In Vitro Pharmacological And Toxicological Assessments

Prior to filing an IND or investigational device exemption (IDE) application with the FDA and subsequent clinical testing in humans, a new product must be adequately studied for efficacy and safety using animal models. The cost- and labor-intensiveness of these in vivo studies impel drug and device researchers to make use of predictive in vitro methodologies wherever technology permits. In vitro models can serve as an initial assessment of a nanomaterial's efficacy and absorption, distribution, metabolism, elimination, and toxicity (ADME/Tox), allowing a more strategic approach to animal studies. Used iteratively with in vivo studies, the two approaches can inform each other and help narrow investigations of the physiological and biochemical pathways that contribute to ADME/Tox behavior.

A variety of cell-based in vitro systems are available, including perfused organs, tissue slices, cell cultures based on a single cell line or combination of cell lines, and primary cell preparations freshly derived from organ and tissue sources. In vitro models allow examination of biochemical mechanisms under controlled conditions, including specific toxicological pathways that may occur in target organs and tissues. Examples of mechanistic toxicological endpoints assessed in vitro include inhibition of protein synthesis and microtubule injury. These mechanistic endpoints can provide information not only as to the potential mechanisms of cell death, but also can identify compounds that may cause chronic toxicities that often results from sublethal mechanisms that may not cause overt toxicity in cytotoxicity assays. Common mechanistic paradigms associated with nanoparticle toxicity include oxidative stress, apoptosis, and mitochondrial dysfunction. Due to the nanoparticle- and approach-specific nature of pharmacology studies, it is beyond the scope of this chapter to discuss pharmacological assay specifics. Where appropriate models exist, chemothera-peutic efficacy can be examined in vitro. In certain cases, targeting of chemotherapeutic agents may be demonstrated as well, using optimized treatment/wash-out schemes in cell lines expressing the targeted receptor. Though nanoparticle metabolism or enzyme induction has yet to be demonstrated, certain nanomaterials with attractive chemistries may be subjected to phase-I/II metabolism and induction studies using cell-based, microsomal, and/or recombinant enzyme systems.

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