Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 58
Filtrar
1.
ACS Omega ; 9(32): 34268-34280, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39157138

RESUMO

Stimuli-responsive polymeric micelles decorated with cancer biomarkers represent an optimal choice for drug delivery applications due to their ability to enhance therapeutic efficacy while mitigating adverse side effects. Accordingly, we synthesized a digoxin-modified novel multifunctional redox-responsive disulfide-linked poly(ethylene glycol-b-poly(lactic-co-glycolic acid) copolymer (Bi(Dig-PEG-PLGA)-S2) for the targeted and controlled release of doxorubicin (DOX) in cancer cells. Within the micellar aggregate, the disulfide bond confers redox responsiveness, while the presence of the digoxin moiety acts as a targeting agent and chemosensitizer for DOX. Upon self-assembly in aqueous solution, Bi(Dig-PEG-PLGA)-S2 formed uniformly distributed spherical micelles with a hydrodynamic diameter (D h ) of 58.36 ± 0.78 nm and a zeta potential of -24.71 ± 1.01 mV. The micelles exhibited desirable serum and colloidal stability with a substantial drug loading capacity (DLC) of 6.26% and an encapsulation efficiency (EE) of 83.23%. In addition, the release of DOX demonstrated the redox-responsive behavior of the micelles, with approximately 89.41 ± 6.09 and 79.64 ± 6.68% of DOX diffusing from DOX@Bi(Dig-PEG-PLGA)-S2 in the presence of 10 mM GSH and 0.1 mM H2O2, respectively, over 96 h. Therefore, in HeLa cell lines, DOX@Bi(Dig-PEG-PLGA)-S2 showed enhanced intracellular accumulation and subsequent apoptotic effects, attributed to the targeting ability and chemosensitization potential of digoxin. Hence, these findings underscore the promising characteristics of Bi(Dig-PEG-PLGA)-S2 as a multifunctional drug delivery vehicle for cancer treatment.

2.
Colloids Surf B Biointerfaces ; 241: 114028, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38905811

RESUMO

Biotin receptors are overexpressed in various cancer cell types, essential in tumor development, metabolism, and metastasis. Chemotherapeutic agents may be more effective and have fewer adverse effects if they specifically target the biotin receptors on cancer cells. Polymeric micelles (PMs) with nanoscale size via the EPR effect to accumulate near tumor tissue. We utilized the solvent exchange technique to crate polymeric Biotin-PEG-SeSe-PBLA micelles. This underwent self-assembly to create uniformly dispersed PMs with a hydrodynamic diameter of 81.54 ± 0.23 nm. The resulting PMs characterized by 1HNMR, 13CNMR, FTIR, and Raman spectroscopy. PMs exhibited a high efficacy of Doxorubicin encapsulation (EE) and loading content (DLC), with values of 5.93 wt% and 74.32 %, respectively. DOX@Biotin-PEG-SeSe-PBLA micelles showed optimal DOX release, around 89 % and 74 % in 10 mM glutathione and 0.1 % H2O2, respectively, within 72 hours, in the simulated cancer redox pool. Fascinatingly, the blank Biotin-PEG-SeSe-PBLA micelles did not affect the HaCaT or HeLa cell lines; approximately 85 % of the cells were metabolically active. Contrarily, at a 5 µg/ml concentration, DOX@Biotin-PEG-SeSe-PBLA specifically inhibited the proliferation of roughly 76 % of HeLa cells and 11 % of HaCaT cells. The fluorescence microscopy results demonstrated that biotin-decorated micelles were more successfully internalized by HeLa cells, which overexpress the biotin receptor, than by non-targeted micelles in vitro. In summary, the diselenide-linked Biotin-PEGSeSe-PBLA formed smart PMs that could offer DOX specific to cancer cells with precision and are physiologically durable.


Assuntos
Biotina , Doxorrubicina , Liberação Controlada de Fármacos , Micelas , Oxirredução , Polietilenoglicóis , Humanos , Doxorrubicina/farmacologia , Doxorrubicina/química , Biotina/química , Polietilenoglicóis/química , Células HeLa , Propriedades de Superfície , Sistemas de Liberação de Medicamentos , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Tamanho da Partícula , Sobrevivência Celular/efeitos dos fármacos , Polímeros/química , Portadores de Fármacos/química
3.
Nanomedicine (Lond) ; 18(6): 555-576, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-37199287

RESUMO

Optical imaging modalities have emerged as a keystone in oncological research, capable of providing molecular and cellular information on cancer with the advantage of being minimally invasive toward healthy tissues. Photothermal therapy (PTT) has shown great potential, with the exceptional advantages of high specificity and noninvasiveness. Combining surface-enhanced Raman spectroscopy (SERS)-based optical imaging with PTT has shown tremendous potential in cancer theranostics (therapeutics + diagnosis). This comprehensive review article provides up-to-date information by exploring recent works focused mainly on the development of plasmonic nanoparticles for medical applications using SERS-guided PTT, including the fundamental principles behind SERS and the plasmon heating effect for PTT.


