Rabies virus glycoprotein (RVG), a 505 amino acid type-1 glycoprotein, is responsible for the neurotrophic nature of the rabies virus infection. Despite varying reports in the literature as to which receptor is ultimately responsible for interaction of RVG with the nervous system, there is a strong argument for major nicotinic acetylcholine receptor (nAChR) involvement. Peptide derivatives of RVG, such as rabies virus-derived peptide (RDP) and RVG-29 are emerging as promising targeting ligands for the delivery of therapeutics to the central nervous system (CNS). The neurotrophic nature of RVG and indeed its derivatives may be due to interaction with ubiquitous nAChRs principally, but also association with other neural cell-specific molecules such as neural cell adhesion molecule (NCAM). It is possible that nAChR-mediated uptake of RVG-derived peptides may serve as an attractive new approach for targeting drug delivery to the brain. Potential application of this type of drug delivery system extends to many diseases affecting the CNS, where specific and effective drug delivery is normally a challenging process.
Drug delivery to the brain is still a major challenge in the field of therapeutics, especially for large and hydrophilic compounds. In order to achieve drug delivery of therapeutic concentration in the central nervous system, the problematic blood brain barrier (BBB) must be overcome. This work presents the formulation of a targeted nanoparticle-based drug delivery system using a specific neural cell targeting ligand, rabies virus derived peptide (RDP). Characterization studies revealed that RDP could be conjugated to drug-loaded PLGA nanoparticles of average diameter 257.10±22.39nm and zeta potential of -5.51±0.73mV. In vitro studies showed that addition of RDP to nanoparticles enhanced drug accumulation in a neural cell line specifically as opposed to non-neural cell lines. It was revealed that this drug delivery system is reliant upon nicotinic acetylcholine receptor (nAChR) function for RDP-facilitated effects, supporting a cellular uptake mechanism of action. The specific neural cell targeting capabilities of RDP via the nAChR offers a non-toxic, non-invasive and promising approach to the delivery of therapeutics to the brain.
In recent years, rabies virus-derived peptide (RDP) has shown promise as a specific neural cell targeting ligand, however stability of the peptide in human serum was unknown. Herein, we report the molecular modelling and design of an optimised peptide sequence based on interactions of RDP with the 7 subunit of the nicotinic acetylcholine receptor (nAChR). The new sequence, named DAS, designed around a 5-mer sequence which demonstrated optimal nAChR binding in silico, showed greatly improved stability for up to 8 hours in human serum in comparison to RDP, which degraded within 2 hours at 37 °C. In vitro analysis using SH-SY5Y neuroblastoma cells showed that DAS-conjugated nanoparticles containing the cytotoxic drug doxorubicin (DAS-Dox-NP) displayed significantly enhanced cytotoxicity compared with untargeted doxorubicin-loaded nanoparticles (Dox-NP). DAS-Dox-NP had no significant effect on non-neural cell types, confirming its neural-specific targeting properties. This is the first time that In this manuscript, we report the design and testing of an optimised peptide ligand, conjugated to a nanoparticulate delivery vehicle and specifically targeted to neural cells., has been reported. Future impact of an innovative targeting peptide ligand combining the ability to selectively identify the target and facilitate cellular internalisation could enable the successful treatment of many neural cell disorders.
ObjectivesThe main aim was to develop a process to estimate critical care drug requirements to robustly inform regional procurement planning and preparedness in response to the COVID-19 pandemic. The objectives were to identify critical care drugs required, obtain patient usage data and consider current regional practice to establish the requirement.MethodHealth and Social Care (HSC) Trusts across Northern Ireland (NI) identified critical care drugs required and an estimation of average daily usage data. The Microsoft Excel database was constructed to compile Trust data and establish regional requirement. The database was refined further according to real-world data from NI HSC Trusts, Intensive Care National Audit and Research Centre report on COVID-19 in critical care, daily regional COVID-19 figures and other available National data. Components of a tool originally developed for H1N1 and updated for COVID-19 were adapted to reflect the NI context and used in the regional database. The database was clinically reviewed to ensure that it accurately reflected current regional practice given the evolving nature of the pandemic.ResultsThe critical care drugs required in the pandemic, usage data and current regional practice were identified to establish requirement. A regional database was constructed and used to produce a model for calculating approximate critical drug requirements. The model was used to map critical drug requirements to available stock in Trusts and wholesalers/suppliers, enabling the identification of treatment capacity for these medicines regionally, both currently and for projected surges. Data have also been used in the preparation of weekly regional situation reports provided to both the HSC Board and the Department of Health.ConclusionThe process developed is a robust approach to assist in informing regional critical care drug requirements in response to the COVID-19 pandemic. Further application has been demonstrated in regional procurement planning and preparedness.
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