RESUMEN
For the development of delivery systems, the solubilization of hydrophobic guest molecules in water is an important yet challenging task. This can be achieved by preparing stable aqueous solutions with a high concentration of guest molecules using a natural product as a solubilizing agent and a mechanochemical high-speed vibration milling apparatus as a solubilizing method. Various solubilizing agent-guest molecule complexes can be obtained via the exchange between solubilizing agents, which enables the "on-off" switching of the properties of functional guest molecules, such as fluorescence intensity, and photodynamic activity. In the exchange method, guest molecules can transfer into cell membranes such as lysosomes and exosomes. Therefore, the exchange method of the solubilizing agents not only creates novel solubilizing agent-guest molecule complexes but also is applied to drug delivery systems.
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Sistemas de Liberación de Medicamentos , Agua , Agua/químicaRESUMEN
Minimally invasive boron neutron capture therapy (BNCT) is an elegant approach for cancer treatment. The highly selective and efficient deliverability of boron agents to cancer cells is the key to maximizing the therapeutic benefits of BNCT. In addition, enhancement of the frequencies to achieve boron neutron capture reaction is also significant in improving therapeutic efficacy by providing a highly concentrated boron agent in each boron nanoparticle. As the density of the thermal neutron beam remains low, it is unable to induce high-efficiency cell destruction. Herein, we report phospholipid-coated boronic oxide nanoparticles as agents for BNCT that can provide a highly concentrated boron atom in each nanoparticle. The current system exhibited inâ vitro BNCT activity seven times higher than that of commercial boron agents. Furthermore, the system could penetrate cancer spheroids deeply, efficiently suppressing thermal neutron irradiation-induced growth.
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Terapia por Captura de Neutrón de Boro , Nanopartículas , Boro , Fosfolípidos , Compuestos de Boro/uso terapéutico , ÓxidosRESUMEN
Tetrakis(4-aminophenyl)porphyrin (1) and tetrakis(4-acetamidophenyl)porphyrin (2) were dissolved in water with the incorporation of a polysaccharide (λ-carrageenan (CGN)) as a water-solubilizing agent. Although the photodynamic activity of the CGN-2 complex was considerably lower than that of the CGN-1 complex, the selectivity index (SI; IC50 in a normal cell/IC50 in a cancer cell) of the CGN-2 complex was considerably higher than that of the CGN-1 complex. This is because the photodynamic activity of the CGN-2 complex was significantly affected by the intracellular uptakes by the normal and cancer cells. During inâ vivo experiments, the CGN-2 complex inhibited tumor growth under light irradiation with high blood retention compared with the CGN-1 complex and Photofrin, which exhibited lower blood retention. This study showed that the photodynamic activity and SI are influenced by substituent groups of arene in the meso-positions of porphyrin analogs.
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Neoplasias , Animales , Humanos , Ratones , Acetilación , Línea Celular Tumoral , Liposomas , Neoplasias/química , Neoplasias/terapia , Fotoquímica/métodos , Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , Porfirinas/químicaRESUMEN
Herein, trimethyl-ß-cyclodextrin (TMe-ß-CDx) and γ-cyclodextrin (γ-CDx) could dissolve a tetraphenylethylene derivative (TPE-OH4 ) in water through high-speed vibration milling. The fluorescence intensity of the TMe-ß-CDx-TPE-OH4 complex was much higher than that of the γ-CDx-TPE-OH4 complex, as the rotation of the central C=C double bond of TPE-OH4 after photoactivation was inhibited in a smaller TMe-ß-CDx cavity in comparison with the γ-CDx cavity. In contrast, the fluorescence intensity of the γ-CDx-TPE-OH4 complex was very weak; nevertheless, it increased after the addition of liposomes due to the transfer of TPE-OH4 from the γ-CDx cavity to the lipid membrane as a "turn-on" phenomenon. Furthermore, to apply temperature sensor, it was demonstrated that the fluorescence intensity in the liposomes depended on the phase-transition temperature. By using the fluorescence turn-on phenomenon, TPE-OH4 could detect the presence of HeLa cells and E. coli by fluorescence.
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Ciclodextrinas , Humanos , Ciclodextrinas/química , Liposomas , Escherichia coli , Células HeLaRESUMEN
Boron neutron capture therapy (BNCT) is a promising modality for cancer treatment because of its minimal invasiveness. To maximize the therapeutic benefits of BNCT, the development of efficient platforms for the delivery of boron agents is indispensable. Here, carborane-integrated immunoliposomes were prepared via an exchanging reaction to achieve HER-2-targeted BNCT. The conjugation of an anti-HER-2 antibody to carborane-integrated liposomes successfully endowed these liposomes with targeting properties toward HER-2-overexpressing human ovarian cancer cells (SK-OV3); the resulting BNCT activity toward SK-OV3 cells obtained using the current immunoliposomal system was 14-fold that of the l-BPA/fructose complex, which is a clinically available boron agent. Moreover, the growth of spheroids treated with this system followed by thermal neutron irradiation was significantly suppressed compared with treatment with the l-BPA/fructose complex.
