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Pazopanib (PAZ), an oral multi-tyrosine kinase inhibitor, demonstrates promising cytostatic activities against various human cancers. However, its clinical utility is limited by substantial side effects and therapeutic resistance. We developed a nanoplatform capable of delivering PAZ for enhanced anti-breast cancer therapy. Nanometer-sized PAZ@Fe-MOF, compared to free PAZ, demonstrated increased anti-tumor therapeutic activities in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. High-throughput single-cell RNA sequencing (scRNAseq) revealed that PAZ@Fe-MOF significantly reduced pro-tumorigenic M2-like macrophage populations at tumor sites and suppressed M2-type signaling pathways, such as ATF6-TGFBR1-SMAD3, as well as chemokines including CCL17, CCL22, and CCL24. PAZ@Fe-MOF reprogramed the inhibitory immune microenvironment and curbed tumorigenicity by blocking the polarization of M2 phenotype macrophages. This platform offers a promising and new strategy for improving the cytotoxicity of PAZ against breast cancers. It provides a method to evaluate the immunological response of tumor cells to PAZ-mediated treatment.
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Antineoplásicos , Neoplasias de la Mama , Indazoles , Macrófagos , Estructuras Metalorgánicas , Nanopartículas , Pirimidinas , Sulfonamidas , Animales , Femenino , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Humanos , Macrófagos/efectos de los fármacos , Indazoles/farmacología , Indazoles/química , Ratones , Pirimidinas/farmacología , Pirimidinas/química , Línea Celular Tumoral , Nanopartículas/química , Sulfonamidas/farmacología , Sulfonamidas/química , Antineoplásicos/farmacología , Antineoplásicos/química , Ratones Endogámicos BALB C , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Severe endoplasmic reticulum (ER) stress elicits apoptosis to suppress lung cancer. Our previous research identified that Cepharanthine (CEP), a kind of phytomedicine, possessed powerful anti-cancer efficacy, for which the underlying mechanism was still uncovered. Herein, we investigated how CEP induced ER stress and worked against lung cancer. METHODS: The differential expression genes (DEGs) and enrichment were detected by RNA-sequence. The affinity of CEP and NRF2 was analyzed by cellular thermal shift assay (CETSA) and molecular docking. The function assay of lung cancer cells was measured by western blots, flow cytometry, immunofluorescence staining, and ferroptosis inhibitors. RESULTS: CEP treatment enriched DEGs in ferroptosis and ER stress. Further analysis demonstrated the target was NRF2. In vitro and in vivo experiments showed that CEP induced obvious ferroptosis, as characterized by the elevated iron ions, ROS, COX-2 expression, down-regulation of GPX4, and atrophic mitochondria. Moreover, enhanced Grp78, CHOP expression, ß-amyloid mass, and disappearing parallel stacked structures of ER were observed in CEP group, suggesting ER stress was aroused. CEP exhibited excellent anti-lung cancer efficacy, as evidenced by the increased apoptosis, reduced proliferation, diminished cell stemness, and prominent inhibition of tumor grafts in animal models. Furthermore, the addition of ferroptosis inhibitors weakened CEP-induced ER stress and apoptosis. CONCLUSION: In summary, our findings proved CEP drives ferroptosis through inhibition of NRF2 for induction of robust ER stress, thereby leading to apoptosis and attenuated stemness of lung cancer cells. The current work presents a novel mechanism for the anti-tumor efficacy of the natural compound CEP.
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Bencilisoquinolinas , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico , Ferroptosis , Neoplasias Pulmonares , Factor 2 Relacionado con NF-E2 , Bencilisoquinolinas/farmacología , Bencilisoquinolinas/uso terapéutico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Ferroptosis/efectos de los fármacos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Humanos , Animales , Ratones , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Células A549 , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Simulación del Acoplamiento Molecular , BenzodioxolesRESUMEN
Breakthroughs in actual clinical applications have begun through vaccine-based cancer immunotherapy, which uses the body's immune system, both humoral and cellular, to attack malignant cells and fight diseases. However, conventional vaccine approaches still face multiple challenges eliciting effective antigen-specific immune responses, resulting in immunotherapy resistance. In recent years, biomimetic nanovaccines have emerged as a promising alternative to conventional vaccine approaches by incorporating the natural structure of various biological entities, such as cells, viruses, and bacteria. Biomimetic nanovaccines offer the benefit of targeted antigen-presenting cell (APC) delivery, improved antigen/adjuvant loading, and biocompatibility, thereby improving the sensitivity of immunotherapy. This review presents a comprehensive overview of several kinds of biomimetic nanovaccines in anticancer immune response, including cell membrane-coated nanovaccines, self-assembling protein-based nanovaccines, extracellular vesicle-based nanovaccines, natural ligand-modified nanovaccines, artificial antigen-presenting cells-based nanovaccines and liposome-based nanovaccines. We also discuss the perspectives and challenges associated with the clinical translation of emerging biomimetic nanovaccine platforms for sensitizing cancer cells to immunotherapy.
