The approval of drugs for human use by the US Food and Drug Administration (FDA) through the Center for Drug Evaluation and Research (CDER) is a time-consuming and expensive process, and approval rates are low (DiMasi et al., J Health Econ 22:151-185, 2003; Marchetti and Schellens, Br J Cancer 97:577-581, 2007). In general, the FDA drug approval process can be separated into preclinical, clinical, and postmarketing phases. At each step from the point of discovery through demonstration of safety and efficacy in humans, drug candidates are closely scrutinized. Advances in nanotechnology are being applied in the development of novel therapeutics that may address a number of shortcomings of conventional small molecule drugs and may facilitate the realization of personalized medicine (Ferrari, Curr Opin Chem Biol 9:343-346, 2005; Ferrari, Nat Rev Cancer 5:161-171, 2005; Ferrari and Downing, BioDrugs 19:203-210, 2005). Appealingly, nanoparticle drug candidates often represent multiplexed formulations (e.g., drug, targeting moiety, and nanoparticle scaffold material). By tailoring the chemistry and identity of variable nanoparticle constituents, it is possible to achieve targeted delivery, reduce side effects, and prepare formulations of unstable (e.g., siRNA) and/or highly toxic drugs (Ferrari, Curr Opin Chem Biol 9:343-346, 2005; Ferrari, Nat Rev Cancer 5:161-171, 2005; Ferrari and Downing, BioDrugs 19:203-210, 2005). With these benefits arise new challenges in all aspects of regulated drug development and testing.This chapter distils the drug development and approval process with an emphasis on special considerations for nanotherapeutics. The chapter concludes with a case study focused on a nanoparticle therapeutic, CALAA-01, currently in human clinical trials, that embodies many of the potential benefits of nanoparticle therapeutics (Davis, Mol Pharm 6:659-668, 2009). By choosing CALAA-01, reference is made to the infancy of the therapeutic nanoparticle field; in 2008, CALAA-01 was the first targeted siRNA nanoparticle therapeutic administered to humans. Certainly, there will be many more that will follow the lead of CALAA-01 and each will have its own unique challenges; however, much can be learned from this drug in the context of nanotherapeutics and the evolving development and approval process as it applies to them.

Nanoparticles (NP) have emerged as a novel class of therapeutic agents that overcome many of the limitations of current cancer chemotherapeutics. However, a major challenge to many current NP platforms is unfavorable biodistribution, and limited tumor uptake, upon systemic delivery. Delivery, therefore, remains a critical barrier to widespread clinical adoption of NP therapeutics. To overcome these limitations, we have adapted the techniques of image-guided local drug delivery to develop nano-ablation and nano-embolization. Nano-ablation is a tumor ablative strategy that employs image-guided placement of electrodes into tumor tissue to electroporate tumor cells, resulting in rapid influx of NPs that is not dependent on cellular uptake machinery or stage of the cell cycle. Nano-embolization involves the image-guided delivery of NPs and embolic agents directly into the blood supply of tumors. We describe the design and testing of our innovative local delivery strategies using doxorubicin functionalized superparamagnetic iron oxide nanoparticles (DOX-SPIOs) in cell culture, and the N1S1 hepatoma and VX2 tumor models, imaged by high resolution 7T MRI. We demonstrate that local delivery techniques result in significantly increased intra-tumoral DOX-SPIO uptake, with limited off-target delivery in tumor bearing animal models. The techniques described are versatile enough to be extended to any NP platform, targeting any solid organ malignancy that can be accessed via imaging guidance.

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PURPOSE-An animal model of pancreatic cancer that is large enough to permit imaging and catheterization would be desirable for interventional radiologists to develop novel therapies for pancreatic cancer. The purpose of this study was to test the hypothesis that the VX2 rabbit model of pancreatic cancer could be developed as a suitable platform to test future interventional therapies. MATERIALS AND METHODS-The authors implanted and grew three pancreatic VX2 tumors per rabbit in six rabbits. Magnetic resonance (MR) imaging was performed at two weeks to confirm tumor growth. At three weeks, the authors selectively catheterized the gastroduodenal artery under guidance of x-ray digital subtraction angiography (DSA). T2-weighted anatomic, diffusion-weighted (DWI), and transcatheter intraarterial perfusion (TRIP) MR imaging were then performed. Following imaging, tumors were confirmed at necropsy and histopathology. Size of tumors at two and three weeks was compared using a paired t-test (P = .05).RESULTS-VX2 pancreatic tumors were grown in 6/6 rabbits. The difference between tumor size at two and three weeks, 1.29 cm (± 0.39) and 1.91 cm (±0.50) respectively, was statistically significant (p < .001). All tumors were confirmed to be located within pancreatic tissue via histopathology. DSA, TRIP MR, DWI and anatomic MR imaging was successful in 5/6 rabbits. DWI and anatomic MR imaging was successful in 6/6 rabbits.CONCLUSION-The VX2 rabbit model of pancreatic cancer is feasible, as verified by imaging and pathologic correlation, and may be a suitable platform to test future interventional therapies.

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