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Boranos , Terapia por Captura de Neutrón de Boro , Humanos , Liposomas , Terapia por Captura de Neutrón de Boro/métodos , Boro , Compuestos de Boro , FructosaRESUMEN
Protein-based drug carriers are ideal drug-delivery platforms because of their biocompatibility, biodegradability, and low toxicity. Many types and shapes of protein-based platforms, including nanoparticles, hydrogels, films, and minipellets, have been prepared to deliver drug molecules. In this study, protein films containing the desired amounts of doxorubicin (DOX) as cancer drugs were developed using a simple mixing method. The release ratio and rate of DOXs were dependent on the surfactant concentration. The drug release ratio was controlled within the range of 20-90% depending on the amount of the surfactant used. The protein film surface was analyzed using a microscope before and after drug release, and the relationship between the degree of film swelling and the drug release ratio was discussed. Moreover, the effects of cationic surfactants on the protein film were investigated. Non-toxic conditions of the protein films were confirmed in normal cells, while the toxicity of the drug-encapsulated protein film was confirmed in cancer cells. Remarkably, it was observed that the drug-encapsulated protein film could eliminate 10-70% of cancer cells, with the extent of efficacy varying based on the surfactant amount.
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Sistemas de Liberación de Medicamentos , Nanopartículas , Dodecil Sulfato de Sodio , Preparaciones de Acción Retardada/farmacología , Sistemas de Liberación de Medicamentos/métodos , Portadores de Fármacos/toxicidad , Doxorrubicina/farmacología , Proteínas , Liberación de Fármacos , TensoactivosRESUMEN
Porphyrin-fullerene composite systems are attracting great attention as photodynamic agents; however, water-soluble derivatives are still scarce. Herein, we prepared noncovalently a lipid membrane-incorporated porphyrin-fullerene composite system with relative stability in aqueous solution. As in the case of porphyrin-fullerene composite systems in nonpolar solvents, efficient formation of singlet oxygen occurred via photoinduced energy transfer between porphyrin and fullerene as the predominant pathway in the photodynamic activity under the hydrophobic conditions of the lipid membranes, resulting in enhanced photodynamic activity toward Colon26 and HeLa cells compared with the individual porphyrin and fullerene components. Furthermore, the porphyrin-fullerene composite system exhibited high selectivity toward HeLa cells over normal mouse fibroblast L929 cells.
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Fulerenos , Porfirinas , Animales , Ratones , Humanos , Porfirinas/farmacología , Porfirinas/química , Fulerenos/farmacología , Fulerenos/química , Células HeLa , Transferencia de Energía , LípidosRESUMEN
Phenazine-2,3-diol-based dyes, KY-1Na and KY-2Na bearing one and two carboxylic acid sodium salts, respectively, have been newly developed as water-soluble photosensitizers (PSs) possessing the ability to generate singlet oxygen (1O2). In order to evaluate the solubility of KY-1Na and KY-2Na in water, the hydrophobicity/hydrophilicity of the two PSs was investigated by experimental measurement of the logarithms (log Po/w) of the 1-octanol/water partition coefficient (Po/w) for the PS. The log Po/w values of both KY-1Na and KY-2Na were determined to be -0.9, indicating that both the PSs are more hydrophilic than Rose Bengal (-0.6) and have hydrophilicity equivalent to methylene blue (-0.9). Both the PSs in water show a broad photoabsorption band in the range of 500 to 600 nm. Thus, we estimated the 1O2 quantum yields (ΦΔ) of KY-1Na and KY-2Na in water by using 9,10-anthracenediyl-bis(methylene)dimalonic acid (ABDA) as a water-soluble 1O2 scavenger. It was found that in water the ΦΔ value (0.19) of KY-2Na is higher than that of KY-1Na (0.06). Density functional theory (DFT) calculations suggested that the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) distributions for the molecular structure of KY-2Na are adequately separated, leading to a decrease in the energy gap (ΔEST) between the singlet state (S1) and the triplet state (T1) that causes efficient intersystem crossing (ISC), compared to that for the molecular structure of KY-1Na. Indeed, time-dependent DFT (TD-DFT) calculations demonstrated that the ΔEST(S1-T1) value (0.82 eV) of KY-2Na is smaller than that (0.98 eV) of KY-1Na, resulting in a relatively high ΦΔ value of KY-2Na. Consequently, we demonstrate that phenazine-2,3-diol-based PSs bearing carboxylic acid salts possess high solubility and moderate 1O2 generation ability in water.
