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The lethality and chemotherapy resistance of pancreatic cancer necessitates the urgent development of innovative strategies to improve patient outcomes. To address this issue, we designed a novel drug delivery system named GDMCN2,which uses iron-based metal organic framework (Fe-MOF) nanocages encased in a covalent organic framework (COF) and modified with the pancreatic cancer-specific antibody, NRP2. After being targeted into tumor cells, GDMCN2 gradually release the sonosensitizer sinoporphyrin sodium (DVDMS) and chemotherapeutic gemcitabine (GEM) and simultaneously generated reactive oxygen species (ROS) under ultrasound (US) irradiation. This system can overcome gemcitabine resistance in pancreatic cancer and reduce its toxicity to non-targeted cells and tissues. In a mechanistic cascade, the release of ROS activates the mitochondrial transition pore (MPTP), leading to the release of Ca2+ and induction of endoplasmic reticulum (ER) stress. Therefore, microtubule-associated protein 1A/1B-light chain 3 (LC3) is activated, promoting lysosomal autophagy. This process also induces autophagy-dependent ferroptosis, aided by the upregulation of Nuclear Receptor Coactivator 4 (NCOA4). This mechanism increases the sensitivity of pancreatic cancer cells to chemotherapeutic drugs and increases mitochondrial and DNA damage. The findings demonstrate the potential of GDMCN2 nanocages as a new avenue for the development of cancer therapeutics.
Assuntos
Ferroptose , Estruturas Metalorgânicas , Neoplasias Pancreáticas , Humanos , Estruturas Metalorgânicas/metabolismo , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Apoptose , Anticorpos Monoclonais/uso terapêutico , Autofagia , Gencitabina , Neoplasias Pancreáticas/tratamento farmacológico , Retículo Endoplasmático/metabolismo , Neoplasias PancreáticasRESUMO
The hypoxic character of tumors and the poor targeting ability of photosensitizers often limit the efficacy of photodynamic therapy (PDT). In recent years, the discovery of metal nanoenzymes and nanocarriers has improved PDT. Thereby, to improve the effective utilization of photosensitizers and oxygen (O2 ) in tumors, herein, a nanosystem (LS-HB@HvCeO2 -NRP1 mAb, LHCN1) is reported, in which a hollow virus-like cerium oxide (HvCeO2 ) is surface-decorated with tumor-targeting neuropilin-1 monoclonal antibody (NRP1 mAb), and loaded with a photosensitizer (chlorin e6-C-15-ethyl ester, LS-HB). In vitro and in vivo experiments demonstrate that LHCN1 can efficiently accumulate within the tumor sites via the targeting guidance of NRP1 mAb and is then rapidly endocytosed into cells. Furthermore, HvCeO2 with catalase-mimetic activity can decompose the endogenous hydrogen peroxide (H2 O2 ) to promote O2 via the valence transformation between Ce4+ and Ce3+ , relieving tumor hypoxia and improving the PDT efficacy. Upon near-infrared laser irradiation, LS-HB produces large amounts of cytotoxic reactive oxygen species. Moreover, LHCN1 is used in fluorescence/photoacoustic multimodal imaging for in vivo drug localization, and its use in PDT evidently helps inhibit tumor growth with no apparent toxicity to normal tissues. Thus, LHCN1 may provide a promising strategy for precise tumor-specific diagnosis and treatment.
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Nanopartículas , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fotoquimioterapia/métodos , Vírus Oncogênicos , Linhagem Celular Tumoral , Peróxido de Hidrogênio , OxigênioRESUMO
The high mortality rate associated with gastric cancer (GC) has resulted in an urgent need to identify novel therapeutic targets for GC. This study aimed to investigate whether GAIP interacting protein, C terminus 1 (GIPC1) represents a therapeutic target and its regulating mechanism in GC. GIPC1 expression was elevated in GC tissues, liver metastasis tissues, and lymph node metastases. GIPC1 knockdown or GIPC1 blocking peptide blocked the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT signaling pathway, and inhibited the proliferation and migration of GC cells. Conversely, GIPC1 overexpression markedly activated the PDGFR/PI3K/AKT signaling pathway, and promoted GC cell proliferation and migration. Furthermore, platelet-derived growth factor subunit BB (PDGF-BB) cytokines and the AKT inhibitor attenuated the effect of differential GIPC1 expression. Moreover, GIPC1 silencing decreased tumor growth and migration in BALB/c nude mice, while GIPC1 overexpression had contrasting effects. Taken together, our findings suggest that GIPC1 functions as an oncogene in GC and plays a central role in regulating cell proliferation and migration via the PDGFR/PI3K/AKT signaling pathway.