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Células Presentadoras de Antígenos , Vacunas contra el Cáncer , Inmunoterapia , Nanopartículas , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Inmunoterapia/métodos , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/inmunología , Nanopartículas/administración & dosificación , Células Presentadoras de Antígenos/inmunología , Biomimética/métodos , Materiales Biomiméticos/administración & dosificación , Animales , Liposomas , NanovacunasRESUMEN
Drug resistance surveillance is a major integral part of malaria control programs. Molecular methods play a pivotal role in drug resistance detection and related molecular research. This study aimed to develop a rapid and accurate detection method for drug resistance of Plasmodium falciparum (P. falciparum). A quantitative real-time PCR (qPCR) assay has been developed that identifies the mutation at locus A256T in the P.falciparum multi-drug resistance(pfmdr1) gene producing amino acid change at position 86. The results of 198 samples detected by qPCR were consistent with nested PCR and sequencing, giving an accuracy of 94.3%. The sensitivity, specificity, positive and negative predictive value of qPCR were 85.7%, 97.6%, 90.0% and 96.4%, respectively. The results of qPCR are basically consistent with the nested PCR, which is expected to replace the nested PCR as a new molecular biological method for drug resistance detection, providing reliable technical support for global malaria prevention and control.
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Malaria Falciparum , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Plasmodium falciparum , Reacción en Cadena en Tiempo Real de la Polimerasa , Sensibilidad y Especificidad , Plasmodium falciparum/genética , Humanos , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Malaria Falciparum/parasitología , Malaria Falciparum/diagnóstico , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Mutación , Resistencia a Medicamentos/genéticaRESUMEN
Enhancement of malignant cell immunogenicity to relieve immunosuppression of lung cancer microenvironment is essential in lung cancer treatment. In previous study, we have demonstrated that dihydroartemisinin (DHA), a kind of phytopharmaceutical, is effective in inhibiting lung cancer cells and boosting their immunogenicity, while the initial target of DHA's intracellular action is poorly understood. The present in-depth analysis aims to reveal the influence of DHA on the highly expressed TOM70 in the mitochondrial membrane of lung cancer. The affinity of DHA and TOM70 was analyzed by microscale thermophoresis (MST), pronase stability, and thermal stability. The functions and underlying mechanism were investigated using western blots, qRT-PCR, flow cytometry, and rescue experiments. TOM70 inhibition resulted in mtDNA damage and translocation to the cytoplasm from mitochondria due to the disruption of mitochondrial homeostasis. Further ex and in vivo findings also showed that the cGAS/STING/NLRP3 signaling pathway was activated by mtDNA and thereby malignant cells underwent pyroptosis, leading to enhanced immunogenicity of lung cancer cells in the presence of DHA. Nevertheless, DHA-induced mtDNA translocation and cGAS/STING/NLRP3 mobilization were synchronously attenuated when TOM70 was replenished. Finally, DHA was demonstrated to possess potent anti-lung cancer efficacy in vitro and in vivo. Taken together, these data confirm that TOM70 is an important target for DHA to disturb mitochondria homeostasis, which further activates STING and arouses pyroptosis to strengthen immunogenicity against lung cancer thereupon. The present study provides vital clues for phytomedicine-mediated anti-tumor therapy.
