Phytomedicines Targeting Cancer Stem Cells: Therapeutic Opportunities and Prospects for Pharmaceutical Development.

The presence of small subpopulations of cells within tumor cells are known as cancer stem cells (CSCs). These cells have been the reason for metastasis, resistance with chemotherapy or radiotherapy, and tumor relapse in several types of cancers. CSCs underwent to epithelial-mesenchymal transition (EMT) and resulted in the development of aggressive tumors. CSCs have potential to modulate numerous signaling pathways including Wnt, Hh, and Notch, therefore increasing the stem-like characteristics of cancer cells. The raised expression of drug efflux pump and suppression of apoptosis has shown increased resistance with anti-cancer drugs. Among many agents which were shown to modulate these, the plant-derived bioactive agents appear to modulate these key regulators and were shown to remove CSCs. This review aims to comprehensively scrutinize the preclinical and clinical studies demonstrating the effects of phytocompounds on CSCs isolated from various tumors. Based on the available convincing literature from preclinical studies, with some clinical data, it is apparent that selective targeting of CSCs with plants, plant preparations, and plant-derived bioactive compounds, termed phytochemicals, may be a promising strategy for the treatment of relapsed cancers.

Cost effective and practically viable oil spillage mitigation: Comprehensive study with biochar.

Biochar is carbonaceous mass that is produced from pyrolysis or gasification of biomass. It is so far majorly explored for soil remediation application, but recently it has attracted a lot of interest because of its unexplored applications in the area of adsorption. In this work, detailed study on biochars produced from two different feeds (rice husk and saw dust), at two different temperatures (450 and 550°C) and two different rates (fast and slow) of pyrolysis are discussed for oil spill mitigation. Biochar is characterized in detail by various techniques such as FTIR, 13C CPMAS, FESEM, RAMAN, TGA to determine the structural composition and observe the extent of pyrolysis. Tests to assess the performance of produced biochars as sorbents for oil spill mitigation have been demonstrated. The as produced biochars selectively absorbed crude oil from oil/water biphasic mixtures in various capacities.

Protective immune-response of aluminium hydroxide gel adjuvanted phage lysate of Brucella abortus S19 in mice against direct virulent challenge with B. abortus 544.

The prophylactic efficacies of plain and alum adsorbed lysate were evaluated by direct virulent challenge in mice model. A recently isolated brucellaphage 'ϕLd' was used for generation of lysates. Twenty four h incubated Brucella abortus S19 broth cultures standardized to contain approximately 10(8) CFU/ml were found suitable for generation of lysates. Three lysate batches produced through separate cycles did not show any significant variation with respect to protein and polysaccharide contents, endotoxin level and phage counts, indicating that compositionally stable lysate preparations can be generated through an optimized production process. Three polypeptides of ∼16, 19 and 23 kDa could be identified as immuno-dominant antigens of the lysate which induced both humoral and cell-mediated immune responses in a dose dependent manner. Results of efficacy evaluation trial confirmed dose-dependent protective potencies of lysate preparation. The lysate with an antigenic dose of 0.52 µg protein and 60 µg CHO adsorbed on aluminium gel (0.1 percent aluminium concentration) exhibited the highest protective potency which was greater than that induced by standard S19 vaccine. Phage lysate methodology provides a very viable option through which an improved immunizing preparation with all desirable traits can be developed against brucellosis, and integrated with immunization programmes in a more efficient manner.

pH- and redox-responsive self-assembly of amphiphilic hyperbranched poly(amido amine)s for controlled doxorubicin delivery.

Vinyl-terminated hyperbranched poly(amido amine)s is obtained by Michael addition polymerization of 4-(aminomethyl)piperidine (AMPD) with a double molar N,N-cystaminebis(acrylamide) (BAC). Then an amphiphilic hyperbranched poly(BAC2-AMPD1)-PEG is produced via converting the vinyl groups to amines followed by PEGylation. Transmission electron microscopy (TEM), dynamic light scattering (DLS), and (1)H nuclear magnetic resonance (NMR) results indicate that the micelles can be obtained via self-assembly of hyperbranched poly(BAC2-AMPD1)-PEG. Further an anti-cancer drug, doxorubicin (DOX), can be loaded into the micelles. pH- and redox-response of the micelles of hyperbranched poly(BAC2-AMPD1)-PEG without and with DOX are investigated. The results of confocal microscopy and flow cytometry reflect that FITC tagged or DOX loaded micelles of hyperbranched poly(BAC2-AMPD1)-PEG can enter HepG2 and MCF-7 cells, and DOX can be observed in the nucleus of the cells. The cytotoxicity of the micelles without and with DOX is evaluated in HepG2 and MCF-7 cells, and the efficacy to kill the cancer cells is discussed in comparison with free DOX.

Fluorescent carbon dot (C-dot) nanoclusters.

