RESUMO
Investigating the interactions between nanomaterials and the cells they are likely to encounter in vivo is a critical aspect of designing nanomedicines for imaging and therapeutic applications. Immune cells such as dendritic cells, macrophages, and myeloid derived suppressor cells have a frontline role in the identification and removal of foreign materials from the body, with interactions shown to be heavily dependent on variables such as nanoparticle size, charge, and surface chemistry. Interactions such as cellular association or uptake of nanoparticles can lead to diminished functionality or rapid clearance from the body, making it critical to consider these interactions when designing and synthesizing nanomaterials for biomedical applications ranging from drug delivery to imaging and biosensing. We investigated the interactions between PEGylated organosilica nanoparticles and naturally endocytic immune cells grown from stem cells in murine bone marrow. Specifically, we varied the particle size from 60 nm up to 1000 nm and investigated the effects of size on immune cell association, activation, and maturation with these critical gatekeeper cells. These results will help inform future design parameters for in vitro and in vivo biomedical applications utilizing organosilica nanoparticles.
Assuntos
Nanopartículas , Compostos de Organossilício , Animais , Nanopartículas/química , Camundongos , Compostos de Organossilício/química , Compostos de Organossilício/farmacologia , Tamanho da Partícula , Polietilenoglicóis/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/citologia , Macrófagos/imunologia , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismoRESUMO
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.
Assuntos
Compostos de Boro , Glutationa , Imunoterapia , Animais , Compostos de Boro/química , Compostos de Boro/farmacologia , Camundongos , Imunoterapia/métodos , Glutationa/química , Glutationa/metabolismo , Compostos de Organossilício/química , Compostos de Organossilício/farmacologia , Camundongos Endogâmicos BALB C , Humanos , Tamanho da Partícula , Tiofenos/química , Tiofenos/farmacologia , Propriedades de Superfície , Fotoquimioterapia , Nanopartículas/química , Fototerapia/métodos , Linhagem Celular Tumoral , Feminino , Proliferação de Células/efeitos dos fármacos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , PorosidadeRESUMO
Background: Drug therapy for eye diseases has been limited by multiple protective mechanisms of the eye, which can be improved using well-designed drug delivery systems. Mesoporous silica nanoparticles (MSNs) had been used in many studies as carriers of therapeutic agents for ocular diseases treatment. However, no studies have focused on ocular biosafety. Considering that MSNs containing tetrasulfur bonds have unique advantages and have drawn increasing attention in drug delivery systems, it is necessary to explore the ocular biosafety of tetrasulfur bonds before their widespread application as ophthalmic drug carriers. Methods: In this study, hollow mesoporous silica nanoparticles (HMSNs) with different tetrasulfur bond contents were prepared and characterized. The ocular biosafety of HMSN-E was evaluated in vitro on the three selected ocular cell lines, including corneal epithelial cells, lens epithelial cells and retinal endothelial cells (HREC), and in vivo by using topical eye drops and intravitreal injections. Results: In cellular experiments, HMSNs caused obvious S content-dependent cytotoxic effect. HMSNs with the highest tetrasulfur bond content (HMSN-E), showed the highest cytotoxicity among all the HMSNs, and HREC was the most vulnerable cell to HMSN-E. It was shown that HMSN-E could react with intracellular GSH to generate H2S and decrease intracellular GSH concentration. Treatment of HREC with HMSN-E increased intracellular ROS, decreased mitochondrial membrane potential, and induced cell cycle arrest at the G1/S checkpoint, finally caused apoptosis and necrosis of HREC. Topical eye drops of HMSN-E could cause corneal damage. The intravitreal injection of HMSN-E could induce inflammation in the vitreum and ganglion cell layers, resulting in vitreous opacities and retinal abnormalities. Conclusion: The incorporation of tetrasulfur bonds into HMSN can have toxic effects on ocular tissues. Therefore, when mesoporous silica nanocarriers are designed for ophthalmic pharmaceuticals, the ocular toxicity of the tetrasulfur bonds should be considered.
