Core and Corona Modifications for the Design of Polymeric Micelle DrugDelivery Systems

The effective treatment of human diseases using smallmolecule and macromolecular therapeutics continues to present significant challenges to the biomedical community. In part, this stems from the physical properties of individual drug candidates, which are typically hydrophobic and poorly aqueous soluble. This necessitates the use of excipients to solubilize these compounds for delivery, which often have their own associated toxicity. The poor selectivity of many small-molecule therapeutics also often results in dose-limiting side effects when delivered systemically. Alternative macromolecular therapeutics under development that use RNA, DNA and proteins display good solubility in aqueous conditions, but can suffer from degradation and short circulation times in vivo. Nanoparticles have been studied as an alternative strategy to circumvent the broad distribution profile of smallmolecule therapeutics, to protect sensitive biomacromolecules and deliver them more selectively to a required site of action. A key feature of these composite nanoparticles is that they demonstrate value added properties, that is, they can serve as delivery and diagnostic vehicles and/or deliver multiple molecules simultaneously. Moreover, such materials can now accurately interface with both small molecules and biological macromolecules in a manner that does not significantly disrupt their innate function. Continuing efforts are now focused on developing these materials to meet the stringent requirements for benign in vivo circulation and improved pharmacokinetic properties. The synergistic properties intrinsic to numerous nanoparticle platforms continue to make them attractive as potential drug-delivery systems for cancer, viral infections, cardiovascular disease, pulmonary and urinary tract infections. Despite the range of current nanoscale drug-delivery systems in development, such as colloidal metals, liposomes and polymeric nanoparticles, few have successfully reached the clinic. Creating particles that contain a clinically relevant drug dose that can release this payload within the diseased cell remains a challenge. Keeping the nanoparticle diameter below 200 nm and including poly(ethylene glycol) (PEG) on the surface have been shown to partially decrease mononuclear phagocytic system (MPS) clearance. Additionally, nanoparticle shape plays a significant role in delivery-system efficacy, specifically in relation to circulation time and the mechanism of cellular internalization. Most of the current successes in nanoparticle drug delivery have been with cancer chemotherapeutics, where nanoparticles accumulate in tumours due to the enhanced permeability and retention (EPR) effect. However, variations in tumour/vasculature physiology and the many biological transport mechanisms involved in biodistribution still require better control of nanoparticle surface functionalization to achieve directed delivery. Towards this goal, optimizing ligand density has become an important factor to balance the degree of targeting and clearance. Specifically, the degree of avidity and multi-valency for a given nanoparticle platform has been shown to significantly impact internalization rates and biodistribution based on the in vitro