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Neoplasias Gástricas , Humanos , Animais , Camundongos , Neoplasias Gástricas/genética , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Camundongos Nus , Transdução de Sinais , Proteínas Adaptadoras de Transdução de SinalRESUMO
Aldo-keto reductase family one, member B10 (AKR1B10) has been reported to be involved in the tumorigenesis of various cancers. It has been reported that colorectal cancer is closely associated with chronic inflammation, but the underlying molecular mechanisms are still elusive. In our study, we evaluated the relationship between AKR1B10 expression and clinicopathological characteristics of colon cancer and showed that AKR1B10 expression was significantly correlated with the T stage and clinical stage of colon cancer. Knockdown of AKR1B10 significantly decreased the expression of the inflammatory cytokines IL1α and IL6 induced by lipopolysaccharide by inhibiting the NF-κB signaling pathway. Furthermore, AKR1B10 depends on its reductase activity to affect the NF-κB signaling pathway and subsequently affect the production of inflammatory cytokines. In addition, knockdown of AKR1B10 effectively reduced cell proliferation and clonogenic growth, indicating the biological role of AKR1B10 in colon cancer. Together, our findings provide important insights into a previously unrecognized role of AKR1B10 in colon cancer.
Assuntos
Aldo-Ceto Redutases , Neoplasias do Colo , Citocinas , NF-kappa B , Transdução de Sinais , Aldo-Ceto Redutases/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Citocinas/metabolismo , Humanos , NF-kappa B/metabolismoRESUMO
The self-delivery of sonosensitizers and immunomodulators to tumor areas, which is highly recommended for enhancing sonodynamic immunotherapy, remains a challenge. Herein, a self-delivering nanodrug (HB-NLG8189, drug loading: ≈100 wt%) is developed by the small-molecule self-assembly of "HB" (a new clinical photosensitizer) and NLG8189 (indoleamine-(2,3)-dioxygenase (IDO) pathway inhibitor) for sonodynamic-augmented immunotherapy; this preparation method ensures the absence of excipient-related toxicity and immunogenicity. To evade immune recognition and prolong the circulation time, the HB-NLG8189 nanodrugs are camouflaged using macrophage cell membranes (MPCMs). The constructed HB-NLG8189@MPCM nanodrugs show an ability to preferentially accumulate within tumors. Upon ultrasound triggering, the HB-NLG8189@MPCM is able to generate reactive oxygen species efficiently for robust sonodynamic therapy; it induces immunogenic cell death, initiates an antitumor immune response to activate tumor-specific effector T cells, and promotes the secretion of inflammatory cytokines. The concomitant delivery of NLG8189 reverses the immunosuppressive tumor microenvironment by restraining IDO-1 activation and the intratumoral infiltration of regulatory T cells. Sonodynamic-augmented immunotherapy with HB-NLG8189@MPCM significantly inhibits the growth of both primary and distant tumors with little systemic toxicity. The biomimetic self-delivery nanodrug provides a promising paradigm for improving sonodynamic immunotherapy.
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Nanopartículas , Neoplasias , Linhagem Celular Tumoral , Humanos , Fatores Imunológicos/uso terapêutico , Imunoterapia , Indolamina-Pirrol 2,3,-Dioxigenase , Macrófagos/patologia , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Microambiente TumoralRESUMO
Chlorin e6-C-15-ethyl ester (LS-HB), a newly identified photosensitizer, was isolated from chlorin e6. The mechanism of tumor cell death induced by photodynamic therapy with LS-HB (LS-HB-PDT) is still unknown. Here, we investigated the photophysical properties of LS-HB, evaluated the antitumor effect on melanoma in vitro and in vivo, and explored its possible mechanisms. LS-HB not only has an optimal spectral band of red wavelength (660 nm) for photosensitization but also has favorable photostability. More importantly, LS-HB-PDT elicited a potent dose-dependent phototoxic effect in vitro. We discovered that LS-HB located in the mitochondria of B16F10 cells was able to generate excess reactive oxygen species, which subsequently resulted in mitochondrial membrane potential loss and induced apoptosis via caspase-9 and caspase-3 pathways. Moreover, PDT with LS-HB markedly inhibited the growth of melanoma in vivo. Therefore, LS-HB is expected to be an effective potential photosensitizer in antitumor therapy.
