Tumour‐Targeted Drug Delivery with Mannose‐Functionalized Nanoparticles Self‐Assembled from Amphiphilic β‐Cyclodextrins

Multivalent mannose‐functionalized nanoparticles self‐assembled from amphiphilic β‐cyclodextrins (β‐CDs) facilitate the targeted delivery of anticancer drugs to specific cancer cells. Doxorubicin (DOX)‐loaded nanoparticles equipped with multivalent mannose target units were efficiently taken up via receptor‐mediated endocytosis by MDA‐MB‐231 breast cancer cells that overexpress the mannose receptor. Upon entering the cell, the intracellular pH causes the release of DOX, which triggers apoptosis. Targeting by multivalent mannose significantly improved the capability of DOX‐loaded nanoparticles to inhibit the growth of MDA‐MB‐231 cancer cells with minimal side effects in vivo. This targeted and controlled drug delivery system holds promise as a nanotherapeutic for cancer treatment.     

Aurovertin‐Type Polyketides from Calcarisporium arbuscula with Potent Cytotoxic Activities against Triple‐Negative Breast Cancer

Two new polyene polyketides, namely aurovertins T and U ( 1 and 2 ), were isolated from Calcarisporium arbuscula, together with aurovertins B ( 3 ), D and E ( 4 and 5 ), and M ( 6 ). The structures were elucidated by extensive spectroscopic methods (especially 2D‐NMR techniques). The cytotoxic activities of all isolates against human triple‐negative breast cancer cell line (MDA‐MB‐231) were evaluated. As a result, compounds 3 , 4 , and 6 exhibited more potent cytotoxic activities against MDA‐MB‐231 cell line than the positive control taxol. Also, discussion about the relationships between structure and activity of these aurovertins was presented.     

Curcumin loaded PEG400‐OA nanoparticles: A suitable system to increase apoptosis,decrease migration,and deregulate miR‐125b/miR182 in MDA‐MB‐231 human breast cancer cells

Curcumin is an anti‐cancerous agent, but its low‐solubility limits its clinical use. The relationship between deregulation of miRNAs and their targets suggested that miRNAs can be interest targets of curcumin in treatment of different cancers. In this study, to overcome essential defects of the clinical usage of this golden drug, curcumin‐encapsulated polymersome nanoparticles (CPNs) have been developed, and the cytotoxicity effects were studied on MDA‐MB‐231 breast cancer cells. The expression level of miR‐182/125b and the expression pattern of some potential targets in apoptotic pathway, predicted by in silico approaches, were analyzed by RT‐qPCR in CPNs‐treated and untreated cells. Moreover, the amount of CASP9 and CASP8 proteins were determined by Western blotting. The effect of CPNs on cell migration were studied by scratch test and the level of EGFR, E‐cadherin, and beta‐catenin proteins were monitored in CPNs‐treated and untreated cells by western blotting. RT‐qPCR analysis identified the downregulation of miR‐125b and miR‐182 in CPNs‐treated cells and the upregulation of some predicted apoptotic target genes such as P53, CASP9 and BAX after 24 hours. Western blotting confirmed the effects of curcumin on the increase of cleaved CASP9 protein. Based on data from the current experiment, the migration of MDA‐MB‐231 cells was decreased after CPNs treatment. According to the results, CPNs, as suitable and compatible nanocarriers, can deliver curcumin into cancerous cells more effectively and can increase the therapeutic effects of curcumin on MDA‐MB‐231 cells partly by suppression of miR‐125b and miR‐182 as well as induction of apoptosis and inhibition of metastatic progression.     

Synthesis and In Vitro Anticancer Activity of Novel 1,3,4‐Oxadiazole‐Linked 1,2,3‐Triazole/Isoxazole Hybrids

A series of new 1,3,4‐oxadiazole‐linked 1,2,3‐triazole/isoxazole derivatives were designed and synthesized. All the synthesized compounds were screened for in vitro anticancer activity against four human cancer cells: HeLa (cervical), MDA‐MB‐231 (breast), DU‐145 (prostate), and HEPG2 (liver). Among 17 compounds tested, 7a , 7c , and 7d showed potent activity toward four cell lines.     

