RESUMO
With their low immunogenicity and excellent deliverability, extracellular vesicles (EVs) are promising platforms for drug delivery systems. In this study, hydrophobic molecule loading techniques were developed via an exchange reaction based on supramolecular chemistry without using organic solvents that can induce EV disruption and harmful side effects. To demonstrate the availability of an exchanging reaction to prepare drug-loading EVs, hydrophobic boron cluster carborane (CB) was introduced to EVs (CB@EVs), which is expected as a boron agent for boron neutron capture therapy (BNCT). The exchange reaction enabled the encapsulation of CB to EVs without disrupting their structure and forming aggregates. Single-particle analysis revealed that an exchanging reaction can uniformly introduce cargo molecules to EVs, which is advantageous in formulating pharmaceuticals. The performance of CB@EVs as boron agents for BNCT was demonstrated in vitro and in vivo. Compared to L-BPA, a clinically available boron agent, and CB delivered with liposomes, CB@EV systems exhibited the highest BNCT activity in vitro due to their excellent deliverability of cargo molecules via an endocytosis-independent pathway. The system can deeply penetrate 3D cultured spheroids even in the presence of extracellular matrices. The EV-based system could efficiently accumulate in tumor tissues in tumor xenograft model mice with high selectivity, mainly via the enhanced permeation and retention effect, and the deliverability of cargo molecules to tumor tissues in vivo enhanced the therapeutic benefits of BNCT compared to the L-BPA/fructose complex. All of the features of EVs are also advantageous in establishing anticancer agent delivery platforms.
RESUMO
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.
RESUMO
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.
RESUMO
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.
RESUMO
Metal-free room-temperature phosphorescent (RTP) materials are attracting attention in such applications as organic light-emitting diodes and bioimaging. However, the chemical structures of RTP materials reported thus far are mostly predominantly based on π-conjugated systems incorporating heavy atoms such as bromine atoms or carbonyl groups, resulting in limited structural diversity. On the other hand, triarylboranes are known for their strong Lewis acidity and deep LUMO energy levels, but few studies have reported on their RTP properties. In this study, we discovered that compounds based on a tetracyclic structure containing boron, referred to as benzo[d]dithieno[b,f]borepins, exhibit strong solid-state reddish phosphorescence even in air. Quantum chemical calculations, including those for model compounds, revealed that the loss of planarity of the tetracyclic structure increases spin-orbit coupling matrix elements, thereby accelerating the intersystem crossing process. Moreover, single-crystal X-ray structural analysis and natural energy decomposition analysis suggested that the borepin compounds without bromine or oxygen atoms, unlike typical RTP materials, exhibit red-shifted phosphorescence in the crystalline state owing to structural relaxation in the T1 state. Additionally, the borepin compounds showed potential application as bioimaging dyes.
RESUMO
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.
Assuntos
Boranos , Terapia por Captura de Nêutron de Boro , Humanos , Lipossomos , Terapia por Captura de Nêutron de Boro/métodos , Boro , Compostos de Boro , FrutoseRESUMO
The development of boron agents with integrated functionality, including biocompatibility, high boron content, and cancer cell targeting, is desired to exploit the therapeutic efficacy of boron neutron capture therapy (BNCT). Here, we report the therapeutic efficacy of BNCT using a HER-2-targeted antibody-conjugated boron nitride nanotube/ß-1,3-glucan complex. The anticancer effect of BNCT using our system was 30-fold that of the clinically available boron agent l-BPA/fructose complex.
RESUMO
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.
Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas , Dodecilsulfato de Sódio , Preparações de Ação Retardada/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Portadores de Fármacos/toxicidade , Doxorrubicina/farmacologia , Proteínas , Liberação Controlada de Fármacos , TensoativosRESUMO
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.
Assuntos
Neoplasias , Animais , Humanos , Camundongos , Acetilação , Linhagem Celular Tumoral , Lipossomos , Neoplasias/química , Neoplasias/terapia , Fotoquímica/métodos , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/químicaRESUMO
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.
Assuntos
Fulerenos , Porfirinas , Animais , Camundongos , Humanos , Porfirinas/farmacologia , Porfirinas/química , Fulerenos/farmacologia , Fulerenos/química , Células HeLa , Transferência de Energia , LipídeosRESUMO
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.
RESUMO
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.
Assuntos
Terapia por Captura de Nêutron de Boro , Nanopartículas , Boro , Fosfolipídeos , Compostos de Boro/uso terapêutico , ÓxidosRESUMO
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.
Assuntos
Terapia por Captura de Nêutron de Boro , Neoplasias , Humanos , Nanogéis , Boro , Neoplasias/radioterapia , Neoplasias/tratamento farmacológico , Compostos de Boro , FrutoseRESUMO
Benzophenone and its derivatives emit crystallization-induced phosphorescence despite their simple structures. To easily modify their phosphorescence properties, we prepared phosphorescence-emitting aqueous solutions of polysaccharide-benzophenone and polysaccharide-4,4'-difluorobenzophenone complexes, which exhibit excellent biocompatibility and biodegradability.
