporally restricted competence window, and that organoid response to stretch is mediated extracellularly by matrix stiffness and intracellularly by cytoskeleton contractility and planar cell polarity. Exerting active mechanical forces on organoids using the approaches developed here is widely applicable and should enable the generation of more reproducible, programmable organoid shape, identity and patterns, opening avenues for the use of these tools in regenerative medicine and disease modelling applications.


Assuntos
Tubo Neural/citologia , Organoides/fisiologia , Engenharia Tecidual/métodos , Técnicas de Cultura de Células/instrumentação , Técnicas de Cultura de Células/métodos , Diferenciação Celular/fisiologia , Linhagem Celular , Matriz Extracelular/fisiologia , Humanos , Hidrogéis/química , Mecanotransdução Celular/fisiologia , Células-Tronco Pluripotentes , Polietilenoglicóis/química , RNA-Seq , Medicina Regenerativa/métodos , Análise de Célula Única , Engenharia Tecidual/instrumentação
18.
Int J Nanomedicine ; 16: 3407-3427, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34040371

RESUMO

Purpose: Plasmonic photothermal cancer therapy by gold nanorods (GNRs) emerges as a promising tool for cancer treatment. The goal of this study was to design cationic oligoethylene glycol (OEG) compounds varying in hydrophobicity and molecular electrostatic potential as ligand shells of GNRs. Three series of ligands with different length of OEG chain (ethylene glycol units = 3, 4, 5) and variants of quaternary ammonium salts (QAS) as terminal functional group were synthesized and compared to a prototypical quaternary ammonium ligand with alkyl chain - (16-mercaptohexadecyl)trimethylammonium bromide (MTAB). Methods: Step-by-step research approach starting with the preparation of compounds characterized by NMR and HRMS spectra, GNRs ligand exchange evaluation through characterization of cytotoxicity and GNRs cellular uptake was used. A method quantifying the reshaping of GNRs was applied to determine the effect of ligand structure on the heat transport from GNRs under fs-laser irradiation. Results: Fourteen out of 18 synthesized OEG compounds successfully stabilized GNRs in the water. The colloidal stability of prepared GNRs in the cell culture medium decreased with the number of OEG units. In contrast, the cellular uptake of OEG+GNRs by HeLa cells increased with the length of OEG chain while the structure of the QAS group showed a minor role. Compared to MTAB, more hydrophilic OEG compounds exhibited nearly two order of magnitude lower cytotoxicity in free state and provided efficient cellular uptake of GNRs close to the level of MTAB. Regarding photothermal properties, OEG compounds evoked the photothermal reshaping of GNRs at lower peak fluence (14.8 mJ/cm2) of femtosecond laser irradiation than the alkanethiol MTAB. Conclusion: OEG+GNRs appear to be optimal for clinical applications with systemic administration of NPs not-requiring irradiation at high laser intensity such as drug delivery and photothermal therapy inducing apoptosis.


Assuntos
Ouro/química , Ouro/metabolismo , Nanotubos/química , Polietilenoglicóis/química , Compostos de Amônio Quaternário/química , Temperatura , Transporte Biológico , Coloides , Estabilidade de Medicamentos , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligantes
19.
AAPS PharmSciTech ; 22(5): 159, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34019243

RESUMO

Chitosan-based carriers have coined their position as delivery agents. When assembled with polyanions into nanogels (NG), these vectors have enabled the delivery of drugs, genes, and proteins to a myriad of applications. However, the chemical and colloidal instability of chitosan nanoformulations in physiologically compatible media prejudices in vitro biocompatibility and, thus, scale-up applications. To overcome this issue, we envisaged the coating of chitosan nanogel with phospholipids. In this investigation, we report a two-stage synthesis of hybrid lipid-coated chitosan nanogels, named nanolipogels (NLG), to improve colloidal stability and in vitro biocompatibility over chitosan NG. Practically, we employed a mixing platform to first prepare chitosan NG by ionic gelation, dilute the suspension, and, in a second stage, coat the NG with lipids. We demonstrate that lipid coating increased particle size and reversed the ζ-potential to negative values, suggesting the successful formation of NLG, while maintaining a homogeneous size distribution (PDI < 0.25). Furthermore, multiple light scattering analysis confirmed NLG improved colloidal stability in phosphate buffer saline and cell culture medium, with respect to NG. Finally, lipid coating completely abrogated the cytotoxicity of NG when incubated at 50 µg·mL-1 with HeLa, U87, or b.End3 cell lines and significantly improved the biocompatibility at 100 and 150 µg·mL-1. Future investigations will explore how the lipid coating affects drug loading, release profile, and the ability of NLG to deliver drugs and genes in vitro.


Assuntos
Materiais Biocompatíveis/química , Quitosana/química , Coloides/química , Lipídeos/química , Nanogéis/química , Polietilenoglicóis/química , Polietilenoimina/química , Portadores de Fármacos , Humanos , Técnicas In Vitro
20.
J Med Chem ; 64(10): 6802-6813, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33974422

RESUMO

Coagulation factor XI (FXI) has emerged as a promising target for the development of safer anticoagulation drugs that limit the risk of severe and life-threatening bleeding. Herein, we report the first cyclic peptide-based FXI inhibitor that selectively and potently inhibits activated FXI (FXIa) in human and animal blood. The cyclic peptide inhibitor (Ki = 2.8 ± 0.5 nM) achieved anticoagulation effects that are comparable to that of the gold standard heparin applied at a therapeutic dose (0.3-0.7 IU/mL in plasma) but with a substantially broader estimated therapeutic range. We extended the plasma half-life of the peptide via PEGylation and demonstrated effective FXIa inhibition over extended periods in vivo. We validated the anticoagulant effects of the PEGylated inhibitor in an ex vivo hemodialysis model with human blood. Our work shows that FXI can be selectively targeted with peptides and provides a promising candidate for the development of a safe anticoagulation therapy.


Assuntos
Anticoagulantes/química , Fator XIa/antagonistas & inibidores , Peptídeos Cíclicos/química , Sequência de Aminoácidos , Animais , Anticoagulantes/metabolismo , Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Fator XIa/metabolismo , Meia-Vida , Humanos , Isomerismo , Modelos Biológicos , Tempo de Tromboplastina Parcial , Biblioteca de Peptídeos , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/farmacologia , Polietilenoglicóis/química , Coelhos , Diálise Renal
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