Antitumor Studies Research Articles

Structural Optimization and Improving Antitumor Potential of Moreollic Acid from Gamboge.

Moreollic acid, a caged-tetraprenylated xanthone from Gamboge, has been indicated as a potent antitumor molecule. In the present study, a series of moreollic acid derivatives with novel structures were designed and synthesized, and their antitumor activities were determined in multifarious cell lines. The preliminary screening results showed that all synthesized compounds selectively inhibited human colon cancer cell proliferation. TH12-10, with an IC50 of 0.83, 1.10, and 0.79 μM against HCT116, DLD1, and SW620, respectively, was selected for further antitumor mechanism studies. Results revealed that TH12-10 effectively inhibited cell proliferation by blocking cell-cycle progression from G1 to S. Besides, the apparent structure–activity relationships of target compounds were discussed. To summarize, a series of moreollic acid derivatives were discovered to possess satisfactory antitumor potentials. Among them, TH12-10 displays the highest antitumor activities against human colon cancer cells, in which the IC50 values in DLD1 and SW620 are lower than that of 5-fluorouracil.

Targeted Extracellular Vesicles Delivered Verrucarin A to Treat Glioblastoma.

Glioblastomas, accounting for approximately 50% of gliomas, comprise the most aggressive, highly heterogeneous, and malignant brain tumors. The objective of this study was to develop and evaluate a new targeted therapy, i.e., highly potent natural compound verrucarin A (Ver-A), delivered with monoclonal antibody-directed extracellular vesicle (mAb-EV). First, the high surface expression of epidermal growth factor receptor (EGFR) in glioblastoma patient tissue and cell lines was confirmed using immunohistochemistry staining, flow cytometry, and Western blotting. mAb-EV-Ver-A was constructed by packing Ver-A and tagging anti-EGFR mAb to EV generated from HEK293F culture. Confocal microscopy and the In Vivo Imaging System demonstrated that mAb-EV could penetrate the blood–brain barrier, target intracranial glioblastoma xenografts, and deliver drug intracellularly. The in vitro cytotoxicity study showed IC50 values of 2–12 nM of Ver-A. The hematoxylin and eosin staining of major organs in the tolerated dose study indicated minimal systemic toxicity of mAb-EV-Ver-A. Finally, the in vivo anti-tumor efficacy study in intracranial xenograft models demonstrated that EGFR mAb-EV-Ver-A effectively inhibited glioblastoma growth, but the combination with VEGF mAb did not improve the therapeutic efficacy. This study suggested that mAb-EV is an effective drug delivery vehicle and natural Ver-A has great potential to treat glioblastoma.

Corrigendum

Journal of the Chinese Chemical SocietyVolume 69, Issue 2 p. 398-398 CORRIGENDUMFree Access Corrigendum This article corrects the following: Synthesis, Spectral Characterization, Antitumor, Antioxidant, and Antimicrobial Studies of New Potential ONS Schiff Base Complexes Amani S. Alturiqi, Abdel-Nasser M.A. Alaghaz, Reda A. Ammar, Volume 64Issue 11Journal of the Chinese Chemical Society pages: 1270-1285 First Published online: October 13, 2017 First published: 04 January 2022 https://doi.org/10.1002/jccs.202181000AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat In the referenced article entitled “Synthesis, Spectral Characterization, Antitumor, Antioxidant, and Antimicrobial Studies of New Potential ONS Schiff Base Complexes”,[1] the published affiliation (a) of the first author, Amani S. Alturiqi is incorrect. The corrected affiliation is shown below. The published affiliation states: aDepartment of Chemistry, College of Science, Princess Nourah bint Abdul Rahman University, Saudi Arabia The corrected information should be: aDepartment of Chemistry, College of Science, Princess Nourah Bint Abdulrahman University, Saudi Arabia We apologize for any inconvenience caused by this error. REFERENCE 1A. S. Alturiqi, A.-N. M.A. Alaghaz, R. A. Ammar, J. Chin. Chem. Soc. 2017, 64, 1270– 1285. https://doi.org/10.1002/jccs.201700072 Volume69, Issue2February 2022Pages 398-398 ReferencesRelatedInformation

An erythrocyte membrane-camouflaged biomimetic nanoplatform for enhanced chemo-photothermal therapy of breast cancer.

