Abstract: Controlling the pharmacokinetics and targeting of small molecule drugs and diagnostics is at the core of medicinal chemistry, pharmaceutical science and biomedical imaging. The intense interest in nanoscale vehicles designed for targeted delivery and detection in vivo is predicated on the idea that such materials may infer their pharmacokinetic, bioavailability and targeting properties on small molecules and other cargo including biomolecules. Such nanoscale packaging strategies have a key role in alleviating dose-limiting side effects associated with many otherwise clinically effective chemotherapeutic drugs presenting a major hurdle in the treatment of cancer. In addition, targeting diagnostics efficiently and selectively to given tissues while avoiding non-specific accumulation greatly enhances signal to noise in in vivo imaging applications. The naturally efficient targeting and infectious properties of biological disease vectors, in particular viruses, has made them models in efforts to design and develop synthetic and semisynthetic nanoscale vectors for targeted drug delivery. Therefore, research has focused on the development of appropriately decorated spherical particles of various sizes, degradability profiles, surface chemistry and material constitution. More recently, the extraordinary diversity of virus morphologies and an increasing ability to synthesize complex nanoscale structures, has inspired investigations into how shape can affect synthetic nanoscale particle interactions with cells and their behavior in vivo. In particular filamentous (or rod shaped) morphologies have been shown to have significantly different properties relative to their spherical analogues including longer blood circulation times and extended cell-uptake rates. The intriguing shape and size dependence of these key properties of delivery vectors inspires our proposal to develop nanoscale particles with switchable, transformable morphologies. We propose a novel class of materials capable of switchable, programmed pharmacokinetic profiles in vivo with utility in a range of functions including differential uptake into particular tissue types (e.g. tumor targeting vs liver uptake), stimulated renal clearance from systemic circulation, and evasion of macrophage uptake coupled with selective targeting. The goal of this research program is to develop materials capable of switching their pharmacokinetic and tissue targeting profiles in response to specific biochemical stimuli. This will be achieved utilizing a novel mechanism - stimuli-responsive nanoparticle morphology transitions. We propose a number of experiments for exploring the viability and validating this approach to vector directed targeting. Our preliminary pharmacokinetic data will be further validated in healthy mice and in vitro with macrophages, to examine our ability to control and switch several factors including: tissue accumulation, mode of clearance, circulation half-life, immune- response and degradation. Investigations will include targeted drug delivery, and targeting of diagnostics in the form of fluorescent labels and MRI-agents to human cancer cell lines in vitro and mouse cancer models in vivo. Public Health Relevance: The ability to accurately detect, diagnose and target diseased tissue is a key challenge in treating patients. This research program aims to discover new methods for specifically masking and targeting toxic anticancer drugs specifically to tumor cells and for labeling them for diagnosis. This is a novel approach to pharmaceutical and biomedical imaging science with broad, general implications for programmed, """"""""smart"""""""" therapeutics for tackling as yet unsolved problems in the treatment of human disease including allevation of chemotherapy side-effects and early, accurate diagnoses.
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