Derivatization of Hyaluronan to Target Neuroblastoma and Neuroglioma Expressing CD44.

Therapeutics for actively targeting over-expressed receptors are of great interest because the majority of diseased tissues originate from normal cells and do not possess a unique receptor from which they can be differentiated. One such receptor is CD44, which has been shown to be highly overexpressed in many breast cancers and other types of cancer cells. While CD44 has been documented to express low levels in normal adult neurons, astrocytes, and microglia, this receptor may be overexpressed by neuroblastoma and neuroglioma. If differential expression exists between normal and cancerous cells, hyaluronan (HA) could be a useful carrier that targets carcinomas. Thus, HA was conjugated with resveratrol (HA-R), and its efficacy was tested on cortical-neuroblastoma hybrid, neuroblastoma, and neuroglioma cells. Confocal and flow cytometry showed these cells express CD44 and are able to bind and uptake HA-R. The toxicity of HA-R correlated well with CD44 expression in this study. Therefore, conjugating resveratrol and other chemotherapeutics to HA could minimize the side effects for normal cells within the brain and nervous system and could be a viable strategy for developing targeted therapies.

pH Sensitive Drug Delivery Behavior of Palmyra Palm Kernel Hydrogel of Chemotherapeutic Agent.

This study examined the gel behavior of naturally-occurring palmyra palm kernel (PPK). Due to the presence of polysaccharide in PPK hydrogels, they exhibit excellent swelling behavior in response to pH. Chemotherapeutic drug 5-fluorouracil (5-FU) was encapsulated in these gels using an equilibrium swelling technique. It was found that 5-FU had an encapsulation efficiency of up to 62%. To demonstrate the drug stability in the gels, the PPK hydrogels were characterized using fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. The results showed that the PPK hydrogel matrix contained molecularly dispersed 5-FU drug. The PPK hydrogel exhibited a denser structure and a rough surface, according to images obtained by scanning electron microscopy. In vitro release tests were carried out at pH 1.2 (gastric fluid) and 7.4 (intestinal fluid). The efficacy of the encapsulation and the release patterns were influenced by the network topology of the PPK hydrogel. The release patterns showed that 5-FU was released gradually over a time internal of more than 12 h. The findings suggest that naturally-occurring PPK hydrogels loaded with chemotherapeutic drugs could be employed to treat colon cancer.

Strychnos Potatorum L. Seed Polysaccharide-Based Stimuli-Responsive Hydrogels and Their Silver Nanocomposites for the Controlled Release of Chemotherapeutics and Antimicrobial Applications.

Natural Strychnos potatorum L. (SPL) polysaccharide-based dual-responsive semi-IPN-type (SPL-DMA) hydrogels have been fabricated using dimethylaminoethyl methacrylate by simple free radical polymerization. Furthermore, a facial and eco-friendly method has been developed for the green synthesis of silver nanoparticles on SPL-DMA hydrogel templates (SPL-DMA-Ag) using an aqueous leaf extract of Carissa spinarum (as a bioreducing agent). SPL-DMA and SPL-DMA-Ag were characterized using Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), thermogravimetry analysis (TGA), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), transmission electron microscopy (TEM), dynamic light scattering (DLS), and evaluated network parameters. 5-Fluorouracil and doxorubicin were successfully encapsulated, and in vitro drug release studies were performed at pH values of 1.2 and 7.4 and at 25 and 37 °C. To understand the drug release mechanism of SPL-DMA hydrogels, various kinetic parameters were calculated. Biocompatibility and anticancer activities of SPL-DMA hydrogels were proved by an antioxidant activity study and in vitro cell viability studies against HeLa and 3T3-L1 cell lines. SPL-DMA-Ag hydrogels were used for antibacterial application.

Dual Responsive poly(vinyl caprolactam)-Based Nanogels for Tunable Intracellular Doxorubicin Delivery in Cancer Cells.

In this work, doxorubicin (Dox)-encapsulated poly(vinyl caprolactam) (PVCL)-based three-dimensional nanogel networks were developed and were crosslinked with disulfide linkages. The nanogels degrade rapidly to low molecular weight chains in the presence of the typical intracellular concentration of glutathione. Doxorubicin (Dox) was successfully encapsulated into these nanogels. The nanogels have a high drug loading of 49% and can be tailored to 182 nm to deliver themselves to the targeted cells and release Dox under dual stimuli conditions, such as redox and temperature. By evaluating cell viability in the HepG2 cell line, we observed that Dox-loaded nanogels effectively killed the cancer cell. Fluorescence microscopy results show that the nanogels could easily be internalized with HepG2 cells. The results confirm that the nanogels destabilized in intracellular cytosol via degradation of disulfide bonds in nanogels networks and release of the Dox nearby the nucleus. These carriers could be promising for cancer drug delivery.

Fabrication of Eco-Friendly Polyelectrolyte Membranes Based on Sulfonate Grafted Sodium Alginate for Drug Delivery, Toxic Metal Ion Removal and Fuel Cell Applications.

