Potential Candidate For Cancer Therapy Research Articles

Oncolytic Activity of Canine Distemper Virus in Human Ductal Breast Carcinoma Cells

Introduction: Oncolytic virotherapy is a novel strategy for cancer treatment in humans and companion animals. Canine distemper virus (CDV) is known to induce apoptosis in tumor cells, thus serving as a potential candidate for oncolytic therapy. However, the mechanism of viral oncolytic activity is less studied and varies depending on the type of cancer and cell lines. Methods: In the present study, the susceptibility of the MCF-7 cell line to CDV infection was assessed using the CDV strain, which was confirmed previously through sequence analysis in the Vero cell line. The impact of CDV infection on cell proliferation and apoptosis was studied by evaluating the expression of four target genes including the myeloid cell leukemia 1 (MCL-1), phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), transcription factor (SP1), and DNA (cytosine-5)-methyltransferase 3A (DNMT3A). Results: CDV replication in the cells induced cytopathic effect and decreased in the cell proliferation rates compared to the uninfected control. MCL-1, SP1, and PIK3R1 gene expression was down-regulated, while the expression of DNMT3A was up-regulated 3 days post-infection. The expression levels of the target genes suggest that CDV may be inducing the intrinsic apoptotic pathway in the cancer cell line. Conclusion: Overall, the results strongly propose CDV strain as a potential candidate for cancer therapy after detailed studies.

Pharmacological Ascorbate Elicits Anti-Cancer Activities against Non-Small Cell Lung Cancer through Hydrogen-Peroxide-Induced-DNA-Damage.

Non-small cell lung cancer (NSCLC) poses a significant global health burden with unsatisfactory survival rates, despite advancements in diagnostic and therapeutic modalities. Novel therapeutic approaches are urgently required to improve patient outcomes. Pharmacological ascorbate (P-AscH-; ascorbate at millimolar concentration in plasma) emerged as a potential candidate for cancer therapy for recent decades. In this present study, we explore the anti-cancer effects of P-AscH- on NSCLC and elucidate its underlying mechanisms. P-AscH- treatment induces formation of cellular oxidative distress; disrupts cellular bioenergetics; and leads to induction of apoptotic cell death and ultimately reduction in clonogenic survival. Remarkably, DNA and DNA damage response machineries are identified as vulnerable targets for P-AscH- in NSCLC therapy. Treatments with P-AscH- increase the formation of DNA damage and replication stress markers while inducing mislocalization of DNA repair machineries. The cytotoxic and genotoxic effects of P-AscH- on NSCLC were reversed by co-treatment with catalase, highlighting the roles of extracellular hydrogen peroxide in anti-cancer activities of P-AscH-. The data from this current research advance our understanding of P-AscH- in cancer treatment and support its potential clinical use as a therapeutic option for NSCLC therapy.

Amomum subulatum Fruit Extract Mediated Green Synthesis of Silver and Copper Oxide Nanoparticles: Synthesis, Characterization, Antibacterial and Anticancer Activities

This research presents a straightforward, effective, and eco-friendly method for the production of silver nanoparticles (AgNPs) and copper oxide nanoparticles (CuONPs) using the dried fruit of Amomum subulatum as a reducing, stabilizing, and capping agent. The formation of AgNPs and CuONPs is supported by the presence of a surface plasmon resonance band (SPR) at 440 nm for AgNPs and 245 nm for CuONPs. Additionally, the identification of specific biomolecules responsible for the synthesis of AgNPs and CuONPs was confirmed through FTIR spectra analysis. The Transmission electron microscope (TEM) images demonstrated that AgNPs and CuONPs had spherical shapes, with mean particle diameters of 20.6 nm and 24.7 nm, respectively. X-ray diffraction and selected area electron diffraction (SAED) analyses provided evidence of the crystalline nature of the synthesized AgNPs and CuONPs. Additionally, the presence of silver and copper elements was observed through energy-dispersive X-ray spectroscopy (EDS) analysis. Furthermore, the antibacterial activity of AgNPs was found to be superior to that of CuONPs against human pathogens such as Escherichia coli, Staphylococcus aureus, and Bacillus subtilis. The cytotoxic activity of the biosynthesized nanoparticles (NPs) was evaluated in vitro against human cervical cells (HeLa) and human breast cells (MCF-7). In MCF-7 cells, the IC50 value for AgNPs was estimated to be 39.79 µg/mL, while that of CuONPs was 83.89 µg/mL. In HeLa cells, the IC50 value for AgNPs was 45.5 µg/mL, and for CuONPs, it was 97.07 µg/mL. For the first time, an eco-friendly method for the synthesis of AgNPs and CuONPs from fruit extract of Amomum subulatum has been discussed along with their comparative evaluation study. These results highlight the promising applications of the eco-friendly synthesized AgNPs and CuONPs as effective agents against microbial infections and potential candidates for cancer therapy.

