RESUMEN
The clearance of senescent cells may be detrimental to low cell density diseases, such as intervertebral disc degeneration (IVDD), and rejuvenating these cells presents a formidable obstacle. In this study, we investigate a mild-alkalization strategy employing magnesium boride-alginate (MB-ALG) hydrogels to rejuvenate senescent cells associated with age-related diseases. MB-ALG hydrogels proficiently ensnare senescent cells owing to their surface roughness. The hydrolysis of MB-ALG hydrogels liberates hydroxide ions (OH-), effecting a transition from an acidic microenvironment (pH â¼ 6.2) to a mildly alkaline state (pH â¼ 8.0), thereby fostering senescent cell proliferation via activation of the PI3K/Akt/mTOR pathway. Additionally, H2 aids in ROS clearance, which reduces cellular oxidative stress. And, Mg2+ rejuvenates senescent cells by inhibiting Ca2+ influx and fine-tuning the sirt1-p53 signaling pathways. Both in vitro and in vivo experiments conducted on rat intervertebral discs corroborate the sustained antisenescence and rejuvenation properties of MB-ALG hydrogels, with effects persisting for up to 12 weeks postoperation. These discoveries elucidate the role of mild-alkalization in dictating cellular destiny and provide key insights for addressing age-related diseases.
Asunto(s)
Alginatos , Senescencia Celular , Hidrogeles , Alginatos/química , Alginatos/farmacología , Hidrogeles/química , Hidrogeles/farmacología , Animales , Senescencia Celular/efectos de los fármacos , Ratas , Proliferación Celular/efectos de los fármacos , Ratas Sprague-Dawley , Compuestos de Boro/química , Compuestos de Boro/farmacología , Humanos , Estrés Oxidativo/efectos de los fármacos , Magnesio/química , Magnesio/farmacología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Therapy-induced modulation of the tumor microenvironment (TME) to overcome the immunosuppressive TME is considered to be an opportunity for cancer treatment. However, monitoring of TME modulation during the therapeutic process to accurately determine immune responses and adjust treatment plans in a timely manner remains to be challenging. Herein, we report a carrier-free nanotheranostic system (CANPs) assembled by two boron dipyrromethene (BODIPY) dyes, a sonophotosensitizer C-BDP, and a nitric oxide (NO) probe amino-BODIPY (A-BDP). CANPs can exert combined sonophototherapeutic effects of C-BDP under ultrasound and light irradiation and simultaneously induce inflammatory TME, as well as emit bright fluorescence via A-BDP by monitoring tumor-associated macrophages (TAMs) repolarization through the released NO in vitro and in vivo. Of note, transforming growth factor-ß (TGF-ß) could be the key cytokine involved in the sonophototherapy-induced TME reprogramming. By virtue of high physiological stability, good biocompatibility, and effective tumor targetability, CANPs could be a potential nanotheranostic system for the simultaneous induction and detection of TME reprogramming triggered by sonophototherapy.
Asunto(s)
Nanomedicina Teranóstica , Microambiente Tumoral , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Animales , Ratones , Porfobilinógeno/análogos & derivados , Porfobilinógeno/química , Porfobilinógeno/farmacología , Humanos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Compuestos de Boro/química , Compuestos de Boro/farmacología , Óxido Nítrico/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Femenino , Nanopartículas/química , Colorantes Fluorescentes/química , Colorantes Fluorescentes/farmacología , Células RAW 264.7RESUMEN
Cationic polymers have great potential for cancer therapy due to their unique interactions with cancer cells. However, their clinical application remains limited by their high toxicity. Here we show a cell membrane-targeting cationic polymer with antineoplastic activity (Pmt) and a second near-infrared (NIR-II) fluorescent biodegradable polymer with photosensitizer Bodipy units and reactive oxygen species (ROS) responsive thioketal bonds (PBodipy). Subsequently, these two polymers can self-assemble into antineoplastic nanoparticles (denoted mt-NPBodipy) which could further accumulate at the tumor and destroy cell membranes through electrostatic interactions, resulting in cell membrane destabilization. Meanwhile, the photosensitizer Bodipy produces ROS to induce damage to cell membranes, proteins, and DNAs to kill cancer cells concertedly, finally resulting in cell membrane lysis and cancer cell death. This work highlights the use of near-infrared light to spatially and temporarily control cationic polymers for photodynamic therapy, photo-immunotherapy, and NIR-II fluorescence for bio-imaging.