RESUMEN
Boron neutron capture therapy shows is a promising approach to cancer therapy, but the delivery of effective boron agents is challenging. To address the requirements for efficient boron delivery, we used a hybrid nanoparticle comprising a carborane = bearing pullulan nanogel and hydrophobized boron oxide nanoparticle (HBNGs) enabling the preparation of highly concentrated boron agents for efficient delivery. The HBNGs showed better anti-cancer effects on Colon26 cells than a clinically boron agent, L-BPA/fructose complex, by enhancing the accumulation and retention amount of the boron agent within cells in vitro. The accumulation of HBNGs in tumors, due to the enhanced permeation and retention effect, enabled the delivery of boron agents with high tumor selectivity, meeting clinical demands. Intravenous injection of boron neutron capture therapy (BNCT) using HBNGs decreased tumor volume without significant body weight loss, and no regrowth of tumor was observed three months after complete regression. The therapeutic efficacy of HBNGs was better than that of L-BPA/fructose complex. BNCT with HBNGs is a promising approach to cancer therapeutics.
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Terapia por Captura de Neutrón de Boro , Neoplasias , Humanos , Nanogeles , Boro , Neoplasias/radioterapia , Neoplasias/tratamiento farmacológico , Compuestos de Boro , FructosaRESUMEN
Developing photoactivatable theranostic platforms with integrated functionalities of biocompatibility, targeting, imaging contrast, and therapy is a promising approach for cancer diagnosis and therapy. Here, we report a theranostic agent based on a hybrid nanoparticle comprising fullerene nanocrystals and gold nanoparticles (FGNPs) for photoacoustic imaging and photothermal therapy. Compared to gold nanoparticles and fullerene crystals, FGNPs exhibited stronger photoacoustic signals and photothermal heating characteristics by irradiating light with an optimal wavelength. Our studies demonstrated that FGNPs could kill cancer cells due to their photothermal heating characteristics in vitro. Moreover, FGNPs that are accumulated in tumor tissue via the enhanced permeation and retention effect can visualize tumor tissue due to their photoacoustic signal in tumor xenograft model mice. The theranostic agent with FGNPs shows promise for cancer therapy.
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Fulerenos , Nanopartículas del Metal , Nanopartículas , Neoplasias , Técnicas Fotoacústicas , Animales , Línea Celular Tumoral , Fulerenos/química , Oro/química , Humanos , Nanopartículas del Metal/uso terapéutico , Ratones , Nanopartículas/química , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Técnicas Fotoacústicas/métodos , Fototerapia/métodos , Terapia Fototérmica , Medicina de Precisión , Nanomedicina Teranóstica/métodosRESUMEN
In cancer therapeutics, boron neutron capture therapy (BNCT) requires a platform for selective and efficient 10B delivery into tumor tissues for a successful treatment. However, the use of carborane, a promising candidate with high boron content and biostability, has significant limitations in the biomedical field due to its poor water-solubility and tumor-selectivity. To overcome these hurdles, we present in this study a fluorescent nano complex, combining fluorescent carborane and sodium hyaluronate for high boron concentration and tumor-selectivity. Tumor cells actively internalized the complex through binding hyaluronan to CD44, overexpressed on the tumor cell surface. Furthermore, the subcellular distribution of this complex could also be detected due to its fluorescent properties. Moreover, after thermal neutron irradiations, the complex produced excellent cytotoxicity, equal to or greater than that of the clinically-used BPA-fructose. Therefore, this novel complex could be potentially more suitable for BNCT than the boron agent.
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Boranos/uso terapéutico , Terapia por Captura de Neutrón de Boro , Ácido Hialurónico/uso terapéutico , Neoplasias/terapia , Animales , Línea Celular Tumoral , Supervivencia Celular , Humanos , Ácido Hialurónico/ultraestructura , Ratones , Células RAW 264.7RESUMEN
The purpose of a drug delivery system is to efficiently deliver drugs to a desired target, while simultaneously reducing the side effects caused by these drugs and maximizing their efficacy. However, in the manufacture of a drug delivery system, it is difficult to control the amount of drug encapsulation. In this study, we developed a simple formation process of self-assembled hydrogels that made it easier to package the desired amount of anticancer drugs. A self-assembled hydrogel was prepared by simply mixing transferrin, dithiothreitol, and an anticancer drug in a salt solvent. The structural conditions of the hydrogel were determined in order to control the concentration of the transferrin protein, dithiothreitol, and salt in the solvent. The self-assembled hydrogels contained the desired amount of anticancer drugs. With this system, changes in pH and temperature control the release rate and the release ratio of anticancer drugs. The cytotoxicity of the drug-loaded hydrogel was evaluated, which showed that 80% of the treated cells had been killed following 48 h of incubation.