Assuntos
Nanopartículas Metálicas , Nanopartículas , Neoplasias , Humanos , Medicina de Precisão , Terapia Fototérmica , Análise Espectral Raman/métodos , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Nanopartículas/uso terapêutico , Nanopartículas Metálicas/uso terapêutico , Nanopartículas Metálicas/química , Ouro/química
4.
Biomater Adv ; 139: 213015, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35882161

RESUMO

Core-crosslinking of micelles (CCMs) appears to be a favorable strategy to enhance micellar stability and sustained release of the loaded drug. In this study, the DOX-conjugated pH-sensitive polymeric prodrug Methoxy Poly (ethylene oxide)-b-Poly (Aspartate-Hydrazide) (mPEG-P [Asp-(Hyd-DOX)] was created using ring-opening polymerization. To further enhance the micellar system, 3,3'-diselanediyldipropanoic acid (DSeDPA) was applied to link the hydrophobic segment via click reaction to form pH/redox-responsive CCMs. Dual anti-cancer drugs, DOX as a pro-drug and SN-38 as a targeting drug, were used to enhance inhibition. DLS confirmed that the non-cross-linked micelle (NCMs) showed a higher (96.43 nm) particle size compared to the CCMs (72.63 nm). Due to micellar shrinkage after crosslinking, CCMs displayed SN-38 drug loading (7.32 %) and encapsulation efficiency (86.23 %). The mPEG-P(Asp-Hyd) copolymer's in vitro cytotoxicity on HeLa and HaCaT cell lines found that 84.52 % of the cells are alive, and zebrafish (Danio rerio) embryos and larvae are highly biocompatible. The DOX/SN-38@CCMs had a sustained discharge profile in vitro, unlike the DOX/SN-38@NCMs. In DOX/SN-38@CCMs, HeLa cells were inhibited 50.90 % more than HaCaT (14.25 %) at the maximum drug dose (10 µg/mL). The CCMs successfully targeted and supplied DOX/SN-38 in HeLa cells rather than HaCaT cells, based on cellular uptake of 2D cell culture. CCMs, unlike NCMs, inhibit the growth of spheroids for extended periods of time due to the prolonged release of the loaded drug. Overall, CCMs are good-looking for use as regulated delivery of DOX/SN-38 in cancer cells because of all of these appealing characteristics.


Assuntos
Antineoplásicos , Neoplasias , Pró-Fármacos , Animais , Antineoplásicos/farmacologia , Sobrevivência Celular , Doxorrubicina/farmacologia , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Irinotecano/farmacologia , Micelas , Neoplasias/tratamento farmacológico , Oxirredução , Pró-Fármacos/farmacologia , Peixe-Zebra
5.
ACS Biomater Sci Eng ; 8(6): 2403-2418, 2022 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-35649177

RESUMO

The efficiency of chemotherapy is frequently affected by its multidrug resistance, immune suppression, and severe side effects. Its combination with immunotherapy to reverse immune suppression and enhance immunogenic cell death (ICD) has emerged as a new strategy to overcome the aforementioned issues. Herein, we construct a pH-responsive PAMAM dendritic nanocarrier-incorporated hydrogel for the co-delivery of immunochemotherapeutic drugs. The stepwise conjugation of moieties and drug load was confirmed by various techniques. In vitro experimental results demonstrated that PAMAM dendritic nanoparticles loaded with a combination of drugs exhibited spherical nanosized particles, facilitated the sustained release of drugs, enhanced cellular uptake, mitigated cell viability, and induced apoptosis. The incorporation of PAB-DOX/IND nanoparticles into thermosensitive hydrogels also revealed the formation of a gel state at a physiological temperature and further a robust sustained release of drugs at the tumor microenvironment. Local injection of this formulation into HeLa cell-grafted mice significantly suppressed tumor growth, induced immunogenic cell death-associated cytokines, reduced cancer cell proliferation, and triggered a CD8+ T-cell-mediated immune response without obvious systemic toxicity, which indicates a synergistic ICD effect and reverse of immunosuppression. Hence, the localized delivery of immunochemotherapeutic drugs by a PAMAM dendritic nanoparticle-incorporated hydrogel could provide a promising strategy to enhance antitumor activity in cancer therapy.