Nano drug delivery systems are a research hotspot in the field of tumor therapy. In this work, molybdenum disulfide (MoS2) nanosheets were selected as the base material and a natural red blood cell membrane (RBC membrane) was camouflaged on the nanosheets to enhance their dispersibility and tumor targeting profile. The camouflaged molybdenum disulfide nanocomposites (MoS2-RBC) were successfully prepared by incubation. This nanomaterial has good stability and biocompatibility with a good immune evasion ability. MoS2 has a large specific surface area and unique layered structure, which provides favorable conditions for the loading of anticancer drugs. Adriamycin hydrochloride (DOX) was used as the model drug and the drug loading capacity was 98.98%. In the tumor microenvironment, the red cell membrane modified MoS2 drug delivery system (MoS2-RBC-DOX) showed obvious pH-dependent release behavior. In addition, the excellent photothermal properties of MoS2 are conducive to the release of drugs, thus improving the efficacy. According to the cell tests, MoS2-RBC had no cytotoxicity toward tumor cells, while DOX loading induced dose-dependent cytotoxicity. Furthermore, MoS2-RBC has a favorable photothermal effect, and chemotherapy combined with photothermal therapy is more effective than any single therapy. In vivo fluorescence imaging and in vivo photothermal imaging experiments confirmed the promoted accumulation of carrier materials at the tumor site after RBC membrane modification. Finally, in vivo antitumor studies showed that photothermal/chemotherapy combined with MoS2-RBC could completely inhibit tumor growth, and the body weights of mice fluctuated within the normal range without significant decrease. In summary, this MoS2-RBC drug delivery system provides a safe, rapid and effective option for future treatment of breast cancer.

Taurine and Its Anticancer Functions: In Vivo and In Vitro Study.

Taurine (2-aminoethanesulfonic acid) is a natural amino acid that is found widely in all mammalian tissues. Several studies have demonstrated that taurine has anti-inflammatory, antioxidant, and hypoglycemic effects. Recently, taurine not only mitigates the side effects of chemotherapy in cancer but also possesses antitumor properties, including inhibiting cancer cell proliferation and inducing apoptosis in certain cancers by differential regulating proapoptotic and antiapoptotic proteins. Antitumor studies of taurine are still in their infancy, and the mechanism of its antitumor effect is not fully understood. In this regard, it is worthwhile to study the antitumor mechanism of taurine, which may provide clues to develop new synthetic therapeutic molecules. In this mini review, we summarize the main effects of taurine that have shown suppressing actions in the initiation and progression of cancers. The underlying molecular mechanism also suggested that taurine can be a potential clinical application in tumor therapy. In addition, with the in-depth study of different biological functions of taurine, we found that many systemic diseases are associated with taurine. In this review, the research progress of taurine's antitumor effect is briefly summarized including the in vivo and in vitro studies in our laboratory.

Mild phototherapy mediated by manganese dioxide-loaded mesoporous polydopamine enhances immunotherapy against colorectal cancer.

One of the main challenges in applying the immune checkpoint blockade to treat colorectal cancer (CRC) is the immunosuppressive tumor microenvironment. Owing to its excellent cancer cell killing ability and immune activation, mild photothermal therapy (PTT) has shown bright promise to sensitize tumors to immune checkpoint inhibition through turning the immunologically "cold" tumors into "hot" ones. Herein, a mild photothermal effect-assisted theragnostic nanodrug (MnO2@MPDA-PEG NPs) is developed by incorporating MnO2 into PEGylated-mesoporous polydopamine nanoparticles (MPDA-PEG NPs). The presence of PEG endows the theragnostic nanodrug with high biostability. After accumulation in colorectal tumor, the theragnostic nanodrug responds to the tumor microenvironment, leading to the simultaneous release of Mn2+ which serves as a magnetic resonance imaging (MRI) contrast agent for tumor imaging. The released Mn2+ could also promote mild photothermal treatment-induced immune response, including the maturation of BMDC cells. In vivo antitumor studies on a CT26 model demonstrate that MnO2@MPDA-PEG NPs could be a promising dual-imaging theragnostic nanodrug to potentiate the systemic antitumor immunities.