RESUMO
Chitosan is a natural polysaccharide with the advantageous qualities of biocompatibility and biodegradability, and it has recently been spotlighted as a soft material for a sustainable society. Advantages such as these are in demand for application in various biomaterials. Although extensive studies have been conducted on the preparation of chitosan films, overcoming the problems of weak mechanical properties remains a significant barrier. In the present study, we developed stretchable doxorubicin-loaded biocompatible chitosan films by adding acetic acid in controlled concentrations. The stretchable properties of doxorubicin-loaded chitosan film at various concentrations of acetic acid were measured. Elongation to the point of breakage reached 27% with a high concentration of acetic acid, which could be described as high stretchability. The release ratio of doxorubicin from chitosan film reached 70% with a high acetic acid concentration. The cytotoxicity of doxorubicin-loaded chitosan films was measured, and cancer spheroids had completely collapsed after 7 days. According to the results of skin permeability testing, use of the doxorubicin-loaded chitosan film is a plausible choice for a drug sealant.
RESUMO
The prevalence of allergic disorders has increased worldwide in recent decades. Polyphenols, including resveratrol and curcumin, are posited to have potential as therapeutic agents for allergy; however, their use has been limited by poor water solubility. Accordingly, a highly concentrated, water dispersible, supramolecular complexes of polyphenols with polypeptides (poly-L-lysine, poly-γ-glutamic acid) and gelatin using high-speed vibration milling are developed. The complex exhibits resistance to photobleaching and thermal radiation. Treatment of a rat basophilic leukemia cell line (RBL-2H3) with polypeptide complexes containing resveratrol is suppressed allergic responses in vitro. Moreover, aerosolized administration of polypeptide complexes demonstrates excellent bioavailability and inhibition of immediate hypersensitivity reactions in ear tissue in vivo. Furthermore, the method avoids the use of organic solvent and therefore reduces undesirable biological responses.
Assuntos
Hipersensibilidade , Polifenóis , Ratos , Animais , Polifenóis/farmacologia , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Água , Imunoglobulina E/metabolismo , Imunoglobulina E/uso terapêutico , Hipersensibilidade/tratamento farmacológico , Peptídeos/farmacologia , Peptídeos/uso terapêuticoRESUMO
Polypeptides were used to solubilize functional hydrophobic molecules via a high-speed vibrational milling method. Poly-l-lysine and poly-γ-glutamic acid, which are polypeptides, were able to prepare more highly concentrated water-dispersible complexes of hydrophobic compounds, including fullerenes, organic dyes, and porphyrin derivatives, than conventional water solubilizers, such as cyclodextrins and pullulan. In addition, the polypeptide systems endowed the complexes with long-term stability and resistance against thermal stress, which is advantageous for industrial applications. Furthermore, complexes of polypeptides and porphyrin derivatives showed a photodynamic activity against cancer cells, and the current system improved the dispersibility and storability of guest molecules without compromising their functionality.
RESUMO
In this work, we demonstrate that liposome gels in which liposomes are connected by polyethylene glycol terminated by cholesterol groups at both ends can store hydrophilic and hydrophobic drugs in the gel interiors, inner aqueous phases, and lipid membranes. The addition of cyclodextrins (CDxs) as extrinsic stimuli led to the release of drug-entrapping liposomes due to the interactions between CDxs and cholesteryl groups and/or the alkyl chains of lipids. The addition of aqueous solutions of ß-CDx, dimethyl-ß-CDx, trimethyl-ß-CDx, and γ-CDx (final concentration: 7.5 mM) induced the solation of liposome gels and the release of liposomes accompanying the solation. Furthermore, the addition of ß-CDx led to the partial release of hydrophilic drugs encapsulated in the liposomes, although the drug release was scarcely observed in other CDxs. In particular, the addition of trimethyl-ß-CDx, which has low cytotoxicity, accelerated solation, and cationic liposomes released from the gels were effectively taken up by murine colon cancer (Colon26) cells. Thus, we propose that liposomes released from liposome gels can function as drug carriers.
RESUMO
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.
Assuntos
Fulerenos , Nanopartículas Metálicas , Nanopartículas , Neoplasias , Técnicas Fotoacústicas , Animais , Linhagem Celular Tumoral , Fulerenos/química , Ouro/química , Humanos , Nanopartículas Metálicas/uso terapêutico , Camundongos , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Técnicas Fotoacústicas/métodos , Fototerapia/métodos , Terapia Fototérmica , Medicina de Precisão , Nanomedicina Teranóstica/métodosRESUMO
A dyad system comprising a lipid membrane-incorporated fullerene derivative with an N,N-dimethylpyrrodinium group (C60-1) and a photoantenna molecule (DiD) did not exhibit the high photodynamic activity expected based on its singlet oxygen generation ability. Comparison with a fullerene derivative with an amide substituent (C60-2) suggested the cause to be that some of the fullerene derivative had been released from the liposomes, partly disrupting the dyad system. The dyad system of C60-2 and DiD exhibited about twice the photodynamic activity toward HeLa cells as that of C60-1 and DiD, due to the suppression of the release of the fullerene derivative from the liposomes. The hydrophobicity/hydrophilicity balance of the substituent in fullerene derivatives was shown to be very important to obtain a dyad system in liposomes characterized by high photodynamic activity.