Assuntos
Nanopartículas , Dióxido de Silício , Humanos , Animais , Nanopartículas/química , Dióxido de Silício/química , Dióxido de Silício/toxicidade , Linhagem Celular , Porosidade , Portadores de Fármacos/química , Apoptose/efeitos dos fármacos , Coelhos , Sobrevivência Celular/efeitos dos fármacos , Olho/efeitos dos fármacos , Soluções Oftálmicas/química , Soluções Oftálmicas/farmacologia , Compostos de Organossilício/química , Compostos de Organossilício/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Injeções IntravítreasRESUMO
In this work, a polyhedral silsesquioxane (POSS) was used as an engineered drug delivery system for two oxindolimine-copper(II) anticancer complexes, [Cu(isaepy)]+ and [Cu(isapn)]+. The interest in hybrid POSS comes from the necessity of developing materials that can act as adjuvants to improve the cytotoxicity of non-soluble metallodrugs. Functionalization of POSS with a triazole ligand (POSS-atzac) permitted the anchorage of such copper complexes, producing hybrid materials with efficient cytotoxic effects. Structural and morphological characterizations of these copper-POSS systems were performed by using different techniques (IR, NMR, thermogravimetric analysis). A combination of continuous-wave (CW) and pulsed EPR (HYSCORE) spectroscopies conducted at the X-band have enabled the complete characterization of the coordination environment of the copper ion in the POSS-atzac matrix. Additionally, the cytotoxic effects of the loaded materials, [Cu(isapn)]@POSS-atzac and [Cu(isaepy)]@POSS-atzac, were assessed toward melanomas (SK-MEL), in comparison to non-tumorigenic cells (fibroblast P4). Evaluation of their nuclease activity or ability to facilitate cleavage of DNA indicated concentrations as low as 0.6 µg mL-1, while complete DNA fragmentation was observed at 25 µg mL-1. By using adequate scavengers, investigations on active intermediates responsible for their cytotoxicity were performed, both in the absence and in the presence of ascorbate as a reducing agent. Based on the observed selective cytotoxicity of these materials toward melanomas, investigations on the reactivity of these complexes and corresponding POSS-materials with melanin, a molecule that contributes to melanoma resistance to chemotherapy, were carried out. Results indicated the main role of the binuclear copper species, formed at the surface of the silica matrix, in the observed reactivity and selectivity of these copper-POSS systems.
Assuntos
Antineoplásicos , Complexos de Coordenação , Cobre , Melanoma , Compostos de Organossilício , Cobre/química , Cobre/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Compostos de Organossilício/química , Compostos de Organossilício/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Macromolecule branching upon polyhedral oligomeric silsesquioxanes (POSS) via "click" chemistry has previously been reported for promoting natural biological responses in vitro, particularly when regarding their demonstrated biocompatibility and structural robustness as potential macromolecule anchoring points. However, "clicking" of large molecules around POSS structures uncovers two main challenges: (1) a synthetic challenge encompassing multi-covalent attachment of macromolecules to a single nanoscale-central position, and (2) purification and separation of fully adorned nanocages from those that are incomplete due to their similar physical characteristics. Here we present peptide decoration to a T8POSS nanocage through the attachment of azido-modified trimers. Triglycine- and trialanine-methyl esters "clicked" to 97% and 92% completion, respectively, resulting in 84% and 68% yields of the fully-adorned octamers. The "clicks" halt within 27-h of the reaction time, and efforts to further increase the octamer yield were of negligible benefit. Exploration of reaction conditions reveals multiple factors preventing full octa-arm modification to all available POSS nanocages, and offers insights into macromolecule attachment between both peptides and small inorganic-organic structures, all of which require consideration for future work of this nature.
Assuntos
Química Click , Compostos de Organossilício , Peptídeos , Peptídeos/química , Compostos de Organossilício/química , Nanoestruturas/química , Azidas/químicaRESUMO
The thioredoxin system is involved in cancer development and therefore is a promising target for cancer chemotherapy. Thioredoxin reductase (TrxR) is a key component of the thioredoxin (Trx) system, and is overexpressed in many cancers to inhibit apoptosis-related proteins. Alternatively, inhibition of thioredoxin reductase and upregulation of apoptosis factors provide a therapeutic strategy for anti-tumor treatment. In this study, an ultrasound-activatable meso-organosilica nanomedicine was prepared by integrating chloroquine (CQ) into hollow mesoporous organosilica (CQ@MOS). The meso-organosilica nanomedicine can inhibit the activity of thioredoxin reductase, elevate cellular reactive oxygen species (ROS) levels, upregulate the pro-apoptotic factors in the c-Jun N-terminal kinase (JNK) apoptosis pathway and induce autophagy inhibition, further resulting in mitochondrial membrane potential (MMP) depolarization and cellular ATP content decrease, ultimately causing significant damage to tumor cells. Moreover, CQ@MOS can efficiently deliver chloroquine into cancer cells and promote an enhanced sonodynamic effect for effective anti-tumor chemotherapy and sonodynamic therapy. This study may enlighten us on a new anti-tumor strategy and suggest its promising applications in cancer treatments.