Enhanced Oral Bioavailability of Paclitaxel in Presence of P-gp Blockers: Smart Extraction Procedure, Antitumor and Side Effects Study in Mice

Enhanced Oral Bioavailability of Paclitaxel in Presence of P-gp Blockers: Smart Extraction Procedure, Antitumor and Side Effects Study in Mice

One-Pot Synthesis of Phosphinylphosphonate Derivatives and Their Anti-Tumor Evaluations.

This paper reports on the synthesis of new hydroxymethylene-(phosphinyl)phosphonates (HMPPs). A methodology has been developed to propose an optimized one-pot procedure without any intermediate purifications. Various aliphatic and (hetero)aromatic HMPPs were synthesized in good to excellent yields (53–98%) and the influence of electron withdrawing/donating group substitution on aromatic substrates was studied. In addition, the one-pot synthesis of HMPP was monitored by 31P NMR spectroscopy, allowing effective control of the end of the reaction and identification of all phosphorylated intermediate species, which enabled us to propose a reaction mechanism. Optimized experimental conditions were applied to the preparation of biological relevant aminoalkyl-HMPPs. A preliminary study of the complexation to hydroxyapatite (bone matrix) was carried out in order to verify its lower affinity towards bone compared to bisphosphonate molecules. Moreover, in vitro anti-tumor activity study revealed encouraging antiproliferative activities on three human cancer cell lines (breast, pancreas and lung).

Photodynamic Therapy-Mediated Immune Responses in Three-Dimensional Tumor Models.

Photodynamic therapy (PDT) is a promising non-invasive phototherapeutic approach for cancer therapy that can eliminate local tumor cells and produce systemic antitumor immune responses. In recent years, significant efforts have been made in developing strategies to further investigate the immune mechanisms triggered by PDT. The majority of in vitro experimental models still rely on the two-dimensional (2D) cell cultures that do not mimic a three-dimensional (3D) cellular environment in the human body, such as cellular heterogeneity, nutrient gradient, growth mechanisms, and the interaction between cells as well as the extracellular matrix (ECM) and therapeutic resistance to anticancer treatments. In addition, in vivo animal studies are highly expensive and time consuming, which may also show physiological discrepancies between animals and humans. In this sense, there is growing interest in the utilization of 3D tumor models, since they precisely mimic different features of solid tumors. This review summarizes the characteristics and techniques for 3D tumor model generation. Furthermore, we provide an overview of innate and adaptive immune responses induced by PDT in several in vitro and in vivo tumor models. Future perspectives are highlighted for further enhancing PDT immune responses as well as ideal experimental models for antitumor immune response studies.

Pillar[6]arene-Based Supramolecular Nanocatalysts for Synergistically Enhanced Chemodynamic Therapy by the Intracellular Cascade Reaction.

Chemodynamic therapy (CDT) based on the intracellular Fenton reaction has become increasingly explored in cancer treatment. However, the mildly acidic tumor microenvironment and the limited amount of intracellular hydrogen peroxide (H2O2) will create issues for CDT to perform a sustained and high-efficiency treatment. Therefore, how to selectively reduce the pH value and augment the amount of H2O2 in tumor tissues has become the key factor for realizing excellent CDT. Besides, the majority of the reported CDT systems have been constructed from iron-based inorganic or metal-organic framework nanomaterials due to the decisive role of metals in CDT, which restricts the development of CDT. In this study, inspired by the host-guest interactions between pillar[6]arene and ferrocene, a ternary pillar[6]arene-based supramolecular nanocatalyst (GOx@T-NPs) for CDT is reported for the first time. GOx@T-NPs not only exhibited a high-efficiency catalytic ability to convert glucose into hydroxyl radicals (•OH) and to reduce the pH value inside cancer cells for significant enhancement of the CDT effect, but they also showed sensitive glutathione-induced camptothecin (CPT) prodrug release capacity for further improving the efficiency of CDT. Hence, GOx@NPs possessed excellent ability to synergistically enhance the CDT. Additionally, an antitumor mechanism study showed that the prominent tumor inhibition capacity of GOx@T-NPs was derived from trimodal synergistic interactions of CDT, starvation therapy, and chemotherapy. Moreover, GOx@T-NPs manifested good biocompatibility and tumor selectivity with few side effects in major organs. This work broadens the range of materials available for CDT and demonstrates new developments in pillar[n]arene-based multimodal synergistic treatment systems.

