Effective co-delivery of nutlin-3a and p53 genes via core–shell microparticles for disruption of MDM2–p53 interaction and reactivation of p53 in hepatocellular carcinoma

The tumor suppressor protein p53 is the most frequently inactivated, mutated, or deleted transcriptional factor in tumor cells. Recent studies have shown that the negative regulation of p53 by the murine double minute 2 (MDM2) protein in human cells interrupts the p53 apoptotic pathway and causes tumorigenesis. Therefore, the disruption of the MDM2–p53 complex by small molecules such as nutlin-3a and the administration of the active p53 protein can effectively restore the apoptotic activity of the p53 protein in tumor cells. This study aims to introduce a unique combined p53-based gene and chemotherapy approach using core–shell polymeric microparticles for the localized treatment of cancers. Core–shell microparticles were successfully fabricated in a single step using a modified electrohydrodynamic atomization (EHDA) technique, where the core and shell layers were loaded with nutlin-3a and β-cyclodextrin-g-chitosan/p53 nanoparticles, respectively. The grafting of β-cyclodextrin (β-CD) onto chitosan chains demonstrated remarkable cellular uptake (∼5-fold) compared to pure chitosan at N/P = 6, attributed to a strong interaction and temporary disruption of the lipid bilayer in the cell membrane by the synthesized copolymer. The therapeutic efficiencies of single- and dual-agent loaded microparticle formulations were also evaluated and compared against free-drug treatment in terms of cell viability and intracellular expression of p53, caspase 3, and MDM2 proteins via an MTS assay, an enzyme-linked immunosorbent assay, and an immunostaining assay. The results revealed that the controlled and sustained release of both agents from the microparticles synergistically enhanced the anti-proliferative efficacy of the agents via the continuous overexpression of p53 and caspase 3 proteins over 5 days. However, MDM2 protein expression remained at the basal level over that period. The findings also indicated that nutlin-3a could impose excessive oxidative stress on cancer cells, where the overproduction of reactive oxygen species (ROS) with irreversible destructive effects on subcellular organelles such as the nucleus (DNA) and mitochondria could be considered as a secondary apoptotic pathway induced by nutlin-3a. Inspired by the observations, the proposed drug delivery system can serve as a unique and powerful drug and gene delivery system with a far-reaching application in human cancer therapy

Hierarchically Built Hetero-superstructure Arrays with Structurally Controlled Material Compositions

Hierarchical assemblies are repeatedly encountered in nature, and when replicated in synthetic patterns and materials, can enhance their functionality or impart multifunctionality. In order to assemble a hierarchical superstructure that consists of components made up of multiple nanostructures, control over placement and stoichiometry is desirable. Macroscopic arrays that present up to three levels of hierarchy are demonstrated here and are achieved using the self-assembly of soft, collapsible block copolymer nanospheres for the first two levels, followed by directed self-assembly of metal nanospheres for the third. The fabrication approach combines advantages of soft sphere self-assembly to yield non-close-packed and variable array pitch values, with the inherent chemical functionality presented by the polymer-based soft spheres; these assemblies can then be transformed into a range of different materials, including metal or semiconductor nanostructures, or further tailored with an additional level of complexity. Structural investigation shows the superstructure formation to be governed by generic design rules that can be extended across different material combinations

Novel Hierarchical Copper-Based Metal-Organic Frameworks for Improved Catalytic Performance

Introducing additional meso- or macroporosity into traditionally microporous metal-organic frameworks (MOFs) is a very promising way to improve the catalytic performance of these materials, mostly due to the resultant reductions of diffusional barriers during liquid-phase or gas-phase reactions. Here we show that HKUST-1 can be successfully synthesised either via post-synthetic treatment (etching prepared HKUST-1 samples in phosphoric acid, here called HKUST AE) or via in situ crystallisation (exposing the MOF precursor solution to supercritical CO2, here called HKUST CO2) to produce hierarchically porous structures that are highly beneficial for catalysis. These hierarchical MOFs were characterised by powder X-ray diffraction (PXRD), scanning electron microscopy (SEM) and gas sorption to confirm the preservation of the microscopic structure and the appearance of macropores in the crystallites. More importantly, the benefits of introducing these hierarchical porous structures into this MOF for improving the diffusion accessibility of reagents to the sample in catalysed liquid- and gas-phase reactions were quantified for the first time. It was found that the hierarchical pore structure helped to increase the reaction conversion of styrene oxide methanolysis (by ~65 % using either HKUST AE and HKUST CO2, at 40 oC in 25 min) and CO oxidation (by 55 % using HKUST CO2 at 260 oC). These findings demonstrate the advantage of using hierarchical porous MOFs in catalysis.</p

