RESUMO
BACKGROUND: The purpose of this study was to investigate the protective effect of Silibinin-loaded polymeric micelles from human hair against UV-B radiation. METHODS: Eight formulations with different concentrations of Silibinin, Pluronic F-127, and Labrasol-Labrafil were made by a solvent evaporation method, and the selected formulation was chosen by examining their properties like particle size and loading efficiency. Six groups of human hair, including a group that received the selected formulation, were exposed to UV-B radiation and by calculating its factors such as peak-to-valley roughness, RMS roughness, FTIR, and the amount of protein loss, the protective effect of the selected formulation was judged. RESULTS: According to the results, the loading efficiency and particle size of the selected formulation were 45.34% and 43.19 nm. The Silibinin release profile had two parts, fast and slow, which were suitable for creating a drug depot on hair. Its zeta potential also confirmed the minimum electrostatic interference between the formulation and hair surface. The zeta potential of selected formulation was -5.9 mv. Examination of AFM images showed that the selected formulation was able to prevent the increase in peak-to-valley roughness and RMS roughness caused by UV-B radiation. RMS roughness after 600 h of UV radiation in Groups 5 and 6 was significantly lower than the negative control group and the amount of this factor did not differ significantly between 0 and 600, so it can be concluded that the selected formulation containing Silibinin and the positive control group was able to prevent the increase of RMS roughness and hair destruction. In other hands, the two positive control groups and the selected formulation containing Silibinin were able to effectively reduce hair protein loss. CONCLUSION: Silibinin-loaded polymeric micelles were able to effectively protect hair from structural and chemical changes caused by UV-B radiation.
Assuntos
Cabelo , Micelas , Tamanho da Partícula , Silibina , Raios Ultravioleta , Humanos , Raios Ultravioleta/efeitos adversos , Silibina/farmacologia , Silibina/administração & dosagem , Silibina/química , Cabelo/efeitos dos fármacos , Cabelo/efeitos da radiação , Silimarina/farmacologia , Silimarina/administração & dosagem , Silimarina/química , Polímeros/química , Liberação Controlada de Fármacos/efeitos da radiação , Antioxidantes/farmacologia , Antioxidantes/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/efeitos da radiaçãoRESUMO
Hypericin (Hy) is a hydrophobic photosensitizer used in photodynamic therapy for cancer therapeutic. In this study, Hy-loaded oil-in-water (O/W) nanoemulsions (NEs) were produced by the ultrasonication method combing different biocompatible oils and surfactants to enhance Hy aqueous solubility and bioavailability. Experimental parameters were optimized by the characterization of droplet size, zeta potential, and physicochemical properties. In vitro studies based on the release profile, cytotoxicity, cell morphology, and Hy intracellular accumulation were assayed. Hy at 100 mg L-1 was incorporated into the low viscosity (~0.005 Pa s) NEs with spherical droplets averaging 20-40 nm in size and polydispersity index <0.02. Hy release from the NE was significantly higher (4-fold) than its suspension (p < 0.001). The NEs demonstrated good physical stability during storage at 5 °C for at least six months. The Hy-loaded NEs exhibited an IC50 value 6-fold lower than Hy suspension during PDT against breast cancer cell lines (MCF-7). Cell microscopy imaging confirmed the increased cytotoxic effects of Hy-loaded NEs, showing damaged and apoptotic cells. Confocal laser scanning microscopy evidenced greater Hy delivery through NE into MCF-7 cells followed by improved intracellular ROS generation. Our results suggest that the Hy-loaded NEs can improve hypericin efficacy and assist Hy-PDT's preclinical development as a cancer treatment.
Assuntos
Antracenos/química , Emulsões/química , Nanoestruturas/química , Perileno/análogos & derivados , Fotoquimioterapia/métodos , Radiossensibilizantes/química , Antracenos/metabolismo , Antracenos/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos/efeitos da radiação , Estabilidade de Medicamentos , Humanos , Luz , Células MCF-7 , Óleos/química , Perileno/química , Perileno/metabolismo , Perileno/farmacologia , Radiossensibilizantes/metabolismo , Radiossensibilizantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sonicação , Temperatura , Água/químicaRESUMO
Retinoblastoma is one of the most severe ocular diseases, of which current chemotherapy is limited to the repetitive intravitreal injections of chemotherapeutics. Systemic drug administration is a less invasive route; however, it is also less efficient for ocular drug delivery because of the existence of blood-retinal barrier and systemic side effects. Here, a photoresponsive drug release system is reported, which is self-assembled from photocleavable trigonal small molecules, to achieve light-triggered intraocular drug accumulation. After intravenous injection of drug-loaded nanocarriers, green light can trigger the disassembly of the nanocarriers in retinal blood vessels, which leads to intraocular drug release and accumulation to suppress retinoblastoma growth. This proof-of-concept study would advance the development of light-triggered drug release systems for the intravenous treatment of eye diseases.
