Bactericidal Activity of Superabsorbent Polymer Granules for Their Applications in Respiratory Fluid Solidification Systems.

Disposal of respiratory secretions from patients having contagious diseases (e.g., COVID-19 and tuberculosis) poses a high risk of infection for healthcare workers. AcryloSorb canister liner bags are highly efficient for the safe handling of contagious respiratory secretions via solidification and disinfection processes. The canister liner bags are lined with disinfectant-impregnated superabsorbent polymer (DSAP) granules. The liner structure in the bag has a patented design that has upward progressive absorbent availability (Indian Patent application # 202041019872). AcryloSorb canister liner bags can decontaminate the fluid secretions absorbed in the bag and solidify within 10 min. The present study focused on the bactericidal effect of DSAP using Gram-negative bacteria, Klebsiella pneumoniae, and Gram-positive bacteria, methicillin-resistantStaphylococcus aureus (MRSA). Disinfectants such as peracetic acid (ethaneperoxic acid), sodium dichloroisocyanurate (sodium 3,5-dichloro-2,4,6-trioxo-1,3,5-triazinan-1-ide), rose bengal (disodium; 2,3,4,5-tetrachloro-6-(2,4,5,7-tetraiodo-3-oxido-6-oxoxanthen-9-yl) benzoate), and N,N-dimethyl-N-[3-(triethoxysilyl)propyl]octadecan-1-aminium chloride at different weight ratios were impregnated in superabsorbent polymer (SAP) granules. The bactericidal activities of DSAP were studied along with its solidification capacity. Disinfectants showed different bactericidal activities when impregnated with SAP granules. For example, peracetic acid-impregnated SAP granules (DSAP-P) showed 100% bactericidal activity for both Klebsiella pneumoniae and MRSA at 0.5 wt % peracetic acid. Sodium dichloroisocyanurate-impregnated SAP granules showed 100% bactericidal activity only at 5 wt % sodium dichloroisocyanurate (DSAP-S5). Even though peracetic acid was highly effective, SAP granules collapsed when impregnated with peracetic acid. The ease of handling, disinfection efficacy, and preserving the morphology of SAP granules make DSAP-S5, a suitable candidate for AcryloSorb canister liner bags.

Arginine-Modified Polymers Facilitate Poly (Lactide-Co-Glycolide)-Based Nanoparticle Gene Delivery to Primary Human Astrocytes.

PURPOSE: Astrocyte dysfunction is a hallmark of central nervous system injury or infection. As a primary contributor to neurodegeneration, astrocytes are an ideal therapeutic target to combat neurodegenerative conditions. Gene therapy has arisen as an innovative technique that provides excellent prospect for disease intervention. Poly (lactide-co-glycolide) (PLGA) and polyethylenimine (PEI) are polymeric nanoparticles commonly used in gene delivery, each manifesting their own set of advantages and disadvantages. As a clinically approved polymer by the Federal Drug Administration, well characterized for its biodegradability and biocompatibility, PLGA-based nanoparticles (PLGA-NPs) are appealing for translational gene delivery systems. However, our investigations revealed PLGA-NPs were ineffective at facilitating exogenous gene expression in primary human astrocytes, despite their success in other cell lines. Furthermore, PEI polymers illustrate high delivery efficiency but induce cytotoxicity. The purpose of this study is to develop viable and biocompatible NPsystem for astrocyte-targeted gene therapy. MATERIALS AND METHODS: Successful gene expression by PLGA-NPs alone or in combination with arginine-modified PEI polymers (AnPn) was assessed by a luciferase reporter gene encapsulated in PLGA-NPs. Cytoplasmic release and nuclear localization of DNA were investigated using fluorescent confocal imaging with YOYO-labeled plasmid DNA (pDNA). NP-mediated cytotoxicity was assessed via lactate dehydrogenase in primary human astrocytes and neurons. RESULTS: Confocal imaging of YOYO-labeled pDNA confirmed PLGA-NPs delivered pDNA to the cytoplasm in a dose and time-dependent manner. However, co-staining revealed pDNA delivered by PLGA-NPs did not localize to the nucleus. The addition of AnPn significantly improved nuclear localization of pDNA and successfully achieved gene expression in primary human astrocytes. Moreover, these formulations were biocompatible with both astrocytes and neurons. CONCLUSION: By co-transfecting two polymeric NPs, we developed an improved system for gene delivery and expression in primary human astrocytes. These findings provide a basis for a biocompatible and clinically translatable method to regulate astrocyte function during neurodegenerative diseases and disorders.

Reaching for the Stars in the Brain: Polymer-Mediated Gene Delivery to Human Astrocytes.