Assuntos
Antineoplásicos , Apoptose , Nanomedicina , Tiorredoxina Dissulfeto Redutase , Humanos , Apoptose/efeitos dos fármacos , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/administração & dosagem , Regulação para Cima/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Cloroquina/farmacologia , Cloroquina/química , Compostos de Organossilício/química , Compostos de Organossilício/farmacologia , Animais , Linhagem Celular Tumoral , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Terapia por UltrassomRESUMO
We present a novel approach for iodide sensing based on the heavy-atom effect to quench the green fluorescent emission of organosilicon nanoparticles (OSiNPs). The fluorescence of OSiNPs was significantly quenched (up to 97.4% quenching efficiency) in the presence of iodide ions (I-) through oxidation by hydrogen peroxide. Therefore, OSiNPs can serve as a fluorescent probe to detect I- with high selectivity and sensitivity. The highly selective response is attributed to the hydrophilic surface enabling good dispersion in aqueous solutions and the lipophilic core allowing the generated liposoluble I2 to approach and quench the fluorescence of OSiNPs. The linear working range for I- was from 0 to 50 µM, with a detection limit of 0.1 µM. We successfully applied this nanosensor to determine iodine content in edible salt. Furthermore, the fluorescent OSiNPs can be utilized for the determination of total antioxidant capacity (TAC). Antioxidants reduce I2 to I-, and the extent of quenching by the remaining I2 on the OSiNPs indicates the TAC level. The responses to ascorbic acid, pyrogallic acid, and glutathione were investigated, and the detection limit for ascorbic acid was as low as 0.03 µM. It was applied to the determination of TAC in ascorbic acid tablets and fruit juices, indicating the potential application of the OSiNP-based I2 sensing technique in the field of food analysis.
Assuntos
Antioxidantes , Corantes Fluorescentes , Iodetos , Limite de Detecção , Nanopartículas , Iodetos/análise , Iodetos/química , Nanopartículas/química , Antioxidantes/análise , Antioxidantes/química , Corantes Fluorescentes/química , Compostos de Organossilício/química , Espectrometria de Fluorescência/métodos , Ácido Ascórbico/análise , Sucos de Frutas e Vegetais/análiseRESUMO
Understanding of the interactions between macrophages and multifunctional nanoparticles is important for development of novel macrophage-based immunotherapies. Here, we investigated the effects of fluorescent thiol-organosilica particle size and surface properties on cell-particle interactions, including mitochondrial activity, using the mouse macrophage cell line J774A.1. Three different sizes of thiol-organosilica particles (150, 400, and 680 nm in diameter) containing fluorescein (OS/F150, OS/F400, and OS/F680) and particles surface functionalized with polyethylenimine (PEI) (OS/F150PEI, OS/F400PEI, and OS/F680PEI) were prepared. Flow cytometric analysis, time-lapse imaging, and single-cell analysis of particle uptake and mitochondrial activity of J774A.1 cells demonstrated variations in uptake and kinetics depending on the particle size and surface as well as on each individual cell. Cells treated with OS/F150 and OS/F150PEI showed higher uptake and mitochondrial activity than those treated with other particles. The interaction between endosomes and mitochondria was observed using 3D fluorescent imaging and was characterized by the involvement of iron transport into mitochondria by iron-containing proteins adsorbed on the particle surface. Scanning electron microscopy of the cells treated with the particles revealed alterations in cell membrane morphology, depending on particle size and surface. We performed correlative light and electron microscopy combined with time-lapse and 3D imaging to develop an integrated correlation analysis of particle uptake, mitochondrial activity, and cell membrane morphology in single macrophages. These cell-specific characteristics of macrophages against functional particles and their evaluation methods are crucial for understanding the immunological functions of individual macrophages and developing novel immunotherapies.