Assuntos
Hidrogéis , Nanopartículas , Animais , Preparações de Ação Retardada , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Células HeLa , Humanos , Imunidade , Morte Celular Imunogênica , Imunoterapia , Camundongos , Nanopartículas/uso terapêutico
6.
Anal Chim Acta ; 1199: 339567, 2022 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-35227379

RESUMO

Electrically conductive polymer nanomaterials signify a promising class of sensing platforms in the field of electrochemistry, but their applications as electrocatalysts are commonly limited by their poor colloidal stability in aqueous media and large particle sizes. Inspired by biomineralization approaches for integrating nanoscale materials, herein, a gadolinium (Gd)-integrated polypyrrole (PPy) electrocatalyst (namely, BSA@PPy-Gd) was successfully prepared by choosing bovine serum albumin (BSA) as a stabilizer for biomimetic mineralization and polymerization in a "one-step" manner. BSA@PPy-Gd possesses outstanding water dispersibility, nanoscale morphology, and improved electrical conductivity. The electrocatalytic competency of the electrochemical (EC) sensing platform fabricated for the sensitive detection of nicardipine (NCD) was assessed. The synergy of remarkable conductivity, superior active surface area, and electrostatic interactions stimulated by the combination of BSA with the NH group of PPy on BSA@PPy-Gd and Gd increases the fast electron transfer at the analyte-electrode junction. The fabricated EC sensor, BSA@PPy-Gd/glassy carbon electrode (GCE), exhibits a current intensity greater than that of PPy/GCE, BSA/GCE, and bare GCE in terms of peak height at a pH of 7.0 in phosphate buffer solution. The newly fabricated EC sensing platform shows excellent electrocatalytic activities for the electroreduction of NCD in terms of a low detection limit (2 nM), good sensitivity, linear dynamic detection ranges (0.01-575 µM), operational stability, and repeatability and was also tested on rat and human serum specimens.


Assuntos
Polímeros , Pirróis , Animais , Biomimética , Eletrodos , Gadolínio , Nicardipino , Ratos
7.
Colloids Surf B Biointerfaces ; 213: 112391, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35158218

RESUMO

Enhancement of drug efficacy is essential in cancer treatment. The immune stimulator ovalbumin (Ova)-coated citric acid (AC-)-stabilized iron oxide nanoparticles (AC-IO-Ova NPs) and enhanced permeability and retention (EPR)-based tumor targeted 4.5 generation poly(amidoamine) dendrimer(4.5GDP)-cisplatin (Cis-pt) nanocomplex (NC) (4.5GDP-Cis-pt NC) were used for enhanced anticancer efficiency. The formations of 4.5GDP-Cis-pt NC, AC-IO, and AC-IO-Ova NPs were examined via FTIR spectroscopy, X-ray diffraction, Raman spectroscopy, and X-ray photoelectron spectroscopy. The conjugation of Cis-pt with 4.5GDP was confirmed using carbon NMR spectroscopy. The tumor-specific 4.5GDP-Cis-pt NC provided 45%and 28% cumulative cisplatin release in 72 h at pH 6.5 and 7.4, respectively. A significant immune response with high TNF-α and IL-6 cytokine secretion was confirmed for the co-incubation of AC-IO-Ova with RAW 264.7 or HaCaT cells. AC-IO-Ova NPs were biocompatible with different cell lines, even at a high concentration (200 µg mL-1). However, AC-IO-Ova NPs mixed with 4.5GDP-Cis-pt NC (Cis-pt at 15 µg mL-1) significantly increased the cytotoxicity against the cancer cells in a dose-dependent manner with the increasing AC-IO-Ova NPs concentrations. The increased anticancer effects may be attributed to the generation of reactive oxygen species (ROS). Moreover, AC-IO-Ova NPs might assist the efficiency of anticancer cells, inducing an innate immune response via M1 macrophage polarization. We provide a novel synergistic chemoimmunotherapeutic strategy to enhance the anticancer efficacy of cisplatin via a chemotherapeutic agent 4.5GDP-Cis-pt NC and induce proinflammatory cytokines stimulating innate immunity through AC-IO-Ova NPs against tumors.