A Palladium‐Catalyzed Carbonylation Approach to Eight‐Membered Lactam Derivatives with Antitumor Activity

The reactivity of 2‐(2‐alkynylphenoxy)anilines under PdI₂/KI‐catalyzed oxidative carbonylation conditions has been studied. Although a different reaction pathway could have been operating, N‐palladation followed by CO insertion was the favored pathway with all substrates tested, including those containing an internal or terminal triple bond. This led to the formation of a carbamoylpalladium species, the fate of which, as predicted by theoretical calculations, strongly depended on the nature of the substituent on the triple bond. In particular, 8‐endo‐dig cyclization preferentially occurred when the triple bond was terminal, leading to the formation of carbonylated ζ‐lactam derivatives, the structures of which have been confirmed by XRD analysis. These novel medium‐sized heterocyclic compounds showed antitumor activity against both estrogen receptor‐positive (MCF‐7) and triple negative (MDA‐MB‐231) breast cancer cell lines. In particular, ζ‐lactam 3 j′ may represent a novel and promising antitumor agent because biological tests clearly demonstrate that this compound significantly reduces cell viability and motility in both MCF‐7 and MDA‐MB‐231 breast cancer cell lines, without affecting normal breast epithelial cell viability.     

Cold atmospheric plasma modification of curcumin loaded in tri‐phosphate chitosan nanoparticles enhanced breast cancer cells apoptosis

The anti‐cancer mechanisms of curcumin have been reported to include suppressions of angiogenesis and tumor proliferation. The main goal of this research is to increase the solubility of curcumin by cold atmospheric plasma (CAP) and assess the effects of modified curcumin by charging with tri‐polyphosphate chitosan nanoparticles for MCF‐7, MDA‐MB‐231 breast cancer cells, and human fibroblast cells. Curcumin modification was done by CAP and its solubility was evaluated by spectrophotometry. After loading modified curcumin into nano‐chitosan‐TPP, nanocurcumin was characterized by scanning electron microscopy. Cellular viability and apoptosis of treated cells were assessed by MTT and Annexin V. The changes of messenger RNA expression of TP5353 and VEGF genes were analyzed by real‐time PCR. CAP was able to transform the curcumin to possess hydrophilic characteristics after 90 seconds. The mean diameter of Curcumin loaded chitosannanoparticles (NPs) were determined as 48 nm. MTT results showed that the IC₅₀ of nano Cur‐chitosan‐TPP was effectively decreased compared to free curcumin in MCF‐7 (15 μg/mL at 72 hours vs 20 μg/mL at 48 hours). Additionally, nano Cur‐chitosan‐TPP had no significant effect on normal cells (Human dermal fibroblas: HDF), whereas it also decreased the viability of triple negative breast cancer cell line (MDA‐MB‐231). Real‐time PCR results showed that expression level of TP53 gene was upregulated (P = .000), whereas VEGF gene downregulated (P = .000) in treated MCF‐7 cells. Curcumin loaded chitosan nanoparticles have led to an induction of apoptosis (79.93%) and cell cycle arrest (at S and G2M). Modified‐curcumin‐tri‐polyphosphate chitosan nanoparticles using CAP can be considered as a proper candidate for breast cancer treatment.     

Studies of proteasome inhibition and apoptosis induction in triple‐negative breast cancer cells by novel amino acid–polypyridine–copper complex

An innovative ternary copper(II) complex, [Cu(Cl‐PIP)(Tyr)Cl]_n, has been synthesized and characterized using infrared spectroscopy, elemental analysis and single‐crystal X‐ray diffraction analysis. X‐ray crystallography indicates that the Cu atom is five‐coordinated in a square‐pyramidal configuration. The unit forms a one‐dimensional chain along the crystallographic c‐axis. The complex was screened for cytotoxicity against a panel of eight human cancer cell lines, namely MDA‐MB‐231, CAL‐51, K562, HeLa, SGC‐7901, A549, MCF‐7 and SMMC‐7721. The best anticancer activity was obtained with triple‐negative breast cancer CAL‐51 and MDA‐MB‐231 cell lines, with IC₅₀ values in the range 0.035–0.10 μM, and this was better than using carboplatin. The complex inhibits proteasomal chymotrypsin‐like activity, and docking studies reveal its interaction with 20S proteasome. In addition, the complex causes accumulation of ubiquitinated proteins, induces apoptosis and inhibits cell proliferation, indicating its great potential as a novel therapy for triple‐negative breast cancer.     