Asunto(s)
Membrana Celular , Inmunoterapia , Rayos Infrarrojos , Nanopartículas , Fotoquimioterapia , Fármacos Fotosensibilizantes , Especies Reactivas de Oxígeno , Humanos , Nanopartículas/química , Membrana Celular/metabolismo , Membrana Celular/efectos de los fármacos , Inmunoterapia/métodos , Animales , Especies Reactivas de Oxígeno/metabolismo , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Ratones , Fotoquimioterapia/métodos , Línea Celular Tumoral , Compuestos de Boro/química , Compuestos de Boro/farmacología , Neoplasias/terapia , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Polímeros/química , Antineoplásicos/farmacología , Antineoplásicos/química , FemeninoRESUMEN
Excessive reactive oxygen species (ROS) in cellular environments leads to oxidative stress, which underlies numerous diseases, including inflammatory diseases, neurodegenerative diseases, cardiovascular diseases, and cancer. Oxidative stress can be particularly damaging to biological membranes such as those found in mitochondria, which are abundant with polyunsaturated fatty acids (PUFAs). Oxidation of these biological membranes results in concomitant disruption of membrane structure and function, which ultimately leads to cellular dysfunction. Graphene quantum dots (GQDs) have garnered significant interest as a therapeutic agent for numerous diseases that are linked to oxidative stress. Specifically, GQDs have demonstrated an ability to protect mitochondrial structure and function under oxidative stress conditions. However, the fundamental mechanisms by which GQDs interact with membranes in oxidative environments are poorly understood. Here, we used C11-BODIPY, a fluorescent lipid oxidation probe, to develop quantitative fluorescence assays that determine both the extent and rate of oxidation that occurs to PUFAs in biological membranes. Based on kinetics principles, we have developed a generalizable model that can be used to assess the potency of antioxidants that scavenge ROS in the presence of biological membranes. By augmenting our fluorescence assays with 1H NMR spectroscopy, the results demonstrate that GQDs scavenge nascent hydroxyl and peroxyl ROS that interact with membranes and that GQDs are potent inhibitors of ROS-induced lipid oxidation in PUFA-containing biological membranes. The antioxidant potency of GQDs is comparable to or even greater than established antioxidant molecules, such as ascorbic acid and Trolox. This work provides mechanistic insights into the mitoprotective properties of GQDs under oxidative stress conditions, as well as a quantitative framework for assessing antioxidant interactions in biological membrane systems.
Asunto(s)
Grafito , Peroxidación de Lípido , Puntos Cuánticos , Puntos Cuánticos/química , Grafito/química , Grafito/farmacología , Peroxidación de Lípido/efectos de los fármacos , Membrana Celular/metabolismo , Membrana Celular/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Antioxidantes/farmacología , Antioxidantes/química , Ensayo de Materiales , Compuestos de Boro/química , Compuestos de Boro/farmacología , Estrés Oxidativo/efectos de los fármacos , Tamaño de la Partícula , Humanos , Colorantes Fluorescentes/química , Ácidos Grasos Insaturados/química , Ácidos Grasos Insaturados/farmacología , Ácidos Grasos Insaturados/metabolismo , Estructura MolecularRESUMEN
Boron neutron capture therapy (BNCT) is a unique radiotherapy of selectively eradicating tumor cells using boron compounds (e.g., 4-borono-L-phenylalanine [BPA]) that are heterogeneously taken up at the cellular level. Such heterogenicity potentially reduces the curative efficiency. However, the effects of temporospatial heterogenicity on cell killing remain unclear. With the technical combination of radiation track detector and biophysical simulations, this study revealed the cell cycle-dependent heterogenicity of BPA uptake and subsequent biological effects of BNCT on HeLa cells expressing fluorescent ubiquitination-based cell cycle indicators, as well as the modification effects of polyvinyl alcohol (PVA). The results showed that the BPA concentration in the S/G2/M phase was higher than that in the G1/S phase and that PVA enhances the biological effects both by improving the uptake and by canceling the heterogenicity. These findings might contribute to a maximization of therapeutic efficacy when BNCT is combined with PVA and/or cell cycle-specific anticancer agents.