Assuntos
Portadores de Fármacos/farmacologia , Liberação Controlada de Fármacos/efeitos dos fármacos , Retina/efeitos dos fármacos , Retinoblastoma/tratamento farmacológico , Administração Intravenosa , Animais , Humor Aquoso/efeitos da radiação , Barreira Hematorretiniana/efeitos dos fármacos , Modelos Animais de Doenças , Portadores de Fármacos/química , Liberação Controlada de Fármacos/efeitos da radiação , Humanos , Lentes Intraoculares , Luz , Camundongos , Retina/patologia , Retina/efeitos da radiação , Retinoblastoma/genética , Retinoblastoma/patologia , Topotecan/química , Topotecan/farmacologia , Corpo Vítreo/efeitos dos fármacos , Corpo Vítreo/efeitos da radiaçãoRESUMO
Polydopamine (PDA) nanoparticles (NPs) have recently acquired considerable attention for the development of nanoplatforms with multifunctional properties including photothermal (PTT) and photodynamic (PDT) activities. In addition to their high PTT performance, they can be easily conjugated to different types of photosensitizers (PSs) to acquire PDT activity. However, because of PDA free-radical scavenging properties, grafting the PSs directly to PDA surfaces may lead to an inefficient PDT outcome. Thus, the present work aims at synthesizing and characterizing a new PEGylated PDA-based nanoplatform with bifunctional PTT and PDT properties, which allows bimodal cancer therapy with the possibility to release the PS on demand in a spatiotemporal fashion. To do so, PDA NPs with a well-defined size and shape were prepared by the auto-oxidative self-polymerization process of dopamine hydrochloride in mild alkaline solution. The impact of the size on the PTT conversion efficiency was then determined. This allowed us to choose the optimal PDA NP size for PTT applications. Next, PDA NPs were decorated with SH-PEG polymers that bear at their extremity a thioketal reactive oxygen species-cleavable linker coupled to trisulfonated-tetraphenylporphyrin (TPPS3) chosen as a hydrophilic PS. The grafting efficiency of PS-conjugated PEG on PDA was demonstrated in situ using a quartz crystal microbalance with dissipation monitoring. In addition, the photoinduced release of the PS was demonstrated by 1H NMR. Finally, PTT/PDT bimodal therapy was assessed in vitro on human squamous esophageal cells by illuminating the PDA NPs at two different wavelengths, which showed the strong synergistic effect of combining PTT and PDT within this nanoplatform.
Assuntos
Sistemas de Liberação de Fármacos por Nanopartículas/química , Neoplasias/terapia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Terapia Fototérmica/métodos , Animais , Linhagem Celular Tumoral , Liberação Controlada de Fármacos/efeitos da radiação , Ensaios de Seleção de Medicamentos Antitumorais , Difusão Dinâmica da Luz , Humanos , Indóis/química , Luz , Neoplasias/patologia , Polietilenoglicóis/química , Polímeros/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
This article describes the synthesis and characterization of ß-cyclodextrin-based nano-sponges (NS) inclusion compounds (IC) with the anti-tumor drugs melphalan (MPH) and cytoxan (CYT), and the addition of gold nanoparticles (AuNPs) onto both systems, for the potential release of the drugs by means of laser irradiation. The NS-MPH and NS-CYT inclusion compounds were characterized using scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), energy dispersive spectroscopy (EDS), thermogravimetric analysis (TGA), UV-Vis, and proton nuclear magnetic resonance (1H-NMR). Thus, the inclusion of MPH and CYT inside the cavities of NSs was confirmed. The association of AuNPs with the ICs was confirmed by SEM, EDS, TEM, and UV-Vis. Drug release studies using NSs synthesized with different molar ratios of ß-cyclodextrin and diphenylcarbonate (1:4 and 1:8) demonstrated that the ability of NSs to entrap and release the drug molecules depends on the crosslinking between the cyclodextrin monomers. Finally, irradiation assays using a continuous laser of 532 nm showed that photothermal drug release of both MPH and CYT from the cavities of NSs via plasmonic heating of AuNPs is possible.