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Artemisininas , Neoplasias Pulmonares , Mitocondrias , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Piroptosis , Neoplasias Pulmonares/tratamiento farmacológico , Artemisininas/farmacología , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Piroptosis/efectos de los fármacos , Ratones , Animales , Línea Celular Tumoral , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , ADN Mitocondrial , Células A549 , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos BALB CRESUMEN
Chemotherapeutic agents can inhibit the proliferation of malignant cells due to their cytotoxicity, which is limited by collateral damage. Dihydroartemisinin (DHA), has a selective anti-cancer effect, whose target and mechanism remain uncovered. The present work aims to examine the selective inhibitory effect of DHA as well as the mechanisms involved. The findings revealed that the Lewis cell line (LLC) and A549 cell line (A549) had an extremely rapid proliferation rate compared with the 16HBE cell line (16HBE). LLC and A549 showed an increased expression of NRAS compared with 16HBE. Interestingly, DHA was found to inhibit the proliferation and facilitate the apoptosis of LLC and A549 with significant anti-cancer efficacy and down-regulation of NRAS. Results from molecular docking and cellular thermal shift assay revealed that DHA could bind to epidermal growth factor receptor (EGFR) molecules, attenuating the EGF binding and thus driving the suppressive effect. LLC and A549 also exhibited obvious DNA damage in response to DHA. Further results demonstrated that over-expression of NRAS abated DHA-induced blockage of NRAS. Moreover, not only the DNA damage was impaired, but the proliferation of lung cancer cells was also revitalized while NRAS was over-expression. Taken together, DHA could induce selective anti-lung cancer efficacy through binding to EGFR and thereby abolishing the NRAS signaling pathway, thus leading to DNA damage, which provides a novel theoretical basis for phytomedicine molecular therapy of malignant tumors.
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Artemisininas , Proliferación Celular , Daño del ADN , Receptores ErbB , GTP Fosfohidrolasas , Neoplasias Pulmonares , Proteínas de la Membrana , Transducción de Señal , Receptores ErbB/metabolismo , Humanos , Proliferación Celular/efectos de los fármacos , Artemisininas/farmacología , Daño del ADN/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , GTP Fosfohidrolasas/metabolismo , Animales , Apoptosis/efectos de los fármacos , Simulación del Acoplamiento Molecular , Células A549 , Ratones , Antineoplásicos/farmacología , Línea Celular Tumoral , Unión ProteicaRESUMEN
Exploring efficient alkaline hydrogen oxidation reaction (HOR) electrocatalysts is of great concern for constructing anion exchange membrane fuel cells (AEMFCs). Herein, d-band center modulated PdCo alloys with ultralow Pd content anchored onto the defective carbon support (abbreviated as PdCo/NC hereafter) are proposed as highly efficient HOR catalyst. The as-prepared catalyst exhibits exceptional HOR performance compared to the Pt/C catalyst, achieving thermodynamically spontaneous and kinetically preferential reactions. Specifically, the resultant PdCo/NC demonstrates a marked enhancement in alkaline HOR performance, with the highest mass and specific activities of 1919.6 mA mgPd-1 and 1.9 mA cm-2, 51.1 and 4.2 times higher than those of benchmark of Pt/C, along with an excellent stability in a chronoamperometry test. In the analysis of in situ Raman spectra, it was discovered that tetrahedrally coordinated H-bonded water molecules were formed during the HOR process. This indicates that the promotion of interfacial water molecule formation and enhancement of HOR activities in PdCo/NC are facilitated by defect engineering and the turning of d-band center in PdCo alloy. The essential knowledge obtained in this study could open up a new direction for modifying the electronic structure of cost-effective HOR catalysts through electronic structure engineering.
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Environmental pollution, including air pollution, plastic contamination, and heavy metal exposure, is a pressing global issue. This crisis contributes significantly to pollution-related diseases and is a critical risk factor for chronic health conditions, including cancer. Mounting evidence underscores the pivotal role of N6-methyladenosine (m6A) as a crucial regulatory mechanism in pathological processes and cancer progression. Governed by m6A writers, erasers, and readers, m6A orchestrates alterations in target gene expression, consequently playing a vital role in a spectrum of RNA processes, covering mRNA processing, translation, degradation, splicing, nuclear export, and folding. Thus, there is a growing need to pinpoint specific m6A-regulated targets in environmental pollutant-induced carcinogenesis, an emerging area of research in cancer prevention. This review consolidates the understanding of m6A modification in environmental pollutant-induced tumorigenesis, explicitly examining its implications in lung, skin, and bladder cancer. We also investigate the biological mechanisms that underlie carcinogenesis originating from pollution. Specific m6A methylation pathways, such as the HIF1A/METTL3/IGF2BP3/BIRC5 network, METTL3/YTHDF1-mediated m6A modification of IL 24, METTL3/YTHDF2 dynamically catalyzed m6A modification of AKT1, METTL3-mediated m6A-modified oxidative stress, METTL16-mediated m6A modification, site-specific ATG13 methylation-mediated autophagy, and the role of m6A in up-regulating ribosome biogenesis, all come into play in this intricate process. Furthermore, we discuss the direction regarding the interplay between pollutants and RNA metabolism, particularly in immune response, providing new information on RNA modifications for future exploration.