Novel amphiphilic hydroxyethyl starch-based nanoparticles loading camptothecin exhibit high anticancer activity in HepG2 cells and zebrafish

Camptothecin is a naturally occurred anticancer drug but exhibits limitations including poor aqueous solubility, low bioavailability, and high level of adverse drug reactions on normal organs. To overcome these problems, this paper developed a novel amphiphilic Lau-Leu-HES carrier using hydroxyethyl starch, lauric acid, and L-leucine as starting materials. The carrier was successfully applied to prepare Lau-Leu-HES nanoparticles loading camptothecin. The drug loading efficiency and encapsulation efficiency of the nanoparticles were calculated to be 29.04% and 81.85%, respectively. The nanoparticles exhibited high zeta potential (–15.51 mV) and small hydrodynamic diameter (105.4 nm). Camptothecin in nanoparticles could be rapidly released under acidic condition (pH = 4.5), thereby indicating the high sensitivity under cancer microenvironments. Anticancer investigation revealed that the nanoparticles could inhibit the proliferation of HepG2 cells in vitro. Compared with commercial available drug doxorubicin, the nanoparticles could significantly inhibit the expression of krasv12 oncogene in transgenic Tg (EGFP-krasV12) zebrafish. These results indicate that the camptothecin-loaded Lau-Leu-HES nanoparticles are expected to be a potential candidate for cancer therapy.

"Synthesized Biomaterial is Potential Candidate for Cancer Therapy & NUV LED Chips"

"Synthesized Biomaterial is Potential Candidate for Cancer Therapy & NUV LED Chips"

Design and fabrication of chitosan-based AIE active micelles for bioimaging and intelligent delivery of paclitaxel

In this study, cetyl 4-formylbenzoate alkyl and 4-(2-hydroxyethoxy) benzophenonesalicylaldazide modified biotinylated chitosan (CS-BT-HBS-CB) featured with aggregation-induced emission (AIE) characteristic, active tumor-targeting ability and pH-responsive drug release property was designed and synthesized. The polymer was fabricated by introducing hydrophobic segment, tumor targeting ligand, acid-sensitive bond and AIE fluorophore to the backbone of chitosan. Due to its amphiphilicity, the polymer could self-assemble into micelles and encapsulate paclitaxel (PTX) to form PTX-loaded CS-BT-HBS-CB micelles. The mean size of the micelles was 167 nm, which was beneficial to the EPR effect. Moreover, with the help of above functional groups, the micelles exhibited excellent AIE effect, triggered drug release behavior by acidic condition, selective internalization by MCF-7 cells and excellent cellular imaging capability. In vivo studies revealed that the PTX-loaded CS-BT-HBS-CB micelles could enhance the antitumor efficacy with low systemic toxicity. This micellar system would be a potential candidate for cancer therapy and bioimaging.

Gold Tablets: Gold Nanoparticles Encapsulated into Dextran Tablets and Their pH-Responsive Behavior as an Easy-to-Use Platform for Multipurpose Applications.