Assuntos
Dendrímeros , Nanopartículas , Neoplasias , Sobrevivência Celular , Cisplatino/farmacologia , Dendrímeros/farmacologia , Humanos , Nanopartículas Magnéticas de Óxido de Ferro , Nanopartículas/química , Neoplasias/terapia , Ovalbumina , Poliaminas
8.
Int J Biol Macromol ; 191: 324-334, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34530038

RESUMO

In humans, excessive bleeding during civilian accidents, and surgery account for 40% of the mortality worldwide. Hence, the development of biocompatible hemostatic materials useful for rapid hemorrhage control has become a fundamental research problem in the biomedicine community. In this study, we prepared biocompatible gelatin-tannic acid-κ-carrageenan (GTC) microparticles using a facile Tween 80 stabilized water-in-oil (W/O) emulsion method for rapid hemostasis. The formation of GTC microparticles occurs via polyelectrolyte interactions between gelatin and k-carrageenan as well as hydrogen bonding from tannic acid. In addition, the GTC microparticles formulated in our study showed high water adsorption ability with a low volume-swelling ratio for a particle size of 46 µm. In addition, the GTC microparticles displayed >80% biocompatibility in NIH 3T3 cells and <5% hemocompatibility in hemolysis ratio tests. Notably, the GTC microparticles induced rapid blood clotting in 50 s and blood loss of approximately 46 mg in the femoral artery of BALB/c female mice with a 100% survival rate that was significantly better than the control group (blood clot time:250 s; blood loss: 259 mg). Thus, the findings from our study collectively suggest that GTC microparticles may play a promising clinical role in medical applications to tackle hemorrhage control.


Assuntos
Carragenina/química , Gelatina/química , Hemostáticos/química , Polieletrólitos/química , Taninos/química , Animais , Reagentes de Ligações Cruzadas/química , Feminino , Hemorragia/tratamento farmacológico , Hemostáticos/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3
9.
J Mater Chem B ; 9(34): 6770-6801, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34350452

RESUMO

Selenium is capable of forming a dynamic covalent bond with itself and other elements and can undergo metathesis and regeneration reactions under optimum conditions. Its dynamic nature endows selenium-containing polymers with striking sensitivity towards some environmental alterations. In the past decade, several selenium-containing polymers were synthesized and used for the preparation of oxidation-, reduction-, and radiation-responsive nanocarriers. Recently, thioredoxin reductase, sonication, and osmotic pressure triggered the cleavage of Se-Se bonds and swelling or disassembly of nanostructures. Moreover, some selenium-containing nanocarriers form oxidation products such as seleninic acids and acrylates with inherent anticancer activities. Thus, selenium-containing polymers hold promise for the fabrication of ultrasensitive and multifunctional nanocarriers of radiotherapeutic, chemotherapeutic, and immunotherapeutic significance. Herein, we discuss the most recent developments in selenium-containing polymeric micelles in light of their architecture, multiple stimuli-responsive properties, emerging immunomodulatory activities, and future perspectives in the delivery and controlled release of anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Materiais Biocompatíveis/farmacologia , Desenvolvimento de Medicamentos , Fatores Imunológicos/farmacologia , Neoplasias/tratamento farmacológico , Polímeros/farmacologia , Selênio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Liberação Controlada de Fármacos , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Teste de Materiais , Micelas , Tamanho da Partícula , Polímeros/síntese química , Polímeros/química , Selênio/química
10.
Polymers (Basel) ; 13(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072354

RESUMO

Fucoidan is an abundant marine sulfated polysaccharide extracted from the cell wall of brown macroalgae (seaweed). Recently, fucoidan has been highly involved in various industrial applications, such as pharmaceuticals, biomedicals, cosmetics, and food. However, the presence of a sulfate group (negative surface charge) in the fucoidan structure limits its potential and biological activity for use in biomedical applications during cellular uptake. Thus, we aimed to improve the uptake of fucoidan by using an L-arginine uptake enhancer within an in vitro study. A Fucoidan-L-Arginine (Fuc-L-Arg) fiber complex was prepared via α-helical electrostatic interactions using a freeze-drying technique and confirmed using field-emission scanning electron microscopy, Fourier transform infrared spectroscopy, and nuclear magnetic resonance spectroscopy. In addition, fucoidan was conjugated with cyanine 3 (Cy3) dye to track its cellular uptake. Furthermore, the results of Fuc-L-Arg (1:1, 1:2.5) complexes revealed biocompatibility >80% at various concentrations (5, 10, 25, 50, 100 µg/mL). Owing to the higher internalization of the Fuc-L-Arg (1:5) complex, it exhibited <80% biocompatibility at higher concentrations (25, 50, 100 µg/mL) of the complex. In addition, improved cellular internalization of Fuc-L-Arg complexes (1:5) in HeLa cells have been proved via flow cytometry quantitative analysis. Hence, we highlight that the Fuc-L-Arg (1:5) fiber complex can act as an excellent biocomplex to exhibit potential bioactivities, such as targeting cancers, as fucoidan shows higher permeability in HeLa cells.