Biocompatible stimuli‐responsive nanogels for controlled antitumor drug delivery

Herein, the synthesis and potential application as cargo delivery systems of thermo‐responsive poly(N‐vinylcaprolactam) (PVCL)‐based, pH‐responsive poly(2‐(diethylamino)ethyl) methacrylate (PDEAEMA)‐based, and thermo‐, and pH‐responsive PDEAEMA/PVCL‐based core–shell nanogels are reported. All the nanogels have been synthesized using different dextran‐methacrylates (Dex‐MAs) as macro‐cross‐linkers. Doxorubicin hydrochloride (DOXO), an anticancer drug, has been effectively loaded into nanogels via hydrogen‐bonding interactions between ? OH groups of DOXO and ? OH groups of Dex‐MA chains. Drug‐release profiles at various pHs, and the cytocompatibility of the DOXO‐loaded nanogels have been assessed in vitro using cervical cancer HeLa and breast cancer MDA‐MB‐231 cell lines. In all the cases, the DOXO release is controlled by Fickian diffusion and case‐II transport, being the diffusional process dominant. In addition, DOXO‐loaded nanogels are efficiently internalized by HeLa and MDA‐MB‐231 cells and DOXO is progressively released in time. Therefore, nanogels synthesized could be suitable and potentially useful as nanocarriers for antitumor drug delivery. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 1694–1705     

Ferrocene‐substituted 3,3′‐diindolylmethanes with improved anticancer activity

A series of ferrocene‐substituted derivatives ( 2a , 2b , 2c , 2d , 2e , 2f , 2g ) of the known drug 3,3′‐diindolylmethane ( DIM ) were prepared and tested for their in vitro antitumor activity. The derivatives 2a (featuring indole moiety), 2b (featuring 2‐methylindole moiety) and 2f (featuring 5‐nitroindole moiety) were growth‐inhibiting in vitro at lower concentrations than DIM in various tumor cells including pancreas cancer (BcPC‐3), three DIM‐resistant cancer cell lines (518 A2, KB‐V1/Vbl, HT‐29), triple‐negative breast cancer (MDA‐MB‐231) and prostate cancer (PC‐3). Derivatives 2a , 2b and 2f were the most active compounds of this series, qualifying as drug candidates for various cancer diseases. Copyright © 2016 John Wiley & Sons, Ltd.     

Treating Tumors at Low Drug Doses Using an Aptamer–Peptide Synergistic Drug Conjugate

Combination chemotherapy must strike a difficult balance between safety and efficacy. Current regimens suffer from poor therapeutic impact because drugs are given at their maximum tolerated dose (MTD), which compounds the toxicity risk and exposes tumors to non‐optimal drug ratios. A modular framework has been developed that selectively delivers drug combinations at synergistic ratios via tumor‐targeting aptamers for effective low‐dose treatment. A nucleolin‐recognizing aptamer was coupled to peptide scaffolds laden with precise ratios of doxorubicin (DOX) and camptothecin (CPT). This construct had an extremely low IC₅₀ (31.9 nm ) against MDA‐MB‐231 breast cancer cells in vitro, and exhibited in vivo efficacy at micro‐dose injections (500 and 350 μg kg^?1 dose^?1 of DOX and CPT, respectively) that are 20–30‐fold lower than their previously‐reported MTDs. This approach represents a generalizable strategy for the safe and consistent delivery of combination drugs in oncology.     