Many applications using gold nanoparticles (AuNPs) require (i) their functionalization with a biopolymer to increase their stability and (ii) their transformation into an easy-to-handle material, which provide them with specific properties. In this research, a portable tablet platform is presented based on dextran-encapsulated gold nanoparticles (AuNPs-dTab) by a ligand exchange reaction between citrate-capped gold nanoparticles (AuNPs-Cit) and dextran. These newly fabricated tablets were characterized utilizing ultraviolet–visible spectroscopy (UV–vis), Fourier transform infrared spectroscopy–attenuated total reflectance (FTIR–ATR), transmission electron microscopy (TEM), dynamic light scattering (DLS), X-ray diffraction spectroscopy (XRD), differential scanning calorimetry (DSC), and atomic force microscopy (AFM) techniques. The results showed that dextran-capped gold nanoparticles in a tablet platform (AuNPs-dTab) were well-dispersed and highly stable for at least a year at room temperature. In addition to particle and surface characterization of AuNPs-dTab, the tablet morphology in terms of thickness, diameter, density, and opacity was also measured using 6 and 10% dextran with 2, 4 and 8 nM AuNPs-Cit. We further investigated the pH-responsive behavior of AuNPs-dTab in the presence and absence of sodium chloride. Results showed that neutral and alkaline environments were suitable to render AuNPs dispersed in a tablet, while an acidic condition controls the aggregation rate of AuNPs as confirmed by concentration-dependent aggregation phenomena. Besides the easy fabrication, these tablets were portable and low-cost (approx. 1.22 CAD per 100 tablets of a 100 μL solution of dextran-capped gold nanoparticles (AuNPs-dSol)). The biocompatible nature of dextran along with the acidic medium trigger nature of AuNPs makes our proposed tablet a potential candidate for cancer therapy due to the acidic surrounding of tumor tissues as compared to normal cells. Also, our proposed tablet approach paves the way for the fabrication of portable and easy-to-use optical sensors based on the AuNPs embedded in a natural polymeric architecture that would serve as a colorimetric recognition indicator for detecting analytes of interest.

Photothermolysis Mediated by Gold Nanorods Conjugated with Epidermal Growth Factor Receptor (EGFR) Monoclonal Antibody Induces Apoptosis via the Mitochondrial Apoptosis Pathway in Laryngeal Squamous Cell Cancer.

Gold nanorods (AuNRs) have unique optical properties and biological affinity and can be used to treat tumors when conjugated with other protein molecules. Our previous studies have shown that EGFR monoclonal antibody (EGFRmAb)-modified AuNRs exert strong antitumor activity in vitro by inducing apoptosis. In this study, we tested the effects of EGFRmAb-modified AuNRs on laryngeal squamous cell cancer (LSCC) in vitro and in vivo. The in vitro results showed that EGFRmAb-modified AuNRs inhibited NP-69, BEAS-2B and Hep-2 cell growth and induced mitochondria-dependent apoptosis. The mitochondrial membrane potential was reduced, leading to the release of cytochrome C (Cyt C) and consequent activation of the intrinsic mitochondrial apoptosis pathway. Moreover, we observed that the occurrence of mitochondrial apoptosis is related to the destruction of the lysosome-mitochondria axis. To verify the effects in vivo, we also established a laryngeal tumor model in nude mice by subcutaneous transplantation. In model mice treated with EGFRmAb-modified AuNRs and irradiated with an NIR laser, tumor cell apoptosis and tumor growth were inhibited. These results suggest that EGFRmAb-modified AuNRs induced apoptosis through the intrinsic mitochondrial apoptotic pathway and are a potential candidate for cancer therapy.

Alternative splicing perturbation landscape identifies RNA binding proteins as potential therapeutic targets in cancer

Alternative splicing (AS) plays an important role in gene regulation, and AS perturbations are frequently observed in cancer. RNA binding protein (RBP) is one of the molecular determinants of AS, and perturbations in RBP-gene network activity are causally associated with cancer development. Here, we performed a systematic analysis to characterize the perturbations in AS events across 18 cancer types. We showed that AS alterations were prevalent in cancer and involved in cancer-related pathways. Given that the extent of AS perturbation was associated with disease severity, we proposed a computational pipeline to identify RBP regulators. Pan-cancer analysis identified a number of conserved RBP regulators, which play important roles in regulating AS of genes involved in cancer hallmark pathways. Our application analysis revealed that the expression of 68 RBP regulators helped in cancer subtyping. Specifically, we identified four subtypes of kidney cancer with differences in cancer hallmark pathway activities and prognosis. Finally, we identified the small molecules that can potentially target the RBP genes and suggested potential candidates for cancer therapy. In summary, our comprehensive AS perturbation landscape analysis identified RBPs as potential therapeutic targets in cancer and provided novel insights into the regulatory functions of RBPs in cancer.

An NRP1/MDM2-Targeted D-Peptide Supramolecular Nanomedicine for High-Efficacy and Low-Toxic Liver Cancer Therapy.