Design, synthesis and bioactivity evaluation of novel evodiamine derivatives with excellent potency against gastric cancer

Gastric cancer represents a significant health burden worldwide. Previously, inspired by the traditional Chinese medicine Wu-Chu-Yu to treat the spleen and stomach system for thousands of years, we identified N14-phenyl substituted evodiamine derivatives as potential antitumor agents with favorable inhibition on Top1. Herein, structural optimization and structure-activity relationship studies (SARs) led us to discovering a highly active evodiamine derivative compound 6t against gastric cancer. Further anti-tumor mechanism studies revealed that compound 6t played as the inhibition of topoisomerase 1 (Top1), effectively induced apoptosis, obviously arrested the cell cycle at the G2/M phase, and significantly inhibited the migration and invasion of SGC-7901 and MGC-803 cell lines in a dose-dependent manner. Moreover, the compound 6t was low toxicity in vivo and exhibited excellent anti-tumor activity (TGI = 70.12%) in the MGC-803 xenograft models. In summary, compound 6t represents a promising candidate as a potential chemotherapeutic agent against gastric cancer.

Annonaceous acetogenins nanosuspensions stabilized by poloxamer 188: Preparation, properties and in vivo evaluation

Annonaceous acetogenins (ACGs) have extensive antitumor activities. However, the poor solubility limits their clinical application. In this research, ACGs nanosuspensions (ACGs-NSps) were prepared by antisolvent-precipitation method using poloxamer 188 (P188) as stabilizer. The prepared P188-ACGs-NSps had a mean particle size of 115.9 nm, the polydispersity index (PDI) was 0.208. P188-ACGs-NSPs were stable in different physiological media and displayed a sustained drug release behavior until 144 h.Lyophilized P188-ACGs-NSps using 0.5% glucose as lyoprotectant were stable for long-term storage. P188-ACGs-NSps significantly enhanced the cytotoxicity against 4T1 and HeLa cell lines compared with ACGs solution (IC50:1.426 ± 0.308 vs.3.106 ± 0.691, IC50: 0.718 ± 0.1934 vs. 1.521 ± 0.1992). In vivo antitumor study indicated that P188-ACGs-NSps exhibited great antitumor efficacy against 4T1 tumor with an inhibition rate of 63% at a low intravenous injection dose of 0.4 mg/kg. P188-ACGs-NSps seem to be a promising drug delivery system for ACGs to improve their solubility that can be applied in clinic in the future.

Antitumor and toxicity study of mitochondria-targeted triptolide derivatives using triphenylphosphine (TPP+) as a carrier

Based on the higher mitochondrial membrane potential (Δψm) of tumor cells than normal cells, a mitochondria-targeting strategy using delocalized lipophilic cations as carriers is a promising way to improve the antitumor effect of small molecules and to reduce toxicity. Triptolide (TP) has a strong antitumor effect but is limited in the clinic due to high systemic toxicity. Mitochondria-targeted TP derivatives were designed and synthesized using triphenylphosphine cations as carriers. The optimal derivative not only maintained the antitumor activity of TP but also showed a tumor cell selectivity trend. Moreover, the optimal derivative increased the release of lactate dehydrogenase and the production of ROS, decreased Δψm, and arrested HepG2 cells in G0/G1 phase. In a zebrafish HepG2 xenograft tumor model, the inhibitory effect of the optimal derivative was comparable to that of TP, while it had no obvious toxic effect on multiple indicators in zebrafish at the test concentrations. This work provided some evidence to support the mitochondria-targeting strategy.