Comprehensive two‐dimensional PC‐3 prostate cancer cell membrane chromatography for screening anti‐tumor components from Radix Sophorae flavescentis

Radix Sophorae flavescentis is generally used for the treatment of different stages of prostate cancer in China. It has ideal effects when combined with surgical treatment and chemotherapy. However, its active components are still ambiguous. We devised a comprehensive two‐dimensional PC‐3 prostate cancer cell membrane chromatography system for screening anti‐prostate cancer components in Radix Sophorae flavescentis . Gefitinib and dexamethasone were chosen as positive and negative drugs respectively for validation and optimization the selectivity and suitability of the comprehensive two‐dimensional chromatographic system. Five compounds, sophocarpine, matrine, oxymatrine, oxysophocarpine, and xanthohumol were found to have significant retention behaviors on the PC‐3 cell membrane chromatography and were unambiguously identified by time‐of‐flight mass spectrometry. Cell proliferation and apoptosis assays confirmed that all five compounds had anti‐prostate cancer effects. Matrine and xanthohumol had good inhibitory effects, with half maximal inhibitory concentration values of 0.893 and 0.137 mg/mL, respectively. Our comprehensive two‐dimensional PC‐3 prostate cancer cell membrane chromatographic system promotes the efficient recognition and rapid analysis of drug candidates, and it will be practical for the discovery of prostate cancer drugs from complex traditional Chinese medicines.     

Design and Synthesis of 2‐(5‐Phenylindol‐3‐yl)benzimidazole Derivatives with Antiproliferative Effects towards Triple‐Negative Breast Cancer Cells by Activation of ROS‐Mediated Mitochondria Dysfunction

Benzimidazole derivatives are widely studied because of their broad‐spectrum biological activity, such as antitumor properties and excellent fluorescence performance. Herein, two types of 2‐(5‐phenylindol‐3‐yl)benzimidazole derivatives ( 1 a – 1 h and 2 a – 2 e ) were rationally designed and synthesized. When these compounds were investigated in vitro anti‐screening assays, we found that all of them possessed antitumor effect, in particular compound 1 b , which showed an outstanding antiproliferative effect on MDA‐MB‐231 cells (IC₅₀≈2.6 μm ). A study of the drug action mechanisms in cells showed that the antitumor activity of the compounds is proportional to their lipophilicity and cellular uptake; the tested compounds all entered the lysosome of MDA‐MB‐231 cells and caused changes in the levels of reactive oxygen species (ROS), and then caused mitochondrial damage. Apparent differences in the ROS levels for each compound suggest that the lethality of these compounds towards MDA‐MB‐231 cells is closely related to the ROS levels. Taken together, this study not only provides a theoretical basis for 2‐(5‐phenylindol‐3‐yl)benzimidazole anticarcinogens but also offers new thinking on the rational design of next‐generation antitumor benzimidazole derivatives.     

Anti‐tumor platinum (IV) complexes bearing the anti‐inflammatory drug naproxen in the axial position

The role of inflammation in cancer generation is gaining importance in the field of cancer research. The chemo‐anti‐inflammatory strategy that involves using non‐steroidal anti‐inflammatory drug compounds as effective anti‐tumor agents is being acceded globally. In the present study, seven new Pt (IV) complexes based on cisplatin, carboplatin and oxaliplatin scaffold bearing the anti‐inflammatory drug naproxen in the axial position were synthesized and characterized by elemental analysis, ESI‐MS, Fourier transform‐infrared, ¹H‐ and ¹⁹⁵Pt‐NMR spectroscopy. The reduction behavior in the presence of ascorbic acid was studied using high‐performance liquid chromatography. The cytotoxicity against two human breast cell lines and the anti‐inflammatory properties were evaluated. All the complexes are able to promote a comparable activity, with average three‐ and 13‐fold more cytotoxic than cisplatin against MCF7 and MDA‐MB‐231 cell lines, respectively. The complexes show remarkable anti‐inflammatory effects, which indicated their potential in treating cancer associated with inflammation and reducing side‐effects of chemotherapy.     

