A bivalent cyclic RGD-siRNA conjugate enhances the antitumor effect of apatinib via co-inhibiting VEGFR2 in non-small cell lung cancer xenografts.
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ABSTRACT:
SUBMITTER: Liao L
PROVIDER: S-EPMC8274511 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The PI3K-AKT-mTOR-signaling pathway is frequently activated in glioblastoma (GBM). Inhibition of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB)/p110? (a PI3K catalytic isoform) by RNAi substantially suppresses GBM growth with less toxicity to normal astrocytes. However, insufficient and non-specific small interfering RNA (siRNA) delivery may limit the efficacy of RNAi-based therapies against GBM. Here we prepared a novel methoxy-modified PIK3CB siRNA molecule (siPIK3CB) that was covalently conjugated to a [cyclo(Arg-Gly-Asp-D-Phe-Lys)-Ahx]2-Glu-PEG-MAL (biRGD) peptide, which selectively binds to integrin ?v?3 receptors. The ?v?3-positive U87MG cell line was selected as a representative for GBM. An orthotopic GBM xenograft model based on luciferase-expressing U87MG was established and validated in vivo to investigate bio-distribution and anti-tumor efficacy of biRGD-siPIK3CB. In vitro, biRGD-siPIK3CB specifically entered and silenced PIK3CB expression in GBM cells in an ?v?3 receptor-dependent manner, thus inhibiting cell cycle progression and migration and enhancing apoptosis. In vivo, intravenously injected biRGD-siPIK3CB substantially slowed GBM growth and prolonged survival by reducing tumor viability with silencing PIK3CB expression. Furthermore, biRGD-siPIK3CB led to mild tubulointerstitial injury in the treatment of GBM without obvious hepatotoxicity, whereas co-infusion of Gelofusine obviously alleviated this injury without compromising anti-tumor efficacy. These findings revealed a great translational potential of biRGD-siPIK3CB conjugate as a novel molecule for GBM therapy.
| S-EPMC6178240 | biostudies-literature
Project description:Purpose:Apatinib is an inhibitor of VEGFR2 (vascular endothelial growth factor receptor 2) that has attracted a great deal of attention due to its promotion of anticancer activity. In the present study, we investigated the therapeutic effects of apatinib against colorectal cancer (CRC) and examined the underlying mechanism. Materials and Methods:Both in vivo and in vitro assays were conducted to study the effect of apatinib on CRC. To elucidate the associated mechanism, RNA-seq (transcriptome) analysis was conducted on apatinib-treated HCT116 cells. Results:Apatinib showed antiproliferative and proapoptotic effects, induced G0/G1 arrest and blocked cell migration and invasion in CRC. An analysis of the mechanism associated with apatinib activity demonstrated that by interacting with VEGFR2, apatinib decreased p-Src, p-Akt, and p-GSK3? levels, which further increased ?-catenin ubiquitination and reduced the nuclear translocation of ?-catenin. Furthermore, apatinib strongly suppressed CT26 cell growth in mouse xenograft models by inhibiting ?-catenin signaling and angiogenesis. Conclusion:Overall, the results of the present study here indicated that by inhibiting the VEGFR2-?-catenin-mediated malignant phenotype, apatinib significantly suppresses the growth of CRC, suggesting that the use of apatinib is a promising therapeutic strategy for CRC.
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Project description:Human retinal pigment epithelial cells are promising target sites for small interfering RNA (siRNA) that might be used for the prevention and/or treatment of choroidal neovascularization by inhibiting the expression of angiogenic factor; for example, by downregulating expression of the vascular endothelial growth factor gene.A novel functional lipid, DSPE-PEG-RGD, a Arg(R)-Gly(G)-Asp(D) motif peptide conjugated to 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine- N-[maleimide (polyethylene glycol)-2000], was synthesized for the preparation of siRNA-loaded RGD-PEGylated liposomes to enhance uptake of encapsulated siRNA in retinal pigment epithelial cells. Various liposomes, with 1 mol% and 5 mol% PEGylated lipid or 1 mol% and 5 mol% RGD-PEGylated lipid, were fabricated.Characterization of the liposomes, including siRNA entrapment efficiency, average particle size and ζ-potential, were determined to be as follows: >96%, 129.7 ± 51 to 230.7 ± 60.7 nm, and 17.3 ± 0.6 to 32 ± 1.3 mV, respectively. For the in vitro retinal pigment epithelial cell studies, the RGD-PEGylated liposomes had high delivery efficiency with siRNA delivery, about a four-fold increase compared with the PEGylated liposomes. Comparison of the various liposomes showed that the 1 mol% RGD-modified liposome had less cytotoxicity and higher siRNA delivery efficiency than the other liposomes. The antibody blocking assay confirmed that uptake of the 1 mol% RGD-PEGylated liposome was via integrin receptor- mediated endocytosis in retinal pigment epithelial cells.The results of this study suggest that RGD-PEGylated liposomes might be useful for siRNA delivery into retinal pigment epithelial cells by integrin receptor-medicated endocytosis.