Asunto(s)
Compuestos de Boro , Terapia por Captura de Neutrón de Boro , Ciclo Celular , Alcohol Polivinílico , Humanos , Terapia por Captura de Neutrón de Boro/métodos , Células HeLa , Alcohol Polivinílico/química , Ciclo Celular/efectos de la radiación , Ciclo Celular/efectos de los fármacos , Compuestos de Boro/farmacología , Fenilalanina/análogos & derivados , Fenilalanina/farmacologíaRESUMEN
The spin-orbit charge transfer intersystem crossing (SOCT-ISC) photophysical process has shown great potential for constructing heavy-atom-free photosensitizers (PSs) for photodynamic therapy (PDT) of tumors. However, for almost all such PSs reported to date, the SOCT-ISC is driven by the acceptor-excited photoinduced electron transfer (a-PeT). In this work, for the first time the donor-excited photoinduced electron transfer (d-PeT)-driven SOCT-ISC mechanism is utilized to construct the heavy-atom-free PSs for PDT of tumors by directly installing the electron-deficient N-alkylquinolinium unit (as an electron acceptor) into the meso-position of the near-infrared (NIR) distyryl Bodipy chromophore (as an electron donor). In the less polar environment, the PSs exist as the monomer and promote the production of singlet oxygen (1O2) (Type-II) relying on the d-PeT-driven population of the triplet excited state via SOCT-ISC, whereas in the aqueous environment, they exist as nanoaggregates and induce the generation of superoxides (O2-â¢) and hydroxyl radicals (HOâ¢) (Type-I) via the d-PeT-driven formation of the delocalized charge-separated state. The PSs could rapidly be internalized into cancer cells and induce the simultaneous production of intracellular 1O2, O2-â¢, and HO⢠upon NIR light irradiation, endowing the PSs with superb photocytotoxicity with IC50 values up to submicromolar levels whether under normoxia or under hypoxia. Based on the PSs platform, a tumor-targetable PS is developed, and its abilities in killing cancer cells and in ablating tumors without damage to normal cells/tissues under NIR light irradiation are verified in vitro and in vivo. The study expands the design scope of PSs by introducing the d-PeT conception, thus being highly valuable for achieving novel PSs in the realm of tumor PDT.
Asunto(s)
Fotoquimioterapia , Fármacos Fotosensibilizantes , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/efectos de la radiación , Humanos , Ratones , Animales , Transporte de Electrón/efectos de los fármacos , Oxígeno Singlete/metabolismo , Oxígeno Singlete/química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Compuestos de Boro/química , Compuestos de Boro/farmacología , Compuestos de Boro/efectos de la radiación , Línea Celular Tumoral , Rayos Infrarrojos , Supervivencia Celular/efectos de los fármacos , Hipoxia Tumoral/efectos de los fármacos , Ratones Endogámicos BALB CRESUMEN
Photoimmunotherapy represents an innovative approach to enhancing the efficiency of immunotherapy in cancer treatment. This approach involves the fusion of immunotherapy and phototherapy (encompassing techniques like photodynamic therapy (PDT) and photothermal therapy (PTT)). Boron-dipyrromethene (BODIPY) has the potential to trigger immunotherapy owing to its excellent PD and PT efficiency. However, the improvements in water solubility, bioavailability, PD/PT combined efficiency, and tumor tissue targeting of BODIPY require introduction of suitable carriers for potential practical application. Herein, a disulfide bond-based hollow mesoporous organosilica (HMON) with excellent biocompatibility and GSH-responsive degradation properties was used as a carrier to load a bithiophene Aza-BODIPY dye (B5), constructing a sample chemotherapy reagent-free B5@HMON nanoplatform achieving triple-synergistic photoimmunotherapy. HMON, involving disulfide bond, is utilized to improve water solubility, tumor tissue targeting, and PD efficiency by depleting GSH and enhancing host-guest interaction between B5 and HMO. The study reveals that HMON's large specific surface area and porous properties significantly enhance the light collection and oxygen adsorption capacity. The HMON's rich mesoporous structure and internal cavity achieved a loading rate of B5 at 11â¯%. It was found that the triple-synergistic nanoplatform triggered a stronger anti-tumor immune response, including tumor invasion, cytokine production, calreticulin translocation, and dendritic cell maturation, eliciting specific tumor-specific immunological responses in vivo and in vitro. The BALB/c mouse model with 4T1 tumors was used to assess tumor suppression efficiency in vivo, showing that almost all tumors in the B5@HMON group disappeared after 14 days. Such a simple chemotherapy reagent-free B5@HMON nanoplatform achieved triple-synergistic photoimmunotherapy.