11.
Mater Sci Eng C Mater Biol Appl ; 120: 111704, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33545863

RESUMO

A novel thioether-terminated triazole bridge-containing covalent organic framework (TCOF) was constructed via a simple click chemistry between alkyne and azide monomers for dual-sensitive [pH and glutathione (GSH)] anticancer drug delivery systems. The synthesized TCOFs were crystalline in nature with a pore size of approximately 10-30 nm, as confirmed by powder X-ray diffraction spectroscopy and Brunauer-Emmett-Teller technique. Owing to the flexible nature of the synthesized COF, polyethylene glycol (PEG) modification was easily performed to yield a stable TCOF (TCOF-PEG) colloidal solution. Doxorubicin (DOX)-loaded TCOF-PEG (TCOF-DOX-PEG) exhibited sensitivity to lysosomal pH 5 and GSH environments. DOX release was four times higher under GSH environment (relative to pH 7.4) and three times higher under pH 5 condition because of the dynamic nature of triazole. In contrast, DOX-loaded COF without the triazole ring (I-COF) did not show any significant drug release in pH 7.4 and acidic pH; however, drug release was observed in GSH environment. MTT drug internalization data demonstrated sustained release of DOX from TCOF-DOX-PEGs. Finally, we demonstrated the utility of TCOF-PEG as an in vitro drug delivery system in HeLa cells. TCOF-DOX-PEG exhibited time-dependent release of DOX followed by internalization. Thus, the novel TCOF system reported here opens a new window in COF research for sensitive drug carrier systems.


Assuntos
Estruturas Metalorgânicas , Doxorrubicina , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Polietilenoglicóis , Sulfetos , Triazóis
12.
Mikrochim Acta ; 188(2): 35, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420619

RESUMO

Two-dimensional (2D) MoS2core-shell nanoparticles were synthesized using an eco-friendly surface functionalization-agent with L-glutathione and cystamine (L-GSH-MoS2-CYS) using ultrasonic frequency of 20-25 kHz. The novel modified electrode was evaluated for the electrochemical detection of doxorubicin (DOX), through cyclic and differential pulse voltammetric techniques. The electro-catalytic oxidation currents of DOX exhibited a linear relationship in the concentration ranges 0.1-78.3 and 98.3-1218 µM, with a detection limit of 31 nM. A sensitivity of 0.017µA µM-1 cm-2 was acquired at 0.48 V. The fabricated L-GSH-MoS2-CYS modified electrode showed excellent precision, selectivity, repeatability, and reproducibility during the determination of DOX levels in blood serum samples. Thus, the fabricated L-GSH-MoS2-CYS/GCE modified electrode has potential for clinical applications for optimization of chemotherapeutic drugs owing to its selectivity, ease of preparation, and long-term stability. Graphical abstract.


Assuntos
Cistamina/química , Dissulfetos/química , Doxorrubicina/sangue , Glutationa/química , Nanopartículas Metálicas/química , Molibdênio/química , Carbono/química , Doxorrubicina/química , Técnicas Eletroquímicas/instrumentação , Técnicas Eletroquímicas/métodos , Eletrodos , Humanos , Limite de Detecção , Oxirredução , Reprodutibilidade dos Testes
13.
Biotechnol Bioeng ; 118(3): 1213-1223, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33289076

RESUMO

In this study, we prepared ferulic acid (FA) and paclitaxel (PTX) co-loaded polyamidoamine (PAMAM) dendrimers conjugated with arginyl-glycyl-aspartic acid (RGD) to overcome P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). FA was released in greater extent (80%) from the outer layer of the dendrimers compared with PTX (70%) from the interior of the dendrimers. FA improved intracellular availability of PTX via P-gp modulation in drug-resistant cells. In vitro drug uptake data show higher PTX delivery with RGD-PAMAM-FP than with PAMAM-FP in drug resistant KB CH-R 8-5 cell lines. This indicates that RGD facilitates intracellular PTX accumulation through active targeting in multidrug-resistant KB CH-R 8-5 cells. The terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick-end labeling assay data and membrane potential analysis in mitochondria confirm the enhanced anticancer potential of RGD-PAMAM-FP nanoaggregates in drug-resistant cells. We also confirmed by the increased protein levels of proapoptotic factors such as caspase 3, caspase 9, p53, and Bax after treatment with RGD-PAMAM-FP nanoaggregates and also downregulates antiapoptotic factors. Hence, FA-PTX co-loaded, RGD-functionalized PAMAM G4.5 dendrimers may be considered as an effective therapeutic strategy to induce apoptosis in P-gp-overexpressing, multidrug-resistant cells.