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Adenosina , Carcinogénesis , Contaminantes Ambientales , Animales , Humanos , Adenosina/análogos & derivados , Carcinogénesis/inducido químicamente , Contaminantes Ambientales/toxicidad , ARN/genética , Metilación de ARNRESUMEN
We have previously identified a latent interaction mechanism between non-small cell lung cancer cells (NSCLCC) and their associated macrophages (TAM) mediated by mutual paracrine activation of the HMGB1/RAGE/NF-κB signaling. Activation of this mechanism results in TAM stimulation and PD-L1 upregulation in the NSCLCC. In the present work, we found that free DOX at a low concentration that does not cause DNA damage could activate the HMGB1/RAGE/NF-κB/PD-L1 pathway byinducing oxidative stress. It was thus proposed that a combination of low-dose DOX and a PD-L1 blocker delivered in the NSCLC tumor would achieve synergistic TAM stimulation and thereby synergetic anti-tumor potency. To prove this idea, DOX and BMS-202 (a PD-L1 blocker) were loaded to black phosphorus (BP) nanoparticles after dosage titration to yield the BMS-202/DOX@BP composites that rapidly disintegrated and released drug cargo upon mild photothermal heating at 40 °C. In vitro experiments then demonstrated that low-dose DOX and BMS-202 delivered via BMS-202/DOX@BP under mild photothermia displayed enhanced tumor cell toxicity with a potent synergism only in the presence of TAM. This enhanced synergism was due to an anti-tumor M1-like TAM phenotype that was synergistically induced by low dose DOX plus BMS-202 only in the presence of the tumor cells, indicating the damaged tumor cells to be the cardinal contributor to the M1-like TAM stimulation. In vivo, BMS-202/DOX@BP under mild photothermia exhibited targeted delivery to NSCLC graft tumors in mice and synergistic anti-tumor efficacy of delivered DOX and BMS-202. In conclusion, low-dose DOX in combination with a PD-L1 blocker is an effective strategy to turn TAM against their host tumor cells exploiting the HMGB1/RAGE/NF-κB/PD-L1 pathway. The synergetic actions involved highlight the value of TAM and the significance of modulating tumor cell-TAM cross-talk in tumor therapy. Photothermia-responsive BP provides an efficient platform to translate this strategy into targeted, efficacious tumor therapy.
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B-Myb has received considerable attention for its critical tumorigenic function of supporting DNA repair. However, its modulatory effects on chemotherapy and immunotherapy have rarely been reported in colorectal cancer. Bortezomib (BTZ) is a novel compound with chemotherapeutic and immunotherapeutic effects, but it fails to work in colorectal cancer with high B-Myb expression. The present study was designed to investigate whether B-Myb deletion in colorectal cancer could potentiate the immune efficacy of BTZ against colorectal cancer and to clarify the underlying mechanism. Stable B-Myb knockdown was induced in colorectal cancer cells, which increased apoptosis of the cancer cells relative to the control group in vitro and in vivo. We found that BTZ exhibited more favourable efficacy in B-Myb-defective colorectal cancer cells and tumor-bearing mice. BTZ treatment led to differential expression of genes enriched in the p53 signaling pathway promoted more powerful downstream DNA damage, and arrested cell cycle in B-Myb-defective colorectal cancer. In contrast, recovery of B-Myb in B-Myb-defective colorectal cancer cells abated BTZ-related DNA damage, cell cycle arrest, and anticancer efficacy. Moreover, BTZ promoted DNA damage-associated enhancement of immunogenicity, as indicated by potentiated expression of HMGB1 and HSP90 in B-Myb-defective cells, thereby driving M1 polarization of macrophages. Collectively, B-Myb deletion in colorectal cancer facilitates the immunogenic death of cancer cells, thereby further promoting the immune efficacy of BTZ by amplifying DNA damage. The present work provides an effective molecular target for colorectal cancer immunotherapy with BTZ.
