"Targeting" nanoparticles: the constraints of physical laws and physical barriers.

In comparison to the complexities of the body, its organs, its normal and aberrant cells, many nanoparticles will appear to be relatively simple objects. This view is deceptive because the physicochemical properties of nanosystems, although quite well understood on the basis of material science, surface science and colloid theory, are far from simple in practice. While their properties are largely controllable in vitro, often purportedly "designed", their administration by any route changing environments conspires to produce additional layers of complexity. Some of the key physical laws and physicochemical parameters governing the fate of nanoparticles on their journey from point of intravenous administration to desired destinations such as tumors are discussed. Much of the science relevant to nanocarrier based targeting has been elaborated in studying purely physical phenomena, but there can be found therein many analogies with biological systems. These include factors that impede quantitative targeting: diffusion in complex media, aggregation and flocculation, hindered behavior of particles in confined spaces, jamming and dispersion in flow. All of these have the ability to influence fate and destination. Most of the critical processes are particle size dependent but not always linearly so. Virtually all processes in vivo involve an element of probability. Particle size and properties can be controlled to a large extent, but stochastic processes cannot by definition. Progress has been made, but the quantitative delivery of a nanocarrier to defined sites in tumors is neither inevitable nor yet predictable.