Asunto(s)
Compuestos de Boro , Glutatión , Inmunoterapia , Animales , Compuestos de Boro/química , Compuestos de Boro/farmacología , Ratones , Inmunoterapia/métodos , Glutatión/química , Glutatión/metabolismo , Compuestos de Organosilicio/química , Compuestos de Organosilicio/farmacología , Ratones Endogámicos BALB C , Humanos , Tamaño de la Partícula , Tiofenos/química , Tiofenos/farmacología , Propiedades de Superficie , Fotoquimioterapia , Nanopartículas/química , Fototerapia/métodos , Línea Celular Tumoral , Femenino , Proliferación Celular/efectos de los fármacos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Supervivencia Celular/efectos de los fármacos , PorosidadRESUMEN
The potential of using image-guided photodynamic therapy (ig-PDT) for cancer, especially with highly biocompatible fluorescent agents free of heavy atoms, is well recognized. This is due to key advantages related to minimizing adverse side effects associated with standard cancer chemotherapy. However, this theragnostic approach is strongly limited by the lack of synthetically-accessible and easily-modulable chemical scaffolds, enabling the rapid design and construction of advanced agents for clinical ig-PDT. In fact, there are still very few ig-PDT agents clinically approved. Herein we report a readily accessible, easy-tunable and highly fluorescent all-organic small photosensitizer, as a model design for accelerating the development and translation of advanced ig-PDT agents for cancer. This scaffold is based on BODIPY, which assures high fluorescence, accessibility, and ease of performance adaptation by workable chemistry. The optimal PDT performance of this BODIPY dye, tested in highly resistant pancreatic cancer cells, despite its high fluorescent behavior, maintained even after fixation and cancer cell death, is based on its selective accumulation in mitochondria. This induces apoptosis upon illumination, as evidenced by proteomic studies and flow cytometry. All these characteristics make the reported BODIPY-based fluorescent photosensitizer a valuable model for the rapid development of ig-PDT agents for clinical use.
Asunto(s)
Compuestos de Boro , Colorantes Fluorescentes , Fotoquimioterapia , Fármacos Fotosensibilizantes , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/síntesis química , Humanos , Compuestos de Boro/química , Compuestos de Boro/farmacología , Compuestos de Boro/síntesis química , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Estructura Molecular , Línea Celular Tumoral , Imagen Óptica , Supervivencia Celular/efectos de los fármacosRESUMEN
Triple negative breast cancer (TNBC) is a notoriously difficult disease to treat, and many of the existing TNBC chemotherapeutics lack tumor selectivity and the capability for simultaneously visualizing and monitoring their own activity in the biological context. However, TNBC cells have been known to generate high levels of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2). To this end, three novel small molecule theranostics 1a, 1c, and 2 consisting of both H2O2-responsive nitrogen mustard prodrug and profluorophore character have been designed, synthesized, and evaluated as targeted cancer therapeutics and bioimaging agents. The three theranostics comprise of boronate esters that deactivate nitrogen mustard functional groups and fluorophores but allow their selective activation through H2O2-specific oxidative deboronation for the release of the active drug and fluorophore. The three theranostics demonstrated H2O2-inducible DNA-alkylating capability and fluorescence turn-on properties in addition to selective anticancer activity. They are particularly effective in killing TNBC MDA-MB-468 cells with high H2O2 level while safe to normal epithelial MCF-10A cell. The conjugated boron-masked fluorophores in 1c and 2 are highly responsive towards H2O2, which enabled tracking of the theranostics in living cellular mitochondria and nucleus organelles. The three theranostics 1a, 1c, and 2 are capable of both selective release of the active drug to take effect in H2O2-rich cancer sites and simultaneously monitoring its activity. This single molecule system is of utmost importance to understand the function, efficacy, and mechanism of the H2O2-activated prodrugs and theranostics within the living recipient.
