Abstract
Passive targeting with microparticulate drug carrier systems is reviewed. Passive targeting characters of microparticulates such as microspheres, emulsions, and polymeric micelles are determined by their particle size and surface chemical structures. Microparticulates larger than blood capillaries are known to be stuck in capillaries and this phenomenon is utilized in chemoembolization. Particles smaller than ca. 200 nm in diameter can circulate in bloodstream for long time periods by avoiding reticuloendothelial uptake if these particles are large (>ca. 4 nm) enough to avoid the renal excretion. Furthermore, particle surface must be hydrophilic for avoidance of the reticulocndothclial uptake. Present status of three passive targeting particulate carriers is summarized. Microspheres (They are called nanospheres when their diameters are smaller than 1 μm.) are mainly used in chemoembolization with diameters larger than capillaries. A therapy with prostaglandin E1-containing emulsion was approved in Japan in 1988. Emulsions are mainly used for solubilization of hardly water-soluble or water-insoluble drug and for local injection such as arterial infusion. A polymeric micelle is an alternative type drug carrier that is an assembly of polymers with heterogeneous structures, typically block copolymers. Polymeric micelles inherently pos.sess several benefits as drug carriers, e. g., high structural stability, very small size (<100nm), and large drug incorporation capacity. A polymeric micelle system containing an anticancer drug, adriamycin, showed much enhanced in vivo antitumor activity with selective accumulation in solid tumor sites. This is a successful example of passive targeting to solid tumors utilizing the enhanced permeability and retention effect (EPR effect) of tumor vascularture. For passive targeting, deep understanding of vascular endothelial cell structures that are responsible for permeation of particulates is important. However, these structures have not been analyzed enough to present quantitative estimation of particulate permeation. The hypertension chemotherapy using angiotensin II is a successful drug delivery methodology. Angiotensin II increased blood flow selectively at solid tumor sites. This therapy was approved in Japan against stomach tumor using conventional low molecular weight anticancer drugs. Research is further carried out for combination use of angiotensin II with a macromolecular drug carrier system.