Assuntos
Melanoma , Fotoquimioterapia , Porfirinas , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Melanoma/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/farmacologia , Porfirinas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismoRESUMO
Selectively inducing tumor thrombosis and subsequent necrosis is a novel and promising antitumor strategy. We have previously designed a targeting procoagulant protein, called tTF-EG3287, which is a fusion of a truncated tissue factor (tTF) with EG3287, a short peptide against the neuropilin-1 (NRP1) binding site of vascular endothelial growth factor-A 165 (VEGF-A 165). However, off-target effects and high-dose requirements limit the further use of tTF-EG3287 in antitumor therapy. Therefore, we encapsulated tTF-EG3287 into poly(2-ethyl-2-oxazoline)-distearoyl phosphatidyl ethanolamine (PEOz-DSPE)-modified liposomes to construct pH-responsive liposomes as a novel vascular embolization agent, called tTF-EG3287@Liposomes. The liposomes had an average particle size of about 100 nm and showed considerable drug-loading capacity, encapsulation efficiency, and biocompatibility. Under the stimulation of acidic microenvironments (pH 6.5), the lipid membrane of tTF-EG3287@Liposomes collapsed, and the cumulative drug release rate within 72 h was 83 ± 1.26%. When administered to a mouse model of hepatocellular carcinoma (HCC), tTF-EG3287@Liposomes showed prolonged retention and enhanced accumulation in the tumor as well as a superior antitumor effec, compared with tTF-EG3287. This study demonstrates the potential of tTF-EG3287@Liposomes as a novel embolic agent for solid tumors and provides a new strategy for tumor-targeted infarction therapy.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Concentração de Íons de Hidrogênio , Lipossomos/química , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Tromboplastina , Microambiente Tumoral , Fator A de Crescimento do Endotélio VascularRESUMO
The anti-tumor efficacy of single photodynamic therapy (PDT) and radiotherapy (RT) has been greatly affected by inadequate tumor uptake of photo/radiation sensitizers, limited laser penetration depth, and radiation sickness caused by high doses of X-rays. Here, the authors report a biomimetic coronavirus-inspired hollow mesoporous gadolinium/bismuth nanocarrier loaded with a new NIR photosensitizer HB (termed as HB@VHMBi-Gd) for magnetic resonance imaging (MRI)-guided synergistic photodynamic-RT. HB@VHMBi-Gd displayed a faster cellular uptake rate than the conventional spherical HMBi-Gd loaded with HB (HB@SHMBi-Gd) because of rough surface-enhanced adhesion. After intravenous injection, HB@VHMBi-Gd is efficiently delivered to the tumor and rapidly invades the tumor cells by surface spikes. Interestingly, lysosomal acidity can trigger the degradation of VHMBi-Gd to produce ultrasmall nanoparticles to amplify the X-ray attenuation ability and enhance MRI contrast and radiosensitization. Under laser and X-ray irradiation, HB@VHMBi-Gd significantly enhances 1 O2 generation from HB to induce activation of caspase 9/3 and inhibition of C-myc, while enhancing hydroxyl radical generation from Bi2 O3 to induce intense DNA breakage. By synergistically inducing cell apoptosis by distinct reactive oxygen species (ROS), HB@VHMBi-Gd exhibits superior anticancer efficacy with ≈90% tumor inhibition. They envision that biomimetic virus-inspired hollow hybrid metal nanoparticles can provide a promising strategy for imaging-guided synergistic photodynamic-RT.
