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Nanophotothermolysis (NPhT) effect is considered to be an approach for the development of highly selective modalities for anticancer treatment. Herein, we evaluated an antitumor efficacy of NPhT with intravenously injected zinc phthalocyanine particles (ZnPcPs) in murine subcutaneous syngeneic tumor models. In S37 sarcoma-bearing mice a biodistribution of ZnPcPs was studied and the high antitumor efficacy of ZnPcPs-mediated NPhT was shown, including a response of metastatic lesions. The morphological investigation showed the main role of a local NPhT-induced vascular damage in the tumor growth and tumor spread inhibition. Murine tumors of different histological origin were not equally sensitive to the treatment. The results demonstrate a potential of ZnPcPs-mediated NPhT for treatment of surface tumors.
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In the original publication [...].
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The combination of radiation treatment and chemotherapy is currently the standard for management of cancer patients. However, safe doses do not often provide effective therapy, then pre-treated patients are forced to repeat treatment with often already increased tumor resistance to drugs and irradiation. One of the solutions we suggest is to improve primary course of radiation treatment via enhancing radiosensitivity of tumors by magnetic-guided iron oxide nanoparticles (magnetite). We obtained spherical heparinized iron oxide nanoparticles (hIONPs, â¼20â¯nm), characterized it by TEM, Infrared spectroscopy and DLS. Then hIONPs cytotoxicity was assessed for colon cancer cells (XTT assay) and cellular uptake of nanoparticles was analyzed with X-ray fluorescence. Combination of ionizing radiation (IR) and hIONPs in vitro caused an increase of G2/M arrest of cell cycle, mitotic errors and decrease in survival (compared with samples exposed to IR and hIONPs separately). The promising results were shown for magnetic-guided hIONPs in CT26-grafted BALB/C mice: the combination of intravenously administrated hIONPs and IR showed 20,8% T/C ratio (related to non-treated mice), while single radiation had no shown significant decrease in tumor growth (72,4%). Non-guided by magnets hIONPs with IR showed 57,9% of T/C. This indicates that ultra-small size and biocompatible molecule are not the key to successful nano-drug design, in each case, delivery technologies need to be improved when transferred to in vivo model.
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Neoplasias del Colon , Heparina , Nanopartículas Magnéticas de Óxido de Hierro , Ratones Endogámicos BALB C , Fármacos Sensibilizantes a Radiaciones , Animales , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Neoplasias del Colon/radioterapia , Nanopartículas Magnéticas de Óxido de Hierro/química , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Humanos , Ratones , Línea Celular Tumoral , Heparina/química , Heparina/farmacología , Nanopartículas de Magnetita/química , Ensayos Antitumor por Modelo de Xenoinjerto , Supervivencia Celular/efectos de los fármacosRESUMEN
Destroying tumor vasculature is a relevant therapeutic strategy due to its involvement in tumor progression. However, adaptive resistance to approved antiangiogenic drugs targeting VEGF/VEGFR pathway requires the recruitment of additional targets. In this aspect, targeting TRAIL pathway is promising as it is an important component of the immune system involved in tumor immunosurveillance. For dual targeting of malignant cells and tumor vascular microenvironment, we designed a multivalent fusion protein SRH-DR5-B-iRGD with antiangiogenic VEGFR2-specific peptide SRH at the N-terminus and a tumor-targeting and -penetrating peptide iRGD at the C-terminus of receptor-selective TRAIL variant DR5-B. SRH-DR5-B-iRGD obtained high affinity for DR5, VEGFR2 and αvß3 integrin in nanomolar range. Fusion of DR5-B with effector peptides accelerated DR5 receptor internalization rate upon ligand binding. Antitumor efficacy was evaluated in vitro in human tumor cell lines and primary patient-derived glioblastoma neurospheres, and in vivo in xenograft mouse model of human glioblastoma. Multivalent binding of SRH-DR5-B-iRGD fusion efficiently stimulated DR5-mediated tumor cell death via caspase-dependent mechanism, suppressed xenograft tumor growth by >80 %, doubled the lifespan of xenograft animals, and inhibited tumor vascularization. Therefore, targeting DR5 and VEGFR2 molecular pathways with SRH-DR5-B-iRGD protein may provide a novel therapeutic approach for treatment of solid tumors.
