Fate Of Nanoparticles

Successful targeting of nanoparticles to cancers or tumors may involve overcoming multiple biological, physiological, and physical barriers. Site of initial application can be critical. For example, nanoparticles administered into the gut or lung would initially confront epithelial barriers. Metabolic events or cellular responses at an injection site represent another initial barrier to targeted nanoparticle delivery. Once nanoparticles have entered the body, their size, shape, or surface characteristics can initiate events that present a second barrier to targeted delivery—misdirection of the material away from its targeted site through undesired interactions. Access and/or enriched distribution to specific organs or regions of the body may be critical for successful nanoparticle targeting. Finally, once nanoparticles have reached a targeted site, metabolic or physical aspects of the cancer cell or tumor might limit their effectiveness. Here, the intracellular uptake and fate may dictate the potential success of each nanoparticle approach. Events at each of these barriers act in a cumulative fashion to limit the success of any nanoparticle-based targeting strategy. Obviously, the overall fate of nanoparticles might be improved by using materials that are not affected by these barriers or by modification of nanoparticles in ways that can neutralize these barrier issues. Matching the size and composition profile of a nanoparticle delivery system with the targeting strategy allows for an optimized approach that takes advantage of default targeting events as much as possible.

As previously discussed, it is critical that inherent targeting mechanisms associated with a particular nanoparticle does not overwhelm or work in concert with any applied targeting strategy. Once at the target site, the fate of the nanoparticle can significantly affect its potential to provide the desired outcome. The delivery of hybridization-competent antisense oligonucleotides (ODNs) targeted to a cancer cell or tumor would not provide the desired outcome unless this material is efficiently internalized. ODNs covalently conjugated to anionic dendrimers have been shown to effectively deliver through an endocytosis process and down-regulate epidermal growth factor receptor expression in cancer cells.110 Other targeting strategies may not provide the desired outcome if the nanoparticle is internalized by cells. For example, enzyme-coupled nanoparticles targeted to a tumor that would activate a prodrug could fail to provide a desired outcome. Therefore, the potential for nanoparticles to have a successful outcome of targeting cancer cells or tumors requires favorable events at natural barriers of the body and their distribution within the body, but also their fate at the targeted site.

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