Supramolecular nanomedicines based on self-assembly of D-peptides have been of great interest as potential candidates for cancer therapy. Neuropilin-1 (NRP1) and mouse double minute 2 (MDM2) have been considered as the anticancer targets because of their overexpression in cancers. However, NRP1/MDM2-targeted D-peptide supramolecular nanomedicines remain unreported. Here, a potent anticancer D-peptide supramolecular nanomedicine targeting NRP1 and MDM2, termed as NMTP-5, is identified by using structure-based virtual screening techniques. NMTP-5 exhibits good biostability and strong cellular uptake performance. Moreover, NMTP-5 displays strong anticancer activity to SK-Hep-1 cells in vitro and in vivo, with no apparent host toxicity. This work demonstrates that NMTP-5 can be used as a potential chemotherapeutic agent for the treatment of liver cancer.

Synthesis of Curcumin Loaded Smart pH-Responsive Stealth Liposome as a Novel Nanocarrier for Cancer Treatment

The innovation of drug delivery vehicles with controlled properties for cancer therapy is the aim of most pharmaceutical research. This study aims to fabricate a new type of smart biocompatible stealth-nanoliposome to deliver curcumin for cancer treatment. Herein, four different types of liposomes (with/without pH-responsive polymeric coating) were synthesized via the Mozafari method and then characterized with several tests, including dynamic light scattering (DLS), Fourier-transform infrared spectroscopy (FTIR), Zeta potential, and field emission scanning electron microscopes (FE-S EM). The loading and release profile of curcumin were evaluated in two pH of 7.4 and 6.6. Finally, the MTT assay was used to assess the cytotoxicity of the samples. FE-SEM results revealed a mean size of about 40 and 50 nm for smart stealth-liposome and liposome, respectively. The results of drug entrapment revealed that non-coated liposome had about 74% entrapment efficiency, while it was about 84% for PEGylated liposomes. Furthermore, the drug released pattern of the nanocarriers showed more controllable release in stealth-liposome in comparison to non-coated one. The results of the cytotoxicity test demonstrated the toxicity of drug-loaded carriers on cancer cells. Based on the results of this study, the as-prepared smart stealth pH-responsive nanoliposome could be considered as a potential candidate for cancer therapy.

Degradable Spirocyclic Polyacetal-Based Core-Amphiphilic Assemblies for Encapsulation and Release of Hydrophobic Cargo.

Polymeric nanomaterials that degrade in acidic environments have gained considerable attention in nanomedicine for intracellular drug delivery and cancer therapy. Among various acid-degradable linkages, spirocyclic acetals have rarely been used to fabricate such vehicles. In addition to acid sensitivity, they benefit from conformational rigidity that is otherwise not attainable by their non-spirocyclic analogs. Herein, amphiphilic spirocyclic polyacetals are synthesized by Cu-catalyzed alkyne–azide “click” polymerization. Unlike conventional block copolymers, which often form core–shell structures, these polymers self-assemble to form core amphiphilic assemblies capable of encapsulating Nile red as a hydrophobic model drug. In vitro experiments show that while release from these materials can occur at neutral pH with preservation of their integrity, acidic pH accelerates efficient cargo release and leads to the complete degradation of assemblies. Moreover, cellular assays reveal that these materials are fully cytocompatible, interact with the plasma membrane, and can be internalized by cells, rendering them as potential candidates for cancer therapy and/or drug delivery.

The histone deacetylase inhibitor PCI-24781 impairs calcium influx and inhibits proliferation and metastasis in breast cancer.

Histone deacetylases (HDACs) are involved in key cellular processes and have been implicated in cancer. As such, compounds that target HDACs or drugs that target epigenetic markers may be potential candidates for cancer therapy. This study was therefore aimed to identify a potential epidrug with low toxicity and high efficiency as anti-tumor agents.Methods: We first screened an epigenetic small molecule inhibitor library to screen for an epidrug for breast cancer. The candidate was identified as PCI-24781 and was characterized for half maximal inhibitory concentration (IC50), for specificity to breast cancer cells, and for effects on carcinogenesis and metastatic properties of breast cancer cell lines in vitro. A series of in silico and in vitro analyses were further performed of PCI-24781 to identify and understand its target.Results: Screening of an epigenetic inhibitor library in MDA-MB-231 cells, a malignant cancer cell line, showed that PCI-24781 is a potential anti-tumor drug specific to breast cancer. Ca2+ related pathways were identified as a potential target of PCI-24781. Further analyses showed that PCI-24781 inhibited Gαq-PLCβ3-mediated calcium signaling by activating the expression of regulator of G-protein signaling 2 (RGS2) to reduce cell proliferation, metastasis, and differentiation, resulting in cell death in breast cancer. In addition, RGS2 depletion reversed anti-tumor effect and inhibition of calcium influx induced by PCI-24781 treatment in breast cancer cells.Conclusions: We have demonstrated that PCI-24781 is an effective anti-tumor therapeutic agent that targets calcium signaling by activating RGS2. This study also provides a novel perspective into the use of HDAC inhibitors for cancer therapy.