Asunto(s)
Antineoplásicos , Colorantes Fluorescentes , Peróxido de Hidrógeno , Nanomedicina Teranóstica , Humanos , Alquilación , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , ADN/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Fluorescencia , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/farmacología , Peróxido de Hidrógeno/farmacología , Estructura Molecular , Imagen Óptica , Profármacos/farmacología , Profármacos/química , Profármacos/síntesis química , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Cumarinas/síntesis química , Cumarinas/química , Cumarinas/farmacología , Compuestos de Boro/síntesis química , Compuestos de Boro/química , Compuestos de Boro/farmacologíaRESUMEN
The grafting of antimicrobial peptides onto mesoporous silica particles and their controlled release using a green light-responsive linker, which enables tunable release-concentration-time profiles, is presented. The mesoporous silica surface is functionalized with antimicrobial peptides employing sequential functionalization steps, including the grafting of 3-[(2-propynylcarbamate)propyl]triethoxysilane (PPTEOS) as anchor, boron-dipyrromethene (BODIPY) as photosensitive linker, and C14R peptides as antimicrobial agents. Characterization using scanning electron microscopy (SEM), transmission electron microscopy (TEM), attenuated total reflectance infrared (ATR-IR) spectroscopy, and thermogravimetric analysis (TGA) validate the successful fabrication and functionalization of mesoporous silica. The ester-1,2,3-triazole-BODIPY demonstrates high sensitivity to green light and enables C14R antimicrobial peptide release with adjusted concentration-time profiles. Under the applied conditions up to 64 µg mL-1 were released within 40 minutes. The antimicrobial activity of the released C14R on Escherichia coli. BL21(DE3) is demonstrated. Overall, the use of the photosensitive linker not only provides a promising avenue for controlling the release of biomolecules and therapeutics but also opens up opportunities for the development of materials for targeted release in wound dressings, for example.
Asunto(s)
Péptidos Antimicrobianos , Escherichia coli , Dióxido de Silicio , Dióxido de Silicio/química , Porosidad , Péptidos Antimicrobianos/química , Péptidos Antimicrobianos/farmacología , Escherichia coli/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/química , Preparaciones de Acción Retardada/química , Pruebas de Sensibilidad Microbiana , Propiedades de Superficie , Tamaño de la Partícula , Liberación de Fármacos , Compuestos de Boro/química , Compuestos de Boro/farmacologíaRESUMEN
The interplay between humans and their microbiome is crucial for various physiological processes, including nutrient absorption, immune defense, and maintaining homeostasis. Microbiome alterations can directly contribute to diseases or heighten their likelihood. This relationship extends beyond humans; microbiota play vital roles in other organisms, including eukaryotic pathogens causing severe diseases. Notably, Wolbachia, a bacterial microbiota, is essential for parasitic worms responsible for lymphatic filariasis and onchocerciasis, devastating human illnesses. Given the lack of rapid cures for these infections and the limitations of current treatments, new drugs are imperative. Here, we disrupt Wolbachia's symbiosis with pathogens using boron-based compounds targeting an unprecedented Wolbachia enzyme, leucyl-tRNA synthetase (LeuRS), effectively inhibiting its growth. Through a compound demonstrating anti-Wolbachia efficacy in infected cells, we use biophysical experiments and x-ray crystallography to elucidate the mechanism behind Wolbachia LeuRS inhibition. We reveal that these compounds form adenosine-based adducts inhibiting protein synthesis. Overall, our study underscores the potential of disrupting key microbiota to control infections.
Asunto(s)
Microbiota , Wolbachia , Wolbachia/efectos de los fármacos , Humanos , Animales , Leucina-ARNt Ligasa/metabolismo , Leucina-ARNt Ligasa/antagonistas & inhibidores , Aminoacil-ARNt Sintetasas/metabolismo , Aminoacil-ARNt Sintetasas/antagonistas & inhibidores , Cristalografía por Rayos X , Compuestos de Boro/farmacología , Compuestos de Boro/química , Simbiosis , Modelos MolecularesRESUMEN
Boron neutron capture therapy (BNCT) is an emerging approach for treating malignant tumors with binary targeting. However, its clinical application has been hampered by insufficient 10B accumulation in tumors and low 10B concentration ratios of tumor-to-blood (T/B) and tumor-to-normal tissue (T/N). Herein, we developed fluorinated BPA derivatives with different fluorine groups as boron delivery agents for enabling sufficient 10B accumulation in tumors and enhancing T/B and T/N ratios. Our findings demonstrated that fluorinated BPA derivatives had good biological safety. Furthermore, fluorinated BPA derivatives showed improved 10B accumulation in tumors and enhanced T/B and T/N ratios compared to the clinical boron drug fructose-BPA (f-BPA). In particular, in B16-F10 tumor-bearing mice, fluorinated BPA derivatives met the requirements for clinical BNCT even at half of the clinical dose. Thus, fluorinated BPA derivatives are potentially effective boron delivery agents for clinical BNCT in melanoma.