Polyelectrolyte membranes (PEMs) are a novel type of material that is in high demand in health, energy and environmental sectors. If environmentally benign materials are created with biodegradable ones, PEMs can evolve into practical technology. In this work, we have fabricated environmentally safe and economic PEMs based on sulfonate grafted sodium alginate (SA) and poly(vinyl alcohol) (PVA). In the first step, 2-acrylamido-2-methyl-1-propanesulphonic acid (AMPS) and sodium 4-vinylbenzene sulfonate (SVBS) are grafted on to SA by utilizing the simple free radical polymerization technique. Graft copolymers (SA-g-AMPS and SA-g-SVBS) were characterized by 1H NMR, FTIR, XRD and DSC. In the second step, sulfonated SA was successfully blended with PVA to fabricate PEMs for the in vitro controlled release of 5-fluorouracil (anti-cancer drug) at pH 1.2 and 7.4 and to remove copper (II) ions from aqueous media. Moreover, phosphomolybdic acids (PMAs) incorporated with composite PEMs were developed to evaluate fuel cell characteristics, i.e., ion exchange capacity, oxidative stability, proton conductivity and methanol permeability. Fabricated PEMs are characterized by the FTIR, ATR-FTIR, XRD, SEM and EDAX. PMA was incorporated. PEMs demonstrated maximum encapsulation efficiency of 5FU, i.e., 78 ± 2.3%, and released the drug maximum in pH 7.4 buffer. The maximum Cu(II) removal was observed at 188.91 and 181.22 mg.g-1. PMA incorporated with PEMs exhibited significant proton conductivity (59.23 and 45.66 mS/cm) and low methanol permeability (2.19 and 2.04 × 10-6 cm2/s).

Physicochemical characterization, drug release, and biocompatibility evaluation of carboxymethyl cellulose-based hydrogels reinforced with sepiolite nanoclay.

Polymer-clay nanocomposite hydrogel films (PCNCHFs) were prepared from caboxymethyl cellulose, polyvinylpyrrolidone, agar and nanosepiolite clay (0, 0.3, 0.5, 0.7, 0.9 and 1.5% reinforcement) by treating thermally in a simple, rapid, and inexpensive route. The PCNCHFs and its 5-fluorouracil (FU)-loaded composites (PCNCHFs@FU) were tested for FU release and characterized by FTIR, XRD, FE-SEM, EDX, DSC, and TGA analyses to investigate their structural, morphological, and thermal properties. The nanosepiolite-loaded polymer composites (PCNCHF1 to PCNCHF5) exhibited higher tensile strength than the pristine polymer hydrogel (PCNCHF0); consequently, the thermal properties (glass- and melting-transition) were improved. The PCNCHFs@FU demonstrated prolonged FU release at pH 7.4 for 32 h. The biocompatibility of PCNCHFs was tested against human skin fibroblast (CCDK) cells. The viability of cells exposed to all PCNCHFs was >95% after 72 h of culture. The live/dead assay show the proliferation of fibroblast cells, confirming the biocompatibility of the hydrogels. The pH-sensitive PCNCHFs@FU release could be suitable for drug release in cancer therapy, and the developed PCNCHFs may also be useful for tissue engineering, food packaging, and other biological applications.

Tragacanth gum-based multifunctional hydrogels and green synthesis of their silver nanocomposites for drug delivery and inactivation of multidrug resistant bacteria.

This study investigated natural polymer-based stimuli-responsive hydrogels (TGIAVE) and their silver nanocomposites (TGIAVE-Ag). The hydrogels were composed of tragacanth gum, N-isopropyl acrylamide, and 2-(vinlyoxy) ethanol and were prepared via simple redox polymerization using N,N'-methylene-bis-acrylamide as a crosslinker and potassium persulfate as an initiator. The TGIAVE-Ag were synthesized via a green method involving an aqueous extract of Terminalia bellirica seeds. Structural, thermal, crystallinity, morphology, and size characteristics of the TGIAVE and TGIAVE-Ag were investigated by FTIR, UV-Vis, XRD, DSC, SEM, EDS, DLS, and TEM. To understand the physicochemical interaction and diffusion characteristics of TGIAVEs, network parameters such as zero-order, first-order, Hixson-Crowell, Higuchi, and Korsmeyer-Peppas values were calculated by assessing swelling data. TGIAVE hydrogels at pH 1.2 and 7.4 and temperatures of 25 and 37 °C may be used for time-dependent controlled release of 5-fluorouracil, an anticancer drug, TGIAVE-Ag may be applied for the inactivation of multidrug resistant (MDR) bacteria.

Targeting integrins for cancer management using nanotherapeutic approaches: Recent advances and challenges.