Synthesis and evaluation of new thiourea derivatives as antitumor and antiangiogenic agents

A series of novel thiourea derivatives were synthesized and evaluated by biological activities. Among them, compound 10e containing 3,5-bis(trifluoromethyl)phenyl moiety (R1) at the terminal thiourea and phenylamino (R2) at the terminal acyl position showed the best cytotoxic activities against seven cancer cell lines (NCI-H460, Colo-205, HCT116, MDA-MB-231, MCF-7, HepG2, PLC/PRF/5) and HUVECs. Moreover, compound 10e moderately inhibited various RTKs such as VEGFR2, VEGFR3, and PDGFRβ. Notably, 10e exhibited much better inhibitory effect of tumor formation and antiangiogenic activities than Sorafenib and Regorafenib at the same concentration. Further docking studies suggested that 10e could serve as potential candidate for cancer therapy.

Tristetraprolin Posttranscriptionally Downregulates TRAIL Death Receptors.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has attracted attention as a potential candidate for cancer therapy. However, many primary cancers are resistant to TRAIL, even when combined with standard chemotherapy. The mechanism of TRAIL resistance in cancer cells has not been fully elucidated. The TRAIL death receptor (DR) 3′-untranslated region (3′-UTR) is reported to contain AU-rich elements (AREs) that are important for regulating DR mRNA stability. However, the mechanisms by which DR mRNA stability is determined by its 3′-UTR are unknown. We demonstrate that tristetraprolin (TTP), an ARE-binding protein, has a critical function of regulating DR mRNA stability. DR4 mRNA contains three AREs and DR5 mRNA contains four AREs in 3′-UTR. TTP bound to all three AREs in DR4 and ARE3 in DR5 and enhanced decay of DR4/5 mRNA. TTP overexpression in colon cancer cells changed the TRAIL-sensitive cancer cells to TRAIL-resistant cells, and down-regulation of TTP increased TRAIL sensitivity via DR4/5 expression. Therefore, this study provides a molecular mechanism for enhanced levels of TRAIL DRs in cancer cells and a biological basis for posttranscriptional modification of TRAIL DRs. In addition, TTP status might be a biomarker for predicting TRAIL response when a TRAIL-based treatment is used for cancer.

Identification of Matrine as a Novel Regulator of the CXCR4 Signaling Axis in Tumor Cells.

Matrine, a quinolizidine alkaloid, is commonly employed for treating various viral and inflammatory disorders. Here, we have evaluated matrine for its activity on C-X-C chemokine receptor type 4 (CXCR4) and matrix metalloproteinases (MMP-9/2) expression, and its potential to affect tumor metastasis and invasion. The effects of matrine on CXCR4, MMP-9/2, and nuclear factor κB (NF-κB) activation in lung (A549), prostate (DU145), and pancreas (MIA PaCa-2) cells were investigated by diverse techniques. The expression level of CXCR4 and MMP-9/2 was analyzed by western blot analysis and reverse transcription polymerase chain reaction. NF-κB activation was also evaluated by western blot analysis, electrophoretic mobility shift assay as well as immunocytochemical experiments. Furthermore, we monitored cell invasion and metastasis activities by wound healing and Boyden chamber assays. We noted that matrine induced a down-regulation of CXCR4 and MMP-9/2 at both protein and mRNA levels. In addition, matrine negatively regulated human epidermal growth factor receptor 2 (HER2) and C-X-C Motif Chemokine Ligand 12 (CXCL12)-induced CXCR4 expression. Moreover, NF-κB suppression by matrine led to inhibition of metastatic potential of tumor cells. Our results suggest that matrine can block the cancer metastasis through the negative regulation of CXCR4 and MMP-9/2 and consequently it can be considered as a potential candidate for cancer therapy.

