Site of Initial Application

Several extracellular barriers exist for the administration and targeted delivery of nanoparticles. Initial entry into the body represent on obvious barrier. This is not an issue for situations where the cancer cell or tumor targeted is readily accessible by a topical application. Such a situation, however, is rather rare. Entry into the body across mucosal surfaces such as those in the gut or lung is typically very inefficient. Even viral particles are not very successful at this approach with most relying upon infecting cells of the barrier from the apical exposure by only a few viral particles that can replicate inside the cells to allow the basolateral (systemic) release of large numbers of progeny. Viral particle entry at apical surfaces of epithelial cells is decreased by physical barriers such as secreted mucus as well as proteases and other enzymatic barriers. Extracellular (acellular) matrix environments that viruses might encounter after systemic infection could similarly act to diminish cellular targeting and entry. Man-made nanoparticle delivery systems are likely to be impeded by these same physical and biological barriers at epithelial surfaces and within the body. Reduced surface exposure of highly charged or protruding structures is commonly used by viruses to minimize the impact of these extracellular barriers on viral infectivity. Similar considerations may facilitate optimization of nanoparticle delivery strategies.

There are several common methods for administering materials to the body: injection or application to an epithelial surface (skin, intestine, lung, etc.) of the body. Nanoparticles can be absorbed into the skin after topical application.111 Although nanoparticles can be taken up through appendages of the skin (sweat gland ducts, hair follicles) following topical application,112 microneedles can be used to dramatically increase the efficiency of their uptake into and across skin.113 The intravitreous injection of nanoparticles results in transretinal movement with a preferential localization in retinal pigment epithelial cells,114 allowing for a sustained delivery strategy to the inner eye.

Nanoparticles can be absorbed from the lumen of the gut, but this absorption is inefficient.115 A number of factors have been examined related to regulation of nanoparticle uptake from the gut lumen.116 Nanometer-sized liposomes enter into the intestinal mucosa better than larger, multi-lamellar liposomes, and this uptake can be improved by coating with a mucoadhesive polymer such as chitosan.117 It is interesting that lipid-based materials absorbed from the gut partition into the lymphatic system and studies have suggested that these particles have remarkable access to the hepatocytes.118 One way to potentially improve nanoparticle uptake from the gut is to PEGylate these materials in a manner that selectively increases binding to the intestinal mucosa rather than the stomach wall.119 Additionally, anionic PAMAM dendrimers have been shown to rapidly cross the intestinal mucosa in vitro and may provide a method to improving oral delivery of nanoparti-cles.120 Cationic dendrimers also show a transcytosis capability in vitro; in general, cationic dendrimers are more cytotoxic than anionic dendrimers, but this characteristic can be reduced by additional surface modifications using lipids.121 Formulation studies have been performed to identify optimal methods for aerosol delivery of nanoparticles to the lung.122 In general, the uptake of nanoparticles at the lung or gut surface occurs, but the efficiency of this uptake is dramatically improved by incorporation of a specific uptake mechanism. Even without a specific uptake mechanism, an appreciable amount of nanoparticle absorption can occur at these sites if they are sufficiently stable and are not removed by clearance mechanisms.

A large number of studies have been performed to assess nanoparticle absorption following inhalation exposure, and concerns over the safety of such an approach for drug delivery have been raised.123 Nanoparticles deposited in the airways appear to be taken up through transcytosis pathways that allow the passage of these materials across epithelial and endothelial cells to reach the blood and lymphatics.57 Surface properties of nanoparticles greatly affect the capacity of nanoparticles to be taken into cells through the process of endocytosis and uptake following pulmonary deposition. As part of the respiratory tree, intranasal administration of nanoparticles can potentially provide a route into the brain.

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