Assuntos
Ácidos Cumáricos , Dendrímeros , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Neoplasias , Paclitaxel , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacologia , Dendrímeros/química , Dendrímeros/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Paclitaxel/química , Paclitaxel/farmacologia
14.
Int J Mol Sci ; 22(1)2020 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-33375720

RESUMO

Development of stimuli-responsive supramolecular micelles that enable high levels of well-controlled drug release in cancer cells remains a grand challenge. Here, we encapsulated the antitumor drug doxorubicin (DOX) and pro-photosensitizer 5-aminolevulinic acid (5-ALA) within adenine-functionalized supramolecular micelles (A-PPG), in order to achieve effective drug delivery combined with photo-chemotherapy. The resulting DOX/5-ALA-loaded micelles exhibited excellent light and pH-responsive behavior in aqueous solution and high drug-entrapment stability in serum-rich media. A short duration (1-2 min) of laser irradiation with visible light induced the dissociation of the DOX/5-ALA complexes within the micelles, which disrupted micellular stability and resulted in rapid, immediate release of the physically entrapped drug from the micelles. In addition, in vitro assays of cellular reactive oxygen species generation and cellular internalization confirmed the drug-loaded micelles exhibited significantly enhanced cellular uptake after visible light irradiation, and that the light-triggered disassembly of micellar structures rapidly increased the production of reactive oxygen species within the cells. Importantly, flow cytometric analysis demonstrated that laser irradiation of cancer cells incubated with DOX/5-ALA-loaded A-PPG micelles effectively induced apoptotic cell death via endocytosis. Thus, this newly developed supramolecular system may offer a potential route towards improving the efficacy of synergistic chemotherapeutic approaches for cancer.


Assuntos
Antineoplásicos/administração & dosagem , Preparações de Ação Retardada/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Luz , Micelas , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos da radiação , Células HeLa , Humanos , Fotoquimioterapia , Fármacos Fotossensibilizantes , Espécies Reativas de Oxigênio/metabolismo
15.
Pharmaceutics ; 12(11)2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33182410

RESUMO

Maximizing the antitumor efficacy of doxorubicin (DOX) with a new drug delivery strategy is always desired in the field of biomedical science. Because the clinical applications of DOX in the treatment of cancer is limited by the side effects related to the dose. Herein, we report the co-loading of DOX and resveratrol (RESV) using an injectable in situ formed sodium deoxycholate hydrogel (Na-DOC-hyd) at the pH of the tumor extracellular microenvironment. The sequential, controlled, and sustained release of RESV and DOX for synergistic antitumor effects was confirmed by entrapping G4.5-DOX in the RESV-loaded Na-DOC hydrogel (Na-DOC-hyd-RESV). The synergistic antitumor activity of Na-DOC-hyd-RESV+G4.5-DOX was assessed on HeLa cell xenograft tumor in BALB/c nude mice. In the MTT biocompatibility assay, both the G4.5 PAMAM dendrimer and Na-DOC-hyd exhibited negligible cytotoxicity up to the highest dose of 2.0 mg mL-1 in HeLa, MDA-MB-231, and HaCaT cells. The release profiles of DOX and RESV from the Na-DOC-hyd-RESV+G4.5-DOX confirmed the relatively rapid release of RESV (70.43 ± 1.39%), followed by that of DOX (54.58 ± 0.62%) at pH 6.5 in the 7 days of drug release studies. A single intratumoral injection of Na-DOC-hyd-RESV+G4.5-DOX maximally suppressed tumor growth during the 28 days of the treatment period. Na-DOC-hyd-RESV+G4.5-DOX did not cause any histological damage in the major visceral organs. Therefore, this Na-DOC-hydrogel for dual drugs (DOX and RESV) delivery at the pH of the tumor extracellular microenvironment is a promising, safe, and effective combination for antitumor chemotherapy.