Assuntos
Nanopartículas Metálicas , Nanopartículas , Fotoquimioterapia , Bismuto , Linhagem Celular Tumoral , Gadolínio , Imageamento por Ressonância Magnética , Fotoquimioterapia/métodos , Nanomedicina Teranóstica/métodosRESUMO
The development of highly efficient photonic nanomaterials with synergistic biological effects is critical and challenging task for public hygiene health well-being and has attracted extensive interest. In this study, a type of near-infrared (NIR) driven, virus-like heterojunction was first developed for synergistic biological application. The Ag-coated Bi2CO5 nanomaterial (BOCO@Ag) demonstrated good biocompatibility, low cytotoxicity, high antibacterial activity and excellent light utilization stability. The synthesized BOCO@Ag performed a potential high photothermal conversion (efficiency~46.81%) to generate high temperatures when irradiated with near-infrared light illumination. As expected, compared to single Ag+ disinfection, BOCO@Ag can exhibit better antibacterial performance when combined with photothermal energy and released Ag+ . These results suggest that BOCO@Ag can be a promising photo-activate antimicrobial candidate and provide security for humans health and the environment treatment.
Assuntos
Antibacterianos , Nanosferas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Desinfecção , Humanos , Raios Infravermelhos , PrataRESUMO
Synergetic therapy includes the combination of two or more conventional therapeutic approaches and can be used for tumor treatment by combining the advantages and avoiding the drawbacks of each type of treatment. In the present study, truncated tissue factor (tTF)-EG3287 fusion protein-encapsulated gold nanorod (GNR)-virus-inspired mesoporous silica core-shell nanoparticles (vinyl hybrid silica nanoparticles; VSNP) (GNR@VSNP-tTF-EG3287) were synthesized to achieve synergetic therapy by utilizing selective vascular thrombosis therapy (SVTT) and photothermal therapy (PTT). By integrating the targeted coagulation activity of tTF-EG3287 and the high tumor ablation effect of GNR@VSNP, local hyperthermia could induce a high percentage of apoptosis of vascular endothelial cells by using near-infrared light. This provided additional phospholipid sites for tTF-EG3287 and enhanced its procoagulant activity in vitro. In addition, the nanoparticles, which had unique topological viral structures, exhibited superior cellular uptake properties leading to significant antitumor efficacy. The in vivo antitumor results further demonstrated an interaction between SVTT and PTT, whereas the synergetic therapy (SVTT and PTT) achieved an enhanced effect, which was superior to the respective treatment efficacy of each modality or the additive effect of their individual efficacies. In summary, the synthesized GNR@VSNP-tTF-EG3287 exerted synergetic effects and enhanced the antitumor efficiency by avoiding multiple injections and suboptimal administration. These effects simultaneously affected both tumor blood supply and cancer cell proliferation. The data suggested that the integration of SVTT induced by tTF-EG3287 and PTT could provide potential strategies for synergetic tumor therapy.
Assuntos
Antineoplásicos/uso terapêutico , Coagulantes/uso terapêutico , Nanotubos/química , Neoplasias/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Coagulantes/química , Feminino , Ouro/química , Ouro/efeitos da radiação , Ouro/toxicidade , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Raios Infravermelhos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanotubos/efeitos da radiação , Nanotubos/toxicidade , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/uso terapêutico , Terapia Fototérmica , Porosidade , Coelhos , Proteínas Recombinantes de Fusão/química , Dióxido de Silício/química , Dióxido de Silício/efeitos da radiação , Dióxido de Silício/toxicidade , Tromboplastina/química , Tromboplastina/uso terapêutico , Trombose/induzido quimicamente , Fator A de Crescimento do Endotélio Vascular/química , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Traditional combined photodynamic and photothermal therapy (PDT/PTT) was limited in clinical treatment of cancer due to the exceptionally low drug delivery efficiency to tumor sites and the activation by laser excitation with different wavelengths. We have accidentally discovered that our synthesized chlorin e6-C-15-ethyl ester (HB, a new type of photosensitizer) be activated by a laser with an excitation wavelength of 660 nm. Herein, we utilized Au nanorods (AuNRs) as 660 nm-activated PTT carriers to be successively surface-functionalized with HB and tumor-targeting peptide cyclic RGD (cRGD) to develop HB-AuNRs@cRGD for single NIR laser-induced targeted PDT/PTT. The HB-AuNRs@cRGD could be preferentially accumulated within tumor sites and rapidly internalized by cancer cells. Thereby, the HB-AuNRs@cRGD could exhibit amplified therapeutic effects by producing both significant reactive oxygen species (ROS) and hyperthermia simultaneously under the guidance of fluorescence imaging. The tumor inhibition rate on ECA109 esophageal cancer model was approximately 77.04%, and the negligible systematic toxicity was observed. This study proposed that HB-AuNRs@cRGD might be a promising strategy for single NIR laser-induced and imaging-guided targeted bimodal phototherapy.