Design and Synthesis of ZnII‐Coordination Polymers Anchored with NSAIDs: Metallovesicle Formation and Multi‐drug Delivery

A series of coordination polymers synthesized from a bis‐pyridyl linker, namely 4,4′‐azopyridine ( L ), selected non‐steroidal‐anti‐inflammatory drugs (NSAIDs), namely diclofenac ( Dic ), ibuprofen ( Ibu ), flurbiprofen ( Flu ), mefenamic acid ( Mefe ), and naproxen ( Nap ), and Zn(NO₃)₂ were characterized by single crystal X‐ray diffraction. One of the coordination polymers, namely CP3 derived from Flu , was able to form metallovesicles in DMSO, DMSO/H₂O and DMSO/DMEM (biological media) as revealed by TEM, AFM and DLS. Metallovesicle formation by CP3 was further supported by loading a fluorescent dye, namely calcein, as well as an anti‐cancer drug, doxorubicin hydrochloride ( DOX ), as revealed by UV‐vis and emission spectra, and fluorescence microscopy. DOX ‐loaded metallovesicles of CP3 ( DOX@CP3‐vesicle ) could be delivered in vitro to a highly aggressive human breast cancer cell line, namely MDA‐MB‐231, as revealed by MTT and cell migration assays, and also cell imaging performed under laser scanning confocal microscope (LSCM). Thus, a proof of concept for developing a multi‐drug delivery system derived from a metallovesicle for delivering an anti‐cancer drug to cancer cells is demonstrated for the first time.     

Evaluation and application of a mixed‐mode chromatographic stationary phase in two‐dimensional liquid chromatography for the separation of traditional Chinese medicine

In this study, two mixed‐mode chromatography stationary phases (C8SAX and C8SCX) were evaluated and used to establish a two‐dimensional liquid chromatography system for the separation of traditional Chinese medicine. The chromatographic properties of the mixed‐mode columns were systematically evaluated by comparing with other three columns of C8, strong anion exchanger, and strong cation exchanger. The result showed that C8SAX and C8SCX had a mixed‐mode retention mechanism including electrostatic interaction and hydrophobic interaction. Especially, they were suitable for separating acidic and/or basic compounds and their separation selectivities could be easily adjusted by changing pH value. Then, several off‐line 2D‐LC systems based on the C8SAX in the first dimension and C8SAX, C8SCX, or C8 columns in the second dimension were developed to analyze a traditional Chinese medicine—Uncaria rhynchophylla. The two‐dimensional liquid chromatography system of C8SAX (pH 3.0) × C8SAX (pH 6.0) exhibited the most effective peak distribution. Finally, fractions of U. rhynchophylla prepared from the first dimension were successfully separated on the C8SAX column with a gradient pH. Thus, the mixed‐mode stationary phase could provide a platform to separate the traditional Chinese medicine in practical applications.     

Rational Approach Towards Designing Metallogels From a Urea‐Functionalized Pyridyl Dicarboxylate: Anti‐inflammatory,Anticancer, and Drug Delivery

A structural rationale was adopted to design a series of metallogels from a newly synthesized urea‐functionalized dicarboxylate ligand, namely, 5‐[3‐(pyridin‐3‐yl)ureido]isophthalic acid ( PUIA ), that produces metallogels upon reaction with various metal salts (Cu^II, Zn^II, Co^II, Cd^II, and Ni^II salts) at room temperature. The gels were characterized by dynamic rheology and transmission electron microscopy (TEM). The existence of a coordination bond in the gel state was probed by FTIR and ¹H NMR spectroscopy in a Zn^II metallogel (i.e., MG2 ). Single crystals isolated from the reaction mixture of PUIA and Co^II or Cd^II salts characterized by X‐ray diffraction revealed lattice inclusion of solvent molecules, which was in agreement with the hypothesis based on which the metallogels were designed. MG2 displayed anti‐inflammatory response (prostaglandin E₂ assay) in the macrophage cell line (RAW 264.7) and anticancer properties (cell migration assay) on a highly aggressive human breast cancer cell line (MDA‐MB‐231). The MG2 metallogel matrix could also be used to load and release (pH responsive) the anticancer drug doxorubicin. Fluorescence imaging of MDA‐MB‐231 cells treated with MG2 revealed that it was successfully internalized.     