In situ subcutaneously injectable thermosensitive PEG-PLGA diblock and PLGA-PEG-PLGA triblock copolymer composite as sustained delivery of bispecific anti-CD3 scFv T-cell/anti-EGFR Fab Engager (BiTEE)

In this study, PEGylated poly (lactide-co-glycolide) (PLGA) thermosensitive composite hydrogels (DTgels) loaded with bispecific anti-cluster of differentiation 3 (CD3) scFv T-cell/anti-epidermal growth factor receptor (EGFR) Fab engager (BiTEE) were subcutaneously (s.c.) injected for the in situ formation of a drug deposit to resolve limitations of the clinical application of the BiTEE of a short half-life and potential side effects. Three kinds of DTgels prepared with different ratios of methoxy poly (ethylene glycol) (mPEG)-PLGA (diblock copolymer, DP) and PLGA-PEG-PLGA (triblock copolymer, TP) were designated DTgel-1, DTgel-2, and DTgel-2S. All three DTgel formulations showed thermosensitive properties with a sol-gel transition temperature at 28–34 °C, which is suitable for an injection. An in vitro release study showed that all DTgel formulations loaded with stabilized BiTEE extended the release of the BiTEE for up to 7 days. In an animal pharmacokinetics study, an s.c. injection of BiTEE/DTgel-1, BiTEE/DTgel-2, or BiTEE/DTgel-2S respectively prolonged the half-life of the BiTEE by 3.5-, 2.0-, and 2.2-fold compared to an intravenous injection of the BiTEE solution. Simultaneously, BiTEE/DTgel formulations showed almost no proinflammatory cytokine release in mice injected with T cells after s.c. administration. Results of an animal antitumor (MDA-MB-231) study indicated that an s.c. injection of the BiTEE/DTgel formulations significantly improved the antitumor efficacy compared to an intravenous (i.v.) or s.c. injection of the BiTEE solution. Moreover, BiTEE/DTgel formulations led to enhanced T-cell recruitment to solid-tumor sites. In conclusion, the in situ formation of injectable PEGylated PLGA thermosensitive hydrogels loaded with the BiTEE was successfully carried out to increase its half-life, maintain a constant blood level within therapeutic windows, and enhance T-cell recruitment to solid-tumor sites resulting in exceptional treatment efficacy.

Discovery of a cinnamyl piperidine derivative as new neddylation inhibitor for gastric cancer treatment

Targeting neddylation pathway has been recognized as an attractive anticancer therapeutic strategy, thus discovering potent and selective neddylation inhibitors is highly desirable. Our work reported the discovery of novel cinnamyl piperidine compounds and their antitumor activity in vitro and in vivo. Among these compounds, compound 4g was identified as a novel neddylation inhibitor and decreased the neddylation levels of cullin 1, cullin 3 and cullin 5. Mechanistic studies demonstrated that compound 4g could inhibit the migration ability of gastric cancer cells and induce apoptosis partly mediated by the Nrf2-Keap1 pathway. Furthermore, in vivo anti-tumor studies showed that 4g effectively inhibited tumor growth without obvious toxicity. Collectively, the cinnamyl piperidine derivatives could serve as new lead compounds for developing highly effective neddylation inhibitors for gastric cancer therapy.

Mono- and bimetallic complexes of pyrazolone based ligand: Synthesis, characterization, antitumor and molecular docking studies

Cu(II), Ni(II), Co(II) and Mn(II) chloro in addition to Cu(II) acetato complexes of the ligand termed 3-amino-4-(2-(3-chlorophenyl)hydrazono)-1H-pyrazol-5(4H)-one (abbreviated as ACHP) have been isolated. The structural features and geometrical arrangements of the synthesized complexes have been identified through applying alternative analytical and spectroscopic tools including elemental analysis, FTIR, conductivity measurements, UV–vis spectra, magnetic moment measurements and thermogravimetric (TG/DTG) techniques. The applied tools joint together confirmed the formation of the metal complexes in the molar ratio 1:1 (L:M) for Cu(II) and Co(II) complexes and 1:2 (L:M) ratio for both of Ni(II) and Mn(II) chelates. The applied spectral techniques also confirmed the metal chelates to have the formulae [Cu(ACHP)Cl2]·0.5H2O, [Cu(ACHP)(CH3COO)2], [Ni2(ACHP)Cl2(H2O)2]·Cl2, [Co(ACHP)Cl2]·0.5H2O and [Mn2(ACHP)Cl4]. UV–Vis spectra and µeff values of the metal chelates assured the geometry around the metal ion center to be tetrahedral for all the metal complexes except Cu(II) chloro and acetato complexes which afforded square planar and octahedral geometries, respectively. The molecular docking studies have been performed using 3s7s and 5cei, the co-crystal structures of proteins for breast (MCF-7) and colon (HCT-116) cancer cells, respectively, in addition to the antitumor activity investigations contra the two types of tumor cells.