Assuntos
Ciclodextrinas , Ciclofosfamida/administração & dosagem , Portadores de Fármacos , Ouro , Melfalan/administração & dosagem , Nanopartículas Metálicas , Técnicas de Química Sintética , Ciclodextrinas/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos/efeitos da radiação , Ouro/química , Luz , Espectroscopia de Ressonância Magnética , Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , Temperatura , Termogravimetria , Tocoferóis , Difração de Raios XRESUMO
Herein, we demonstrate a novel UV-induced decomposable nanocapsule of natural polysaccharide (HA-azo/PDADMAC). The nanocapsules are fabricated based on layer-by-layer co-assembly of anionic azobenzene functionalized hyaluronic acid (HA-azo) and cationic poly diallyl dimethylammonium chloride (PDADMAC). When the nanocapsules are exposed to 365 nm light, ultraviolet photons can trigger the photo-isomerization of azobenzene groups in the framework. The nanocapsules could decompose from large-sized nanocapsules to small fragments. Due to their optimized original size (~180 nm), the nanocapsules can effectively avoid biological barriers, provide a long blood circulation and achieve high tumor accumulation. It can fast eliminate nanocapsules from tumor and release the loaded drugs for chemotherapy after UV-induced dissociation. Besides, HA is an endogenous polysaccharide that shows intrinsic targetability to CD44 receptors on surface of cancer cells. The intracellular experiment shows that the HA-azo/PDADMAC nanocapsules with CD44 targeting ability and UV-controlled intracellular drug release are promising for cancer chemotherapy.
Assuntos
Compostos Azo/química , Portadores de Fármacos/química , Ácido Hialurônico/química , Nanocápsulas/química , Antineoplásicos/química , Compostos Azo/metabolismo , Compostos Azo/efeitos da radiação , Compostos Azo/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Portadores de Fármacos/metabolismo , Portadores de Fármacos/efeitos da radiação , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos/efeitos da radiação , Endocitose/fisiologia , Células Hep G2 , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/síntese química , Ácido Hialurônico/metabolismo , Ácido Hialurônico/toxicidade , Nanocápsulas/efeitos da radiação , Nanocápsulas/toxicidade , Nanopartículas/química , Nanopartículas/metabolismo , Nanopartículas/toxicidade , Polietilenos/química , Polietilenos/toxicidade , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/toxicidade , Dióxido de Silício/síntese química , Dióxido de Silício/química , Dióxido de Silício/toxicidade , Estereoisomerismo , Raios UltravioletaRESUMO
Rationale: Integration of several monotherapies into a single nanosystem can produce remarkable synergistic antitumor effects compared with separate delivery of combination therapies. We developed near-infrared (NIR) light-triggered nanoparticles that induce a domino effect for multimodal tumor therapy. Methods: The designed intelligent phototriggered nanoparticles (IPNs) were composed of a copper sulfide-loaded upconversion nanoparticle core, a thermosensitive and photosensitive enaminitrile molecule (EM) organogel shell loaded with anticancer drugs, and a cancer cell membrane coating. Irradiation with an NIR laser activated a domino effect beginning with photothermal generation by copper sulfide for photothermal therapy that also resulted in phase transformation of the EM gel to release the anticancer drug. Meanwhile, the NIR light energy was converted to ultraviolet light by the upconversion core to excite the EM, which generated reactive oxygen species for photodynamic therapy. Results: IPNs achieved excellent antitumor effects in vitro and in vivo with little systemic toxicity, indicating that IPNs could serve as a safe and high-performance instrument for synergetic antitumor therapy. Conclusion: This intelligent drug delivery system induced a chain reaction generating multiple antitumor therapies after a single stimulus.
