In recent years, significant effort has been devoted to develop nanotechnology for drug delivery since it offers a suitable means of delivering small molecular weight drugs, as well as macromolecules such as proteins, peptides or genes to cells and tissue. Biodegradable nanoparticles formulated from poly (D,L-lactide-co-glycolide) (PLGA) and polylactide (PLA) have been extensively investigated for different drug delivery applications. Nanoparticles, in general, can be used to provide targeted (cellular/tissue) delivery of drugs, to improve oral bio-availability, to sustain drug/gene effect in target tissue, to solubilize drugs for intravascular delivery, and/or to improve the stability of therapeutic agents against enzymatic degradation (nucleases and proteases).

Research about the mechanism of intracellular uptake of nanoparticles, their trafficking and sorting into different intracellular compartments, exocytosis, and the mechanism of enhanced therapeutic efficacy of nanoparticle-encapsulated agent at cellular level is more recent. Recent studies in our laboratory demonstrated rapid escape of PLGA nanoparticles from the endo-lysosomal compartment into cytosol following their uptake. Surface charge reversal of nanoparticles (from anionic to cationic) selectively in the acidic pH of endo-lysosomes is the mechanism proposed for rapid endo-lysosomal escape of nanoparticles.

Rapid escape of nanoparticles from the degradative endo-lysosomal compartment to the cytoplasmic compartment and their sustained intracellular retention suggest that nanoparticles containing encapsulated therapeutic agent could serve as an efficient sustained release drug/gene delivery system. Based on the above mechanism, various potential applications of nanoparticles for the delivery of therapeutic agents to cells and tissue will be discussed. In our studies, nanoparticle encapsulated therapeutic agent (dexamethasone) demonstrated sustained antiproliferative effect in vascular smooth muscle cells. Similarly, nanoparticle encapsulated DNA demonstrated sustained gene transfection in prostate cancer cell line. As the pathophysiology of disease conditions and their cellular mechanisms are understood, drug delivery systems customized to achieve optimal therapeutic efficacy will be more effective. Nanoparticles, because of their versatility for formulation, sustained release properties, sub-cellular size and bio-compatibility with tissue and cells appear to be a promising system to achieve the above objective.