16.
Macromol Biosci ; 20(12): e2000233, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32869957

RESUMO

Functional supramolecular micelles containing self-complementary multiple hydrogen bonding adenine groups (A-PPG) can spontaneously self-assemble into stable nanosized micelles in aqueous solution. These micelles can be used to selectively deliver anticancer drugs to cancer cells and effectively promote tumor cell death via apoptosis, without harming normal cells. The drug-loaded micelles exhibit tunable drug-loading capacity and rapid pH-triggered drug release under acidic conditions, as well as a high drug-entrapment stability in serum-rich media due to the reversible hydrogen-bonded adenine-adenine interactions within the micellar interior; these properties are critical to achieving effective chemotherapeutic drug delivery and controlled drug release. In vitro assays show that the drug-loaded micelles exert significant cytotoxic effects on cancer cells, with minimal effects on normal cells under physiological conditions. Cytotoxicity assays using A-PPG micelles loaded with different anticancer drugs confirm these effects. Importantly, cellular internalization and flow cytometric analyses demonstrate that the adenine moieties within A-PPG micelles significantly increase selective endocytic uptake of the supramolecular micelles by cancer cells, which in turn induce apoptotic cell death and substantially enhance the response to chemotherapy. Thus, A-PPG micelles can improve the safety and efficacy of cancer chemotherapy.


Assuntos
Adenina/química , Preparações de Ação Retardada , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Adenina/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Liberação Controlada de Fármacos , Humanos , Micelas , Polímeros/química , Polímeros/farmacologia
17.
Anal Chim Acta ; 1125: 210-219, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32674768

RESUMO

Electroactive polypyrrole-molybdenum disulfide (MoP) nanocomposites were synthesized and used for modifying screen-printed carbon electrodes (SPCEs) for ultrasensitive detection of berberine, an anticancer drug, in rat plasma. The electroactive nanocomposites were fabricated by exfoliating MoS2 followed by pyrrole polymerization. The effect of polypyrrole in the MoP nanocomposite was evaluated by varying the pyrrole concentration during polymerization, and the resulting nanocomposites prepared with pyrrole concentrations of 10, 20, 30 µL were named as MoP-1, MoP-2, and MoP-3, respectively. The electrochemical characterization of the three MoP nanocomposite sensors revealed that MoP-2/SPCE exhibited the highest electroactivity. The detection of berberine by the three MoP-coated SPCEs revealed that MoP-2/SPCE exhibited the highest activity against berberine due to a two-electron transfer mechanism on the MoP-2/SPCE electrode surface. The detection limit of berberine using the MoP-2/SPCE sensor was found to be about 0.05 µM, which is remarkably lower than the reported detection limits. The interference study proved the selectivity of the MoP-2/SPCE sensor toward berberine in the presence of other bioactive molecules and metal ions. The designed MoP-2/SPCE sensor retained 92% of its initial activity after 15 days of storage at room temperature, with RSD values of about 2.95% and 3.68% for the repeatability and reproducibility studies. Finally, the detection limit of berberine in a rat plasma sample determined using the MoP-2/SPCE sensor was found to be about 5 µM.


Assuntos
Berberina/sangue , Dissulfetos/química , Molibdênio/química , Nanocompostos/química , Polímeros/química , Pirróis/química , Animais , Carbono/química , Técnicas Eletroquímicas/instrumentação , Técnicas Eletroquímicas/métodos , Eletrodos , Limite de Detecção , Ratos
18.
Pharmaceutics ; 12(6)2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32585885

RESUMO

Polymeric micelles (PMs) have been used to improve the poor aqueous solubility, slow absorption and non-selective biodistribution of chemotherapeutic agents (CAs), albeit, they suffer from disassembly and premature release of payloads in the bloodstream. To alleviate the thermodynamic instability of PMs, different core crosslinking approaches were employed. Herein, we synthesized the poly(ethylene oxide)-b-poly((2-aminoethyl)diselanyl)ethyl l-aspartamide)-b-polycaprolactone (mPEG-P(LA-DSeDEA)-PCL) copolymer which self-assembled into monodispersed nanoscale, 156.57 ± 4.42 nm, core crosslinked micelles (CCMs) through visible light-induced diselenide metathesis reaction between the pendant selenocystamine moieties. The CCMs demonstrated desirable doxorubicin (DOX)-loading content (7.31%) and encapsulation efficiency (42.73%). Both blank and DOX-loaded CCMs (DOX@CCMs) established appreciable colloidal stability in the presence of bovine serum albumin (BSA). The DOX@CCMs showed redox-responsive drug releasing behavior when treated with 5 and 10 mM reduced glutathione (GSH) and 0.1% H2O2. Unlike the DOX-loaded non-crosslinked micelles (DOX@NCMs) which exhibited initial burst release, DOX@CCMs demonstrated a sustained release profile in vitro where 71.7% of the encapsulated DOX was released within 72 h. In addition, the in vitro fluorescent microscope images and flow cytometry analysis confirmed the efficient cellular internalization of DOX@CCMs. The in vitro cytotoxicity test on HaCaT, MDCK, and HeLa cell lines reiterated the cytocompatibility (≥82% cell viability) of the mPEG-P(LA-DSeDEA)-PCL copolymer and DOX@CCMs selectively inhibit the viabilities of 48.85% of HeLa cells as compared to 15.75% of HaCaT and 7.85% of MDCK cells at a maximum dose of 10 µg/mL. Overall, all these appealing attributes make CCMs desirable as nanocarriers for the delivery and controlled release of DOX in tumor cells.