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Antineoplásicos , Neoplasias Colorrectales , Animales , Ratones , Bortezomib/farmacología , Bortezomib/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Muerte Celular Inmunogénica , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , ApoptosisRESUMEN
Expediting the torpid kinetics of the oxygen reduction reaction (ORR) at the cathode with minimal amounts of Pt under acidic conditions plays a significant role in the development of proton exchange membrane fuel cells (PEMFCs). Herein, a novel Pt-N-C system consisting of Pt single atoms and nanoparticles anchored onto the defective carbon nanofibers is proposed as a highly active ORR catalyst (denoted as Pt-N-C). Detailed characterizations together with theoretical simulations illustrate that the strong coupling effect between different Pt sites can enrich the electron density of Pt sites, modify the d-band electronic environments, and optimize the oxygen intermediate adsorption energies, ultimately leading to significantly enhanced ORR performance. Specifically, the as-designed Pt-N-C demonstrates exceptional ORR properties with a high half-wave potential of 0.84 V. Moreover, the mass activity of Pt-N-C reaches 193.8 mA gPt-1 at 0.9 V versus RHE, which is 8-fold greater than that of Pt/C, highlighting the enormously improved electrochemical properties. More impressively, when integrated into a membrane electrode assembly as cathode in an air-fed PEMFC, Pt-N-C achieved a higher maximum power density (655.1 mW cm-2) as compared to Pt/C-based batteries (376.25 mW cm-2), hinting at the practical application of Pt-N-C in PEMFCs.
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The cGAS-STING signaling pathway has emerged as a critical mediator of innate immune responses, playing a crucial role in improving antitumor immunity through immune effector responses. Targeting the cGAS-STING pathway holds promise for overcoming immunosuppressive tumor microenvironments (TME) and promoting effective tumor elimination. However, systemic administration of current STING agonists faces challenges related to low bioavailability and potential adverse effects, thus limiting their clinical applicability. Recently, nanotechnology-based strategies have been developed to modulate TMEs for robust immunotherapeutic responses. The encapsulation and delivery of STING agonists within nanoparticles (STING-NPs) present an attractive avenue for antitumor immunotherapy. This review explores a range of nanoparticles designed to encapsulate STING agonists, highlighting their benefits, including favorable biocompatibility, improved tumor penetration, and efficient intracellular delivery of STING agonists. The review also summarizes the immunomodulatory impacts of STING-NPs on the TME, including enhanced secretion of pro-inflammatory cytokines and chemokines, dendritic cell activation, cytotoxic T cell priming, macrophage re-education, and vasculature normalization. Furthermore, the review offers insights into co-delivered nanoplatforms involving STING agonists alongside antitumor agents such as chemotherapeutic compounds, immune checkpoint inhibitors, antigen peptides, and other immune adjuvants. These platforms demonstrate remarkable versatility in inducing immunogenic responses within the TME, ultimately amplifying the potential for antitumor immunotherapy.
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OBJECTIVE: Photodynamic therapy (PDT) primarily treats skin diseases or cancer by generating reactive oxygen species (ROS) to damage cellular DNA, yet drug resistance limits its application. To tackle this problem, the present study was carried out to improve the efficacy of chlorin e6 (Ce6)-PDT using Cepharanthine (CEP) as well as to reveal the potential molecular mechanism. MATERIALS AND METHODS: Lewis lung cancer cell line (LLC) was utilized as the cancer cell model. chlorin e6 (Ce6) acted as the photosensitizer to induce PDT. The in vitro anti-cancer efficacy was measured by CCK-8, Annexin-V/PI staining, and migration assay. The Ce6 uptake was observed using flow cytometry and confocal microscopy. The ROS generation was detected by the DCFH-DA probe. The analysis of MutT Homolog 1 (MTH1) expression, correlation, and prognosis in databases was conducted by bioinformatic. The MTH1 expression was detected through western blots (WB). DNA damage was assayed by WB, immunofluorescent staining, and comet assay. RESULTS: Ce6-PDT showed robust resistance in lung cancer cells under certain conditions, as evidenced by the unchanged cell viability and apoptosis. The subsequent findings confirmed that the uptake of Ce6 and MTH1 expression was enhanced, but ROS generation with laser irradiation was not increased in LLC, which indicated that the ROS scavenge may be the critical reason for resistance. Surprisingly, bioinformatic and in vitro experiments identified that MTH1, which could prevent the DNA from damage of ROS, was highly expressed in lung cancer and thereby led to the poor prognosis and could be further up-regulated by Ce6 PDT. CEP exhibited a dose-dependent suppressive effect on the lung cancer cells. Further investigations presented that CEP treatment boosted ROS production, thereby resulting in DNA double-strand breakage (DDSB) with activation of MTH1, indicating that CEP facilitated Ce6-PDT-mediated DNA damage. Finally, the combination of CEP and Ce6-PDT exhibited prominent ROS accumulation, MTH1 inhibition, and anti-lung cancer efficacy, which had synergistic pro-DNA damage properties. CONCLUSION: Collectively, highly expressed MTH1 and the failure of ROS generation lead to PDT resistance in lung cancer cells. CEP facilitates ROS generation of PDT, thereby promoting vigorous DNA damage, inactivating MTH1, alleviating PDT resistance, and ameliorating the anti-cancer efficacy of Ce6-PDT, provides a novel approach for augmented PDT.