Assuntos
Ouro/química , Nanotubos/química , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Terapia Fototérmica/métodos , Animais , Linhagem Celular , Feminino , Terapia com Luz de Baixa Intensidade , Camundongos , Camundongos Endogâmicos BALB C , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/farmacocinética , Espécies Reativas de Oxigênio/metabolismoRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with extremely limited treatment; the effective targeting strategy stays an urgent unmet need. Neuropilin-2 (NRP2), a multifunctional transmembrane non-tyrosine-kinase glycoprotein, enhances various signal transduction pathways to modulate cancer progression. However, the application value of NRP2 as a therapeutic target in pancreatic cancer is still unclear. Here, we detected the elevated NRP2 was associated with the poor prognosis of pancreas carcinoma. The mouse monoclonal antibody targeting NRP2 (N2E4) that could specifically bind to PDAC cells was developed. Moreover, N2E4 inhibits PDAC proliferation, migration, and invasion in vitro, and repressed growth and metastasis in vivo. Mechanistically, the effect of N2E4 was mainly related to the blocking of interaction between NRP2 with integrinß1 to inhibit FAK/Erk/HIF-1a/VEGF signaling. Therefore, N2E4 has the potential for targeting therapy of PDAC. This study lays a foundation for the future development of NRP2-based targeted therapy for PDAC.
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X-ray computed tomography (CT) has been widely used in clinical practice, and contrast agents such as Iohexol are often used to enhance the contrast of CT imaging between normal and diseased tissue. However, such contrast agents can have some toxicity. Thus, new CT contrast agents are urgently needed. Owing to the high atomic number (Z = 83), low cost, good biological safety, and great X-ray attenuation property (5.74 cm2 kg-1 at 100 keV), bismuth has gained great interest from researchers in the field of nano-sized CT contrast agents. Here, we synthesized BiF3: Ln@PVP nanoparticles (NPs) with an average particle size of about 380 nm. After coating them with polyvinylpyrrolidone (PVP), the BiF3: Ln@PVP NPs possessed good stability and great biocompatibility. Meanwhile, compared with the clinical contrast agent Iohexol, BiF3: Ln@PVP NPs showed superior in vitro CT imaging contrast. Subsequently, after in situ injection with BiF3: Ln@PVP NPs, the CT value of the tumor site after the injection was significantly higher than that before the injection (the CT value of the pre-injection and post-injection was 48.9 HU and 194.58 HU, respectively). The morphology of the gastrointestinal (GI) tract can be clearly observed over time after oral administration of BiF3: Ln@PVP NPs. Finally, the BiF3: Ln@PVP NPs were completely discharged from the GI tract of mice within 48 h of oral administration with no obvious damage to the GI tract. In summary, our easily synthesized BiF3: Ln@PVP NPs can be used as a potential clinical contrast agent and may have broad application prospects in CT imaging.
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High-efficiency nanotheranostic agents with multimodal imaging guidance have attracted considerable interest in the field of cancer therapy. Herein, novel silver-decorated bismuth-based heterostructured polyvinyl pyrrolidone nanoparticles (NPs) with good biocompatibility (Bi-Ag@PVP NPs) were synthesized for accurate theranostic treatment, which can integrate computed tomography (CT)/photoacoustic (PA) imaging and photodynamic therapy/photothermal therapy (PDT/PTT) into one platform. The Bi-Ag@PVP NPs can enhance light absorption and achieve a better photothermal effect than bismuth NPs. Moreover, after irradiation under an 808 nm laser, the Bi-Ag@PVP NPs can efficiently induce the generation of reactive oxygen species (ROS), thereby synergizing PDT/PTT to exert an efficient tumor ablation effect both in vitro and in vivo. Furthermore, Bi-Ag@PVP NPs can also be employed to perform enhanced CT/PA imaging because of their high X-ray absorption attenuation and enhanced photothermal conversion. Thus, they can be utilized as a highly effective CT/PA imaging-guided nanotheranostic agent. In addition, an excellent antibacterial effect was achieved. After irradiation under an 808 nm laser, the Bi-Ag@PVP NPs can destroy the integrity of Escherichia coli, thereby inhibiting E. coli growth, which can minimize the risk of infection during cancer therapy. In conclusion, our study provides a novel nanotheranostic platform that can achieve CT/PA-guided PDT/PTT synergistic therapy and have potential antibacterial properties. Thus, this work provides an effective strategy for further broad clinical application prospects.