Asunto(s)
Compuestos de Bencidrilo , Terapia por Captura de Neutrón de Boro , Halogenación , Animales , Ratones , Terapia por Captura de Neutrón de Boro/métodos , Compuestos de Bencidrilo/química , Compuestos de Bencidrilo/farmacología , Fenoles/química , Fenoles/farmacología , Humanos , Ratones Endogámicos C57BL , Compuestos de Boro/química , Compuestos de Boro/farmacología , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Estructura MolecularRESUMEN
Senescence is a cellular response having physiological and reparative functions to preserve tissue homeostasis and suppress tumor growth. However, the accumulation of senescent cells would cause deleterious effects that lead to age-related dysfunctions and cancer progression. Hence, selective detection and elimination of senescent cells are crucial yet remain a challenge. A ß-galactosidase (ß-gal)-activated boron dipyrromethene (BODIPY)-based photosensitizer (compound 1) is reported here that can selectively detect and eradicate senescent cells. It contains a galactose moiety connected to a pyridinium BODIPY via a self-immolative nitrophenylene linker, of which the photoactivity is effectively quenched. Upon interactions with the senescence-associated ß-gal, it undergoes enzymatic hydrolysis followed by self-immolation, leading to the release of an activated BODIPY moiety by which the fluorescence emission and singlet oxygen generation are restored. The ability of 1 to detect and eliminate senescent cells is demonstrated in vitro and in vivo, using SK-Mel-103 tumor-bearing mice treated with senescence-inducing therapy. The results demonstrate that 1 can be selectively activated in senescent cells to trigger a robust senolytic effect upon irradiation. This study breaks new ground in the design and application of new senolytic agents based on photodynamic therapy.
Asunto(s)
Senescencia Celular , Fotoquimioterapia , Fármacos Fotosensibilizantes , Porfobilinógeno , beta-Galactosidasa , beta-Galactosidasa/metabolismo , Senescencia Celular/efectos de los fármacos , Fármacos Fotosensibilizantes/farmacología , Animales , Ratones , Fotoquimioterapia/métodos , Humanos , Porfobilinógeno/análogos & derivados , Porfobilinógeno/farmacología , Porfobilinógeno/química , Compuestos de Boro/farmacología , Compuestos de Boro/química , Modelos Animales de Enfermedad , Línea Celular TumoralRESUMEN
As a developing radiation treatment for tumors, neutron capture therapy (NCT) has less side effects and a higher efficacy than conventional radiation therapy. Drugs with specific isotopes are indispensable counterparts of NCT, as they are the indespensable part of the neutron capture reaction. Since the creation of the first and second generations of boron-containing reagents, NCT has significantly advanced. Notwithstanding, the extant NCT medications, predominantly comprised of small molecule boron medicines, have encountered challenges such monofunctionality, inadequate targeting of tumors, and hypermetabolism. There is an urgent need to promote the research and development of new types of NCT drugs. Bio-nanomaterials can be introduced into the realm of NCT, and nanotechnology can give conventional medications richer functionality and significant adaptability. This can complement the advantages of each other and is expected to develop more new drugs with less toxicity, low side effects, better tumor targeting, and high biocompatibility. In this review, we summarized the research progress of nano-drugs in NCT based on the different types and sources of isotopes used, and introduced the attempts and efforts made by relevant researchers in combining nanomaterials with NCT, hoping to provide pivotal references for promoting the development of the field of tumor radiotherapy.
Asunto(s)
Neoplasias , Humanos , Neoplasias/radioterapia , Neoplasias/tratamiento farmacológico , Animales , Terapia por Captura de Neutrón/métodos , Nanopartículas/química , Nanoestructuras/uso terapéutico , Nanoestructuras/química , Nanotecnología/métodos , Terapia por Captura de Neutrón de Boro/métodos , Compuestos de Boro/uso terapéutico , Compuestos de Boro/química , Compuestos de Boro/farmacologíaRESUMEN
Boron neutron capture therapy (BNCT) targets invasive, radioresistant cancers but requires a selective and high B-10 loading boron drug. This manuscript investigates boron-rich poly(ethylene glycol)-block-(poly(4-vinylphenyl boronate ester)) polymer micelles synthesized via atom transfer radical polymerization for their potential application in BNCT. Transmission electron microscopy (TEM) revealed spherical micelles with a uniform size of 43 ± 10 nm, ideal for drug delivery. Additionally, probe sonication proved effective in maintaining the micelles' size and morphology postlyophilization and reconstitution. In vitro studies with B16-F10 melanoma cells demonstrated a 38-fold increase in boron accumulation compared to the borophenylalanine drug for BNCT. In vivo studies in a B16-F10 tumor-bearing mouse model confirmed enhanced tumor selectivity and accumulation, with a tumor-to-blood (T/B) ratio of 2.5, surpassing BPA's T/B ratio of 1.8. As a result, mice treated with these micelles experienced a significant delay in tumor growth, highlighting their potential for BNCT and warranting further research.