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Benzodioxoles , Bencilisoquinolinas , Neoplasias Pulmonares , Fotoquimioterapia , Humanos , Fármacos Fotosensibilizantes/uso terapéutico , Fotoquimioterapia/métodos , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Neoplasias Pulmonares/tratamiento farmacológico , Daño del ADN , ADNRESUMEN
OBJECTIVE: Prompt and effective wound repair is an essential strategy to promote recovery and prevent infection in patients with various types of trauma. Platelets can release a variety of growth factors upon activation to facilitate revascularization and tissue repair, provided that their activation is uncontrollable. The present study is designed to explore the selective activation of platelets by photodynamic and photothermal effects (PDE/PTE) as well as the trauma repair mediated by PDE/PTE. MATERIALS AND METHODS: In the current research, platelets were extracted from the blood of mice. Indocyanine green (ICG) was applied to induce PDE/PTE. The uptake of ICG by platelets was detected by laser confocal microscopy and flow cytometry. The cellular integrity was measured by microscopy. The reactive oxygen species (ROS) generation and temperature of platelets were assayed by 2,7-Dichlorodihydrofluorescein diacetate (DCFH-DA) and temperature detector. The activation of platelets was measured by western blots (WB), dynamic light scattering (DLS), and scanning electron microscopy (SEM). The release of growth factor was detected by enzyme-linked immuno sorbent assay (Elisa), wherein the in vitro cell proliferation was investigated by 5-Ethynyl-2'-deoxyuridine (EDU) assay. The wound infection rates model and histological examination were constructed to assay the ICG-loaded platelet-mediated wound repair. RESULTS: Platelets could load with ICG, a kind of photodynamic and photothermal agent, as carriers and remain intact. Near-infrared (NIR) laser irradiation of ICG-loaded platelets (ICG@PLT) facilitated higher temperature and ROS generation, which immediately activated ICG@PLT, as characterized by increased membrane p-selectin (CD62p), cyclooxygenase-2 (COX-2), thromboxane A2 receptor (TXA2R) expression, elevated hydrated particle size, and prominent aggregation in platelets. Further investigation revealed that massive insulin-like growth factor (IGF) and platelet-derived growth factor (PDGF) were released from the activated ICG@PLT, which also promoted the proliferation of endothelial cells and keratinocytes in co-culture. In consequence, activated platelets and increased neovascularization could be observed in rats with wound infection treated by ICG@PLT in the presence of NIR. More impressively, the hydrogel containing ICG@PLT accelerated wound healing and suppressed inflammation under NIR, exhibiting excellent wound repair properties. CONCLUSION: Taken together, the current work identified that platelets could be activated by PDE/PTE and thereby release growth factor, potentiating wound repair in a controlled manner.
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Fotoquimioterapia , Infección de Heridas , Humanos , Ratones , Ratas , Animales , Verde de Indocianina/farmacología , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Especies Reactivas de Oxígeno/metabolismo , Células Endoteliales/metabolismo , Cicatrización de Heridas , Péptidos y Proteínas de Señalización Intercelular , Línea Celular TumoralRESUMEN
Staging lymph nodes (LN) is crucial in diagnosing and treating cancer metastasis. Biotechnologies for the specific localization of metastatic lymph nodes (MLNs) have attracted significant attention to efficiently define tumor metastases. Bioimaging modalities, particularly magnetic nanoparticles (MNPs) such as iron oxide nanoparticles, have emerged as promising tools in cancer bioimaging, with great potential for use in the preoperative and intraoperative tracking of MLNs. As radiation-free magnetic resonance imaging (MRI) probes, MNPs can serve as alternative MRI contrast agents, offering improved accuracy and biological safety for nodal staging in cancer patients. Although MNPs' application is still in its initial stages, exploring their underlying mechanisms can enhance the sensitivity and multifunctionality of lymph node mapping. This review focuses on the feasibility and current application status of MNPs for imaging metastatic nodules in preclinical and clinical development. Furthermore, exploring novel and promising MNP-based strategies with controllable characteristics could lead to a more precise treatment of metastatic cancer patients.