Carfilzomib and Paclitaxel Co-Loaded Protein Nanoparticles an Effective Therapy Against Pancreatic Adenocarcinomas.

PurposeTherapeutic efficacy of pancreatic adenocarcinomas (PACs) with combined therapy of carfilzomib (CFZ) and paclitaxel (PTX) co-loaded in human serum albumin (HSA) nanoparticles (NPs) was examined.MethodsCFZ and PTX were encapsulated individually or combined into HSA NPs by a simple reverse self-assembly method developed to achieve an optimal combination ratio for synergistic therapy. CFZ or/and PTX loaded HSA nanoparticles were physically characterized and the evaluation of combination index, drug release, pharmacokinetic, anti-tumor, and biodistribution studies were conducted.ResultsAll resultant drug-loaded HSA NPs were spherical with a particle size of <150 nm and a zeta potential of −21.1~−23.0 mV. Drug loading rates and entrapment efficiencies were 9.1%~10.1% and 90.7%~97.1%, respectively. CFZ and PTX demonstrated synergistic effects in an MIA PaCa-2 cytotoxicity at a 1:2 ratio (CI50 were 0.01~0.25). In vitro dissolution revealed that the CFZ/PTX ratio released from the co-loaded HSA NPs (CFZ/PTX/HSA NPs) was about 1.77~2.08, which conformed to the designated loaded ratio. In vivo evaluation showed that the combined therapy of CFZ and PTX at a 1:2 ratio co-loaded in HSA NPs (CFZ/PTX/HSA NPs) demonstrated optimal synergistic improvement of the growth inhibition of MIA PaCa-2 cells with less systematic toxicity, even though the pharmacokinetic profiles observed did not show obvious beneficial and their biodistributions in tumors were found to be smaller.ConclusionThe one-pot reverse assembly method developed was environmentally friendly and capable of co-loading an optimal combination ratio of two chemodrugs into HSA NPs for synergistic therapy.

Cytotoxicity, anti-angiogenic, anti-tumor and molecular docking studies on phytochemicals isolated from Polygonum hydropiper L.

BackgroundAccording to the recent global cancer statistics, breast cancer is the leading cause of deaths among women with 2.3 million new cases globally. Likewise, cervical cancer is also among the leading causes of mortality among women. Polygonum hydropiper is traditionally known for its cytotoxic effects and several bioactive cytotoxic compounds were isolated from it. This study was aimed to isolate potential anticancer compounds from its most potent fractions and evaluate their anticancer potentials.MethodsBased on our earlier studies, active fractions including chloroform and ethyl acetate were subjected to column chromatography for isolation of compounds. Chemical structures of isolated compounds were confirmed via 1H NMR, 13C NMR, mass spectrometry. Purified compounds were tested for cytotoxicity against breast cancer cells (MCF-7), cervical cancer cells (HeLA) and NIH/3T3 fibroblasts cells cultures using MTT assy. Anti-angiogenic potentials of isolated compounds were evaluated via chorioallantoic membrane assay. Anti-tumor studies were done using Agrobacterium tumefaciens induced potato tumor assay. Furthermore, to understand the binding modes of Isolated compounds, molecular docking was performed against EGFR, HER2 and VEGFR using MOE as docking software.ResultsTwo bioactive compounds PH-1 (4-methyl-5-oxo-tetrahydrofuran-3-yl acetate) and PH-2 (methyl 4-hydroxy-3-methoxybenzoate) were purified from the active fractions. In cytotoxicity studies, PH-1 exhibited highest cytotoxicity against HeLA cells with 87.50% lethality at 1 mgmL−1 concentration and LD50 of 60 µgmL−1. Likewise, PH-2 showed 82.33% cytotoxicity against HeLA cells with LD50 of 160 µgmL−1. Similarly, PH-1 and PH-2 exhibited LD50 of 170 and 380 µgmL−1 respectively. Moreover, PH-1 and PH-2 were also very potent cytotoxic compounds against NIH/3T3 cells with 81.45 and 85.55% cytotoxicity at 1 mgL−1 concentration and LD50 of 140 and 58 µgL−1 respectively. Isolated compounds exhibited considerable anti-angiogenic potentials with IC50 of 340 and 500 µgL−1 respectively for PH-1 and PH-2. In anti-tumor assay, PH-1 and PH-2 exhibited 81.15 and 76.09% inhibitions with LD50 of 340 and 550 µgL−1 respectively. Both compounds selectively binds with EGFR and HER2 receptors with low binding energies. Both compounds exhibited stronger interactions with VEGFR through binding pocket residues Lys868, Val916 and Asp1046.ConclusionsBoth compounds cause considerable cytotoxicity against cancer cells. The anti-angiogenic and anti-tumor results suggests additional tumor suppressive properties. Docking analysis suggests that these compound not only has the ability to bind to EGFR and HER2 but also equally binds to VEGFR and may act as potential anti-angiogenic agents.

