There are still urgent needs in the field of pharmaceutical nanotechnology, which are posited below (16), but these might also be suitably modified for many delivery systems.

1. The relevance to the whole animal of in vitro tests of activity, selectivity, uptake, and toxicity of nanoparticulate carrier systems.

In vitro systems are generally static, whereas most interactions between particles and ligands on cell surfaces occur under dynamic conditions. Flow of blood in which nanosystems move generally decreases the interaction between carrier and target, through shear forces at surfaces. Laminar and nonlaminar flow in vessels and other tubules is determined by the variable velocity and velocity gradients in blood vessels (17). Dilution effects and the propensity of nanoparticles to interact with proteins in the blood affect the translation from cell culture to living animal.

2. Scaling factors in animal models and the extrapolation of results to human subjects.

The relevance to the human subject of animal studies, which form the greatest number of sources of data to date, is obscure. Does a 100-nm particle behave in the same way in a mouse and in a human? What is the importance of the distance traveled between the point of entry and the point of interaction with target? How does the physiology of various species influence interpretation of data? Kararli (18) reviewed aspects of the physiological differences between a variety of experimental animals and human subjects in relation to drug absorption. A similar exercise is necessary to determine the influence of species differences on nanocarrier behavior and fate.

3. The causes of the differential uptake and transport of particles in different cell lines in vitro and tissues in vivo.

Studies of transfection of a variety of cell lines with a particular DNA-complexing agent have frequently shown very marked differences in effectiveness. For example, in the case of dendriplexes (dendrimer-DNA complexes), Bayele et al. (19) have shown 1000-fold differences in transfection. These variations have been confirmed by many researchers. Is this due to cell size (i.e., the distance to be traveled), membrane differences, cell culture media, differences in cell division rate, or the nature of the nucleus and cytoplasm of each cell type? Is there a physical cause, rather than a fundamental biological problem? Diffusion in the cytoplasm is, in part, a purely physical phenomenon; the process is akin to diffusion in a complex gel, strongly dependent on the radius of the particle and the "pore size" of the gel as well as the volume fraction of the gelator. Both obstruction effects and adsorption can occur, so that diffusion is slow, and above critical particle radius ceases altogether. With biological therapeutics, their size often controls their release from delivery systems and certainly their escape into and diffusion in tissue.

4. The influence of the nature of the polymer or other construction material in the manufacture of nanosystems on their biological and colloidal behavior.

It is one thing to formulate a protein in a polymeric carrier and another to be able to predict the miscibility of that protein with the polymer and its potential distribution within the matrix of the polymer. Does phase separation occur as the mixing of two macromolecules is not a simple process thermodynamically? Phase separation can lead to rapid release of active. There has been significant concentration on the effect of the size of nanoparticles on physical and biological behavior but perhaps less on the nature of the polymer in as far as this affects the capacity of the system to encapsulate therapeutic agents or the potential to influence particle flocculation and the vital interactions at close approach of the nanoparticles and cell surface receptors. The Hamaker constants (see chap. 11) are fundamental for assessing the attractive forces between surfaces, and for different polymeric materials can be quite different (20,21), as shown in Table 2.

Table 2 Hamaker Constants (in vacuo) for Some Polymers

Polymer A (x1020 J)

Polymer A (x1020 J)

Table 2 Hamaker Constants (in vacuo) for Some Polymers

Polyvinyl chloride

10.8, 7.5


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