Astrocytes, the "star-shaped" glial cells, are appealing gene-delivery targets to treat neurological diseases due to their diverse roles in brain homeostasis and disease. Cationic polymers have successfully delivered genes to mammalian cells and hence present a viable, non-immunogenic alternative to widely used viral vectors. In this study, we investigated the gene delivery potential of a series of arginine- and polyethylene glycol-modified, siloxane-based polyethylenimine analogs in primary cultured human neural cells (neurons and astrocytes) and in mice. Plasmid DNAs encoding luciferase reporter were used to measure gene expression. We hypothesized that polyplexes with arginine would help in cellular transport of the DNA, including across the blood-brain barrier; polyethylene glycol will stabilize polyethylenimine and reduce its toxicity while maintaining its DNA-condensing ability. Polyplexes were non-toxic to human neural cells and red blood cells. Cellular uptake of polyplexes and sustained gene expression were seen in human astrocytes as well as in mouse brains post-intravenous-injections. The polyplexes also delivered and expressed genes driven by astrocyte-restricted glial fibrillary acidic protein promoters, which are weaker than viral promoters. To our knowledge, the presented work validates a biocompatible and effective polymer-facilitated gene-delivery system for both human brain cells and mice for the first time.

Photopolymerization kinetics of methyl methacrylate with reactive and inert nanogels.

The enhanced in situ photopolymerization kinetics of methyl methacrylate (MMA) to poly(methyl methacrylate) (PMMA) through the incorporation of both inert and reactive nanogel (NG) fillers under ambient conditions has been demonstrated. In addition to the polymerization kinetics, the physical and chemical properties of the prepolymeric NG were also utilized to tune the thermoplasticity and mechanical properties of the PMMA polymer network. The protocol followed in this study imparts superior MMA photopolymerization kinetics (≥ 60% double-bond conversion within 15 min for > 35 wt% nanogel loadings and ≥ 95% double-bond conversion in < 60 min for all NG concentrations) when compared with traditional polymerization mechanisms. PMMA remained a glassy material following the incorporation of both inert and reactive NG as demonstrated by the glass transition temperature (Tg) of the ultimate networks. Network linearity is uncompromised following incorporation of inert NG additives, thereby preserving the thermoplasticity of the PMMA network. As the non-functionalized, inert NG content increases, the maintenance of thermoplasticity occurs at the expense of mechanical properties (10× reduction of maximum strength at 25 wt% loading). These effects are less pronounced when reactive nanogels are employed (no significant reduction of maximum strength at 25 wt% loading with minimal crosslinking). The incorporation of NGs enable high chemical tunability within linear polymer networks. Given the wide range of monomers available for the synthesis of NGs, the methodology detailed in this study offers a scheme for the optimization of linear networks for specific targeted applications, hitherto deemed unrealistic under established polymerization protocols.

Thiol-functionalized nanogels as reactive plasticizers for crosslinked polymer networks.

Significant efforts have been expended to mitigate plasticizer migration from crosslinked methacrylic and poly(vinyl chloride) polymer networks by synthesizing reactive plasticizers that can blend homogenously within the networks to reduce polymer property change, acute toxicity and downstream environmental effects of plasticizer migration with limited and varying amount of success. We hypothesized that appropriate thiol-functionalized nanogels synthesized using the same monomers as the parent network to generate highly compact, crosslinked structures will form thermally stable, homogenous networks and perform as optimal reactive plasticizers. Nanogels were synthesized via a thiol-Michael addition solution polymerization and incorporated at different mass ratios within a polyethylene glycol 400 urethane dimethacrylic monomer to form photo-crosslinked networks. While maintaining the inherent hydrolytic stability, thermal stability and biocompatibility of the parent matrix at ~99% acrylic group conversion, the PEG400 urethane dimethacrylic -nanogel networks retained optical clarity with >90% visible light transmission at 20wt% nanogel concentration within the matrix. The addition of the nanogels also enhanced the elongation of the parent matrix by up to 320%, while a 37°C reduction in glass transition temperature (∆Tg) and ≥50% reduction in modulus was observed. A 52% reduction in the shrinkage stress of the material was also noted. The results indicate that the application of thiol-functionalized nanogels as plasticizers to alter the bulk properties of the parent matrix while mitigating plasticizer migration by covalently crosslinking the nanogels within the polymer matrix provides a simple yet efficient technique to generate network-specific plasticizers with the ability to alter targeted properties within polymers.

Cell-penetrating peptide CGKRK mediates efficient and widespread targeting of bladder mucosa following focal injury.

The bladder presents an attractive target for topical drug delivery. The barrier function of the bladder mucosa (urothelium) presents a penetration challenge for small molecules and nanoparticles. We found that focal mechanical injury of the urothelium greatly enhances the binding and penetration of intravesically-administered cell-penetrating peptide CGKRK (Cys-Gly-Lys-Arg-Lys). Notably, the CGKRK bound to the entire urothelium, and the peptide was able to penetrate into the muscular layer. This phenomenon was not dependent on intravesical bleeding and was not caused by an inflammatory response. CGKRK also efficiently penetrated the urothelium after disruption of the mucosa with ethanol, suggesting that loss of barrier function is a prerequisite for widespread binding and penetration. We further demonstrate that the ability of CGKRK to efficiently bind and penetrate the urothelium can be applied toward mucosal targeting of CGKRK-conjugated nanogels to enable efficient and widespread delivery of a model payload (rhodamine) to the bladder mucosa.