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Project description:The newly discovered short (9 amino acid) non-RGD S-S bridged cyclic peptide ALOS-4 (H-cycl(Cys-Ser-Ser-Ala-Gly-Ser-Leu-Phe-Cys)-OH), which binds to integrin αvβ3 is investigated as peptide carrier for targeted drug delivery against human metastatic melanoma. ALOS4 binds specifically the αvβ3 overexpressing human metastatic melanoma WM-266-4 cell line both in vitro and in ex vivo assays. Coupling ALOS4 to the topoisomerase I inhibitor Camptothecin (ALOS4-CPT) increases the cytotoxicity of CPT against human metastatic melanoma cells while reduces dramatically the cytotoxicity against non-cancerous cells as measured by the levels of γH2A.X, active caspase 3 and cell viability. Moreover, conjugating ALOS4 to CPT even increases the chemo-stability of CPT under physiological pH. Bioinformatic analysis using Rosetta platform revealed potential docking sites of ALOS4 on the αvβ3 integrin which are distinct from the RGD binding sites. We propose to use this specific non-RGD cyclic peptide as the therapeutic carrier for conjugation of drugs in order to improve efficacy and reduce toxicity of currently available treatments of human malignant melanoma.
| S-EPMC5352194 | biostudies-literature
Project description:BackgroundOverexpression of Aurora A and B has been reported in a wide range of tumor types, including gastric cancer. Anti-angiogenesis has been considered as an important therapeutic modality in advanced gastric cancer. Here we identified a novel compound TY-011 with promising antitumor activity by targeting mitotic kinases (Aurora A and B) and angiogenic receptor tyrosine kinase (VEGFR2).MethodsHTRF® KinEASE™ assay was used to detect the effect of TY-011 against Aurora A, Aurora B and VEGFR2 activities. Docking simulation study was performed to predict the binding mode of TY-011 with Aurora A and B kinases. CCK-8 assay was used to test cell growth. Cell cycle and cell apoptosis was analyzed by flow cytometry. Gastric cancer cell xenograft mouse models were used for in vivo study. TUNEL kit was used to determine the apoptosis of tumor tissues. Immunohistochemistry analysis and HUVEC tube formation assay were performed to determine the anti-angiogenesis ability. Immunofluorescence and western blot were used to test protein expression.ResultsTY-011 was identified as a potential Aurora A and B inhibitor by HTRF® KinEASE™ assay. It effectively inhibited cellular Aurora A and B activities in a concentration-dependent manner. TY-011 occupied the ATP-binding site of both Aurora A and B kinases. TY-011 demonstrated prominent inhibitory effects on proliferation of gastric cancer cells. TY-011 treatment induced an obvious accumulation of cells at G2/M phase and a modest increase of cells with >4 N DNA content, which then underwent apoptosis. Meaningfully, orally administration of TY-011 demonstrated superior efficacy against the tumor growth in gastric cancer cell xenograft, with ~90% inhibition rate and 100% tumor regression at 9 mg/kg dose, and TY-011 did not affect the body weight of mice. Interestingly, we observed that TY-011 also antagonized tumor angiogenesis by targeting VEGFR2 kinase.ConclusionsThese results indicate that TY-011 is a well-tolerated, orally active compound that targets mitosis and angiogenesis in tumor growth, and provides strong preclinical support for use as a therapeutic for human gastric cancers.