Biomass derived palygorskite-carbon nanocomposites:Synthesis, characterisation and affinity to dye compounds

Clay minerals can act as a uniform dispersion medium for nano-sized carbon particles. However, literature on the preparation and characteristics of palygorskite-carbon nanocomposites is scant. Using a hydrothermal carbonisation technique this study developed two nanocomposites on fibrous palygorskite from starch: the first without a post-synthesis treatment (Composite 1); and the second with an activation at 550°C for 3h (ramp at 10°Cmin-1) under CO2 environment (200mLmin-1) (Composite 2). A uniform dispersion of nano-scale carbon spheres was formed on partially destroyed palygorskite structures. Composite 2, which indicated the formation of graphitised carbon nanoparticles, generated a 17-fold greater specific surface area than Composite 1 and also created micro- and mesopores in its structure. The nanocomposites, especially in Composite 1, contained organic surface functional groups (CH, CC, CO) and indicated variable affinity to cationic and anionic dye compounds. While Composite 2 adsorbed a larger amount of anionic orange II dye (23mgg-1), Composite 1 adsorbed more cationic methylene blue (46.3mgg-1). Isothermal and kinetic modelling of the adsorption data indicated that in addition to electrostatic attraction for methylene blue adsorption on both nanocomposites, a pore diffusion mechanism was involved and the boundary resistance was greater for orange II than methylene blue adsorption. Being a material developed from green biomass (starch) and an abundant natural resource (palygorskite), these nanocomposites have immense potential for application in environmental remediation including in situ immobilisation of contaminants in soil

Double-Walled Microparticles-Embedded Self-Cross-Linked, Injectable, and Antibacterial Hydrogel for Controlled and Sustained Release of Chemotherapeutic Agents

First-line cancer chemotherapy has been prescribed for patients suffered from cancers for many years. However, conventional chemotherapy provides a high parenteral dosage of anticancer drugs over a short period, which may cause serious toxicities and detrimental side effects in healthy tissues. This study aims to develop a new drug delivery system (DDS) composed of double-walled microparticles and an injectable hydrogel for localized dual-agent drug delivery to tumors. The uniform double-walled microparticles loaded with cisplatin (Cis-DDP) and paclitaxel (PTX) were fabricated via coaxial electrohydrodynamic atomization (CEHDA) technique and subsequently were embedded into injectable alginate-branched polyethylenimine. The findings show the uniqueness of CEHDA technique for simply swapping the place of drugs to achieve a parallel or a sequential release profile. This study also presents the simulation of CEHDA technique using computational fluid dynamics (CFD) that will help in the optimization of CEHDA’s operating conditions prior to large-scale production of microparticles. The new synthetic hydrogel provides an additional diffusion barrier against Cis-DDP and confines premature release of drugs. In addition, the hydrogel can provide a versatile tool for retaining particles in the tumor resected cavity during the injection after debulking surgery and preventing surgical site infection due to its inherent antibacterial properties. Three-dimensional MDA-MB-231 (breast cancer) spheroid studies demonstrate a superior efficacy and a greater reduction in spheroid growth for drugs released from the proposed composite formulation over a prolonged period, as compared with free drug treatment. Overall, the new core–shell microparticles embedded into injectable hydrogel can serve as a flexible controlled release platform for modulating the release profiles of anticancer drugs and subsequently providing a superior anticancer response