Water dispersible siloxane nanogels: a novel technique to control surface characteristics and drug release kinetics.

Amphiphilic, water-dispersible, crosslinked siloxane nanogels were synthesized via a free radical solution polymerization and then applied as optically clear, functional coatings on the surface of lens substrates to demonstrate the feasibility of siloxane-nanogels to generate covalently tethered surfaces on intraocular lens substrates. Siloxane nanogels were synthesized from 3-(trimethoxysilyl)propyl methacrylate and polyethylene glycol diacrylate and subsequently chain-end functionalized with mercaptosuccinic acid to yield a clear, water-dispersible nanogel. The nanogels were then spin-coated onto lens substrates as a coating and covalently tethered via a two-part interfacial redox polymerization using N'N'-tetramethylethylenediamine and ammonium persulfate. Covalently crosslinked, stable nanogel coatings on the lens substrate were shown to increase the hydrophilicity of the material surfaces while maintaining optical clarity, with >85% of white light transmittance. No significant changes were observed in the cytocompatibility, refractive index and mechanical properties of the substrate before and after the coatings were generated. The coatings were also modified to facilitate the sustained release of an anti-inflammatory drug dexamethasone in which >90% of the incorporated drug within the nanogel was released within 5 days, thereby demonstrating the feasibility of this approach to also enable the multi-day sustained delivery of an active pharmaceutical agent (API) at therapeutically relevant doses.

Multifunctional drug nanocarriers formed by cRGD-conjugated ßCD-PAMAM-PEG for targeted cancer therapy.

Polyamidoamine (PAMAM) dendrimer was conjugated with both carboxymethyl-ß-cyclodextrin (ßCD) and poly(ethylene glycol) (PEG). Cyclic RGD peptide, used as a tumor targeting ligand, was then selectively conjugated onto the distal ends of the PEG arms. The resulting ßCD-PAMAM-PEG-cRGD polymer was able to form stable and uniform nanoparticles (NPs) in aqueous solution. Doxorubicin (Dox), a model hydrophobic anticancer drug, was effectively encapsulated in the NPs via an inclusion complex formed between the drug and ßCD. The Dox loading level was 16.8 wt%. The cellular uptake of cRGD-conjugated Dox-loaded NPs in the U87MG cell line was much higher than that of non-targeted NPs. Furthermore, the anti-proliferative effect of the cRGD-conjugated NPs was superior to that of free drug and non-targeted NPs. These results suggest that NPs formed by ßCD-PAMAM-PEG-cRGD with a high drug payload may significantly improve the anticancer efficacy by tumor-targeted delivery and enhanced cellular uptake.

Topical gene silencing by iontophoretic delivery of an antisense oligonucleotide-dendrimer nanocomplex: the proof of concept in a skin cancer mouse model.

The study was aimed at investigating the feasibility of using a poly (amidoamine) (PAMAM) dendrimer as a carrier for topical iontophoretic delivery of an antisense oligonucleotide (ASO). Bcl-2, an anti-apoptotic protein implicated in skin cancer, was used as the model target protein to demonstrate the topical gene silencing approach. Confocal laser scanning microscopy studies demonstrated that the iontophoretically delivered ASO-dendrimer complex can reach the viable epidermis in porcine skin. In contrast, passively delivered free or dendrimer complexed ASO was mainly localized to the stratum corneum. The cell uptake of ASO was significantly enhanced by the dendrimer complex and the complex suppressed Bcl-2 levels in the cell. In the skin cancer mouse model, the iontophoretically delivered ASO-dendrimer complex reduced the tumor volume by 45% and was consistent with the reduction in Bcl-2 protein levels. The iontophoretically delivered ASO-dendrimer complex caused significant apoptosis in skin tumor. Overall, the findings from this study demonstrate that dendrimers are promising nanocarriers for developing topical gene silencing approaches for skin diseases.

Different strategies to overcome multidrug resistance in cancer.

The risk of acquisition of resistance to chemotherapy remains a major hurdle in the management of various types of cancer patients. Several cellular and noncellular mechanisms are involved in developing both intrinsic and acquired resistance in cancer cells toward chemotherapy. This review covers the various multidrug resistance (MDR) mechanisms observed in cancer cells as well as the various strategies developed to overcome these MDR mechanisms. Extensive studies have been conducted during the last several decades to enhance the efficacy of chemotherapy by suppressing or evading these MDR mechanisms including the use of new anticancer drugs that could escape from the efflux reaction, MDR modulators or chemosensitizers, multifunctional nanocarriers, and RNA interference (RNAi) therapy.