| S-EPMC5124248 | biostudies-literature
Project description:The main objective of this study is to explore the impact of cyclic RGD peptides and (99m)Tc chelates on biological properties of (99m)Tc radiotracers. Cyclic RGD peptide conjugates, HYNIC-K(NIC)-RGD(2) (HYNIC = 6-hydrazinonicotinyl; RGD(2) = E[c(RGDfK)](2) and NIC = nicotinyl), HYNIC-K(NIC)-3G-RGD(2) (3G-RGD(2) = Gly-Gly-Gly-E[Gly-Gly-Gly-c(RGDfK)](2)), and HYNIC-K(NIC)-3P-RGD(2) (3P-RGD(2) = PEG(4)-E[PEG(4)-c(RGDfK)](2)), were prepared. Macrocyclic (99m)Tc complexes [(99m)Tc(HYNIC-K(NIC)-RGD(2))(tricine)] (1), [(99m)Tc(HYNIC-K(NIC)-3G-RGD(2))(tricine)] (2), and [(99m)Tc(HYNIC-K(NIC)-3P-RGD(2))(tricine)] (3) were evaluated for their biodistribution and tumor-targeting capability in athymic nude mice bearing MDA-MB-435 human breast tumor xenografts. It was found that 1, 2, and 3 could be prepared with high specific activity (?111 GBq/?mol). All three (99m)Tc radiotracers have two major isomers, which show almost identical uptake in tumors and normal organs. Replacing the bulky and highly charged [(99m)Tc(HYNIC)(tricine)(TPPTS)] (TPPTS = trisodium triphenylphosphine-3,3',3?-trisulfonate) with a smaller [(99m)Tc(HYNIC-K(NIC))(tricine)] resulted in less uptake in the kidneys and lungs for 3. Surprisingly, all three (99m)Tc radiotracers shared a similar tumor uptake (1, 5.73 ± 0.40%ID/g; 2, 5.24 ± 1.09%ID/g; and 3, 4.94 ± 1.71%ID/g) at 60 min p.i. The metabolic stability of (99m)Tc radiotracers depends on cyclic RGD peptides (3P-RGD(2) > 3G-RGD(2) ? RGD(2)) and (99m)Tc chelates ([(99m)Tc(HYNIC)(tricine)(TPPTS)] > [(99m)Tc(HYNIC-K(NIC))(tricine)]). Immunohistochemical studies revealed a linear relationship between the ?(v)?(3) expression levels and tumor uptake or tumor/muscle ratios of 3, suggesting that 3 is useful for monitoring the tumor ?(v)?(3) expression. Complex 3 is a very attractive radiotracer for detection of integrin ?(v)?(3)-positive tumors.
| S-EPMC3310279 | biostudies-literature
Project description:BackgroundGlioma is a common tumor that originated from the brain, and molecular targeted therapy is one of the important treatment modalities of glioma. Apatinib is a small-molecule tyrosine kinase inhibitor, which is widely used for the treatment of glioma. However, the underlying molecular mechanism has remained elusive. Recently, emerging evidence has proved the remarkable anticancer effects of ferroptosis. In this study, a new ferroptosis-related mechanism of apatinib inhibiting proliferation of glioma cells was investigated, which facilitated further study on inhibitory effects of apatinib on cancer cells.MethodsHuman glioma U251 and U87 cell lines and normal astrocytes were treated with apatinib. Ferroptosis, cell cycle, apoptosis, and proliferation were determined. A nude mouse xenograft model was constructed, and tumor growth rate was detected. Tumor tissues were collected to estimate ferroptosis levels and to identify the relevant pathways after treatment with apatinib.ResultsTreatment with apatinib could induce loss of cell viability of glioma cells, but not of normal astrocytes, through eliciting ferroptosis in vitro and in vivo. It was also revealed that apatinib triggered ferroptosis of glioma cells via inhibiting the activation of nuclear factor erythroid 2-related factor 2/vascular endothelial growth factor receptor 2 (Nrf2/VEFGR2) pathway. The overexpression of Nrf2 rescued the therapeutic effects of apatinib.ConclusionOur study proved that treatment with apatinib could restrain proliferation of glioma cells through induction of ferroptosis via inhibiting the activation of VEGFR2/Nrf2/Keap1 pathway. Overexpression of Nrf2 could counteract the induction of ferroptosis by apatinib.