Assuntos
Macrófagos , Mitocôndrias , Compostos de Organossilício , Tamanho da Partícula , Propriedades de Superfície , Camundongos , Animais , Mitocôndrias/metabolismo , Macrófagos/metabolismo , Macrófagos/citologia , Compostos de Organossilício/química , Compostos de Organossilício/farmacologia , Linhagem Celular , Polietilenoimina/química , Nanopartículas/químicaRESUMO
BACKGROUND: Chemotherapy, the mainstay treatment for metastatic cancer, presents serious side effects due to off-target exposure. In addition to the negative impact on patients' quality of life, side effects limit the dose that can be administered and thus the efficacy of the drug. Encapsulation of chemotherapeutic drugs in nanocarriers is a promising strategy to mitigate these issues. However, avoiding premature drug release from the nanocarriers and selectively targeting the tumour remains a challenge. RESULTS: In this study, we present a pioneering method for drug integration into nanoparticles known as mesoporous organosilica drugs (MODs), a distinctive variant of periodic mesoporous organosilica nanoparticles (PMOs) in which the drug is an inherent component of the silica nanoparticle structure. This groundbreaking approach involves the chemical modification of drugs to produce bis-organosilane prodrugs, which act as silica precursors for MOD synthesis. Mitoxantrone (MTO), a drug used to treat metastatic breast cancer, was selected for the development of MTO@MOD nanomedicines, which demonstrated a significant reduction in breast cancer cell viability. Several MODs with different amounts of MTO were synthesised and found to be efficient nanoplatforms for the sustained delivery of MTO after biodegradation. In addition, Fe3O4 NPs were incorporated into the MODs to generate magnetic MODs to actively target the tumour and further enhance drug efficacy. Importantly, magnetic MTO@MODs underwent a Fenton reaction, which increased cancer cell death twofold compared to non-magnetic MODs. CONCLUSIONS: A new PMO-based material, MOD nanomedicines, was synthesised using the chemotherapeutic drug MTO as a silica precursor. MTO@MOD nanomedicines demonstrated their efficacy in significantly reducing the viability of breast cancer cells. In addition, we incorporated Fe3O4 into MODs to generate magnetic MODs for active tumour targeting and enhanced drug efficacy by ROS generation. These findings pave the way for the designing of silica-based multitherapeutic nanomedicines for cancer treatment with improved drug delivery, reduced side effects and enhanced efficacy.
Assuntos
Antineoplásicos , Neoplasias da Mama , Sobrevivência Celular , Mitoxantrona , Compostos de Organossilício , Humanos , Neoplasias da Mama/tratamento farmacológico , Feminino , Sobrevivência Celular/efeitos dos fármacos , Compostos de Organossilício/química , Compostos de Organossilício/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Mitoxantrona/farmacologia , Mitoxantrona/química , Mitoxantrona/uso terapêutico , Linhagem Celular Tumoral , Portadores de Fármacos/química , Dióxido de Silício/química , Porosidade , Liberação Controlada de Fármacos , Nanopartículas/química , Células MCF-7 , Nanomedicina/métodos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Bioinspired nanochannel-based sensors have elicited significant interest because of their excellent sensing performance, and robust mechanical and tunable chemical properties. However, the existing designs face limitations due to material constraints, which hamper broader application possibilities. Herein, a heteromembrane system composed of a periodic mesoporous organosilica (PMO) layer with three-dimensional (3D) network nanochannels is constructed for glutathione (GSH) detection. The unique hierarchical pore architecture provides a large surface area, abundant reaction sites and plentiful interconnected pathways for rapid ionic transport, contributing to efficient and sensitive detection. Moreover, the thioether groups in nanochannels can be selectively cleaved by GSH to generate hydrophilic thiol groups. Benefiting from the increased hydrophilic surface, the proposed sensor achieves efficient GSH detection with a detection limit of 1.2 µM by monitoring the transmembrane ionic current and shows good recovery ranges in fetal bovine serum sample detection. This work paves an avenue for designing and fabricating nanofluidic sensing systems for practical and biosensing applications.
Assuntos
Glutationa , Limite de Detecção , Compostos de Organossilício , Glutationa/química , Glutationa/análise , Glutationa/sangue , Porosidade , Compostos de Organossilício/química , Animais , Bovinos , Técnicas Biossensoriais/métodos , Membranas Artificiais , Técnicas Eletroquímicas/métodosRESUMO
As an important source of green cleaning flame retardants, bio-based materials have been widely studied by researchers. However, the development of efficient biobased flame retardants and convenient finishing methods was of great significance for the functional finishing of materials. Herein, a convenient and efficient flame retardant cotton fabric was prepared via layer by layer self-assembly (LbL) by alternating precipitation of a novel bio-based flame retardant phosphorylated sodium alginate (PSA) and alkylammonium functionalized siloxane (A-POSS). The effect of coating number on flame retardancy and thermal properties of coated cotton fabric was systematically studied. Thermogravimetric analysis (TGA) results showed that residual char contents of AP/PS-15BL under air and N2 atmospheres increased by 252.0% and 225.2%, respectively, compared with control cotton. In vertical flammability tests, both the AP/PS-10BL and AP/PS-15BL showed self-extinguishing behavior and successfully passed the UL-94 V-0 rating. More importantly, the LOI value of AP/PS-15BL was significantly increased to 35.0% from 20.0% of pure cotton fabric. Additionally, coated samples showed good mechanical properties and washable resistance. In CONE test, the peak heat release rate (PHRR) and total heat release rate (THR) of AP/PS-15BL decreased by 89.3% and 49.3% respectively, compared with control cotton. Therefore, this green and convenient flame-retardant finishing method has great application potential in the multi-functional finishing of cotton fabrics.
Assuntos
Alginatos , Fibra de Algodão , Retardadores de Chama , Alginatos/química , Fosforilação , Compostos de Organossilício/química , Têxteis , Termogravimetria , Compostos de Amônio Quaternário/químicaRESUMO
This study demonstrates the potential of sono-photodynamic therapy as an effective approach for enhancing singlet oxygen generation using the synthesized Schiff-base diaxially substituted silicon phthalocyanines. In photochemical studies, the singlet oxygen quantum yields (Φ∆) were determined as 0.43 for Si1a, 0.94 for Q-Si1a, 0.58 for S-Si1a, and 0.49 for B-Sia1. In sono-photochemical studies, the Φ∆ values were reached to 0.67 for Si1a, 1.06 for Q-Si1a, 0.65 for S-Si1a, and 0.67 for B-Sia1. In addition, this study demonstrates the therapeutic efficacy of phthalocyanines synthesized as sensitizers on the PC3 prostate cancer cell line through in vitro experiments. The application of these treatment modalities exhibited notable outcomes, leading to a substantial decrease in cell viability within the PC3 prostate cancer cell line. These findings highlight the potential of utilizing these synthesized phthalocyanines as promising therapeutic agents for prostate cancer treatment.
Assuntos
Sobrevivência Celular , Indóis , Compostos de Organossilício , Neoplasias da Próstata , Bases de Schiff , Oxigênio Singlete , Humanos , Indóis/química , Indóis/farmacologia , Bases de Schiff/química , Bases de Schiff/farmacologia , Masculino , Oxigênio Singlete/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Compostos de Organossilício/química , Compostos de Organossilício/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Células PC-3 , Fotoquimioterapia , Processos Fotoquímicos , Linhagem Celular Tumoral , Estrutura MolecularRESUMO
Sonography with its non-invasive and deep tissue-penetrating characteristics, not only contributes to promising developments in clinical disease diagnosis but also obtains acknowledgments as a prospective therapeutic approach in the field of tumor treatment. However, it remains a challenge for sonography simultaneously to achieve efficient imaging and therapeutic functionality. Here, we present an innovative integrated diagnosis and treatment paradigm by developing the nanomedicine of percarbamide-bromide-mesoporous organosilica spheres (MOS) with RGD peptide modification (PBMR) by loading percarbamide and bromide in MOS which were prepared by a one-step O/W microemulsion method. The PBMR nanomedicine effectively modifies the tumor acoustic environment to improve sonoimaging efficacy and induces sonochemical reactions to enhance the production of reactive oxygen species (ROS) for tumor treatment efficiency under sonography. The combination of PBMR nanomedicine and SDT achieved multiple ROS generation through the controlled sonochemical reactions and significantly boosted the potency of sonodynamic therapy and induced significant tumor regression with non-invasive tissue penetrability and minimizing damage to healthy tissues. Simultaneously, the generation of oxygen gas in the sonochemical process augments ultrasound reflection, resulting in a 4.9-fold increase in imaging grayscale. Our research establishes an effective platform for the synergistic integration of sonoimaging and sonodynamic antitumor therapy, offering a novel approach for precise antitumor treatment in the potential clinical applications.
Assuntos
Nanomedicina , Compostos de Organossilício , Espécies Reativas de Oxigênio , Terapia por Ultrassom , Animais , Terapia por Ultrassom/métodos , Humanos , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Compostos de Organossilício/química , Camundongos Endogâmicos BALB C , Neoplasias/terapia , Neoplasias/diagnóstico por imagem , Oligopeptídeos/química , Linhagem Celular Tumoral , Camundongos Nus , Ultrassonografia/métodos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , FemininoRESUMO
A promising therapeutic strategy in cancer treatment merges photodynamic therapy (PDT) induced apoptosis with ferroptosis, a form of programmed cell death governed by iron-dependent lipid peroxidation. Given the pivotal role of mitochondria in ferroptosis, the development of photosensitizers that specifically provoke mitochondrial dysfunction and consequentially trigger ferroptosis via PDT is of significant interest. To this end, we have designed and synthesized a novel nanoparticle, termed FECTPN, tailored to address this requisite. FECTPN harnesses a trifecta of critical attributes: precision mitochondria targeting, photoactivation capability, pH-responsive drug release, and synergistic apoptosis-ferroptosis antitumor treatment. This nanoparticle was formulated by conjugating an asymmetric silicon phthalocyanine, Chol-SiPc-TPP, with the ferroptosis inducer Erastin onto a ferritin. The Chol-SiPc-TPP is a chemically crafted entity featuring cholesteryl (Chol) and triphenylphosphine (TPP) functionalities bonded axially to the silicon phthalocyanine, enhancing mitochondrial affinity and leading to effective PDT and subsequent apoptosis of cells. Upon cellular uptake, FECTPN preferentially localizes to mitochondria, facilitated by Chol-SiPc-TPP's targeting mechanics. Photoactivation induces the synchronized release of Chol-SiPc-TPP and Erastin in the mitochondria's alkaline domain, driving the escalation of both ROSs and lipid peroxidation. These processes culminate in elevated antitumor activity compared to the singular application of Chol-SiPc-TPP-mediated PDT. A notable observation is the pronounced enhancement in glutathione peroxidase-4 (GPX4) expression within MCF-7 cells treated with FECTPN and subjected to light exposure, reflecting intensified oxidative stress. This study offers compelling evidence that FECTPN can effectively induce ferroptosis and reinforces the paradigm of a synergistic apoptosis-ferroptosis pathway in cancer therapy, proposing a novel route for augmented antitumor treatments.
Assuntos
Antineoplásicos , Apoptose , Ferroptose , Indóis , Mitocôndrias , Nanopartículas , Compostos de Organossilício , Fotoquimioterapia , Fármacos Fotossensibilizantes , Indóis/química , Indóis/farmacologia , Apoptose/efeitos dos fármacos , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Nanopartículas/química , Compostos de Organossilício/química , Compostos de Organossilício/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Tamanho da Partícula , Sobrevivência Celular/efeitos dos fármacos , Propriedades de SuperfícieRESUMO
Extracellular vesicles (EVs) are important participants in numerous pathophysiological processes, and could be used as valuable biomarkers to detect and monitor various diseases. However, facile EV isolation methods are the essential and preliminary issue for their downstream analysis and function investigation. In this work, a polyhedral oligomeric silsesquioxanes (POSS) based hybrid monolith combined metal affinity chromatography (MAC) and distearoyl phospholipid ethanolamine (DSPE) function was developed via photo-initiated thiol-ene polymerization. This synthesis process was facile, simple and convenient, and the obtained hybrid monolith could be applied to efficiently isolate EVs from bio-samples by taking advantages of the specific bond of Ti4+ and phosphate groups on the phospholipid membrane of EVs and the synergistic effect of DSPE insertion. Meanwhile, the eluted EVs could maintain their structural integrity and biological activity, suggesting they could be used for downstream application. Furthermore, 75 up-regulated proteins and 56 down-regulated proteins were identified by comparing the urinary EVs of colorectal cancer (CRC) patients and healthy donors, and these proteins might be used as potential biomarkers for early screening of CRC. These results demonstrated that this hybrid monolith could be used as a simple and convenient tool for isolating EVs from bio-samples and for wider applications in biomarker discovery.
Assuntos
Vesículas Extracelulares , Compostos de Organossilício , Humanos , Compostos de Organossilício/química , Polimerização , Interações Hidrofóbicas e Hidrofílicas , Biomarcadores , FosfolipídeosRESUMO
In this study, three new axially disubstituted silicon phthalocyanines (SiPc1-3) and their quaternized phthalocyanine derivatives (QSiPc1-3) were prepared and characterized. The biological properties (antioxidant, antimicrobial, antibiofilm, and microbial cell viability activities) of the water-soluble silicon phthalocyanines were examined, as well. A 1 % DMSO diluted with pure water was used as a solvent in biological activity studies. All the compounds exhibited high antioxidant activity. They displayed efficient antimicrobial and antimicrobial photodynamic therapeutic properties against various microorganisms, especially Gram (+) bacteria. Additionally, they demonstrated high antibiofilm activities against S. aureus and P. aeruginosa. In addition, 100 % bacterial reduction was obtained for all the studied phthalocyanines against E. coli viable cells. Besides, the DNA cleavage and binding features of compounds (QSiPc1-3) were studied using pBR322 DNA and CT-DNA, respectively. Furthermore, the human topoisomerase I enzyme inhibition activities of compounds QSiPc1-3 were studied. Anticancer properties of the water-soluble compounds were investigated using cell proliferation MTT assay. They exhibited anticarcinogenic activity against the human colon cancer cell line (DLD-1). Compounds QSiPc1 and QSiPc3 displayed a high anticarcinogenic effect on the DLD-1â cell line. The obtained results indicated that all the studied compounds may be effective biological agents and anticancer drugs after further investigations.
Assuntos
Anti-Infecciosos , Antineoplásicos , Compostos de Organossilício , Staphylococcus aureus , Humanos , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , DNA/química , Escherichia coli/efeitos dos fármacos , Ligantes , Staphylococcus aureus/efeitos dos fármacos , Compostos de Organossilício/química , Compostos de Organossilício/farmacologia , Ácidos Ftálicos/química , Ácidos Ftálicos/farmacologiaRESUMO
As a new kind of drug carrier, practical applications of hollow periodic mesoporous organosilica (HPMO) have been greatly limited by their low loading capacity for hydrophobic drugs. In this work, we demonstrated the preparation of HPMO capsules with tunable shell thickness by using 1,2-bis(triethoxysilyl)ethane as the precursor. The capsules with thin shells and thus low Young's modulus showed excellent swellability to organic solvents containing hydrophobic drugs. As a result, hydrophobic drugs, i.e., paclitaxel (PTX) could be loaded into the hollow interior of the HPMO capsules with 4 nm shell at an efficiency of ca. 120 %. The as-prepared PTX-loaded HPMO capsules were dispersible in aqueous media and showed improved performance in killing cancer cells compared to free PTX.
Assuntos
Compostos de Organossilício , Compostos de Organossilício/química , Portadores de Fármacos/química , Interações Hidrofóbicas e Hidrofílicas , Paclitaxel/farmacologia , CápsulasRESUMO
Nitrofurazone (NFZ) is carcinogenic and mutagenic to human in long-term ingestion, and it is prohibited to be added in food. In this work, a novel triphenylbenzene (TPB) functionalized fluorescent hybrid porous polymers (POSS@TPB) was constructed by using polyhedral oligomeric silsesquioxane (POSS) as the rigid group and TPB as the core unit of high fluorescence. The morphology and physicochemical properties of POSS@TPB were characterized in detail. Moreover, the synergistic effect of inner filter effect and photoinduced electron transfer is verified by experimental and simulation results. After condition optimization, a NFZ analysis method based on POSS@TPB probe was established with a linear range of 0.4-16.5 mg/L and a detection limit of 0.13 mg/L. In addition, the fluorescent probe has good stability, anti-interference and considerable reusability. At the same time, the selective analysis of trace NFZ in aquatic product and cosmetics was carried out with satisfied recoveries of 87%-110.6% and relative standard deviation less than 4.1%. And the results were verified by high-performance liquid chromatography method. Overall, this fluorescence sensor has excellent performance in NFZ analysis, which provides a broad application prospect for the repeatable and selective residue NFZ analysis in aquatic product and cosmetics.