Asunto(s)
Terapia por Captura de Neutrón de Boro , Micelas , Terapia por Captura de Neutrón de Boro/métodos , Animales , Ratones , Melanoma Experimental/patología , Melanoma Experimental/tratamiento farmacológico , Ácidos Borónicos/química , Línea Celular Tumoral , Polietilenglicoles/química , Polímeros/química , Ratones Endogámicos C57BL , Ésteres/química , Ésteres/farmacología , Compuestos de Boro/química , Compuestos de Boro/farmacologíaRESUMEN
Photomodulable fluorescent probes are drawing increasing attention due to their applications in advanced bioimaging. Whereas photoconvertible probes can be advantageously used in tracking, photoswitchable probes constitute key tools for single-molecule localization microscopy to perform super-resolution imaging. Herein, we shed light on a red and far-red BODIPY, namely, BDP-576 and BDP-650, which possess both properties of conversion and switching. Our study demonstrates that these pyrrolyl-BODIPYs convert into typical green- and red-emitting BODIPYs that are perfectly adapted to microscopy. We also showed that this pyrrolyl-BODIPYs undergo Directed Photooxidation Induced Conversion, a photoconversion mechanism that we recently introduced, where the pyrrole moiety plays a central role. These unique features were used to develop targeted photoconvertible probes toward different organelles or subcellular units (plasma membrane, mitochondria, nucleus, actin, Golgi apparatus, etc.) using chemical targeting moieties and a Halo tag. We notably showed that BDP-650 could be used to track intracellular vesicles over more than 20 min in two-color imagings with laser scanning confocal microscopy, demonstrating its robustness. The switching properties of these photoconverters were studied at the single-molecule level and were then successfully used in live single-molecule localization microscopy in epithelial cells and neurons. Both membrane- and mitochondria- targeted probes could be used to decipher membrane 3D architecture and mitochondrial dynamics at the nanoscale. This study builds a bridge between the photoconversion and photoswitching properties of probes undergoing directed photooxidation and shows the versatility and efficacy of this mechanism in advanced live imaging.
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Compuestos de Boro , Compuestos de Boro/química , Compuestos de Boro/farmacología , Fotoquímica/métodos , Oxidación-Reducción , Supervivencia Celular/efectos de los fármacos , Humanos , Células HeLa , Neuronas/citología , Neuronas/efectos de los fármacosRESUMEN
In this paper, two near-infrared BODIPY photosensitizers, Id-BDPI and Cz-BDPI, were obtained by modifying the indole and carbazole aromatic heterocycles in the core of BODIPY. The maximum absorption wavelengths of Id-BDPI and Cz-BDPI were 694 nm and 722 nm, and their singlet oxygen yields were 48% and 48.4%, respectively. In the simulated tumor cell photodynamic therapy, Id-BDPI and Cz-BDPI could effectively inhibit the growth of A549 tumor cells under near-infrared light. Meanwhile, the lysosomal co-localization coefficients of Id-BDPI and Cz-BDPI with A549 tumor cells were 0.94 and 0.89, respectively, showing high lysosomal targeting ability and biocompatibility. The two-photon absorption cross sections measured at 1050 nm by the Z-scanning method were 661.8 GM and 715.6 GM, respectively, and Cz-BDPI was further successfully applied to two-photon fluorescence imaging and two-photon excited singlet oxygen generation in zebrafish. The above results indicate that the introduction of aromatic heterocycles can effectively enhance the photodynamic efficacy of BODIPY photosensitizers, and the larger two-photon absorption cross section also brings potential for two-photon photodynamic therapy applications.