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Antineoplásicos , Neoplasias , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Hidrogeles , Concentración de Iones de Hidrógeno , TemperaturaRESUMEN
Oligoproline-containing peptides, GPPG and GPPPG, were designed and developed for nanoparticle-based delivery platforms, and their degradation is triggered by reactive oxygen species (ROS). Peptides containing more than two consecutive proline residues were found to be cleavable in 1 mM of ROS generated by hydrogen peroxide in the presence of CuSO4, which corresponds to plant cells under photosynthetic conditions. The nanoparticles formed by the peptides were also ROS-degradable and efficiently encapsulated a hydrophobic dye. The hydrophobic cargo in the peptide nanoparticles was released into the cytosol of plant leaf cells in response to the ROS generated in chloroplasts by light irradiation. Furthermore, local laser irradiation enabled the peptide nanoparticles to release their cargo at only the irradiated cell, promising site-selective cargo release triggered by irradiation.
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Nanopartículas , Peróxido de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Péptidos , Especies Reactivas de OxígenoRESUMEN
Porphyrin derivatives with hydroxyphenyl or dihydroxyphenyl moieties in the meso-position were able to dissolve in water by complexation with two trimethyl-ß-cyclodextrins (TMe-ß-CDxs) without further chemical modification of porphyrins or addition of dimethyl sulfoxide as a co-solvent. TMe-ß-CDx-complexed tetra(hydroxyphenyl)porphyrins (THPPs) with phenols in meso-positions have a much higher photodynamic activity than TMe-ß-CDx-complexed tetrakis(dihydroxyphenyl)porphyrins (TDHPPs) with dihydroxyphenyl in the meso-position. The main reason for the different photoactivity is due to the intracellular uptakes of these complexes. Thus phenols in meso-positions of porphyrin derivatives in the complexes were recognized by HeLa cell receptors. Furthermore, the photodynamic activity of TMe-ß-CDx-complexed THPP was much higher than that of THPP injected as a dimethyl sulfoxide solution.
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PorfirinasRESUMEN
Various cells in vivo secrete exosomes consisting of lipid bilayers. They carry mRNAs and miRNAs capable of controlling cellular functions and can be used as drug delivery system nanocarriers. There is the current need to further improve the efficiency of exosome uptake into target cells. In this study, we prepared a hybrid of exosomes and magnetic nanoparticles, which could be guided to target cells by a magnetic field for efficient uptake. Magnetic nanogels were prepared and hybridized to fluorescently labeled exosomes isolated from PC12 cells. By applying a magnetic field to a hybrid with magnetic nanogel, exosomes were efficiently transferred into target cells as confirmed by confocal laser microscopy. Finally, we found that differentiation of adipose-derived stem cells to neuron-like cells was enhanced by magnetic induction of the exosome-magnetic nanogel hybrid, indicating maintenance of the intrinsic functions of the exosomes in the differentiation of adipose-derived stem cells.
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Sistemas de Liberación de Medicamentos/métodos , Vesículas Extracelulares/metabolismo , Magnetismo , Nanogeles/química , Animales , Diferenciación Celular , Células Madre Mesenquimatosas/citología , Neuronas , Células PC12 , Ratas , TensoactivosRESUMEN
Boron neutron capture therapy, based on the release of thermal neutron irradiation from boron, is a targeted radiation therapy for cancer. Targeted and sufficient accumulation of boron in tumor cells to achieve cytotoxic efficacy and reduce off-target effects remains a challenge. Carborane has been investigated for use as a delivery agent in boron neutron capture therapy because of its high boron content and chemical stability; however, it is cytotoxic, making safe delivery difficult. The aim of this study was to investigate the potential of carborane-bearing pullulan nanogels to safely and effectively deliver boron to tumor cells in vitro and in vivo and, consequently, assess their potential as a boron neutron capture therapeutic. Murine fibrosarcoma cells (CMS5a) were used for in vitro investigations of nanogel cytotoxicity, cell uptake. A mouse fibrosarcoma xenograft model was used to investigate the bio-distribution of nanogels after intravenous administration. The nanogels produced no apparent cytotoxicity and underwent cell uptake in CMS5a cells after a 24 h incubation at up to 2000 µg/mL and 400 µg/mL, respectively. The internalized nanogels were localized around the nuclear membrane. The nanogels were administered intravenously to mice bearing fibrosarcoma xenografts. Nanogel tumor localization likely occurred through the enhanced permeation and retention effect. The nanogels successfully reduced the cytotoxicity of carborane, were internalized into tumor cells, acted as a dual-delivery therapeutic and accumulated in tumors in vivo. Consequently, they demonstrate significant potential as a boron neutron capture therapeutic.