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Glioblastoma , Humanos , Animales , Ratones , Apoptosis , Angiogénesis , Línea Celular Tumoral , Péptidos , Ensayos Antitumor por Modelo de Xenoinjerto , Microambiente TumoralRESUMEN
Prostate cancer is the second most common cancer among men. We designed and synthesized new ligands targeting prostate-specific membrane antigen and suitable for bimodal conjugates with diagnostic and therapeutic agents. In vitro studies of the affinity of the synthesized compounds to the protein target have been carried out. Based on these ligands, a series of bimodal conjugates with a combination of different mitosis inhibitors and antiandrogenic drugs were synthesized. The cytotoxicity of the compounds obtained in vitro was investigated on three different cell lines. The efficacy of the two obtained conjugates was evaluated in vivo in xenograft models of prostate cancer. These compounds have been shown to be highly effective in inhibiting the growth of PSMA-expressing tumors.
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Antagonistas de Andrógenos , Neoplasias de la Próstata , Masculino , Humanos , Antagonistas de Andrógenos/uso terapéutico , Citotoxinas/uso terapéutico , Próstata/patología , Ligandos , Línea Celular Tumoral , Glutamato Carboxipeptidasa II/metabolismo , Antígenos de Superficie/metabolismo , Neoplasias de la Próstata/metabolismoRESUMEN
Herein, we report a new conjugate BChl-S-S-NI based on the second-generation photosensitizer bacteriochlorin e6 (BChl) and a 4-styrylnaphthalimide fluorophore (NI), which is cleaved into individual functional fragments in the intracellular medium. The chromophores in the conjugate were cross-linked by click chemistry via a bis(azidoethyl)disulfide bridge which is reductively cleaved by the intracellular enzyme glutathione (GSH). A photophysical investigation of the conjugate in solution by using optical spectroscopy revealed that the energy transfer process is realized with high efficiency in the conjugated system, leading to the quenching of the emission of the fluorophore fragment. It was shown that the conjugate is cleaved by GSH in solution, which eliminates the possibility of energy transfer and restores the fluorescence of 4-styrylnaphthalimide. The photoinduced activity of the conjugate and its imaging properties were investigated on the mouse soft tissue sarcoma cell line S37. Phototoxicity studies in vitro show that the BChl-S-S-NI conjugate has insignificant dark cytotoxicity in the concentration range from 15 to 20,000 nM. At the same time, upon photoexcitation, it exhibits high photoinduced activity.
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Fotoquimioterapia , Porfirinas , Ratones , Animales , Medicina de Precisión , Línea Celular Tumoral , Fotoquimioterapia/métodos , Porfirinas/química , Colorantes Fluorescentes , Glutatión/químicaRESUMEN
TRAIL (TNF-related apoptosis-inducing ligand) and its derivatives are potentials for anticancer therapy due to the selective induction of apoptosis in tumor cells upon binding to death receptors DR4 or DR5. Previously, we generated a DR5-selective TRAIL mutant variant DR5-B overcoming receptor-dependent resistance of tumor cells to TRAIL. In the current study, we improved the antitumor activity of DR5-B by fusion with a tumor-homing iRGD peptide, which is known to enhance the drug penetration into tumor tissues. The obtained bispecific fusion protein DR5-B-iRGD exhibited dual affinity for DR5 and integrin αvß3 receptors. DR5-B-iRGD penetrated into U-87 tumor spheroids faster than DR5-B and demonstrated an enhanced antitumor effect in human glioblastoma cell lines T98G and U-87, as well as in primary patient-derived glioblastoma neurospheres in vitro. Additionally, DR5-B-iRGD was highly effective in a xenograft mouse model of the U-87 human glioblastoma cell line in vivo. We suggest that DR5-B-iRGD may become a promising candidate for targeted therapy for glioblastoma.