Dielectrophoretic deformation of breast cancer cells for lab on a chip applications

This paper presents the development and experimental analysis of a curved microelectrode platform for the DEP deformation of breast cancer cells (MDA‐MB‐231). The platform is composed of arrays of curved DEP microelectrodes which are patterned onto a glass slide and samples containing MDA‐MB‐231 cells are pipetted onto the platform's surface. Finite element method is utilised to characterise the electric field gradient and DEP field. The performance of the system is assessed with MDA‐MB‐231 cells in a low conductivity 1% DMEM suspending medium. We applied sinusoidal wave AC potential at peak to peak voltages of 2, 5, and 10 V_pp at both 10 kHz and 50 MHz. We observed cell blebbing and cell shrinkage and analyzed the percentage of shrinkage of the cells. The experiments demonstrated higher percentage of cell shrinkage when cells are exposed to higher frequency and peak to peak voltage electric field.     

Synthesis,Anticancer Evaluation,and Molecular Docking Studies of Novel (4‐Hydroxy‐2‐Thioxo‐3,4‐Dihydro‐2H‐[1,3]Thiazin‐6‐Yl)‐Chromen‐2‐Ones via a Multicomponent Approach

A series of coumarin‐substituted 1,3‐thiazine‐2‐thione derivatives ( 4a–m ) were synthesized via the multicomponent reaction of 3‐chloro‐3‐(2‐oxo‐2H‐chromen‐3‐yl)acrylaldehyde ( 1 ) carbon disulfide ( 2 ), and various primary amines ( 3 ), in presence of triethylamine and acetonitrile under stirring with good yields. The structures of all the synthesized compounds were characterized by analytical and spectral studies. Further, the synthesized compounds were screened for their in vitro antiproliferative activities against different cancer cell lines (A549, MDA‐MB‐231, MCF7, HeLa, and B16F10). Studies on the molecular interactions to recognize the hypothetical binding motif of the title compounds with the target Hsp 100 were carried out employing the Schrodinger software. Compounds 4a , 4c and 4m showed activity against all the five cell lines compared with the reference drug, and 4a exhibited the least IC₅₀ concentration of 7.56 ± 1.07 μg/mL against MCF7. This in vitro anticancer result was supported by in silico docking and in silico ADME (absorption, distribution, metabolism, and excretion) studies as well.     

α‐L‐Fucosidase Inhibition by Pyrrolidine–Ferrocene Hybrids: Rationalization of Ligand‐Binding Properties by Structural Studies

Enhanced metabolism of fucose through fucosidase overexpression is a signature of some cancer types, thus suggesting that fucosidase‐targetted ligands could play the role of drug‐delivery vectors. Herein, we describe the synthesis of a new series of pyrrolidine–ferrocene conjugates, consisting of a L ‐fuco‐configured dihydroxypyrrolidine as the fucosidase ligand armed with a cytotoxic ferrocenylamine moeity. Three‐dimensional structures of several of these fucosidase inhibitors reveal transition‐state‐mimicking ³E conformations. Elaboration with the ferrocenyl moiety results in sub‐micromolar inhibitors of both bovine and bacterial fucosidases, with the 3D structure of the latter revealing electron density indicative of highly mobile alkylferrocene compounds. The best compounds show a strong antiproliferative effect, with up to 100 % inhibition of the proliferation of MDA‐MB‐231 cancer cells at 50 μM .     

Synthesis and Cytotoxic Evaluation of Novel 1,2,3‐Triazole‐4‐Linked (2E,6E)‐2‐Benzylidene‐6‐(4‐nitrobenzylidene)cyclohexanones

This work describes the synthesis of novel 1,2,3‐triazole‐4‐linked (2E,6E)‐2‐benzylidene‐6‐(4‐nitrobenzylidene)cyclo‐hexanones starting from cyclohexanone. 1‐(Cyclohex‐1‐en‐1‐yl)piperidine, the enamine from cyclohexanone and piperidine, reacted with 4‐nitrobenzaldehyde to obtain 2‐(4‐nitrobenzylidene)cyclohexanone. Condensation of the latter compound with (prop‐2‐yn‐1‐yloxy)benzaldehyde derivatives under acidic conditions gave (4‐nitrobenzylidene)‐[(prop‐2‐yn‐1‐yloxy)‐benzylidene]cyclohexanones. Finally, ‘click reaction’ of these derivatives and various organic azides led to the title compounds. All compounds were examined by MTT assay for cytotoxic activity in one human breast cancer cell line, MDA‐MB‐231.