Assuntos
Antineoplásicos/administração & dosagem , Liberação Controlada de Fármacos/efeitos da radiação , Nanopartículas/uso terapêutico , Neoplasias/terapia , Fotoquimioterapia , Animais , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Carbocianinas/administração & dosagem , Terapia Combinada , Cobre , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Feminino , Compostos Heterocíclicos com 2 Anéis/efeitos da radiação , Humanos , Lasers , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/efeitos da radiação , Nanopartículas/toxicidade , Nitrilas/efeitos da radiação , Espécies Reativas de Oxigênio , Dióxido de Silício , Organismos Livres de Patógenos Específicos , Sulfetos , Distribuição Tecidual , Raios Ultravioleta , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Gemcitabine and nab-paclitaxel (Abraxane®) is a standard of care chemotherapy combination used in the treatment of patients with advanced pancreatic cancer. While the combination has shown a survival benefit when compared to gemcitabine monotherapy, it is associated with significant off-target toxicity. Ultrasound targeted microbubble destruction (UTMD) has emerged as an effective strategy for the site-specific deposition of drug-payloads. However, loading a single microbubble formulation with two drug payloads can be challenging and often involves several manipulations post-microbubble preparation that can be cumbersome and generally results in low / inconsistent drug loadings. In this manuscript, we report the one-pot synthesis of a gemcitabine functionalised phospholipid and use it to successfully generate stable microbubble formulations loaded with gemcitabine (Lipid-Gem MB) or a combination of gemcitabine and paclitaxel (Lipid-Gem-PTX MB). Efficacy of the Lipid-Gem MB and Lipid-Gem-PTX MB formulations, following ultrasound (US) stimulation, was evaluated in a three-dimensional (3D) PANC-1 spheroid model of pancreatic cancer and a mouse model bearing ectopic BxPC-3 tumours. The results demonstrated a significant reduction in the cell viability in spheroids for both formulations reducing from 90 ± 10% to 62 ± 5% for Lipid-Gem MB and 84 ± 10% to 30 ± 6% Lipid-Gem-PTX MB following US irradiation. When compared with a clinically relevant dose of free gemcitabine and paclitaxel (i.e. non-particle bound) in a BxPC-3 murine pancreatic tumour model, both formulations also improved tumour growth delay with tumours 40 ± 20% and 40 ± 30% smaller than the respective free drug formulation when treated with Lipid-Gem MB and Lipid-Gem-PTX MB respectively, at the conclusion of the experiment. These results highlight the potential of UTMD mediated Gem / PTX as a treatment for pancreatic cancer and the facile preparation of Lipid-Gem-PTX MBs using a gemcitabine functionalised lipid should expedite clinical translation of this technology.
Assuntos
Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxicitidina/análogos & derivados , Portadores de Fármacos/efeitos da radiação , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Albuminas/farmacocinética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Linhagem Celular Tumoral , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacocinética , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos da radiação , Feminino , Humanos , Masculino , Camundongos , Microbolhas , Nanopartículas/química , Nanopartículas/efeitos da radiação , Paclitaxel/farmacocinética , Neoplasias Pancreáticas/patologia , Fosfolipídeos/química , Ondas Ultrassônicas , Ensaios Antitumorais Modelo de Xenoenxerto , GencitabinaRESUMO
In this project, we studied the thermal and chemical method for the synthesis of carbon dots (CDs)/Hematite (α-Fe2O3) quantum dots and the preparation of hydroxypropyl cellulose cross-linked chitosan (HPCCS) and ulvan (UN) was performed by chemical method. Carbon dots/α-Fe2O3 quantum dots with size distribution of 3-5 nm were completely encapsulated in the HPCCS/UN NPs to obtain composites, which indicated unique characteristics with respect to antimicrobial, pH-responsive and optical properties. The CDs-HQDs/HPCCS/UN nanocomposites exhibited a single-excitation (440 nm), dual-emission fluorescence property (505 nm and 628 nm for green and red light from CDs-HQDs and HPCCS/UN NPs). The nanocomposites played as a pH-responsive drug delivery process to release ulvan at a fast rate in pH 7.4 buffer solution but at a slow rate in low pH solutions. The CDs-HQDs/HPCCS/UN nanocomposites gained the highest photocatalytic activity for degrading 4-chlorophenol (4-CPh) as a pollutant (>98% during 70 min under sunlight irradiation). Moreover, the nanocomposites indicated great inhibitory influences towards bacterial and fungal.
Assuntos
Anti-Infecciosos/química , Celulose/análogos & derivados , Quitosana/química , Nanocompostos/química , Pontos Quânticos/química , Luz Solar , Anti-Infecciosos/farmacologia , Carbono/química , Catálise , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Celulose/química , Clorofenóis/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos/efeitos da radiação , Escherichia coli/efeitos dos fármacos , Compostos Férricos/química , Humanos , Concentração de Íons de Hidrogênio , Nanocompostos/toxicidade , Staphylococcus aureus/efeitos dos fármacos , Poluentes Químicos da Água/químicaRESUMO
Carbon monoxide (CO) is an important gaseous signaling molecule. The use of CO-releasing molecules such as metal carbonyls enables the elucidation of the pleiotropic functions of CO. Although metal carbonyls show a broad-spectrum antimicrobial activity, it remains unclear whether the bactericidal property originates from the transition metals or the released CO. Here, we develop nonmetallic CO-releasing micelles via a photooxygenation mechanism of 3-hydroxyflavone derivatives, enabling CO release under red light irradiation (e.g., 650â nm). Unlike metal carbonyls that non-specifically internalize into both Gram-positive and Gram-negative bacteria, the nonmetallic micelles are selectively taken up by S. aureus instead of E. coli cells, exerting a selective bactericidal effect. Further, we demonstrate that the CO-releasing micelles can cure methicillin-resistant S. aureus (MRSA)-infected wounds, simultaneously eradicating MRSA pathogens and accelerating wound healing.