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Glioblastoma , Ligando Inductor de Apoptosis Relacionado con TNF , Humanos , Ratones , Animales , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Integrina alfaVbeta3/genética , Línea Celular Tumoral , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/genética , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , ApoptosisRESUMEN
Photo-induced cytotoxicity and antitumor activity of a series of dual function agents for photodynamic therapy (PDT) and fluorescent imaging based on bacteriochlorin photosensitizer conjugated with various naphthalimide fluorophores was studied in vitro using murine tumor cells of S37 sarcoma and in vivo on mice bearing murine S37 sarcoma. Upon irradiation at the absorption maximum of the photosensitizer, the activity of conjugates was as high as in the case of individual bacteriochlorin, while an additional excitation of the naphthalimide fragment led to an increase in the PDT efficacy due to resonance energy transfer from the fluorophore to photosensitizer. The fluorescence contrast and specific cytotoxic activity measurements indicate that the conjugate of bacteriochlorin with 3,4-dimethoxestyrene-substituted naphthalimide is the most promising agent for the application as theranostic in PDT.
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Naftalimidas/química , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Porfirinas/química , Animales , Línea Celular Tumoral , Rayos Láser , Ratones , Naftalimidas/metabolismo , Neoplasias/diagnóstico , Neoplasias/patología , Imagen Óptica , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/metabolismo , Fármacos Fotosensibilizantes/farmacología , Porfirinas/metabolismo , Distribución Tisular , Trasplante HomólogoRESUMEN
A promising direction in Biopharmaceuticals is the development of specific peptide-based systems to improve drug delivery. This approach may increase tumor specificity and drug penetration into the target cell. Similar systems have been designed for several antitumor drugs. However, for photodynamic therapy drugs, such studies are not yet enough. Previously, we have developed a method of inclusion of chlorin e6 (Ce6), a photosensitizer used in photodynamic therapy, in phospholipid nanoparticles with a diameter of up to 30 nm, and reported an increase in its effectiveness in the experiments in vivo. In this work, we propose to modify a previously developed delivery system for Ce6 by the addition of cell-penetrating (R7) and/or targeting NGR peptides. The interaction of the compositions developed with HepG2 and MCF-7 tumor cells is shown. The expression of CD13 protein with affinity to NGR on the surface of these cells has been studied using flow cytometry. The expression of this protein on the HepG2 cells and its absence on MCF-7 was demonstrated. After incubation of tumor cells with the resulting Ce6 compositions, we evaluated the cellular accumulation, photoinduced, and dark cytotoxicity of the drugs. After irradiation, the highest level of cytotoxicity was observed when R7 peptide was added to the system, either alone or in combination with NGR. In addition to R7, the NGR-motif peptide increased the internalization of Ce6 in HepG2 cells without affecting its photodynamic activity. In this work we also discuss possible mechanisms of action of the cell-penetrating peptide when attached to phospholipid nanoparticles.
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Neoplasias de la Mama/tratamiento farmacológico , Antígenos CD13/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Péptidos de Penetración Celular/metabolismo , Portadores de Fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Nanopartículas , Fosfolípidos/química , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Porfirinas/farmacología , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/patología , Supervivencia Celular/efectos de los fármacos , Péptidos de Penetración Celular/química , Clorofilidas , Composición de Medicamentos , Células Hep G2 , Humanos , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/fisiopatología , Células MCF-7 , Oligopéptidos/química , Oligopéptidos/metabolismo , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/metabolismo , Porfirinas/química , Porfirinas/metabolismoRESUMEN
Despite the weak clinical efficacy of TRAIL death receptor agonists, a search is under way for new agents that more efficiently activate apoptotic signaling. We previously created a TRAIL DR5-selective variant DR5-B without affinity for the DR4, DcR1, DcR2, and OPG receptors and increased proapoptotic activity in tumor cells. Here we showed that DR5-B significantly inhibited tumor growth in HCT116 and Caco-2 but not in HT-29 xenografts. The antitumor activity of DR5-B was 2.5 times higher in HCT116 xenografts compared to TRAIL. DR5-B at a dose of 2 or 10â¯mg/kg/d for 10â¯days inhibited tumor growth in HCT116 xenografts by 26% or 50% respectively, and increased animal survival. Unexpectedly, DR5-B at a higher dose (25â¯mg/kg/d) inhibited tumor growth only during the first 8â¯days of drug exposure, while at the end of the monitoring, no effect or even slight stimulation of tumor growth was observed. The pharmacokinetic parameters of DR5-B were comparable to those of TRAIL, except that the half-life was 3.5 times higher. Thus, enhancing TRAIL selectivity to DR5 may increase both antitumor and proliferative activities depending on the concentration and administration regimens.