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Autophagy is considered to be an important switch for facilitating normal to malignant cell transformation during colorectal cancer development. Consistent with other reports, we found that the membrane receptor Neuropilin1 (NRP1) is greatly upregulated in colon cancer cells that underwent autophagy upon glucose deprivation. However, the mechanism underlying NRP1 regulation of autophagy is unknown. We found that knockdown of NRP1 inhibits autophagy and largely upregulates the expression of aldo-keto reductase family 1 B10 (AKR1B10). Moreover, we demonstrated that AKR1B10 interacts with and inhibits the nuclear importation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and then subsequently represses autophagy. Interestingly, we also found that an NADPH-dependent reduction reaction could be induced when AKR1B10 interacts with GAPDH, and the reductase activity of AKR1B10 is important for its repression of autophagy. Together, our findings unravel a novel mechanism of NRP1 in regulating autophagy through AKR1B10.
Assuntos
Aldeído Redutase , Neoplasias do Colo , Aldeído Redutase/genética , Aldo-Ceto Redutases , Autofagia , Neoplasias do Colo/genética , Glucose , Gliceraldeído-3-Fosfato Desidrogenases , HumanosRESUMO
Photothermal/photodynamic therapy (PTT/PDT) and synergistic therapeutic strategies are often sought after, owing to their low side effects and minimal invasiveness compared to chemotherapy and surgical treatments. However, in spite of the development of the most PTT/PDT materials with good tumor-inhibitory effect, there are some disadvantages of photosensitizers and photothermal agents, such as low stability and low photonic efficiency, which greatly limit their further application. Therefore, in this study, a novel bismuth-based hetero-core-shell semiconductor nanomaterial BiNS-Fe@Fe with good photonic stability and synergistic theranostic functions was designed. On the one hand, BiNS-Fe@Fe with a high atomic number exhibits good X-ray absorption, enhanced magnetic resonance (MR) T2-weighted imaging, and strong photoacoustic imaging (PAI) signals. In addition, the hetero-core-shell provides a strong barrier to decline the recombination of electron-hole pairs, inducing the generation of a large amount of reactive oxygen species (ROS) when irradiated with visible-NIR light. Meanwhile, a Fenton reaction can further increase ROS generation in the tumor microenvironment. Furthermore, an outstanding chemodynamic therapeutic potential was determined for this material. In particular, a high photothermal conversion efficiency (η = 37.9%) is of significance and could be achieved by manipulating surface decoration with Fe, which results in tumor ablation. In summary, BiNS-Fe@Fe could achieve remarkable utilization of ROS, high photothermal conversion law, and good chemodynamic activity, which highlight the multimodal theranostic potential strategies of tumors, providing a potential viewpoint for theranostic applications of tumors.