Assuntos
Antibacterianos/uso terapêutico , Monóxido de Carbono/metabolismo , Liberação Controlada de Fármacos/efeitos da radiação , Luz , Dermatopatias/tratamento farmacológico , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Monóxido de Carbono/química , Monóxido de Carbono/farmacologia , Monóxido de Carbono/uso terapêutico , Escherichia coli/efeitos dos fármacos , Flavanonas/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Camundongos , Micelas , Oxirredução , Fármacos Fotossensibilizantes/química , Dermatopatias/microbiologia , Dermatopatias/patologia , Espectrofotometria , Staphylococcus aureus/efeitos dos fármacos , Cicatrização/efeitos dos fármacosRESUMO
As a noninvasive therapy, high-intensity focused ultrasound (HIFU) shows great potential in inducing anticancer immune responses. However, the overall anticancer efficacy of HIFU is still limited due to the rapid attenuation of ultrasound waves and inadequacy of ultrasound waves to spread to the whole tumor. Here, we combined HIFU with the ultrasound contrast agent/chemotherapeutic drug co-delivery nanodroplets to achieve synergistic enhancement of anticancer efficacy. Different from the widely used thermal HIFU irradiation, by which excessive heating would result in inactivation of immune stimulatory molecules, we used short acoustic pulses to trigger HIFU (mechanical HIFU, mHIFU) to improve anticancer immune responses. The nanodroplets displayed a mHIFU/glutathione (GSH)-dual responsive drug release property, and their cellular uptake efficacy and toxicity against cancer cells increased upon mHIFU irradiation. The generated immunogenic debris successfully induced the exposure of damage-associated molecular patterns on the cell surface for dendritic cells (DCs) maturation. In vivo experiments with tumor-bearing mice showed that the co-delivery nanodroplets in combination with mHIFU could effectively inhibit tumor growth by inducing immunogenic cell death, activating DCs maturation, and enhancing the effector T-cell infiltration within tumors. This work reveals that combined treatment with nanodroplets and mHIFU is a promising approach to eradicate tumors.
Assuntos
Antineoplásicos/farmacocinética , Meios de Contraste/farmacocinética , Ablação por Ultrassom Focalizado de Alta Intensidade/métodos , Imunoterapia/métodos , Neoplasias/terapia , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Terapia Combinada/métodos , Meios de Contraste/administração & dosagem , Células Dendríticas/imunologia , Modelos Animais de Doenças , Liberação Controlada de Fármacos/efeitos da radiação , Sinergismo Farmacológico , Feminino , Humanos , Morte Celular Imunogênica/efeitos dos fármacos , Morte Celular Imunogênica/efeitos da radiação , Camundongos , Nanopartículas/química , Nanopartículas/efeitos da radiação , Neoplasias/imunologia , Distribuição Tecidual , Ondas UltrassônicasRESUMO
Cancer gas therapy is just in an early stage of research and development. Several important gasotransmitters have proven their therapeutic potentials, but handling, delivery and controlled release of these gases remain very challenging for therapeutic purposes. This research develops a versatile nanosystem that is capable of delivering carbon monoxide (CO) gasotransmitter in the form of photo-responsive carbon monoxide-releasing molecule (CORM) for targeted cancer therapy. The core-shell upconversion nanoparticles (UCNPs) were designed to transfer bio-friendly low energy near infrared (NIR) light to ultraviolet (UV) light and trigger CO release from the loaded CORM. The synthesized delivery system demonstrated its ability to mediate the sustained release of CO upon 808 or 980 nm NIR light excitation. The optimized nanoformulation was efficiently taken up by HCT116 cancer cells and showed dose-dependent cytotoxicity to HCT116 and other cancer cells. Intracellular CO release and subsequent therapeutic action involving ROS production were found to significantly contribute to cell apoptosis. Therefore, the current research demonstrates the potency and efficiency of an NIR-mediated UCNP-based CORM prodrug delivery system for targeted cancer gas therapy.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Monóxido de Carbono/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Neoplasias/terapia , Fotoquimioterapia/métodos , Animais , Antimetabólitos Antineoplásicos/farmacocinética , Monóxido de Carbono/farmacocinética , Linhagem Celular Tumoral , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/instrumentação , Liberação Controlada de Fármacos/efeitos da radiação , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Raios Infravermelhos , Lipídeos/química , Camundongos , Nanopartículas/química , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Raios UltravioletaRESUMO
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/metabolismoRESUMO
Boron neutron capture therapy (BNCT) for cancer is on the rise worldwide due to recent developments of in-hospital neutron accelerators which are expected to revolutionize patient treatments. There is an urgent need for improved boron delivery agents, and herein we have focused on studying the biochemical foundations upon which a successful GLUT1-targeting strategy to BNCT could be based. By combining synthesis and molecular modeling with affinity and cytotoxicity studies, we unravel the mechanisms behind the considerable potential of appropriately designed glucoconjugates as boron delivery agents for BNCT. In addition to addressing the biochemical premises of the approach in detail, we report on a hit glucoconjugate which displays good cytocompatibility, aqueous solubility, high transporter affinity, and, crucially, an exceptional boron delivery capacity in the in vitro assessment thereby pointing toward the significant potential embedded in this approach.
Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Boro/administração & dosagem , Portadores de Fármacos/efeitos da radiação , Glucose/efeitos da radiação , Isótopos/administração & dosagem , Neoplasias/radioterapia , Boro/farmacocinética , Linhagem Celular Tumoral , Portadores de Fármacos/síntese química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos/efeitos da radiação , Glucose/análogos & derivados , Glucose/síntese química , Glucose/farmacocinética , Transportador de Glucose Tipo 1/metabolismo , Humanos , Isótopos/farmacocinética , Simulação de Acoplamento MolecularRESUMO
High aggressiveness and recurrence of melanoma tumors require multiple systemic drug administrations, causing discomfort and severe side effects to the patients. Topical treatment strategies that provide repetitively controllable and precise drug administrations will greatly improve treatment effects. Methods: In this study, a spatiotemporally controlled pulsatile release system, which combined dissolving microneedles (DMNs) and thermal-sensitive solid lipid nanoparticles (SLNs), was constructed to realize multiple doses of dual-modal chemo-photothermal therapy in a single administration. Paclitaxel (PTX) and photothermal agent IR-780 were encapsulated into SLNs and were concentrated in the tips of DMNs (PTX/IR-780 SLNs @DMNs). Equipped with several needles, the DMN patch could be directly inserted into the tumor site and provide a stable "Zone accumulation" to constrain the PTX/IR-780 SLNs at the tumor site with uniform distribution. Results:In vitro experiments showed that after irradiation with near-infrared light, the PTX/IR-780 SLNs gradually underwent phase transition, thereby accelerating the release of PTX. When irradiation was switched off, the PTX/IR-780 SLNs cooled to re-solidify with limited drug release. Compared with intravenous and intratumoral injections, very few SLNs from PTX/IR-780 SLNs @DMNs were distributed into other organs, resulting in enhanced bioavailability at the tumor site and good safety. In vivo analysis revealed that PTX/IR-780 SLNs @DMNs exhibited significant anti-tumor efficacy. In particular, the primary tumor was completely eradicated with a curable rate of 100% in 30 days and the highest survival rate of 66.67% after 100 days of treatment. Conclusion: Herein, we developed a DMN system with a unique spatiotemporally controlled pulsatile release feature that provides a user-friendly and low-toxicity treatment route for patients who need long-term and repeat treatments.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Melanoma Experimental/tratamento farmacológico , Paclitaxel/administração & dosagem , Terapia Fototérmica/métodos , Neoplasias Cutâneas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Terapia Combinada/métodos , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos da radiação , Feminino , Humanos , Indóis/administração & dosagem , Lasers , Luz , Melanoma Experimental/patologia , Camundongos , Nanopartículas/química , Paclitaxel/farmacocinética , Fármacos Fotossensibilizantes/administração & dosagem , Terapia Fototérmica/instrumentação , Neoplasias Cutâneas/patologia , Distribuição Tecidual , Adesivo TransdérmicoRESUMO
The limited tumor tissue penetration of many nanoparticles remains a formidable challenge to their therapeutic efficacy. Although several photonanomedicines have been applied to improve tumor penetration, the first near-infrared window mediated by the low optical tissue penetration depth severely limits their anticancer effectiveness. To achieve deep optical tissue and drug delivery penetration, a near-infrared second window (NIR-II)-excited and pH-responsive ultrasmall drug delivery nanoplatform was fabricated based on BSA-stabilized CuS nanoparticles (BSA@CuS NPs). The BSA@CuS NPs effectively encapsulated doxorubicin (DOX) via strong electrostatic interactions to form multifunctional nanoparticles (BSA@CuS@DOX NPs). The BSA@CuS@DOX NPs had an ultrasmall size, which allowed them to achieve deeper tumor penetration. They also displayed stronger NIR II absorbance-mediated deep optical tissue penetration than that of the NIR I window. Moreover, the multifunctional nanoplatform preferentially accumulated in tumor sites, induced tumor hyperthermia, and generated remarkably high ROS levels in tumor sites upon NIR-II laser (1064 nm) irradiation. More importantly, our strategy achieved excellent synergistic effects of chemotherapy and phototherapy (chemophototherapy) under the guidance of photothermal imaging. The developed nanoparticles also showed good biocompatibility and bioclearance properties. Therefore, our work demonstrated a facile strategy for fabricating a multifunctional nanoplatform that is a promising candidate for deep tumor penetration as an effective antitumor therapy.
