Strategies in the design of nanoparticles for therapeutic applications

Abstract

The development of the next generation of nanoparticle therapeutics — based on polymeric nanoparticles that combine the pre-eminent features of traditional delivery vectors such as liposomes and polymer-drug conjugates, but offer new flexibility to overcome some of the key barriers in the field — is gaining momentum. To achieve intracellular drug delivery, strategies for overcoming various biological barriers — from the system level, to the organ level and to the cellular level — are needed. For intravenously injected engineered nanoparticles, the avoidance of multiple organ-level clearance mechanisms, such as those operating in the spleen and in the liver, must be compensated for if the carrier is to reach its intended destination. Ultimately, the effectiveness of any engineered nanoparticle will depend on the efficiency of the carrier to deliver its cargo to the intracellular site of action, which in many cases requires organelle-specific targeting. The size, the surface characteristics and the shape of a nanoparticle have a key role in its biodistribution in vivo. The effects of size have been studied extensively with spherically shaped particles and some general trends have been noted. Particle size is also known to influence the mechanism of cellular internalization. However, current findings indicate that particle shape is just as important, if not more so, than size in controlling key aspects of both biodistribution and nanoparticle internalization. Achieving tailored activated release of therapeutic cargo still represents a key barrier in the field of engineered nanoparticles. The predominant strategies so far incorporate materials that are enzymatically degradable, pH sensitive or reductively labile, which facilitate bond breaking between the drug and the carrier, or destabilization of the carrier on reaching the intended site of action.