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Compuestos de Boro , Rayos Infrarrojos , Fotoquimioterapia , Fotones , Fármacos Fotosensibilizantes , Oxígeno Singlete , Pez Cebra , Compuestos de Boro/química , Compuestos de Boro/farmacología , Compuestos de Boro/síntesis química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/síntesis química , Oxígeno Singlete/metabolismo , Humanos , Animales , Células A549 , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacosRESUMEN
Herein, we report a composite COF material loaded with a Pt nanoenzyme and an organic photosensitizer BODIPY, synthesized via a stepwise post-synthetic modification. The obtained Pt@COF-BDP nanoparticles can efficiently and continuously convert H2O2 to O2, thereby increasing the efficiency of single-linear oxygen production and achieving efficient tumor inhibition.
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Compuestos de Boro , Estructuras Metalorgánicas , Fotoquimioterapia , Fármacos Fotosensibilizantes , Platino (Metal) , Compuestos de Boro/química , Compuestos de Boro/farmacología , Humanos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/síntesis química , Platino (Metal)/química , Platino (Metal)/farmacología , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Estructuras Metalorgánicas/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Ratones , Nanopartículas/química , Hipoxia Tumoral/efectos de los fármacos , Peróxido de Hidrógeno/químicaRESUMEN
Photodynamic Therapy (PDT) is recognized for its exceptional effectiveness as a promising cancer treatment method. However, it is noted that overexposure to the dosage and sunlight in traditional PDT can result in damage to healthy tissues, due to the low tumor selectivity of currently available photosensitizers (PSs). To address this challenge, we introduce herein a new strategy where the small molecule-targeted agent, erlotinib, is integrated into a boron dipyrromethene (BODIPY)-based PS to form conjugate 6 to enhance the precision of PDT. This conjugate demonstrates optical absorption, fluorescence emission, and singlet oxygen generation efficiency comparable to the reference compound 7, which lacks erlotinib. In vitro studies reveal that, after internalization, conjugate 6 predominantly accumulates in the lysosomes of HepG2 cells, exhibiting significant photocytotoxicity with an IC50 value of 3.01 µM. A distinct preference for HepG2 cells over HELF cells is observed with conjugate 6 but not with compound 7. In vivo experiments further confirm that conjugate 6 has a specific affinity for tumor tissues, and the combination treatment of conjugate 6 with laser illumination can effectively eradicate H22 tumors in mice with outstanding biosafety. This study presents a novel and potential PS for achieving precise PDT against cancer.
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Clorhidrato de Erlotinib , Neoplasias Hepáticas , Fotoquimioterapia , Fármacos Fotosensibilizantes , Porfobilinógeno , Humanos , Fotoquimioterapia/métodos , Animales , Ratones , Porfobilinógeno/análogos & derivados , Porfobilinógeno/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Células Hep G2 , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Clorhidrato de Erlotinib/farmacología , Clorhidrato de Erlotinib/química , Compuestos de Boro/química , Compuestos de Boro/farmacologíaRESUMEN
Venous leg ulcers (VLUs) pose a growing healthcare challenge due to aging, obesity, and sedentary lifestyles. Despite various treatments available, addressing the complex nature of VLUs remains difficult. In this context, this study investigates repurposing boronated drugs to inhibit arginase 1 activity for VLU treatment. The molecular docking study conducted by Schrodinger GLIDE targeted the binuclear manganese cluster of arginase 1 enzyme (2PHO). Further, the ligand-protein complex was subjected to molecular dynamic studies at 500â¯ns in Gromacs-2019.4. Trajectory analysis was performed using the GROMACS simulation package of protein RMSD, RMSF, RG, SASA, and H-Bond. The docking study revealed intriguing results where the tavaborole showed a better docking score (-3.957 Kcal/mol) compared to the substrate L-arginine (-3.379 Kcal/mol) and standard L-norvaline (-3.141 Kcal/mol). Tavaborole interaction with aspartic acid ultimately suggests that the drug molecule binds to the catalytic site of arginase 1, potentially influencing the enzyme's function. The dynamics study revealed the compounds' stability and compactness of the protein throughout the simulation. The RMSD, RMSF, SASA, RG, inter and intra H-bond, PCA, FEL, and MMBSA studies affirmed the ligand-protein and protein complex flexibility, compactness, binding energy, van der waals energy, and solvation dynamics. These results revealed the stability and the interaction of the ligand with the catalytic site of arginase 1 enzyme, triggering the study towards the VLU treatment.