Modulating On-Demand Release of Vancomycin from Implant Coatings via Chemical Modification of a Micrococcal Nuclease-Sensitive Oligonucleotide Linker.

Periprosthetic infections are one of the most serious complications in orthopedic surgeries, and those caused by Staphylococcus aureus (S. aureus) are particularly hard to treat due to their tendency to form biofilms on implants and their notorious ability to invade the surrounding bones. The existing prophylactic local antibiotic deliveries involve excessive drug loading doses that could risk the development of drug resistance strains. Utilizing an oligonucleotide linker sensitive to micrococcal nuclease (MN) cleavage, we previously developed an implant coating capable of releasing covalently tethered vancomycin, triggered by S. aureus-secreted MN, to prevent periprosthetic infections in the mouse intramedullary (IM) canal. To further engineer this exciting platform to meet broader clinical needs, here, we chemically modified the oligonucleotide linker by a combination of 2'-O-methylation and phosphorothioate modification to achieve additional modulation of its stability/sensitivity to MN and the kinetics of MN-triggered on-demand release. We found that when all phosphodiester bonds within the oligonucleotide linker 5'-carboxy-mCmGTTmCmG-3-acrydite, except for the one between TT, were replaced by phosphorothioate, the oligonucleotide (6PS) stability significantly increased and enabled the most sustained release of tethered vancomycin from the coating. By contrast, when only the peripheral phosphodiester bonds at the 5'- and 3'-ends were replaced by phosphorothioate, the resulting oligonucleotide (2PS) linker was cleaved by MN more rapidly than that without any PS modifications (0PS). Using a rat femoral canal periprosthetic infection model where 1000 CFU S. aureus was inoculated at the time of IM pin insertion, we showed that the prophylactic implant coating containing either 0PS- or 2PS-modified oligonucleotide linker effectively eradicated the bacteria by enabling the rapid on-demand release of vancomycin. No bacteria were detected from the explanted pins, and no signs of cortical bone changes were detected in these treatment groups throughout the 3 month follow-ups. With an antibiotic tethering dose significantly lower than conventional antibiotic-bearing bone cements, these coatings also exhibited excellent biocompatibility. These chemically modified oligonucleotides could help tailor prophylactic anti-infective coating strategies to meet a range of clinical challenges where the risks for S. aureus prosthetic infections range from transient to long-lasting.

Formulation development of tocopherol polyethylene glycol nanoengineered polyamidoamine dendrimer for neuroprotection and treatment of Alzheimer disease.

Amyloid-beta (Aß) aggregates deposition at extra neuronal sites induces neurotoxicity and major hallmarks of Alzheimer's disease (AD). To reduce the Aß fibril toxicity, multi-functional polyamidoamine (PAMAM) dendrimer was conjugated with tocopheryl polyethylene glycol succinate-1000 (TPGS) which acts as a carrier matrix for the delivery of neuroprotective molecule piperine (PIP). This PIP-TPGS-PAMAM dendrimer was fabricated to mitigate the Aß1-42 fibril toxicity on SHSY5Y cells. TPGS-PAMAM was fabricated through carbodiimide coupling reaction, and PIP was encapsulated in dendrimer through solvent injection method to prepare PIP-TPGS-PAMAM. Antioxidant assay of PIP-TPGS-PAMAM showed 90.18% inhibition of 1, 1-diphenyl-2-picrylhydrazyl (DPPH) free radicals compared to free PIP, which was 28.27%. The SHSY5Y cells showed 37.25% for negative control group and 82.55% cell viability for PIP-TPGS-PAMAM treated group against Aß1-42 toxicity. PIP-TPGS-PAMAM reduced the ROS activity to 15.21% and 48.5% for free PIP treated in cell group. Similarly, extent of Aß1-42-induced apoptosis also reduced significantly from 38.2% to 12.36% in PIP-TPGS-PAMAM treated group. In addition, PIP-TPGS-PAMAM also disaggregated the Aß1-42 fibril in SHSY5Y cells. Our findings suggested that PIP-TPGS-PAMAM showed mitigation of Aß1-42-induced toxicity in neuronal cells, which can offer excellent prospect of neuroprotection and AD therapy.

Potential of nanoparticulate based delivery systems for effective management of alopecia.

In recent times, more than 50 % of the global population is facing hair-related issues (alopecia) which is seen mostly amongst the people in the age group of 30-40 years. The conventional topical dosage forms available in the market falls short in effectively managing alopecia. Despite various advancements in topical dosage forms, it is still disposed to limited clinical application and provides poor penetration of drug molecules into the skin. The exact etiology of alopecia is still unknown and various researchers link lifestyle, hereditary, and auto immune-based events with its existence. Nanoparticulate-based delivery are hence brought in use to enhance the permeability properties of the drug. In comparison to conventional methods nanotechnology-based drug delivery system tames drug molecules to a specific site with much better efficacy. This review is engrossed in the journey and role of nano technological-based drug delivery in the management of alopecia and its clinical application.