| S-EPMC9117021 | biostudies-literature
Project description:Cardamonin (CADMN) exerts an in vitro antiproliferative and apoptotic actions against human hepatocellular carcinoma cells (HepG2). This study aimed to investigate the in vivo anti-tumorigenic action of CADMN against human hepatocellular carcinoma xenografts in an athymic nude mice, as well as to study the molecular docking and safety profile of this compound. Acute toxicity study demonstrated that CADMN is safe and well-tolerated up to 2000 mg/kg in ICR mice. Oral administration of 50 mg/kg/day of CADMN in xenografted nude mice showed a significant suppression in tumor growth as compared to untreated control group without pronounced toxic signs. Immunohistochemistry assay showed downregulation of proliferative proteins such as PCNA and Ki-67 in treated groups as compared to untreated control. Additionally, immunofluorescence analysis showed a significant downregulation in anti-apoptotic Bcl-2 protein, whereas pre-apoptotic Bax protein was significantly upregulated in nude mice treated with 25 and 50 mg/kg CADMN as compared to untreated mice. The findings also exhibited down-regulation of NF-κB-p65, and Ikkβ proteins, indicating that CADMN deactivated NF-κB pathway. The molecular docking studies demonstrated that CADMN exhibits good docking performance and binding affinities with various apoptosis and proliferation targets in hepatocellular cancer cells. In conclusion, CADMN could be a potential anticancer candidate against hepatocellular carcinoma. Other pharmacokinetics and pharmacodynamics properties, however, need to be further investigated in depth.
| S-EPMC7764268 | biostudies-literature
Project description:In recent years, anti-angiogenic therapy has attracted much interest because it is a versatile approach to treating most types of tumors, and therefore would be expected to be applicable for various cancers. Severe adverse events in patients treated with currently available anti-angiogenic therapeutics have, however, been reported, and these are caused by their inhibitory effects in normal tissue. To achieve an efficient anti-angiogenic therapy with minimal toxicity, a drug delivery system (DDS) specific to tumor endothelial cells (TECs) is needed. Cyclic RGD (cRGD) is a well-known ligand against αVβ₃ integrin that is expressed at high levels in the cell surface of TECs. To address this issue, we previously developed a cyclic RGD-equipped liposomal DDS (RGD-MEND) in which small interfering RNA (siRNA) was encapsulated. However, in the previous study, details of the preparation steps were not thoroughly examined. In this paper, to produce the most efficient delivery of therapeutic TECs, we explored optimum preparation conditions and components of the RGD-MEND. The cellular uptake and silencing ability of the RGD-MEND were investigated as a function of ligand density, poly(ethyleneglycol) linker length, and lipid composition. As a result, a knockdown efficiency that was five-fold higher than that of the previously reported one (ED50, from 4.0 to 0.75 mg/kg) was achieved.
| S-EPMC4588203 | biostudies-literature
Project description:PurposeWe previously showed that intravitreal injection of the sFLT morpholino-oligomer (FLT-MO) suppresses laser-induced choroidal neovascularization (CNV) in mice by decreasing the membrane bound form of Flt-1 while increasing the soluble form of Flt-1 via alternative splicing shift. In this study, we examined whether cyclic RGD peptide (cRGD) can promote morpholino-oligomer accumulation in CNV following tail vein injection, and whether systemic cRGD conjugated FLT-MO (cRGD-FLT-MO) suppresses CNV growth.MethodscRGD conjugated fluorescent morpholino-oligomer (cRGD-F-MO) was injected via tail vein into mice with previous retinal laser photocoagulation and examined for cRGD-F-MO accumulation in CNV. To examine whether cRGD-FLT-MO suppresses CNV growth, mice were tail-vein injected with cRGD-FLT-MO, cRGD conjugated standard morpholino-oligomer (cRGD-STD-MO), or Dulbecco's Phosphate-Buffered Saline (DPBS) 1 and 4 days postlaser photocoagulation. Seven days postlaser photocoagulation, eyes were harvested and laser CNV was stained with isolectin GS-IB4, allowing quantification of CNV size by confocal microscopy.ResultscRGD-F-MO accumulation in CNV commenced immediately after tail vein injection and could be observed even 1 day after injection. cRGD-FLT-MO tail vein injection significantly suppressed CNV size (2.7 × 105 ± 0.3 × 105 ?m3, P < 0.05 by Student's t-test) compared with controls (DPBS: 5.1 × 105 ± 0.6 × 105 ?m3 and cRGD-STD-MO: 5.5 × 105 ± 0.8 × 105 ?m3).ConclusionscRGD peptide facilitates morpholino-oligomer accumulation in CNV following systemic delivery. cRGD-FLT-MO suppressed CNV growth after tail-vein injection, demonstrating the potential utility of cRGD peptide for morpholino-oligomer delivery to CNV.Translational relevanceCurrent therapy for neovascular age-related macular degeneration involves intravitreal injection of anti-vascular endothelial growth factor drugs. Our results indicate that CNV can be treated systemically, thus eliminating risks and hazards associated with intravitreal injection.
| S-EPMC5444505 | biostudies-literature