Methotrexate-based ionic liquid as a potent anticancer drug for oral delivery: In vivo pharmacokinetics, biodistribution, and antitumor efficacy

Oral delivery of the sparingly soluble drug methotrexate (MTX) is challenging owing to its poor bioavailability and low solubility. To address this challenge, the present study reports the conversion of MTX into a series of five ionic liquids (ILs) comprising a cationic component—i.e., cholinium (Cho), tetramethylammonium (TMA), tetrabutylphosphonium (TBP), or an amino acid ester—and an anionic component—i.e., MTX. The biocompatibility, pharmacokinetics, tissue distribution, and antitumor efficacy of each MTX-based IL were investigated to determine its usefulness as a pharmaceutical. Oral administration to mice revealed that proline ethyl ester MTX (IL[ProEt][MTX]) had 4.6-fold higher oral bioavailability than MTX sodium, followed by aspartic diethyl ester MTX, IL[TBP][MTX], IL[Cho][MTX], and IL[TMA][MTX]. The peak plasma concentration, elimination half-life, area under the plasma concentration, mean absorption time, and body clearance of IL[ProEt][MTX] were significantly (p < 0.0001) higher by 1.7-, 6.2-, 4.6-, 2.5-, and 3.6-fold, respectively, than those of MTX sodium. MTX accumulation in the lungs, spleen, kidney, and gastrointestinal tract was also reduced by 5.6-, 1.8-, 1.5-, and 1.4-fold, respectively, indicating the IL formulations had lower systemic toxicity than free MTX. Mechanistic studies revealed that the IL[ProEt][MTX] solution formed spherical structures with an average size of 190 nm. This was probably responsible for its improved oral absorption performance in vivo. In vivo antitumor studies also demonstrated that IL[ProEt][MTX] suppressed tumor growth more than MTX sodium. These results suggest that MTX-based ILs provide a simple scalable approach to improving the oral bioavailability of poorly soluble MTX.

Antitumor activity studies of iridium (III) polypyridine complexes-loaded liposomes against gastric tumor cell in vitro

Two iridium (III) polypyridine complexes [Ir(ppy)2(BIP)]PF6 (ppy = 2-phenylpyridine, BIP = 2-biphenyl-1H-imidazo[4,5-f][1,10]phenanthroline, Ir1), [Ir(piq)2(BIP)]PF6 (piq = 1-phenylisoquinoline, Ir2) and their liposomes Ir1lipo and Ir2lipo were synthesized and characterized. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate cytotoxic activity against several cancer cells (A549, HepG2, SGC-7901, Bel-7402, HeLa) and non-cancer cell (mouse embryonic fibroblast, NIH3T3). The results showed that Ir1lipo displays the high cytotoxicity toward SGC-7901 with IC50 value of 5.8 ± 0.2 μM, while the complexes have no cytotoxicity toward A549, HepG2, Bel-7402 and HeLa cells. The cell colony demonstrated that the iridium (III) complexes-loaded liposomes can inhibit cell proliferation, induce cell cycle arrest at G0/G1 phase. Moreover, they also cause autophagy, induce a decrease of mitochondrial membrane potential and increase intracellular reactive oxygen species (ROS) content. These results suggest that the complexes encapsulated liposomes Ir1lipo and Ir2lipo inhibit the growth of SGC-7901 cells through a ROS-mediated mitochondrial dysfunction and activating the PI3K (phosphoinositide-3 kinase)/ AKT (protein kinase B) signaling pathways.