Deposition of zwitteronic polymer brushes in a dense gas medium

10.1016/j.jcis.2015.01.070Journal of Colloid and Interface Science448156-16

Synthesis and characterization of polylactide/rice husk hydrochar composite

Abstract Polymer composites are fabricated by incorporating fillers into a polymer matrix. The intent for addition of fillers is to improve the physical, mechanical, chemical and rheological properties of the composite. This study reports on a unique polymer composite using hydrochar, synthesised by microwave-assisted hydrothermal carbonization of rice husk, as filler in polylactide matrix. The polylactide/hydrochar composites were fabricated by incorporating hydrochar in polylactide at 5%, 10%, 15% and 20 wt% by melt processing in a Haake rheomix at 170 °C. Both the neat polylactide and polylactide/hydrochar composite were characterized for mechanical, structural, thermal and rheological properties. The tensile modulus of polylactide/hydrochar composites was improved from 2.63 GPa (neat polylactide) to 3.16 GPa, 3.33 GPa, 3.54 GPa, and 4.24 GPa after blending with hydrochar at 5%, 10%, 15%, and 20%, respectively. Further, the incorporation of hydrochar had little effect on storage modulus (G′) and loss modulus (G″). The findings of this study reported that addition of hydrochar improves some characteristics of polylactide composites suggesting the potential of hydrochar as filler for polymer/hydrochar composites

The Expression of Allele Changes in NLRP3 (rs35829419) and IL-1β (+3954) Gene Polymorphisms in Periodontitis and Coronary Artery Disease

Background: Inflammasomes have been shown to play a pivotal role in periodontal disease pathogenesis. However, their role in periodontitis subjects with coronary heart disease remains unclear. This study aimed to obtain the expression of NLRP3 (rs35829419) and IL-1β (+3954) gene polymorphisms in the subgingival plaque and blood samples of generalized periodontitis (GP) subjects with and without coronary heart disease (CHD). Methods: A total of 70 subjects were grouped into two; GP and GP with CHD. Demographic variables and periodontal and cardiac parameters were recorded from both the groups. Subgingival plaque and blood samples were obtained from both the groups and were further subjected to the identification of NLRP3 (rs35829419) and IL-1β (+3954) expression and allele change using a conventional polymerase chain reaction (PCR) and gene sequencing (Sanger’s method). Results: Amongst the demographic variables, age and monthly income were statistically significant between the two groups. Plaque index (PI), clinical attachment level (CAL), high-density lipoprotein (HDL), and low density-lipoprotein (LDL) exhibited statistically significant levels between the two groups. The NLRP3 (rs35829419) and IL-1β (+3954) genes showed a statistically significant association with allele change (frequency) among the groups. The general comparison of all the parameters with the allele change of NLRP3 (rs35829419) and IL-1β (+3954) in the subgingival plaque and blood samples showed statistically significant associations among the two groups. Conclusion: The present study highlighted an allele change in IL-1β (+3954) gene polymorphisms which may play an important role in the pathogenesis of periodontitis and coronary heart disease

Isolated Systolic Blood Pressure and Red-Complex Bacteria—A Risk for Generalized Periodontitis and Chronic Kidney Disease

Hypertension is a risk factor for generalized periodontitis (GP) and chronic kidney diseases (CKD). However, the role of isolated systolic blood pressure as one of the major risks for these inflammatory diseases has not been explored. Very limited studies exist identifying the red-complex bacteria in association with the isolated systolic blood pressure. Hence, the main objective of this study was to assess the isolated systolic blood pressure and the red-complex bacteria along with the demographic variables, periodontal parameters, and renal parameters in patients with generalized periodontitis and chronic kidney disease. One hundred twenty participants (age 30–70 years) were divided into four groups—Group C: control (systemically and periodontally healthy subjects), Group GP: generalized periodontitis, Group CKD: subjects with CKD with good periodontal health, Group CKD + GP: subjects with both generalized periodontitis and CKD. Demographic variables and periodontal parameters were measured and recorded. Blood pressure measurements and a detailed history and renal parameters such as serum creatinine, eGFR, and fasting blood sugar were recorded. The red-complex bacteria (RCB) were assessed in the subgingival plaque samples of all four groups using RT-PCR. Older participants (above 50 years) showed worse periodontal scores in the CKD + GP group along with elevated isolated systolic blood pressure, higher serum creatinine, and fasting blood sugar. eGFR was significantly decreased compared to the other groups. Bacterial counts were higher in the GP + CKD group, suggesting that they may be at a higher risk for generalized periodontitis and chronic kidney disease. Isolated systolic blood pressure (ISBP) and RCB were significantly correlated with the renal and periodontal parameters. A log-linear relationship exists between periodontal disease, CKD, RCB, and isolated systolic hypertension levels