19.
Pharmaceutics ; 12(5)2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32403321

RESUMO

Biotin receptors are overexpressed by various types of solid cancer cells and play a significant role in tumor metabolism, growth, and metastasis. Thus, targeting the biotin receptors on tumor cells may enhance the efficiency and reduce the side-effects of chemotherapy. The aim of this study was to develop a biotin-coupled poly(amido)amine (PAMAM) (PG4.5) dendrimer nanoparticle to enhance the tumor-specific delivery and intracellular uptake of anticancer drugs via receptor-mediated endocytosis. We modified PG4.5 with diethylenetriamine (DETA) followed by biotin via an amide bond and characterized the resulting PG4.5-DETA-biotin nanoparticles by 1H NMR, FTIR, and Raman spectroscopy. Loading and releasing of gemcitabine (GEM) from PG4.5-DETA-biotin were evaluated by UV-Visible spectrophotometry. Cell viability and cellular uptake were examined by MTT assay and flow cytometry to assess the biocompatibility, cellular internalization efficiency and antiproliferative activity of PG4.5-DETA-biotin/GEM. Gemcitabine-loaded PG4.5-DETA-biotin nanoparticles were spherical with a particle size of 81.6 ± 6.08 nm and zeta potential of 0.47 ± 1.25 mV. Maximum drug-loading content and encapsulation efficiency were 10.84 ± 0.16% and 47.01 ± 0.71%, respectively. Nearly 60.54 ± 1.99% and 73.96 ± 1.14% of gemcitabine was released from PG4.5-DETA-biotin/GEM nanoparticles after 48 h at the acidic pH values of 6.5 and 5, respectively. Flow cytometry and fluorescence microscopy of cellular uptake results revealed PG4.5-DETA-biotin/GEM nanoparticles selectively targeted cancer cells in vitro. Cytotoxicity assays demonstrated gemcitabine-loaded PG4.5-DETA-biotin significantly reduced cell viability and induced apoptosis in HeLa cells. Thus, biotin-coupled PG4.5-DETA nanocarrier could provide an effective, targeted drug delivery system and selectively convey gemcitabine into tumor cells.

20.
Mater Sci Eng C Mater Biol Appl ; 106: 110245, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31753357

RESUMO

The recent discovery of small interfering RNAs (siRNAs) has opened new avenues for designing personalized treatment options for various diseases. However, the therapeutic application of siRNAs has been confronted with many challenges because of short half-life in circulation, poor membrane penetration, difficulty in escaping from endosomes, and insufficient release into the cytosol. To overcome these challenges, we designed a diethylenetriamine (DETA)- and tetraethylenepentamine (TEPA)-modified polyamidoamine dendrimer generation 4.5 (PDG4.5), and characterized it using 1H nuclear magnetic resonance (NMR), 13C NMR, correlation spectroscopy (COSY), heteronuclear single-quantum correlation spectroscopy (HSQC), and Fourier transform infrared (FTIR) spectroscopy followed by conjugation with siRNA. The PDG4.5-DETA and PDG4.5-TEPA polyplexes exhibited spherical nanosize, ideal zeta potential, and effective siRNA binding ability, protected the siRNA from nuclease attack, and revealed less cytotoxicity of PDG4.5-DETA and PDG4.5-TEPA in HeLa cells. More importantly, the polyplexes also revealed good cellular internalization and facilitated translocation of the siRNA into the cytosol. Thus, PDG4.5-DETA and PDG4.5-TEPA can act as potential siRNA carriers in future medical and pharmaceutical applications.


Assuntos
Dendrímeros/química , Etilenodiaminas/química , Nylons/química , Poliaminas/química , RNA Interferente Pequeno/química , Portadores de Fármacos/química , Células HeLa , Humanos , Espectroscopia de Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA