RESUMEN
Chemo-photodynamic synergistic therapy (CPST) holds tremendous promise for treating cancers. Unfortunately, existing CPST applications suffer from complex synthetic procedures, low drug co-loading efficiency, and carrier-related toxicity. To address these issues, we have developed a supramolecular carrier-free self-sensitized nanoassemblies by co-assembling podophyllotoxin (PTOX) and chlorin e6 (Ce6) to enhance CPST efficiency against tumors. The nanoassemblies show stable co-assembly performance in simulative vivo neural environment (â¼150 nm), with high co-loading ability for PTOX (72.2 wt%) and Ce6 (27.8 wt%). In vivo, the nanoassemblies demonstrate a remarkable ability to accumulate at tumor sites by leveraging the enhanced permeability and retention (EPR) effect. The disintegration of nanoassemblies following photosensitizer bioactivation triggered by the acidic tumor environment effectively resolves the challenge of aggregation-caused quenching (ACQ) effect. Upon exposure to external light stimulation, the disintegrated nanoassemblies not only illuminate cancer cells synergistically but also exert a more potent antitumor effect when compared with PTOX and Ce6 administered alone. This self-sensitized strategy represents a significant step forward in CPST, offering a unique co-delivery paradigm for clinic cancer treatment.
Asunto(s)
Clorofilidas , Nanopartículas , Fotoquimioterapia , Fármacos Fotosensibilizantes , Podofilotoxina , Porfirinas , Fotoquimioterapia/métodos , Porfirinas/administración & dosificación , Porfirinas/química , Animales , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacocinética , Humanos , Línea Celular Tumoral , Nanopartículas/química , Podofilotoxina/administración & dosificación , Podofilotoxina/química , Neoplasias/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , FemeninoRESUMEN
Biofilms, particularly those formed by multiple bacterial species, pose significant economic and environmental challenges, especially in the context of medical implants. Addressing the urgent need for effective treatment strategies that do not exacerbate drug resistance, we developed a novel nanoformulation, Ce6&PMb@BPN, based on black phosphorus nanosheets (BPN) for targeted treatment of mixed-species biofilms formed by Acinetobacter baumannii (A. baumannii) and methicillin-resistant Staphylococcus aureus (MRSA).The formulation leverages polymyxin B (PMb) for bacterial targeting and chlorin e6 (Ce6) for photodynamic action. Upon near-infrared (NIR) irradiation, Ce6&PMb@BPN efficiently eliminates biofilms by combining chemotherapy, photodynamic therapy (PDT) and photothermal therapy (PTT), reducing biofilm biomass significantly within 30 min. In vivo studies on mice infected with mixed-species biofilm-coated catheters demonstrated the formulation's potent antibacterial and biofilm ablation effects. Moreover, comprehensive biosafety evaluations confirmed the excellent biocompatibility of Ce6&PMb@BPN. Taken together, this intelligently designed nanoformulation holds potential for effectively treating biofilm-associated infections, addressing the urgent need for strategies to combat antibiotic-resistant biofilms, particularly mixed-species biofilm, in medical settings.
Asunto(s)
Acinetobacter baumannii , Antibacterianos , Biopelículas , Staphylococcus aureus Resistente a Meticilina , Nanoestructuras , Fósforo , Fotoquimioterapia , Polimixina B , Porfirinas , Animales , Biopelículas/efectos de los fármacos , Polimixina B/administración & dosificación , Polimixina B/farmacología , Fósforo/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Antibacterianos/química , Fotoquimioterapia/métodos , Acinetobacter baumannii/efectos de los fármacos , Nanoestructuras/química , Porfirinas/administración & dosificación , Porfirinas/química , Porfirinas/farmacología , Clorofilidas , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Ratones , Femenino , Terapia Fototérmica/métodos , Ratones Endogámicos BALB C , Farmacorresistencia Bacteriana , Infecciones Estafilocócicas/tratamiento farmacológicoRESUMEN
AIM: To construct a novel nano-carrier with dual ligands to achieve superior anti-tumour efficacy and lower toxic side effects. METHODS: Liposomes were prepared by thin film hydration method. Ultraviolet, high performance liquid chromatography, nano-size analyser, ultrafiltration centrifugation, dialysis, transmission electron microscope, flow cytometry, Cell Counting Kit-8, confocal laser scanning microscopy, transwell, and tumorsphere assay were used to study the characterisations, cytotoxicity, and in vitro targeting of dg-Bcan targeting peptide (BTP-7)/pHA-temozolomide (TMZ)/tetra(4-carboxyphenyl)porphyrin (TCPP)-Lip. RESULTS: BTP-7/pHA-TMZ/TCPP-Lip was a spheroid with a mean diameters of 143 ± 3.214 nm, a polydispersity index of 0.203 ± 0.025 and a surface charge of -22.8 ± 0.425 mV. The drug loadings (TMZ and TCPP) are 7.40 ± 0.23% and 2.05 ± 0.03% (mg/mg); and the encapsulation efficiencies are 81.43 ± 0.51% and 84.28 ± 1.64% (mg/mg). The results showed that BTP-7/pHA-TMZ/TCPP-Lip presented enhanced targeting and cytotoxicity. CONCLUSION: BTP-7/pHA-TMZ/TCPP-Lip can specifically target the tumour cells to achieve efficient drug delivery, and improve the anti-tumour efficacy and reduces the systemic toxicity.
Asunto(s)
Glioblastoma , Liposomas , Temozolomida , Glioblastoma/tratamiento farmacológico , Humanos , Línea Celular Tumoral , Temozolomida/farmacología , Temozolomida/administración & dosificación , Temozolomida/farmacocinética , Temozolomida/química , Porfirinas/química , Porfirinas/administración & dosificación , Porfirinas/farmacología , Sistemas de Liberación de Medicamentos , Neoplasias Encefálicas/tratamiento farmacológico , Péptidos/química , Péptidos/farmacologíaRESUMEN
Background: Challenges such as poor drug selectivity, non-target reactivity, and the development of drug resistance continue to pose significant obstacles in the clinical application of cancer therapeutic drugs. To overcome the limitations of drug resistance in chemotherapy, a viable treatment strategy involves designing multifunctional nano-platforms that exploit the unique physicochemical properties of tumor microenvironment (TME). Methods: Herein, layer-by-layer nanoparticles with polyporous CuS as delivery vehicles, loaded with a sonosensitizer (tetra-(4-aminophenyl) porphyrin, TAPP) and sequentially functionalized with pH-responsive CaCO3, targeting group hyaluronic acid (HA) were designed and synthesized for synergistic treatment involving chemodynamic therapy (CDT), sonodynamic therapy (SDT), photothermal therapy (PTT), and calcium overload. Upon cleavage in an acidic environment, CaCO3 nanoparticles released TAPP and Ca2+, with TAPP generating 1O2 under ultrasound trigger. Exposed CuS produced highly cytotoxic ·OH in response to H2O2 and also exhibited a strong PTT effect. Results: CuS@TAPP-CaCO3/HA (CTCH) delivered an enhanced ability to release more Ca2+ under acidic conditions with a pH value of 6.5, which in situ causes damage to HeLa mitochondria. In vitro and in vivo experiments both demonstrated that mitochondrial dysfunction greatly amplified the damage caused by reactive oxygen species (ROS) to tumor, which strongly confirms the synergistic effect between calcium overload and reactive oxygen therapy. Conclusion: Collectively, the development of CTCH presents a novel therapeutic strategy for tumor treatment by effectively responding to the acidic TME, thus holding significant clinical implications.
Asunto(s)
Carbonato de Calcio , Calcio , Nanopartículas , Microambiente Tumoral , Humanos , Animales , Nanopartículas/química , Calcio/química , Carbonato de Calcio/química , Carbonato de Calcio/farmacología , Microambiente Tumoral/efectos de los fármacos , Células HeLa , Especies Reactivas de Oxígeno/metabolismo , Ratones , Ácido Hialurónico/química , Porfirinas/química , Porfirinas/farmacología , Porfirinas/farmacocinética , Porfirinas/administración & dosificación , Terapia Fototérmica/métodos , Concentración de Iones de Hidrógeno , Terapia por Ultrasonido/métodos , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Antineoplásicos/química , Antineoplásicos/farmacología , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas Capa por CapaRESUMEN
Stimulation of the innate immune stimulator of interferon genes (STING) pathway has been shown to boost anti-tumour immunity. Nevertheless, the systemic delivery of STING agonists to the tumour presents challenges. Therefore, we designed a cyclic dinucleotide (CDN)-based drug delivery system (DDS) combined photothermal therapy (PTT)/photodynamic therapy (PDT)/immunotherapy for cutaneous melanoma. We coencapsulated a reactive oxygen species (ROS)-responsive prodrug thioketone-linked CDN (TK-CDN), and photoresponsive agents chlorin E6 (Y6) within mitochondria-targeting reagent triphenylphosphonium (TPP)-modified liposomes (Lipo/TK-CDN/TPP/Y6). Lipo/TK-CDN/TPP/Y6 exhibited a photothermal effect similar to Y6, along with a superior cellular uptake rate. Upon endocytosis by B16F10 cells, Lipo/TK-CDN/TPP/Y6 generated large amounts of ROS under laser irradiation for PDT. Mice bearing B16F10 tumours were intravenously injected with Lipo/TK-CDN/TPP/Y6 and exposed to irradiation, resulting in a substantial inhibition of tumour growth. Exploration of the mechanism of anti-tumour action showed that Lipo/TK-CDN/TPP/Y6 had a stronger stimulation of STING activation and anti-tumour immune cell infiltration compared to other groups. Hence, the Lipo/TK-CDN/TPP/Y6 nanoparticles offer great potential as a DDS for targeted and on-demand drug release at tumour sites. These nanoparticles exhibit promise as a candidate for precise and controllable combination therapy in the treatment of tumours.
Asunto(s)
Clorofilidas , Liposomas , Melanoma Experimental , Nanopartículas , Fotoquimioterapia , Porfirinas , Profármacos , Especies Reactivas de Oxígeno , Neoplasias Cutáneas , Animales , Ratones , Nanopartículas/química , Fotoquimioterapia/métodos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Especies Reactivas de Oxígeno/metabolismo , Profármacos/farmacología , Profármacos/administración & dosificación , Profármacos/química , Melanoma Experimental/tratamiento farmacológico , Porfirinas/farmacología , Porfirinas/administración & dosificación , Porfirinas/química , Línea Celular Tumoral , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/administración & dosificación , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacología , Compuestos Organofosforados/administración & dosificación , Terapia Fototérmica/métodos , Ratones Endogámicos C57BL , Inmunoterapia/métodos , Melanoma/tratamiento farmacológico , Melanoma/patología , Sistemas de Liberación de Medicamentos , Humanos , Melanoma Cutáneo MalignoRESUMEN
Antitumor agents often lack effective penetration and accumulation to achieve high therapeutic efficacy in treating solid tumors. Nanomotor-based nanomaterials offer a potential solution to address this obstacle. Among them, nitric oxide (NO) based nanomotors have garnered attention for their potential applications in nanomedicine. However, there widespread clinical adoption has been hindered by their complex preparation processes. To address this limitation, we have developed a NO-driven nanomotor utilizing a convenient and scalable nanogel preparation procedure. These nanomotors, loaded with the fluorescent probe / sonosensitizer chlorin e6 (Ce6), were specifically engineered for sonodynamic therapy. Through comprehensive in vitro investigations using both 2D and 3D cell models, as well as in vivo analysis of Ce6 fluorescent signal distribution in solid tumor models, we observed that the self-propulsion of these nanomotors significantly enhances cellular uptake and tumor penetration, particularly in solid tumors. This phenomenon enables efficient access to challenging tumor regions and, in some cases, results in complete tumor coverage. Notably, our nanomotors have demonstrated long-term in vivo biosafety. This study presents an effective approach to enhancing drug penetration and improving therapeutic efficacy in tumor treatment, with potential clinical relevance for future applications.
Asunto(s)
Clorofilidas , Nanogeles , Neoplasias , Óxido Nítrico , Porfirinas , Animales , Óxido Nítrico/administración & dosificación , Óxido Nítrico/metabolismo , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Neoplasias/metabolismo , Porfirinas/administración & dosificación , Porfirinas/farmacocinética , Línea Celular Tumoral , Nanogeles/química , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Polietilenglicoles/química , Ratones Desnudos , Polietileneimina/química , Ratones Endogámicos BALB C , Colorantes Fluorescentes/química , Colorantes Fluorescentes/administración & dosificación , Femenino , Ratones , Terapia por Ultrasonido/métodos , Nanoestructuras/administración & dosificaciónRESUMEN
Triggering pyroptosis is a major new weathervane for activating tumor immune response. However, biodegradable pyroptosis inducers for the safe and efficient treatment of tumors are still scarce. Herein, a novel tumor microenvironment (TME)-responsive activation nanoneedle for pyroptosis induction, copper-tannic acid (CuTA), was synthesized and combined with the sonosensitizer Chlorin e6 (Ce6) to form a pyroptosis amplifier (CuTA-Ce6) for dual activation and amplification of pyroptosis by exogenous ultrasound (US) and TME. It was demonstrated that Ce6-triggered sonodynamic therapy (SDT) further enhanced the cellular pyroptosis caused by CuTA, activating the body to develop a powerful anti-tumor immune response. Concretely, CuTA nanoneedles with quadruple mimetic enzyme activity could be activated to an "active" state in the TME, destroying the antioxidant defense system of the tumor cells through self-destructive degradation, breaking the "immunosilent" TME, and thus realizing the pyroptosis-mediated immunotherapy with fewer systemic side effects. Considering the outstanding oxygen-producing capacity of CuTA and the distinctive advantages of US, the sonosensitizer Ce6 was attached to CuTA via an amide reaction, which further amplified the pyroptosis and sensitized pyroptosis-induced immunotherapy with the two-pronged strategy of CuTA enzyme-catalyzed cascade and US-driven SDT pathway to generate a "reactive oxygen species (ROS) storm". Conclusively, this work provided a representative paradigm for achieving safe, reliable and efficient pyroptosis, which was further enhanced by SDT for more robust immunotherapy.
Asunto(s)
Clorofilidas , Cobre , Inmunoterapia , Ratones Endogámicos BALB C , Porfirinas , Piroptosis , Especies Reactivas de Oxígeno , Microambiente Tumoral , Piroptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Porfirinas/administración & dosificación , Inmunoterapia/métodos , Animales , Cobre/administración & dosificación , Línea Celular Tumoral , Humanos , Femenino , Terapia por Ultrasonido/métodos , Neoplasias/terapia , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , RatonesRESUMEN
Background: Chemo-photodynamic combination therapy has demonstrated significant potential in the treatment of cancer. Triptolide (TPL), a naturally derived anticancer agent, when combined with the photosensitizer Chlorin e6 (Ce6), has shown to provide enhanced anti-tumor benefits. However, the development of stimuli-responsive nanovehicles for the co-delivery of TPL and Ce6 could further enhance the efficacy of this combination therapy. Methods: In this study, we synthesized a pH/ROS dual-responsive mPEG-TK-PBAE copolymer, which contains a pH-sensitive PBAE moiety and a ROS-sensitive thioketal (TK) linkage. Through a self-assembly process, TPL and Ce6 were successfully co-loaded into mPEG-TK-PBAE nanoparticles, hereafter referred to as TPL/Ce6 NPs. We evaluated the pH- and ROS-sensitive drug release and particle size changes. Furthermore, we investigated both the in vitro suppression of cellular proliferation and induction of apoptosis in HepG2 cells, as well as the in vivo anti-tumor efficacy of TPL/Ce6 NPs in H22 xenograft nude mice. Results: The mPEG-TK-PBAE copolymer was synthesized through a one-pot Michael-addition reaction and successfully co-encapsulated both TPL and Ce6 by self-assembly. Upon exposure to acid pH values and high ROS levels, the payloads in TPL/Ce6 NPs were rapidly released. Notably, the abundant ROS generated by the released Ce6 under laser irradiation further accelerated the degradation of the nanosystem, thereby amplifying the tumor microenvironment-responsive drug release and enhancing anticancer efficacy. Consequently, TPL/Ce6 NPs significantly increased PDT-induced oxidative stress and augmented TPL-induced apoptosis in HepG2 cells, leading to synergistic anticancer effects in vitro. Moreover, administering TPL/Ce6 NPs (containing 0.3 mg/kg of TPL and 4 mg/kg of Ce6) seven times, accompanied by 650 nm laser irradiation, efficiently inhibited tumor growth in H22 tumor-bearing mice, while exhibiting lower systemic toxicity. Conclusion: Overall, we have developed a tumor microenvironment-responsive nanosystem for the co-delivery of TPL and Ce6, demonstrating amplified synergistic effects of chemo-photodynamic therapy (chemo-PDT) for hepatocellular carcinoma (HCC) treatment.
Asunto(s)
Apoptosis , Clorofilidas , Diterpenos , Neoplasias Hepáticas , Ratones Desnudos , Fenantrenos , Fotoquimioterapia , Fármacos Fotosensibilizantes , Porfirinas , Especies Reactivas de Oxígeno , Animales , Humanos , Fotoquimioterapia/métodos , Especies Reactivas de Oxígeno/metabolismo , Células Hep G2 , Neoplasias Hepáticas/tratamiento farmacológico , Porfirinas/química , Porfirinas/farmacología , Porfirinas/administración & dosificación , Porfirinas/farmacocinética , Diterpenos/química , Diterpenos/farmacología , Diterpenos/farmacocinética , Diterpenos/administración & dosificación , Concentración de Iones de Hidrógeno , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/administración & dosificación , Apoptosis/efectos de los fármacos , Ratones , Carcinoma Hepatocelular/tratamiento farmacológico , Compuestos Epoxi/química , Compuestos Epoxi/farmacología , Compuestos Epoxi/administración & dosificación , Nanopartículas/química , Ensayos Antitumor por Modelo de Xenoinjerto , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Liberación de Fármacos , Proliferación Celular/efectos de los fármacos , Polietilenglicoles/química , Terapia CombinadaRESUMEN
The high glutathione (GSH) level of the tumor microenvironment severely affects the efficacy of photodynamic therapy (PDT). The current GSH depletion strategies have difficulty meeting the dual needs of security and efficiency. In this study, we report a photosensitizer Chlorin e6 (Ce6) and hypoxia-activated prodrug tirapazamine (TPZ) coloaded cross-linked multifunctional polymersome (TPZ/Ce6@SSPS) with GSH-triggered continuous GSH depletion for enhanced photodynamic therapy and hypoxia-activated chemotherapy. At tumor sites, the disulfide bonds of TPZ/Ce6@SSPS react with GSH to realize decross-linking for on-demand drug release. Meanwhile, the generated highly reactive quinone methide (QM) can further deplete GSH. This continuous GSH depletion will amplify tumor oxidative stress, enhancing the PDT effect of Ce6. Aggravated tumor hypoxia induced by PDT activates the prodrug TPZ, resulting in an enhanced combination of PDT and hypoxia-activated chemotherapy. Both in vitro and in vivo results demonstrate the efficient GSH depletion and potent antitumor activities by TPZ/Ce6@SSPS. This work provides a strategy for the design of a continuous GSH depletion platform, which holds great promise for enhanced combination tumor therapy.
Asunto(s)
Clorofilidas , Glutatión , Fotoquimioterapia , Fármacos Fotosensibilizantes , Profármacos , Tirapazamina , Glutatión/metabolismo , Fotoquimioterapia/métodos , Tirapazamina/farmacología , Animales , Ratones , Humanos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Profármacos/farmacología , Porfirinas/farmacología , Porfirinas/administración & dosificación , Porfirinas/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Microambiente Tumoral/efectos de los fármacosRESUMEN
BACKGROUND: To the best of our knowledge, no studies have been performed to determine the optimal parameters of photodynamic therapy (PDT) combined with subconjunctival injection of bevacizumab for corneal neovascularization. This study aimed to compare the effect of photodynamic therapy with two different sets of parameters combined with subconjunctival injection of bevacizumab for corneal neovascularization. METHODS: Patients with stable corneal neovascularization (CNV) unresponsive to conventional treatment (topical steroid) were included in this study. Patients were divided into two groups, receiving PDT with two different sets of parameters (group 1 receiving fluence of 50 J/cm2 at 15 min after intravenous injection of verteporfin with, group 2 receiving fluence of 150 J/cm2 at 60 min after intravenous injection of verteporfin with). Subconjunctival injection of bevacizumab was performed immediately after PDT. All patients were followed for 6 months. Best-corrected visual acuity and intraocular pressure were evaluated, and slit-lamp biomicroscopy as well as digital photography were performed. Average diameter and cumulative length of corneal neovascular were measured to evaluate the corneal neovascularization. RESULTS: Seventeen patients (20 eyes) were included in this study. At the last visit, the vision was improved in 12 eyes (60 %), steady in 4 eyes (20 %) and worsen in 4 eyes (20 %). The intraocular pressure (IOP) of all patients remained in normal range. A significant decrease in corneal neovascularization was showed in all the eyes after treatment. At 6 months after the combined treatment, the average diameter and cumulative length of vessels significantly decreased to 0.041 ± 0.023 mm (P < 0.05) and 18.78 ± 17.73 mm (P < 0.05), respectively, compared with the pretreatment data (0.062 ± 0.015 mm, 31.48 ± 18.21 mm). The reduction was more remarkable in group 2 compared to group 1.In group 1, the average diameter was 0.062 ± 0.013mm before and 0.056 ± 0.017mm after, the cumulative length of vessels was 38.66 ± 22.55mm before and 31.21 ± 17.30 after. In group 2, the date were 0.061 ± 0.016mm before and 0.029 ± 0.020mm after, 25.60 ± 8.95 mm before and 8.61 ± 8.26 mm. The reported complications included epithelial defect in four eyes, small white filaments in two eyes and corneal epithelial erosion in two eyes. CONCLUSION: The PDT combined with subconjunctival injection of bevacizumab was effective for the chronic corneal neovascularization. A more promising treatment outcome was observed when PDT was performed at 60 min after intravenous injection of verteporfin with fluence of 150 J/cm2. No serious complications or systemic events were observed throughout the follow-up period.
Asunto(s)
Inhibidores de la Angiogénesis , Bevacizumab , Neovascularización de la Córnea , Fotoquimioterapia , Fármacos Fotosensibilizantes , Verteporfina , Agudeza Visual , Humanos , Fotoquimioterapia/métodos , Bevacizumab/administración & dosificación , Bevacizumab/uso terapéutico , Neovascularización de la Córnea/tratamiento farmacológico , Femenino , Masculino , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/uso terapéutico , Verteporfina/uso terapéutico , Inhibidores de la Angiogénesis/administración & dosificación , Persona de Mediana Edad , Agudeza Visual/efectos de los fármacos , Adulto , Anciano , Terapia Combinada , Inyecciones Intraoculares , Presión Intraocular/efectos de los fármacos , Porfirinas/administración & dosificación , Conjuntiva/irrigación sanguíneaRESUMEN
Therapeutic approaches for triple-negative breast cancer (TNBC) have been continuously advancing, but inadequate control over release behavior, insufficient tumor selectivity, and limited drug availability continue to impede therapeutic outcomes in nanodrug systems. In this study, we propose a general hydrophobic antineoplastic delivery system, termed spatiotemporally-controlled hydrophobic antineoplastic delivery system (SCHADS) for enhanced TNBC treatment. The key feature of SCHADS is the formation of metastable photosensitive-antineoplastic complexes (PACs) through the self-assembly of hydrophobic drugs driven by photosensitive molecules. With the further decoration of tumor-targeting peptides coupled with the EPR effect, the PACs tend to accumulate in the tumor site tremendously, promoting drug delivery efficiency. Meanwhile, the disassembly behavior of the metastable PACs could be driven by light on demand to achieve in situ drug release, thus promoting chemotherapeutics availability. Furthermore, the abundant ROS generated by the photosensitizer could effectively kill tumor cells, ultimately realizing an effective combination of photodynamic and chemotherapeutic therapy. As an exemplary presentation, chlorin e6 has been chosen to drive the formation of PACs with the system xc- inhibitor sorafenib. Compared with pure drug treatment, the PACs with the above-described preponderances exhibit superior therapeutic effects both in vitro and in vivo and circumvent the side effects due to off-target. By manipulating the laser irradiation, the PACs-treated cell death mechanism could be dynamically regulated, thus providing the potential to remedy intrinsic/acquired resistance of tumor. Collectively, this SCHADS achieves spatio-temporal control of the drug that greatly enhances the availability of anticarcinogen and realizes synergistic antitumor effect in TNBC treatment, even ultimately being extended to the treatment of other types of tumors.
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Antineoplásicos , Sistemas de Liberación de Medicamentos , Interacciones Hidrofóbicas e Hidrofílicas , Fármacos Fotosensibilizantes , Porfirinas , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Femenino , Animales , Humanos , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Porfirinas/administración & dosificación , Porfirinas/química , Clorofilidas , Ratones Desnudos , Ratones Endogámicos BALB C , Fotoquimioterapia/métodos , Sorafenib/administración & dosificación , Sorafenib/farmacología , Sorafenib/química , Liberación de FármacosRESUMEN
Cryotherapy leverages controlled freezing temperature interventions to engender a cascade of tumor-suppressing effects. However, its bottleneck lies in the standalone ineffectiveness. A promising strategy is using nanoparticle therapeutics to augment the efficacy of cryotherapy. Here, a cold-responsive nanoplatform composed of upconversion nanoparticles coated with silica - chlorin e6 - hyaluronic acid (UCNPs@SiO2-Ce6-HA) is designed. This nanoplatform is employed to integrate cryotherapy with photodynamic therapy (PDT) in order to improve skin cancer treatment efficacy in a synergistic manner. The cryotherapy appeared to enhance the upconversion brightness by suppressing the thermal quenching. The low-temperature treatment afforded a 2.45-fold enhancement in the luminescence of UCNPs and a 3.15-fold increase in the photodynamic efficacy of UCNPs@SiO2-Ce6-HA nanoplatforms. Ex vivo tests with porcine skins and the subsequent validation in mouse tumor tissues revealed the effective HA-mediated transdermal delivery of designed nanoplatforms to deep tumor tissues. After transdermal delivery, in vivo photodynamic therapy using the UCNPs@SiO2-Ce6-HA nanoplatforms resulted in the optimized efficacy of 79% in combination with cryotherapy. These findings underscore the Cryo-PDT as a truly promising integrated treatment paradigm and warrant further exploring the synergistic interplay between cryotherapy and PDT with bright upconversion to unlock their full potential in cancer therapy.
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Ácido Hialurónico , Nanopartículas , Fotoquimioterapia , Animales , Fotoquimioterapia/métodos , Ratones , Ácido Hialurónico/química , Nanopartículas/química , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/tratamiento farmacológico , Crioterapia/métodos , Clorofilidas , Porfirinas/química , Porfirinas/administración & dosificación , Modelos Animales de Enfermedad , Fármacos Fotosensibilizantes/administración & dosificación , Administración Cutánea , Dióxido de Silicio/química , PorcinosRESUMEN
Photoimaging and phototherapy have become major platforms for the diagnosis and treatment of various health complications. These applications require a photosensitizer (PS) that is capable of absorbing light from a source and converting it into other energy forms for detection and therapy. While synthetic inorganic materials such as quantum dots and gold nanorods have been widely explored for their medical diagnosis and photodynamic (PDT) and photothermal (PTT) therapy capabilities, translation of these technologies has lagged, primarily owing to potential cytotoxicity and immunogenicity issues. Of the various photoreactive molecules, the naturally occurring endogenous compound heme, a constituent of red blood cells, and its derivatives, porphyrin, biliverdin and bilirubin, have shown immense potential as noteworthy candidates for clinically translatable photoreactive agents, as evidenced by previous reports. While porphyrin-based photomedicines have attracted significant attention and are well documented, research on photomedicines based on two other heme-derived compounds, biliverdin and bilirubin, has been relatively lacking. In this review, we summarize the unique photoproperties of heme-derived compounds and outline recent efforts to use them in biomedical imaging and phototherapy applications.
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Diagnóstico por Imagen/métodos , Hemo/farmacología , Fármacos Fotosensibilizantes/farmacología , Fototerapia/métodos , Hemo/administración & dosificación , Hemo/farmacocinética , Humanos , Sistema de Administración de Fármacos con Nanopartículas , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/farmacocinética , Porfirinas/administración & dosificación , Porfirinas/farmacologíaRESUMEN
This study reports the synthesis, structural characterization and cytotoxic activity of four new palladium/pyridylporphyrin complexes, with the general formula {TPyP[PdCl(P-P)]4}(PF6)4, where P-P is 1,2-bis(diphenylphosphino)ethane (dppe), 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)butane (dppb) or 1,1'-bis(diphenylphosphino)ferrocene (dppf). The complexes were characterized by elemental analysis, and by FT-IR, UV/Vis, 1H and 31P{1H} NMR (1D/2D) spectroscopy. The slow evaporation of a methanolic solution of {TPyP[PdCl(dppb)]4}(PF6)4 (in an excess of NaBF4 salt) resulted in single crystals suitable for X ray diffraction, allowing the determination of the tridimensional structure of this complex, which crystallized in the P21/a space group. The cytotoxicity of the complexes against MDA-MB-231 (breast cancer cells) and MCF-10A (non-tumor breast cancer cells), was determined by the colorimetric MTT method, which revealed that all four complexes show selective indexes close to 1.2, lower than that of cisplatin for the same cells (12.12). The interaction of the complexes with CT-DNA was evaluated by UV-visible and viscosity measurements and it was determined that the complexes interact moderately with CT-DNA, probably by H-bonding/π-π stacking and electrostatic interactions.
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Antineoplásicos , Complejos de Coordinación , Paladio , Porfirinas , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/administración & dosificación , Complejos de Coordinación/química , ADN/química , Humanos , Paladio/administración & dosificación , Paladio/química , Porfirinas/administración & dosificación , Porfirinas/química , ViscosidadRESUMEN
Successful gene therapy is highly dependent on the efficiency of gene delivery, which is mostly achieved by the carrier. Current gene carriers are generally nontherapeutic and take over most of the proportion in the delivery systems. Therefore, a library of polymerized and cationic photosensitive drugs (polyphotosensitizers, pPSs) with HIF-1α siRNA delivery capability is constructed to realize using "drug" to deliver "gene". The pPS component acts as both a therapeutic carrier for intracellular HIF-1α siRNA delivery and a photosensitive drug with photodynamic therapy (PDT). A reactive oxygen species (ROS)-cleavable linker is used to polymerize PS, allowing the successful segregation of PS monomers in space, avoiding the undesired aggregation-caused quenching (ACQ) effect and enhancing the in vitro and in vivo PDT effect. The complexes formed by pPSs and HIF-1α siRNA exhibited desired siRNA condensation and serum stability at the optimal conditions (pPSs with guanidines/siRNA weight ratio of 15), efficient intracellular internalization, and gene-silencing efficiency (60%) compared with commercial available transfection reagents (40%), as well as synergistic in vitro and in vivo phototoxicity for the combination PDT-gene therapy toward cancer treatment. This study provides a promising paradigm for the design of both the gene delivery carrier and the photosensitizer, as well as for broad utilities in the combination therapy toward cancer treatment.
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Carcinoma Hepatocelular/terapia , Sistemas de Liberación de Medicamentos , Terapia Genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Fotoquimioterapia , Porfirinas/administración & dosificación , ARN Interferente Pequeño/administración & dosificación , Animales , Apoptosis , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Cationes/química , Proliferación Celular , Terapia Combinada , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Ratones , Porfirinas/química , Especies Reactivas de Oxígeno , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Light activatable porphyrinic photosensitizers (PSs) are essential components of anticancer and antimicrobial therapy and diagnostic imaging. However, their biological applications are quite challenging due to the lack of hydrophilicity and biocompatibility. To overcome such drawbacks, photosensitizers can be doped into a biocompatible polymer such as gelatin and further can be used for biomedical applications. Herein, first, a novel A4 type porphyrin PS [5,10,15,20-tetrakis(4-pyridylamidephenyl)porphyrin; TPyAPP] was synthesized via a rational route with good yield. Further, this porphyrin was encapsulated into the gelatin nanoparticles (GNPs) to develop hydrophilic phototherapeutic nanoagents (PTNAs, A4por-GNPs). Notably, the synthesis of such porphyrin-doped GNPs avoids the use of any toxic chemicals or solvents. The nanoprobes have also shown good fluorescence quantum yield demonstrating their applicability in bioimaging. Further, the mechanistic aspects of the anticancer and antimicrobial efficacy of the developed A4por-GNPs were evaluated via singlet oxygen generation studies. Overall, our results indicated porphyrin-doped biodegradable polymeric nanoparticles act as effective phototherapeutic agents against a broad range of cancer cell lines and microbes upon activation by the low-cost LED light.
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Luz , Nanocápsulas/administración & dosificación , Fotoquimioterapia , Fármacos Fotosensibilizantes/administración & dosificación , Porfirinas/administración & dosificación , Materiales Biocompatibles , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Fluorescencia , Células HEK293 , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Teoría Cuántica , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Cancer is one of the diseases that threatens human health and is a leading cause of mortality worldwide. High levels of reactive oxygen species (ROS) have been observed in cancer tissues compared with normal tissues in vivo, and it is not yet known how this influences chemotherapeutic drug action. Cationic porphyrin 5,10,15,20-tetra-(N-methyl-4-pyridyl) porphyrin (TMPyP4) is a photosensitizer used in photodynamic therapy (PDT) and a telomerase inhibitor used in the treatment of telomerase-positive cancer. Here, we investigated the anticancer activity of TMPyP4 in A549 and PANC cells cultured in H2O2. The results showed that compared to TMPyP4 alone, the combination of TMPyP4 and H2O2 exhibited sensitization effects on cell viability and colony formation inhibition and apoptosis in A549 and PANC cells, but had no effect in human normal MIHA cells. Mechanistically, the combination of TMPyP4 and H2O2 activates high ROS and mitochondrial membrane potential in A549 and PANC cells, resulting in intense DNA damage and DNA damage responses. Consequently, compared to TMPyP4 alone, TMPyP4 and H2O2 combined treatment upregulates the expression of BAX, cleaved caspase 3, and p-JNK and downregulates the expression of Bcl-2 in A549 and PANC cells. Taken together, these data suggested that H2O2 enhanced the anticancer activity of TMPyP4-mediated ROS-dependent DNA damage and related apoptotic protein regulation, revealing that the high ROS tumor microenvironment plays an important role in chemotherapeutic drug action.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Mitocondrias/efectos de los fármacos , Neoplasias Pancreáticas/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Células A549 , Línea Celular Tumoral , Ensayo Cometa , Daño del ADN , Hepatocitos/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/administración & dosificación , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/genética , Mitocondrias/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Porfirinas/administración & dosificación , Microambiente Tumoral/efectos de los fármacosRESUMEN
Photodynamic inactivation (PDI) is a promising approach for the efficient killing of pathogenic microbes. In this study, the photodynamic effect of sulfonated polystyrene nanoparticles with encapsulated hydrophobic 5,10,15,20-tetraphenylporphyrin (TPP-NP) photosensitizers on Gram-positive (including multi-resistant) and Gram-negative bacterial strains was investigated. The cell viability was determined by the colony forming unit method. The results showed no dark cytotoxicity but high phototoxicity within the tested conditions. Gram-positive bacteria were more sensitive to TPP-NPs than Gram-negative bacteria. Atomic force microscopy was used to detect changes in the morphological properties of bacteria before and after the PDI treatment.
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Bacterias/efectos de los fármacos , Bacterias/efectos de la radiación , Composición de Medicamentos , Nanopartículas , Procesos Fotoquímicos , Poliestirenos , Porfirinas/administración & dosificación , Porfirinas/química , Microscopía de Fuerza Atómica , Nanopartículas/química , Fotoquimioterapia/métodos , Poliestirenos/químicaRESUMEN
Developing novel activatable photosensitizers with excellent plasma membrane targeting ability is urgently needed for smart photodynamic therapy (PDT). Herein, a tumor acidity-activatable photosensitizer combined with a two-step bioorthogonal pretargeting strategy to anchor photosensitizers on the plasma membrane for effective PDT is developed. Briefly, artificial receptors are first anchored on the cell plasma membrane using cell-labeling agents (Az-NPs) via the enhanced permeability and retention effect to achieve the tumor cell labeling. Then, pH-sensitive nanoparticles (S-NPs) modified with dibenzocyclooctyne (DBCO) and chlorin e6 (Ce6) accumulate in tumor tissue and disassemble upon protonation of their tertiary amines in response to the acidic tumor environment, exposing the contained DBCO and Ce6. The selective, highly specific click reactions between DBCO and azide groups enable Ce6 to be anchored on the tumor cell surface. Upon laser irradiation, the cell membrane is severely damaged by the cytotoxic reactive oxygen species, resulting in remarkable cellular apoptosis. Taken together, the membrane-localized PDT by our bioorthogonal pretargeting strategy to anchor activatable photosensitizers on the plasma membrane provides a simple but effective method for enhancing the therapeutic efficacy of photosensitizers in anticancer therapy.
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Membrana Celular/metabolismo , Ciclooctanos/administración & dosificación , Sistemas de Liberación de Medicamentos , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/administración & dosificación , Porfirinas/administración & dosificación , Animales , Línea Celular Tumoral , Clorofilidas , Ciclooctanos/farmacocinética , Ciclooctanos/uso terapéutico , Humanos , Ratones , Nanopartículas/administración & dosificación , Nanopartículas/uso terapéutico , Neoplasias/metabolismo , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacocinética , Fármacos Fotosensibilizantes/uso terapéutico , Porfirinas/farmacocinética , Porfirinas/uso terapéutico , Receptores Artificiales/metabolismoRESUMEN
The topical photodynamic therapy (PDT) is mainly used in the treatment of dermato-oncological diseases. The distribution and functionality of the photosensitizer Tetrahydroporphyrin-Tetratosylat (THPTS) was investigated using microscopic and spectroscopic methods after topical application to excised porcine skin followed by irradiation. The distribution of THPTS was determined by two-photon tomography combined with fluorescence lifetime imaging (TPT/FLIM) and confocal Raman microspectroscopy (CRM). The radicals were quantified and characterized by electron paramagnetic resonance (EPR) spectroscopy. Results show a penetration depth of THPTS into the skin down to around 12 ± 5 µm. A penetration of THPTS through the stratum corneum was not clearly observable after 1 h penetration time, but cannot be excluded. The irradiation within the phototherapeutic window (spectral range of visible and near infrared light in the range ≈ 650-850 nm) is needed to activate THPTS. An incubation time of 10 min showed the highest radical production. A longer incubation time affected the functionality of THPTS, whereby significant less radicals were detectable. During PDT mainly reactive oxygen species (ROS) and lipid oxygen species (LOS) are produced. Overall, the irradiation dose per se influences the radical types formed in skin. While ROS are always prominent at low doses, LOS increase at high doses, independent of previous skin treatment and the irradiation wavelength used.