Tumor-targeted and self-assembled mixed micelles as carriers for enhanced anticancer efficacy of gemcitabine

CD44 play a pivotal role in tumor progression and metastasis. Targeting CD44 expressing cells using hyaluronic acid (HA) is a promising approach in the treatment of many types of tumors. Here, CD44-targeted conjugate was introduced by hyaluronic acid-deoxycholic acid (HA-DOCA) through the connection of the ester bond. Hydrophilic drug Gemcitabine (GEM) and hydrophobic DOCA are linked by the amide linkage. The DOCA-GEM was mixed with HA-DOCA to form mixed micelles (MMs) with low critical micelle concentration. Dynamic laser light scattering and transmission electron microscope measurements revealed that HA-DOCA/DOCA-GEM MMs displayed sphericity, with an average diameter of 149 ± 3 nm, and negative zeta potential. Hemolysis and cytotoxicity studies confirmed the safety of the HA-DOCA conjugate. The in vitro drug release was investigated, demonstrating that the intracellular-mimicking microenvironment could accelerated the GEM release of the HA-DOCA/DOCA-GEM MMs. The HA-DOCA/DOCA-GEM MMs showed higher cellular uptake efficiency by MCF-7 cells according to confocal laser scanning microscopy and flow cytometry, therefore achieving much stronger anticancer efficacy than free GEM and DOCA-GEM micelles. Our results suggest that HA-DOCA/DOCA-GEM MMs might be a potential candidate for cancer therapy.

Structure-based discovery of novel 4-(2-fluorophenoxy)quinoline derivatives as c-Met inhibitors using isocyanide-involved multicomponent reactions

The c-Met kinase has emerged as a promising target for the development of small molecule antitumor agents because of its close relationship with the progression of many human cancers, poor clinical outcomes and even drug resistance. In this study, two novel series of 6,7-disubstitued-4-(2-fluorophenoxy)quinoline derivatives containing α-acyloxycarboxamide or α-acylaminoamide scaffolds were designed, synthesized, and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (H460, HT-29, MKN-45, and MDA-MB-231). Most of the target compounds exhibited moderate to significant potency and possessed selectivity for H460 and HT-29 cancer cell lines. The preliminary structure-activity relationships indicated that α-acyloxycarboxamide or α-acylaminoamide as 5-atom linker contributed to the antitumor potency. Among these compounds, compound 10m (c-Met IC50 = 2.43 nM, a multitarget tyrosine kinase inhibitor) exhibited the most potent inhibitory activities against H460, HT-29 and MDA-MB-231 cell lines with IC50 of 0.14 ± 0.03 μM, 0.20 ± 0.02 μM and 0.42 ± 0.03 μM, which were 1.7-, 1.3- and 1.6-fold more active than foretinib, respectively. In addition, concentration-dependent assay and time-dependent assay indicated compound 10m can inhibit the proliferation of H460 cell in a time and concentration dependent manner. Moreover, docking studies revealed the common mode of interaction with the c-Met binding site, suggesting that 10m is a potential candidate for cancer therapy deserving further study.

Nanobiomaterials Used in Cancer Therapy: An Up-To-Date Overview.

The disadvantages that come with traditional cancer treatments, such as chemotherapy and radiotherapy, generated a research shift toward nanotechnology. However, even with the important advancements regarding cancer therapy, there are still serious stepping stones that need to be addressed. The use of both nanotechnology and nanomedicine has generated significant improvements in nano-sized materials development and their use as therapeutic, diagnosis, and imaging agents. The biological barriers that come from the healthy body, as well from the tumorous sites, are important parameters that need to be taken into consideration when designing drug delivery systems. There are several aspects of extreme importance such as the tumor microenvironment and vasculature, the reticuloendothelial system, the blood–brain barrier, the blood–tumor barrier, and the renal system. In order to achieve an effective system for cancer therapy, several characteristics of the nanoparticles have been outlined. Moreover, this review has also focused on the different types of nanoparticles that have been studied over the years as potential candidates for cancer therapy.

Exploration of novel pyrrolo[2,1-f][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2

c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50 values ranged from 1.2 to 24.6 nM, especially 27a. In-depth studies demonstrated 27a has great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50 of 2.3 ± 0.1 nM and 5.0 ± 0.5 nM). Furthermore, it also showed the highest anticancer activity with IC50 of 0.71 ± 0.16 nM (better than the positive compound) against BaF3-TPR-Met and 37.4 ± 0.311 nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated 27a has favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that 27a was a potential candidate for cancer therapy deserving further study.