Assuntos
Antineoplásicos/uso terapêutico , Nanopartículas Metálicas/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Nanomedicina Teranóstica/métodos , Animais , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Apoptose/efeitos dos fármacos , Bismuto/química , Células Hep G2 , Humanos , Raios Infravermelhos , Ferro/química , Ferro/efeitos da radiação , Nanopartículas Metálicas/química , Nanopartículas Metálicas/efeitos da radiação , Camundongos , Imagem Multimodal , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Terapia Fototérmica , Espécies Reativas de Oxigênio/metabolismoRESUMO
Photodynamic therapy (PDT) is a relatively safe way for disease diagnosis and treatment that is based on light and photosensitizers. LS-HB is a promising photosensitizer with a light absorption peak of 660 nm. AIMS: The present study aimed to investigate the anticancer effects of LS-HB-PDT on hepatocellular carcinoma and its underlying molecular mechanism. METHODS: In the present study, the MTT assay and xenograft tumor model experiment were used to evaluate its anticancer effects as well as its dark toxicity in hepatocellular carcinoma in vitro and in vivo. Reactive oxygen species assay kit was utilized to detect the reactive oxygen species production induced by LS-HB-PDT. RESULTS: In vitro, the MTT assay results revealed that LS-HB-PDT exhibited significant cytotoxic effects both in a drug- and light dose-dependent manner. The IC50 of LS-HB-PDT on hepatocellular carcinoma cells was 2.685 µg/ml. However, no dark cytotoxicity was observed at the LS-HB concentrations of 0-50 µg/ml, and no light-induced cytotoxicity was observed at the light (660 nm) dosages of 0-40 J/cm2. Furthermore, reactive oxygen species could be induced after LS-HB-PDT in a drug- and light dose-dependent manner. In vivo experiment, the tumor inhibition ratio of tumor-bearing nude mice following LS-HB-PDT was enhanced with the drug and light dose increasing. Notably, tumors in 60.0% of mice disappeared after LS-HB-PDT (2 mg/kg; 100 J/cm2), and the tumor inhibition ratio reached 92.3%. Furthermore, the histological results revealed necrosis and thrombus in tumor tissue caused by LS-HB-PDT, which were not observed in the control, drug alone and light alone groups of mice. CONCLUSIONS: The present study indicated that LS-HB was a promising photosensitizer with excellent anticancer effects and low side effects. LS-HB-PDT induced reactive oxygen species damage in the cells directly and destroyed tumor blood vessels, thus leading to tumor tissue necrosis.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Fotoquimioterapia , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Camundongos Nus , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
In this study, we have designed a magnetic targeting pro-coagulant protein (MTPCP) for the embolic therapy of solid tumours. The MTPCP consists of a magnetic carrier and a pro-coagulant protein. The pro-coagulant protein used in this study is the fusion protein tTF-EG3287 which is not pro-coagulant when free in the blood circulation, but presents strong pro-coagulant ability once bound to the Neuropilin-1(NRP-1) that is highly expressed on tumour-associated vascular endothelial cells. And the magnetic carrier is O-Carboxymethyl chitosan-coated iron oxide nanoparticles (OCMC/Fe3O4). In vitro, we assessed the NRP-1 targeting ability of the MTPCP using confocal microscopy and flow cytometry, and evaluated the potential pro-coagulant activity of the MTPCP using the Spectozyme FXa assay. In vivo, the magnetic targeting ability of the MTPCP was detected using a living imaging system. At last, we assessed the anticancer activity of the MTPCP on HepG2 tumour bearing BALB/c nude mice models including subcutaneous transplantation and orthotopic transplantation. HepG2 tumour bearing mice models revealed that after intravenous administration of the MTPCP, thrombosis specifically occurs on tumour-associated blood vessels, and resulting in tumour growth retardation. No apparent side effects, such as thrombosis in other organs or other treatment-related toxicity, were observed during the treatment. Our data showed that the MTPCP may be a promising embolic agent for the embolic therapy of solid tumours.
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Coagulação Sanguínea/efeitos dos fármacos , Embolização Terapêutica/métodos , Fenômenos Magnéticos , Proteínas Recombinantes de Fusão/farmacologia , Animais , Compostos Férricos/química , Células Hep G2 , Humanos , Camundongos , Nanopartículas/química , Proteínas Recombinantes de Fusão/químicaRESUMO
DVDMS-2 is a novel candidate for photodynamic therapy of tumors. The purpose of the present study was to assess the distribution and elimination of DVDMS-2 in mice bearing hepatoma 22 tumors. DVDMS-2 (1, 2 and 4 mg kg-1 ) was injected intravenously into the mice, extracted from biological tissues and quantified using a fluorescence assay. The data obtained were processed with WinNonlin pharmacokinetic software. The fluorescence assay established for DVDMS-2 quantification was a rapid, reproducible, sensitive and specific method with good linearity. The pharmacokinetics of DVDMS-2 in tumor-bearing mice conformed to a two-compartment model. DVDMS-2 accumulated in tumor tissue to a greater extent than adjacent tissues (skin, muscle) and sustained a relatively high-level concentration 12 to 24 h following administration, which may be the optimal treatment time point. In conclusion, DVDMS-2 selectively accumulated in tumor tissue and was eliminated at a rapid rate in tumor-bearing mice, suggesting that DVDMS-2 may have few side effects, including skin phototoxicity. The present study established the pharmacokinetic characteristics of DVDMS-2, which may be beneficial in future clinical study.