Nanodiamonds as a state-of-the-art material for enhancing the gamma radiation resistance properties of polymeric membranes.

We report, for the first time, the development of gamma radiation resistant polysulfone (Psf)-nanodiamond (ND) composite membranes with varying concentrations of NDs, ranging up to 2 wt% of Psf. Radiation stability of the synthesized membranes was tested up to a dose of 1000 kGy. To understand the structure-property correlationship of these membranes, multiple characterization techniques were used, including field-emission scanning electron microscopy, atomic force microscopy, drop shape analysis, Fourier-transform infrared spectroscopy, X-ray photoelectron spectroscopy, gel permeation chromatography, positron annihilation spectroscopy, and small angle X-ray scattering. All the composite membranes exhibited enhanced radiation resistance properties, with 0.5% loading of NDs as the optimum. Compared to the radiation stability of Psf membranes up to a dose of 100 kGy, the optimum composite membranes are found to be stable up to a radiation dose of 500 kGy, owing to the unique surface chemistry of NDs and interfacial chemistry of Psf-ND composites. Experimental findings along with the Monte Carlo simulation studies confirmed a five times enhanced life-span of the composite membranes in an environment of the intermediate level radioactive waste, compared to the control Psf membrane.

Structure-Activity Relationship of Polyester-Based Cationic Polyrotaxane Vector-Mediated In Vitro siRNA Delivery: Effect on Gene Silencing Efficiency.

A series of linear polyester-based, α-cyclodextrin (CD)-threaded polyrotaxanes (PRTx) were synthesized for siRNA delivery. The investigation into the effect of the presence of polyester linkages in polyrotaxane established the structural-activity relationship between polyrotaxane and siRNA transfection efficiency. The ester-based polyrotaxane exhibited higher threading efficiency than poly(ethylene glycol)-based polyrotaxane. The threading efficiency is the driving force for transfection, as it regulates the positive charge density on polyrotaxane. Polyester-based polyrotaxane formed stable and effective transfection nanoplexes with siRNA at lower N/P ratios, signifying the high gene loading capacity of the developed supramolecular vectors. Our findings suggest that biochemical properties of the transfection complexes depend on the structure of the axis and threading efficiency of polyrotaxane, which further influences the transfection efficiency. The enhanced gene silencing efficiency and safety are compared with those of extensively explored poly(ethylene glycol)-based polyrotaxane, polyethyleneimine (a gold standard), and lipofectamine (a commercial standard), which are used as siRNA delivery vectors.

Biodegradable Polyester of Poly (Ethylene glycol)-sebacic Acid as a Backbone for ß -Cyclodextrin-polyrotaxane: A Promising Gene Silencing Vector.

BACKGROUND: Polyrotaxane, a macromolecular interlocked assembly, consisting of cyclodextrin has excellent inclusion capabilities and functionalization capacity, which makes it a versatile material as a vector for gene delivery applications. OBJECTIVE: A biodegradable linear aliphatic polyester axle composed of Polyethylene Glycol (PEG) and Sebacic Acid (SA) was used to fabricate the ß-Cyclodextrin (ß-CD) based polyrotaxane as a cationic polymeric vector and evaluated for its potential gene silencing efficiency. METHODS: The water-soluble aliphatic polyester was synthesized by the solvent esterification process and characterized using viscometry, GPC, FT-IR and 1H NMR spectroscopy. The synthesized polyester was further evaluated for its biodegradability and cellular cytotoxicity. Hence, this water-soluble polyester was used for the step-wise synthesis of polyrotaxane, via threading and blocking reactions. Threading of ß-CD over PEG-SA polyester axle was conducted in water, followed by end-capping of polypseudorotaxane using 2,4,6-trinitrobenzenesulfonic acid to yield polyester-based polyrotaxane. For gene delivery application, cationic polyrotaxane (PRTx+) was synthesized and evaluated for its gene loading and gene silencing efficiency. RESULTS AND DISCUSSION: The resulting novel macromolecular assembly was found to be safe for use in biomedical applications. Further, characterization by GPC and 1H NMR techniques revealed successful formation of PE-ß-CD-PRTx with a threading efficiency of 16%. Additionally, the cellular cytotoxicity assay indicated biosafety of the synthesized polyrotaxane, exploring its potential for gene delivery and other biomedical applications. Further, the biological profile of PRTx+: siRNA complexes was evaluated by measuring their zeta potential and gene silencing efficiency, which were found to be comparable to Lipofectamine 3000, the commercial transfecting agent. CONCLUSION: The combinatory effect of various factors such as biodegradability, favourable complexation ability, near zero zeta potentials, good cytotoxicity properties of poly (ethylene glycol)-sebacic acid based ß-Cyclodextrin-polyrotaxane makes it a promising gene delivery vector for therapeutic applications.

RNA interference-based therapeutics: molecular platforms for infectious diseases.

The potential uses and therapeutic benefits of RNA interference (RNAi) are enormous. Recent insights into RNAi technologies have highlighted their role in analyzing the functions and regulation of gene expression in eukaryotes and further utilizing this information for identification and amelioration of many diseases. These studies have also established the role of RNAi mediated post-transcriptional gene silencing (PTGS) mechanism in mammals by several endogenous, gene regulation systems including small interfering RNAs (siRNA), micro RNA (miRNA) and small hairpin RNAs (shRNA). Moreover, these RNAi-based therapeutics have demonstrated the capability to silence therapeutically relevant genes in various in vivo models of cancer, infections autoimmune diseases and other genetic disorders. Over the past few decades, infectious diseases have been one of the leading causes of death around the world. Ubiquitously, intracellular obligate or facultative microorganisms cause serious or fatal infections and associated diseases in humans. Currently available literature suggests that infections caused by intracellular pathogens present an intriguing area, wherein RNAi technology may be effectively employed to neutralize the harmful effects of various intracellular pathogens. In this manuscript, we have emphasized on the challenges and opportunities involved in the therapy of such intracellular infections, especially employing RNAi-based interventions. We have focused our discussion on the current state-of-the-art RNAi-based therapies, which have been explored for various intracellular infections mediated by bacteria, fungi, viruses and protozoa. Nanocarrier mediated delivery of siRNA and shRNA molecules have also been found to overcome the various delivery challenges of these biotherapeutics; these have also been briefly summarized here. Furthermore, the outcomes and progresses that have been made in pre-clinical models and clinical trials have also been presented to review the numerous challenges encountered so far. Finally, we have also addressed the various future perspectives that could overcome these challenges and accelerate the progress and commercial success of these systems.