Integrins are the main cell surface receptors and execute multifaceted functions such as the bidirectional transmission of signals (i.e., inside-out and outside-in) and provide communication between cells and their microenvironments. Integrins are the key regulators of critical biological functions and contribute significantly to the promotion of cancer at almost every stage of disease progression from initial tumor formation to metastasis. Integrin expressions are frequently altered in different cancers, and consequently, several therapeutic strategies targeting integrins have been developed. Furthermore, nanotechnology-based approaches have been devised to overcome the intrinsic limitations of conventional therapies for cancer management, and have been shown to more precise, safer, and highly effective therapeutic tools. Although nanotechnology-based approaches have achieved substantial success for the management of cancer, certain obstacles remain such as inadequate knowledge of nano-bio interactions and the challenges associated with the three stages of clinical trials. This review highlights the different roles of integrins and of integrin-dependent signaling in various cancers and describes the applications of nanotherapeutics targeting integrins. In addition, we discuss RGD-based approaches and challenges posed to cancer management.

pH and near-infrared active; chitosan-coated halloysite nanotubes loaded with curcumin-Au hybrid nanoparticles for cancer drug delivery.

In this work, we propose biofriendly in-situ preparation method of Au NPs (hexagonal and rod-shape structures) in the lumen as well as the surface cage of biocompatible halloysite nanotubes (HNTs) using curcumin (CUR) as anticancer drug and subsequently coating with bio-adhesive chitosan (CS) as a polysaccharide. The formation of Au NPs and their interactions with CUR and CS exist in the HNTs has been characterized by FTIR, XRD, XPS, STEM techniques. Interestingly, Au NPs showed longitudinal plasmon resonance bands at 760 and 980 nm that indicate the near-infrared (NIR) responsive property of hybrid nanoparticles. Rod shape and hexagonal structures of Au NPs were produced as confirmed by TEM images. The loading efficiency of CUR was found as much as 12%. Importantly, more CUR release was achieved under acidic conditions (pH 5.5) than basic conditions (pH 7.4). The anticancer potential of HNT hybrid nanoparticles on MCF-7 cancer cells was studied and showed efficient anticancer activity under intracellular tumor cell environment (pH 5.5) than extracellular conditions (pH 7.4). Moreover, the developed HNT hybrid nanoparticles consisting of Au NPs (NIR responsive property) and pH-responsive CUR release could make it suitable for cancer cell-targeted drug delivery platform with NIR-imaging.

Tunable Intracellular Degradable Periodic Mesoporous Organosilica Hybrid Nanoparticles for Doxorubicin Drug Delivery in Cancer Cells.

In this work, a dual (pH and redox)-sensitive cystamine-integrated periodic mesoporous organosilica (Cys-PMO) hybrid nanoparticle has been developed and subsequently loaded with doxorubicin (Dox) as an anticancer drug for intracellular cancer drug delivery. The formation of Cys-PMO was confirmed by FTIR, 13C (CP-MAS), and 29Si MAS NMR spectroscopic techniques. X-ray diffraction and transmission electron microscopy confirmed that the Cys-PMO hybrid nanoparticles possessed mesoscopically ordered 2D hexagonal (P6mm) symmetry with cylindrical shape morphology. The N2 sorption isotherm showed that the Cys-PMO hybrid nanoparticles have a large surface area (691 m2 g-1), pore diameter (3.1 nm), and pore volume (0.59 cm3 g-1). As compared to conventional mesoporous silica materials and other PMO nanoparticles, the developed Cys-PMO hybrid nanoparticles have the capability of holding a high Dox content 50.6% (15.2 mg of Dox per 30 mg of Cys-PMO) at an optimized concentration (20 mg Dox) and avoid premature drug release under extracellular conditions. In vitro, the treatment of HeLa cells with Dox-encapsulated Cys-PMO hybrid nanoparticles results in a significantly greater cytotoxicity in response to intracellular acidic pH and a redox environment due to the degradation of disulfide bonds available in the framework of Cys-PMO hybrid nanoparticles. Further, confocal microscope images show the colocalization of Dox-loaded Cys-PMO hybrid nanoparticles inside the HeLa cells. Upon internalization inside HeLa Cells, the Cys-PMO use intracellular pH and redox environments to release Dox to the nucleus. Thus, the pH and reduction sensitivity of Cys-PMO hybrid nanoparticles make them suitable for intracellular drug delivery applications.

MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression.

Hedgehog (Hh) signalling regulates hepatic fibrogenesis. MicroRNAs (miRNAs) mediate various cellular processes; however, their role in liver fibrosis is unclear. Here we investigate regulation of miRNAs in chronically damaged fibrotic liver. MiRNA profiling shows that expression of miR-378 family members (miR-378a-3p, miR-378b and miR-378d) declines in carbon tetrachloride (CCl4)-treated compared with corn-oil-treated mice. Overexpression of miR-378a-3p, directly targeting Gli3 in activated hepatic stellate cells (HSCs), reduces expression of Gli3 and profibrotic genes but induces gfap, the inactivation marker of HSCs, in CCl4-treated liver. Smo blocks transcriptional expression of miR-378a-3p by activating the p65 subunit of nuclear factor-κB (NF-κB). The hepatic level of miR-378a-3p is inversely correlated with the expression of Gli3 in tumour and non-tumour tissues in human hepatocellular carcinoma. Our results demonstrate that miR-378a-3p suppresses activation of HSCs by targeting Gli3 and its expression is regulated by Smo-dependent NF-κB signalling, suggesting miR-378a-3p has therapeutic potential for liver fibrosis.