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Terapia por Captura de Neutrón de Boro/métodos , Boro/administración & dosificación , Polietilenglicoles/administración & dosificación , Polietilenglicoles/química , Polietileneimina/administración & dosificación , Polietileneimina/química , Animales , Boro/farmacocinética , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/métodos , Fibrosarcoma/tratamiento farmacológico , Fibrosarcoma/radioterapia , Glucanos/química , Ratones Endogámicos BALB C , Nanogeles , Polietilenglicoles/farmacocinética , Polietileneimina/farmacocinética , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Protein pharmaceuticals show great therapeutic promise, but effective intracellular delivery remains challenging. To address the need for efficient protein transduction systems, we used a magnetic nanogel chaperone (MC): a hybrid of a polysaccharide nanogel, a protein carrier with molecular chaperone-like properties, and iron oxide nanoparticles, enabling magnetically guided delivery. The MC complexed with model proteins, such as BSA and insulin, and was not cytotoxic. Cargo proteins were delivered to the target HeLa cell cytosol using a magnetic field to promote movement of the protein complex toward the cells. Delivery was confirmed by fluorescence microscopy and flow cytometry. Delivered ß-galactosidase, inactive within the MC complex, became enzymatically active within cells to convert a prodrug. Thus, cargo proteins were released from MC complexes through exchange interactions with cytosolic proteins. The MC is a promising tool for realizing the therapeutic potential of proteins.
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Portadores de Fármacos/química , Compuestos Férricos/química , Nanopartículas del Metal/química , Polietilenglicoles/química , Polietileneimina/química , Proteínas/metabolismo , Animales , Bovinos , Colorantes Fluorescentes/química , Glucanos/química , Células HeLa , Humanos , Insulina/química , Insulina/metabolismo , Magnetismo , Microscopía Confocal , Chaperonas Moleculares/química , Chaperonas Moleculares/metabolismo , Nanogeles , Proteínas/química , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/metabolismoRESUMEN
Boron neutron capture therapy (BNCT) is one of the most promising modalities for cancer treatment due to its minimal invasiveness. Although two types of boron agents are clinically used, several issues persist in their delivery, including poor water solubility, instability in aqueous media, selectivity toward cancer cells, accumulation in cancer cells, retention time in tumor tissue, and efficiency in achieving the boron neutron capture reaction. Addressing these challenges, numerous groups have explored various boron agents to enhance the therapeutic benefits of BNCT. This review summarizes delivery platforms based on natural products for BNCT.
RESUMEN
Studies have shown that folate receptors are highly expressed in various cancer cells. Here, we synthesized folic acid-conjugated pullulan (FAPL) as a solubilizing agent to improve the photodynamic activity of porphyrin derivative-polysaccharide complexes. The porphyrin derivative-FAPL complex exhibited long-term stability in an aqueous solution, attributed to the folic acid modification. Furthermore, in vitro and in vivo experiments highlighted the enhanced photodynamic activity of the porphyrin derivative-FAPL complex toward 4T1 breast-cancer cells, compared with the activities of the porphyrin derivative-pullulan complex and Photofrin. This enhanced activity is attributed to the improvement of intracellular uptake by the folate receptor.
RESUMEN
Photoacoustic (PA) imaging is a novel biological imaging technique with superior depth resolution compared to fluorescence imaging. The efficacy of PA imaging depends on contrast agents that possess considerable absorbance at longer wavelengths, coupled with high permeability in biological tissue and minimal fluorescence, achieved through mitigating aggregation-caused quenching (ACQ) that attenuates PA intensity. Despite the successful transfer of porphyrin 2 featuring amino moieties from polysaccharides to liposomes, most of 2 incorporated within λ-carrageenan (CGN-2 complex) remained in CGN under acidic lysosomal conditions (pHâ 5.0). Consequently, the CGN-2 complex exhibited a strong PA signal under 680â nm photoirradiation in Colon26 cells owing to the ACQ of 2. Moreover, the PA intensity of the CGN-2 complex was further enhanced under 780â nm photoirradiation owing to the increased absorbance at 780â nm facilitated by the redshift of the Q-band at pHâ 5.0.