Fluorescent carbon dot (C-dot) nanoclusters composed of C-dot-loaded hollow silica spheres are obtained via the dehydration of mannose, which is adsorbed onto hollow silica spheres or poly(ethylene glycol)-graft-hollow silica spheres (PEG-g-hollow silica). The structure of C-dot nanoclusters are confirmed using 1H NMR, FTIR, TEM and TGA. C-dot nanoclusters show a redshifted fluorescence emission with an increased excitation wavelength. Passivation with PEG diamines improve the quantum yields to ∼2%. Confocal laser scanning microscopy (CLSM) results reflect the fact that C-dot nanoclusters can provide good cytoplasm imaging of live Hep G2 cells and live MCF-7 cells, and the imaging obtained is brighter and more even than those from free C-dots. With their combination of good photostability and low cytotoxicity, C-dot nanoclusters are promising for the production of higher quality bioimaging.

pH- and redox-responsive poly(ethylene glycol) and cholesterol-conjugated poly(amido amine)s based micelles for controlled drug delivery.

An optimized condition is identified to prepare linear poly(amido amine)s via Michael Addition polymerization of trifunctional amine, 4-(aminomethyl)piperidine (AMPD), with an equimolar diacrylamide, N,N-cystaminebis(acrylamide) (BAC). Poly(ethylene glycol) (PEG) and cholesterol (CE) are conjugated to linear poly(BAC-AMPD) through the reactions with the secondary amino groups in the backbone, respectively, to form poly(BAC-AMPD)-g-PEG-g-CE. The chemical structures of poly(BAC-AMPD) and poly(BAC-AMPD)-g-PEG-g-CE are characterized using NMR and gel permeation chromatography (GPC). Transmission electron microscopy (TEM), dynamic light scattering (DLS) and (1)H NMR results show that micelles with PEG shells and hydrophobic cores composed of poly(BAC-AMPD) and CE are formed via self-assembly of poly(BAC-AMPD)-g-PEG-g-CE in aqueous solution, and the micelles of poly(BAC-AMPD)-g-PEG-g-CE can be degraded by the presence of L-dithiothreitol and show a limited cytotoxicity in vitro. The anti-cancer drug, doxorubicin (DOX), can be loaded into the micelles. The DOX loaded micelles of poly(BAC-AMPD)-g-PEG-g-CE show pH- and redox-responsive drug release and redox-induced formation of aggregates, and it is shown that the DOX loaded micelles can deliver DOX into cells and show a higher efficacy in killing cancer cells than free drug.

A rocket-like encapsulation and delivery system with two-stage booster layers: pH-responsive poly(methacrylic acid)/poly(ethylene glycol) complex-coated hollow silica vesicles.

Rocket-like vesicles formed are composed of poly(acrylic aicd) (PMAA )/poly(ethylene glycol) (PEG) complex coated hollow silica spheres, and the structure and composition of the vesicles are characterized using TGA, (1)H NMR, FTIR, and TEM. Although only one-third of EG units of PEG brushes grafted to hollow silica spheres form the complex with PMAA via hydrogen bonding, the first "booster" layer composed of PMAA/PEG complex can provide secure encapsulation of model compound calcein blue under an acidic condition. The second "booster" layer composed of PEG brushes can be formed by changing acidic pH to 7.4 through the disassociation of the PMAA/PEG complex. A higher molecular weight PMAA exhibits a faster disassembly due to the formation of a looser PMAA/PEG complex on the surfaces of hollow silica spheres.

Redox-responsive hyperbranched poly(amido amine)s with tertiary amino cores for gene delivery.

Redox-responsive hyperbranched poly(amido amine)s (PAAs) with tertiary amino cores and amine, poly(ethylene glycol) (PEG) and hydroxyl terminal groups were prepared for DNA delivery respectively. The DNA condensation capability of PAAs was investigated using gel electrophoresis, and the results showed that PAA terminated with 1-(2-aminoethyl)piperazine (AEPZ) (BAA) is the most efficient in binding plasmid DNA (pDNA). The diameter and zeta-potential of polyplexes from PAAs were characterized using dynamic light scattering (DLS), and the morphology of the polyplexes was obtained using atomic force microscopy (AFM). All the PAAs were able to condense pDNA into nanoparticles with diameters between 50 and 200 nm with a positive surface charge when the weight ratio of polymer/DNA was higher than 20. Glutathione (GSH)-induced DNA release from polyplexes and the buffering capability of PAAs were investigated as well. Cytotoxicity of PAAs and in vitro gene transfection of polyplexes were evaluated in HEK293, COS-7, MCF-7 and Hep G2 cell lines, respectively. The results reflect that PAAs show remarkably low or even no cytotoxicity, and that PAA with amino terminal groups mediates the most efficient gene transfection with the transfection efficiency comparable to that of 25 kDa polyethylenimine. Further the effects of the presence of buthionine sulfoximine (BSO) on the transfection efficiency and cytotoxicity of BAA polyplexes were investigated.

Efficient synthesis of dendrimers via a thiol-yne and esterification process and their potential application in the delivery of platinum anti-cancer drugs.

A combination of thiol-yne chemistry and esterification reactions were successfully applied for the preparation of dendrimers with an array of terminal functionalities via the divergent growth strategy; maximizing the number of reactive chain ends whilst minimizing the number of reaction steps required in the process.