In the last decade, remarkable scientific progress in the development of novel, nanoscale technologies has generated rising expectations for this enabling technology to advance our efforts in the prevention, diagnosis and treatment of human disease. These nanotechnologies, commonly referred to as nanomedicines when applied to the treatment, diagnosis, monitoring, and control of biological systems, incorporate a multitude of diverse and often unique nanosized products including new and/or improved therapeutic drugs, diagnostic/surgical devices, and targeted drug delivery systems.1 The list of nanoparticle medicines approved and/or currently being developed is quite large; these products range from early forms of drug-encapsulating liposomes (e.g., liposomes containing doxorubicin for treatment of breast and ovarian cancer) and simple polymeric structures (e.g., actinomycin D adsorbed on poly(methylcryanoacrylate) (PMCA) and poly(ethylcryanoacry-late) (PECA) nanosized particles)2 to more intricate multifunctional "nanoplatforms" and diagnostic devices, including polymeric dendrimers, nanocrystal quantum dots, carbon-based fullerenes, and nanoshells, to name a few (see Table 8.1). The vast majority of these products are being developed to improve early detection of cancer and/or to provide alternative clinical therapeutic approaches to fighting cancer, some of these products have been approved by the Food and Drug Administration for clinical use.75

Although there have been many articles published on the in vitro toxicity of certain nanomaterials, very little in vivo safety data evaluating the general toxicity of these novel products is available in the published literature. Many in vitro assays (cell-based, organelle-based, and cell/or-ganelle-free systems) have been used to evaluate the cytotoxicity of nanomaterials to help predict the relative safety and general biocompatibility of the nanoproducts in vivo. Several such studies include viability assays in vascular endothelial cells exposed to C60;76 fullerene induction/inhibition of oxidative stress and lipid peroxidation in isolated microsomes, dermal fibroblasts, and

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cultured cortical neurons; cytotoxicity of metal oxide nanoparticles to BRL 3A liver cells; and macrophage apoptosis after exposure to carbon nanomaterials and ultrafine particles.81_83 Although a vast amount of useful information has been obtained from these various in vitro models, the relevance and application of these findings to human drug safety remain uncertain until validated with in vivo studies with identical nanomaterials.

Targeted in vivo efficacy data is readily available for many of the novel, potential nanother-apeutics; however, necessary in vivo data indicating mechanism of action, general pharmacology/toxicity profiles, and optimal product characterization efforts rarely appear in the published literature. Much of our current understanding of the biocompatibility of nanomaterials comes from focused inhalation and dermal studies using nanosized products and ultrafine contaminants, as a model of environmental and occupational risk.84_87 However, there are questions regarding the level of applicability of these studies to human drug safety assessment due to the variability in size and purity of the chemical or structural composition reported or not reported in these studies, the route of primary exposure, and the complex differences in the structure and function of the affected organs.88 In addition, other in vivo studies, which identify intrinsic anti-oxidant and oxidative stress-inducing properties of unsubstituted fullerenes in a rodent and fish species, respectively, have important but limited value in drug discovery in the absence of systemic, whole animal toxicology data67,89.

While the enthusiasm and expectations for success in utilizing nanomaterials and nanometer-sized structures in biomedical applications grow, so do the concerns regarding the potential impact of such products on the environment and human health.88 The absence of available safety information for a vast majority of these novel nanosized materials and nanoparticlized drugs in biological systems only further supports the need for additional research into any potential toxic mechanisms in humans. The questions that appear most often in deciding the safety of any nanos-cale material include:

• Are nanomaterials and nanotechnology new to the United States Food and Drug Administration (FDA)?

• How do existing regulations ensure the development of safe and effective nanotech-nology-based drugs and how is the FDA preparing to deal with nanotechnology?

• What are the scientific considerations that raise unique concerns for nanotechnology-based therapeutics?

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