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Nanopartículas de Magnetita , Neoplasias , Humanos , Neoplasias/diagnóstico por imagen , Fenómenos Físicos , Biotecnología , Ganglios Linfáticos/diagnóstico por imagenRESUMEN
Infiltration of tumor-associated macrophages (TAM) characterized by an M2 phenotype is an overriding feature in malignant tumors. Reprogramming TAM is the most cutting-edge strategy for cancer therapy. In the present study, an iron-based metal-organic framework (MOF) nanoreactor loaded with dihydroartemisinin (DHA) is developed, which provides high uptake by TAM and retains their viability, thus effectively addressing the inefficiency of the DHA at low concentrations. Impressively, DHA@MIL-101 can selectively accumulate in tumor tissues and remodel TAM to the M1 phenotype. The results of RNA sequencing further suggest that this nanoreactor may regulate ferroptosis, a DNA damage signaling pathway in TAM. Indeed, the outcomes confirm that DHA@MIL-101 triggers ferroptosis in TAM. In addition, the findings reveal that DNA damage induced by DHA nanoreactors activates the intracellular cGAS sensor, resulting in the binding of STING to IRF3 and thereby up-regulating the immunogenicity. In contrast, blocking ferroptosis impairs DHA@MIL-101-induced activation of STING signaling and phenotypic remodeling. Finally, it is shown that DHA nanoreactors deploy anti-tumor immunotherapy through ferroptosis-mediated TAM reprogramming. Taken together, immune efficacy is achieved through TAM's remodeling by delivering DHA and iron ions into TAM using nanoreactors, providing a novel approach for combining phytopharmaceuticals with nanocarriers to regulate the immune microenvironment.
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Ferroptosis , Macrófagos , Inmunoterapia , Hierro , Nanotecnología , Microambiente TumoralRESUMEN
Timely control of coagulopathy bleeding can effectively reduce the probability of wound infection and mortality. However, it is still a challenge for microsphere hemostatic agents to achieve timely control of coagulopathy bleeding. In this work, the CCM-g-AA@DA hemostatic agent based on carboxymethyl chitin microspheres, CCM, was synthesized using electron beam irradiation-induced grafting polymerization of acrylic acid and coupling with dopamine. Irradiation grafting endowed the microspheres with excellent adsorption performance and a rough surface. The microspheres showed a strong affinity to blood cells, especially red blood cells. The maximum adsorption of red blood cells is up to approximately 100 times that of the original microspheres, the CCM. The introduction of dopamine increased the tissue adhesion of the microspheres. At the same time, the microspheres still possessed good blood compatibility and biodegradability. Furthermore, the CCM-g-AA@DA with Fe3+ achieved powerful procoagulant effects in the rat anticoagulant bleeding model. The bleeding time and blood loss were both reduced by about 90% compared with the blank group, which was superior to that of the commercially available collagen hemostatic agent Avitene™. In summary, the CCM-g-AA@DA hemostatic agent shows promising potential for bleeding control in individuals with coagulation disorders.
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Hemostáticos , Ratas , Animales , Hemostáticos/uso terapéutico , Hemostáticos/farmacología , Microesferas , Adsorción , Dopamina , Electrones , Hemorragia/tratamiento farmacológico , Quitina/uso terapéutico , EritrocitosRESUMEN
Dihydroartemisinin (DHA), a natural product derived from the herbal medicine Artemisia annua, is recently used as a novel anti-cancer agent. However, some intrinsic disadvantages limit its potential for clinical management of cancer patients, such as poor water solubility and low bioavailability. Nowadays, the nanoscale drug delivery system emerges as a hopeful platform for improve the anti-cancer treatment. Accordingly, a metal-organic framework (MOF) based on zeolitic imidazolate framework-8 was designed and synthesized to carry DHA in the core (ZIF-DHA). Contrast with free DHA, these prepared ZIF-DHA nanoparticles (NPs) displayed preferable anti-tumor therapeutic activity in several ovarian cancer cells accompanied with suppressed production of cellular reactive oxygen species (ROS) and induced apoptotic cell death. 4D-FastDIA-based mass spectrometry technology indicated that down-regulated reactive oxygen species modulator 1 (ROMO1) might be regarded as potential therapeutic targets for ZIF-DHA NPs. Overexpression of ROMO1 in ovarian cancer cells significantly reversed the cellular ROS-generation induced by ZIF-DHA, as well as the pro-apoptosis effects. Taken together, our study elucidated and highlighted the potential of zeolitic imidazolate framework-8-based MOF to improve the activity of DHA to treat ovarian cancer. Our findings suggested that these prepared ZIF-DHA NPs could be an attractive therapeutic strategy for ovarian cancer.