Assuntos
Cosméticos , Compostos de Organossilício , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Nitrofurazona , Compostos de Organossilício/química , Polímeros/química , PorosidadeRESUMO
Bacterial pathogens are progressively adapting to current antimicrobial therapies with severe consequences for patients and global health care systems. This is critically underscored by the rise of methicillin resistant Staphylococcus aureus (MRSA) and other biofilm-forming staphylococci. Accordingly, alternative strategies have been explored to fight such highly multidrug resistant microorganisms, including antimicrobial photodynamic therapy (aPDT) and phage therapy. aPDT has the great advantage that it does not elicit resistance, while phage therapy allows targeting of specific pathogens. In the present study, we aimed to merge these benefits by conjugating the cell-binding domain (CBD3) of a Staphylococcus aureus phage endolysin to a photoactivatable silicon phthalocyanine (IRDye 700DX) for the development of a Staphylococcus-targeted aPDT approach. We show that, upon red-light activation, the resulting CBD3-700DX conjugate generates reactive oxygen species that effectively kill high loads of planktonic and biofilm-resident staphylococci, including MRSA. Furthermore, CBD3-700DX is readily internalized by mammalian cells, where it allows the targeted killing of intracellular MRSA upon photoactivation. Intriguingly, aPDT with CBD3-700DX also affects mammalian cells with internalized MRSA, but it has no detectable side effects on uninfected cells. Altogether, we conclude that CBD3 represents an attractive targeting agent for Staphylococcus-specific aPDT, irrespective of planktonic, biofilm-embedded, or intracellular states of the bacterium. IMPORTANCE Antimicrobial resistance is among the biggest threats to mankind today. There are two alternative antimicrobial therapies that may help to control multidrug-resistant bacteria. In phage therapy, natural antagonists of bacteria, lytic phages, are harnessed to fight pathogens. In antimicrobial photodynamic therapy (aPDT), a photosensitizer, molecular oxygen, and light are used to produce reactive oxygen species (ROS) that inflict lethal damage on pathogens. Since aPDT destroys multiple essential components in targeted pathogens, aPDT resistance is unlikely. However, the challenge in aPDT is to maximize target specificity and minimize collateral oxidative damage to host cells. We now present an antimicrobial approach that combines the best features of both alternative therapies, namely, the high target specificity of phages and the efficacy of aPDT. This is achieved by conjugating the specific cell-binding domain from a phage protein to a near-infrared photosensitizer. aPDT with the resulting conjugate shows high target specificity toward MRSA with minimal side effects.
Assuntos
Antibacterianos/farmacologia , Endopeptidases/farmacologia , Fotoquimioterapia , Infecções Estafilocócicas/microbiologia , Fagos de Staphylococcus/química , Staphylococcus/efeitos dos fármacos , Staphylococcus/fisiologia , Animais , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla , Endopeptidases/química , Endopeptidases/metabolismo , Humanos , Indóis/química , Luz , Compostos de Organossilício/química , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/metabolismo , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus/virologia , Fagos de Staphylococcus/metabolismoRESUMO
For the first time a hybrid molecularly imprinted polymer (MIP) doped with 3-(trimethoxysilyl) propyl methacrylate (γ-MPS)-modified mesoporous molecular sieve SBA-15 for target peptide recognition has been developed. Zinc acrylate and methacrylic acid were used as binary functional monomers, and ethylene dimethacrylate was used as cross-linking agent to prepare an imprinted monolith against Val-Tyr-Ala-Leu-Lys(glutarylation) (VYALKglu). The morphology of the polymers was characterized by scanning electron microscopy, FT-IR spectroscopy, energy dispersive spectroscopy, and 1H NMR. The SBA-15-MPS MIP showed high recovery of 87.1% and the IF of 12.9 for the enrichment of the template peptide. When the template peptide concentration ranged from 5 to 90 µg mL-1, the correlation coefficients (R2) for the calibration function obtained was better 0.999. The limit of detection (LOD, 0.30 µg mL-1) and limit of quantification (LOQ, 1.0 µg mL-1) were achieved for signal-to-noise ratios of 3:1 and 10:1, respectively. When other kinds of synthetic peptides were used as analogs, the selectivity of the SBA-15-MPS MIP was much better than the SBA-15-MPS NIP (without template peptides) with relative selectivity coefficients of 52.8-265. In contrast, little quinolones and biogenic amines are adsorbed with the SBA-15-MPS MIP. The SBA-15-MPS MIP could enrich VYALKglu from spiked histone digestion with the average recovery of 87.8% and the relative standard deviation (RSD) of 0.99%. As a conclusion, doping of SBA-15 is an effective approach to the improvement of performance of molecularly imprinted monolith.