Assuntos
Doxorrubicina/administração & dosagem , Portadores de Fármacos/efeitos da radiação , Nanopartículas/efeitos da radiação , Neoplasias/tratamento farmacológico , Fototerapia/métodos , Animais , Linhagem Celular Tumoral/transplante , Sobrevivência Celular , Modelos Animais de Doenças , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Liberação Controlada de Fármacos/efeitos da radiação , Humanos , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Lasers , Camundongos , Nanopartículas/química , Neoplasias/patologia , Fototerapia/instrumentação , Distribuição TecidualRESUMO
Nanoparticles are widely used as theranostic agents for the treatment of various pathologies, including cancer. Among all, dendrimers-based nanoparticles represent a valid approach for drugs delivery, thanks to their controllable size and surface properties. Indeed, dendrimers can be easily loaded with different payloads and functionalized with targeting agents. Moreover, they can be used in combination with other materials such as metal nanoparticles for combinatorial therapies. Here, we present the formulation of an innovative nanostructured hybrid system composed by a metallic core and a dendrimers-based coating that is able to deliver doxorubicin specifically to cancer cells through a targeting agent. Its dual nature allows us to transport nanoparticles to our site of interest through the magnetic field and specifically increase internalization by exploiting the T7 targeting peptide. Our system can release the drug in a controlled pH-dependent way, causing more than 50% of cell death in a pancreatic cancer cell line. Finally, we show how the system was internalized inside cancer cells, highlighting a peculiar disassembly of the nanostructure at the cell surface. Indeed, only the dendrimeric portion is internalized, while the metal core remains outside. Thanks to these features, our nanosystem can be exploited for a multistage magnetic vector.
Assuntos
Antineoplásicos/farmacologia , Dendrímeros/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas de Magnetita/química , Animais , Antineoplásicos/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/efeitos da radiação , Liberação Controlada de Fármacos/efeitos da radiação , Humanos , Concentração de Íons de Hidrogênio , Magnetismo , Nanopartículas de Magnetita/efeitos da radiação , Nanopartículas de Magnetita/ultraestrutura , Camundongos , Microscopia Eletrônica de Transmissão , Células NIH 3T3 , Tamanho da PartículaRESUMO
With the development of nanotechnology, Tumor Physical Stimuli-Responsive Therapies (TPSRTs) have reached a new stage because of the remarkable characteristics of nanocarriers. The nanocarriers enable such therapies to overcome the drawbacks of traditional therapies, such as radiotherapy or chemotherapy. To further explore the possibility of the nanocarrier-assisted TPSRTs, scientists have combined different TPSRTs via; the platform of nanocarriers into combination TPSRTs, which include Photothermal Therapy (PTT) with Magnetic Hyperthermia Therapy (MHT), PTT with Sonodynamic Therapy (SDT), MHT with Photodynamic Therapy (PDT), and PDT with PTT. To achieve such therapies, it requires to fully utilize the versatile functions of a specific nanocarrier, which depend on a pellucid understanding of the traits of those nanocarriers. This review covers the principles of different TPSRTs and their combinations, summarizes various types of combination TPSRTs nanocarriers and their therapeutic effects on tumors, and discusses the current disadvantages and future developments of these nanocarriers in the application of combination TPSRTs.
Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/efeitos da radiação , Nanopartículas/efeitos da radiação , Neoplasias/terapia , Nanomedicina Teranóstica/métodos , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Portadores de Fármacos/química , Liberação Controlada de Fármacos/efeitos da radiação , Humanos , Luz , Magnetoterapia/métodos , Magnetoterapia/tendências , Camundongos , Nanopartículas/química , Neoplasias/patologia , Fotoquimioterapia/métodos , Fotoquimioterapia/tendências , Terapia Fototérmica/métodos , Nanomedicina Teranóstica/tendências , Terapia por Ultrassom/métodos , Terapia por Ultrassom/tendências , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Soluble microneedles (MNs) of four different hydrophilic polymers namely sodium carboxymethyl cellulose (CMC), polyvinylpyrrolidone (PVP) K30, PVP K90 and sodium hyaluronate (HU) were fabricated by mold casting technique. When exposed to gamma radiation, a dose of 25 kilogray (kGy) was found to render the microneedle (MN) sterile. However, CMC was found to form MNs with poor mechanical properties, whereas PVP K30 MNs were drastically deformed upon exposure to applied dose as observed in bright field microscopy. Scanning electron microscopy (SEM) revealed that morphology of PVP K90 and HU MNs were not significantly affected at the applied dose. The appearances of characteristic peaks of irradiated MNs of PVP K90 and HU in Fourier-transform infrared spectra suggested structural integrity of the polymers on irradiation. Differential scanning calorimetry (DSC) indicated gamma irradiation failed to alter the glass transition temperature and thus mechanical properties of PVP K90 MNs. However, DSC and Powder X-ray Diffraction (PXRD) conclusively indicated that the degree in crystallinity of HU was substantially reduced on irradiation. In vitro dissolution profiles of sterile PVP K90 and HU MNs were similar to un-irradiated MNs with a similarity factor (f2) of 64 and 54, respectively. In vivo dissolution studies in human subjects indicated that sterile MNs of PVP K90 and HU exhibited dissolution of 78.45 ± 1.09 and 78.57 ± 0.70%, respectively, after 20 min. The studies suggested that PVP K90 and HU could be suitable polymers to fabricate soluble MNs as the structural, morphological, microstructural and dissolution properties remained unaltered post γ sterilization.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Raios gama/efeitos adversos , Polímeros/efeitos da radiação , Esterilização/métodos , Adesivo Transdérmico , Varredura Diferencial de Calorimetria , Carboximetilcelulose Sódica/química , Carboximetilcelulose Sódica/farmacocinética , Carboximetilcelulose Sódica/efeitos da radiação , Liberação Controlada de Fármacos/efeitos da radiação , Ácido Hialurônico/química , Ácido Hialurônico/farmacocinética , Ácido Hialurônico/efeitos da radiação , Interações Hidrofóbicas e Hidrofílicas/efeitos da radiação , Polímeros/química , Polímeros/farmacocinética , Povidona/análogos & derivados , Povidona/química , Povidona/farmacocinética , Povidona/efeitos da radiação , Solubilidade , Difração de Raios XRESUMO
Objective: In vitro, optimization, characterization, and cytotoxic studies of NAR nanoparticles (NPs) to against pancreatic cancer.Method: The sonication tailored Naringenin (NARG)-loaded poly (lactide-co-glycolic acid) (PLGA) NPs was fabricated for potential cytotoxic effect against pancreatic cancer. NARG NPs were prepared by emulsion-diffusion evaporation technique applying BoxBehnken experimental design based on three-level and three-factors. The effect of independent variables surfactant concentration (X1), polymer concentration (X2), and sonication time (X3) were studied on responses particle size (Y1), and drug release % (Y2). NPs characterized for particles size and size distribution, polydispersity index (PDI), zeta potential, transmission electron microscope (TEM), scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FT-IR), Differential scanning calorimeter (DSC), and X-ray diffraction (XRD) studies. Further, the studies was fitted to various drug release kinetic model and cytotoxicity evaluated in vitro.Results: The nanosized particles were spherical, uniform with an average size of 150.45 ± 12.45 nm, PDI value 0.132 ± 0.026, zeta potential -20.5 ± 2.5 mV, and cumulative percentage release 85.67 ± 6.23%. In vitro release of NARG from nanoparticle evaluated initially burst followed by sustained release behavior. The Higuchi was best fitted model to drug release from NARG NPs. The cytotoxicity study of NARG NPs apparently showed higher cytotoxic effect over free NARG (p < 0.05). The stability study of optimized formulation revealed no significant physico-chemical changes during 3 months.Conclusions: Thus, NARG-loaded NPs gave ameliorated anticancer effect over plain NARG.