Asunto(s)
Estructuras Metalorgánicas , Nanopartículas , Neoplasias Ováricas , Humanos , Femenino , Especies Reactivas de Oxígeno , Neoplasias Ováricas/tratamiento farmacológico , Apoptosis , Proteínas de la Membrana , Proteínas MitocondrialesRESUMEN
Exploring high-performance non-precious metal-based electrocatalysts for the sluggish oxygen evolution reaction (OER) process is fundamentally significant for the development of multifarious renewable energy conversion and storage systems. Oxygen vacancy (Vo) engineering is an effective leverage to boost the intrinsic activity of OER, but the underlying catalytic mechanism remains anfractuous. Herein, we realize the construction of oxygen vacancy-enriched porous NiO/ln2O3 nanofibers (designated as Vo-NiO/ln2O3@NFs hereafter) via a facile fabrication strategy for efficient oxygen evolution electrocatalysis. Theoretical calculations and experimental results uncover that, compared with the no-plasma engraving component, the presence of abundant oxygen vacancies in the Vo-NiO/ln2O3@NFs is conducive to modulating the electronic configuration of the catalyst, altering the adsorption of intermediates to reduce the OER overpotential and promote O* formation, upshifting the d band center of metal centers near the Fermi level (Ef), and also increasing the electrical conductivity and enhancing the OER reaction kinetics simultaneously. In situ Raman spectra proclaim that the oxygen vacancy can render the NiO/ln2O3 more easily reconstructible on the surface during the OER course. Therefore, the as-obtained Vo-NiO/ln2O3@NFs demonstrated distinguished OER activity, with an overpotential of only 230 mV at 10 mA cm-2 and excellent stability in alkaline medium, surmounting the majority of the previously reported representative non-noble metal-based candidates. The fundamental insights gained from this work can pave a new path for the electronic structure modulation of efficient, inexpensive OER catalysts via Vo engineering.
RESUMEN
Sonodynamic therapy (SDT) has aroused great interest for its potential in the treatment of glioblastoma (GBM). SDT relies on tumor-selective accumulation of a sonosensitizer that is activated by ultrasound irradiation (UI) to generate cytotoxic actions. The efficacy of GBM-SDT depends on sufficient sonosensitizer buildup in the tumor, which is, however, seriously hampered by the anatomical and biochemical barriers of the GBM. To overcome this difficulty, we herein propose a delivery strategy of 'platelets with ultrasound-triggered release property', which takes advantage of 1) the platelets' ability to carry cargo and release cargo upon activation, and 2) the ROS-generating property of SDT. To provide proof of concept for the strategy, we first stably loaded platelets with IOPD-Ce6, a nano-formed sonosensitizer consisting of iron oxide nanoparticles coated with polyglycerol and doxorubicin and loaded with chlorine e6. UI of the IOPD-Ce6-loaded platelets (IOPD-Ce6@Plt) elicited ROS generation in the IOPD-Ce6@Plt, which were immediately activated to release IOPD-Ce6 into GBM cells in co-culture which, when subjected to a second time of UI, exhibited pronounced ROS production, DNA injury, viability loss, and cell death in the GBM cells. In the in vivo experiments, mice bearing intracranial GBM grafts exhibited substantial tumor distribution of IOPD-Ce6 following intravenous injection of IOPD-Ce6@Plt and subsequent UI at the tumor site. The GBM grafts then exhibited pronounced cell injury and death after another round of UI of the tumors. Finally, the growth of intra-cranial GBM grafts was significantly slowed when an SDT protocol consisting of an intravenous IOPD-Ce6@Plt injection followed by multiple times of tumor UI had been applied twice to the mice. Our results are strong evidence for the idea that platelets are sound and amenable carriers to deliver sonosensitizers in the GBM in an ultrasound-triggered manner and thus to produce highly targeted and effective SDT of GBM.