The advent of nanotechnology holds the promise of new modalities for the treatment of disease inman. In particular, the multifunctional nature of nanoplatforms is well-suited for complex diseases thatinvolve several different cellular compartments, such as cancer. The overall objective of project 6 is todevelop and test programmable, or 'smart' nanoplatforms (SNaPs) that are based on common nanoplatformcores. Nanoplatforms have been designed which will undergo spontaneous self-assembly, based on hostguestchemical interactions. The assembly is dependent upon integration of polyethyleneglycol polymer(PEG)-conjugated molecular guests, where the distal terminus of the PEG polymer can be conjugated to'programmable' elements. This host-guest based nanoplatform provides several advantages over ourexisting platforms: the poor pharmacological properties associated with many potent drugs are actuallyexploited in this approach, with fewer expected side effects, the design is highly flexible, accommodatingmultiple therapeutic, imaging, targeting or other effector functions within each nanoplatform, and thenanoplatforms are easily and rapidly programmable by-simple coincubation of the host and guest moieties.The capacity to incorporate multiple targeting elements into the SNaPs will be used to evaluate whether lowaffinity/high avidity modes of targeting represent an improvement in target cognition over current highaffinity/low avidity approaches. We hypothesize that moderate-to-low affinity, high-avidity dependentinteractions offer increased opportunities for true 'recognition' of the platform target, particularly ifheterogenous recognition of several different 'sensor-ligands' is required. Finally, we will test the capacity ofthe programmable nanoplatform to target distinct cell populations that contribute to tumor growth andmalignancy, including both vascular and tumor elements, using syngeneic and transgenic models of disease.A focus of these investigations will be the efficacy of the nanoplatform, when used to eradicate residual andmetastatic disease, after ablation of the primary tumor. The capacity for SNaPs to hunt and kill residualdisease is a potential strength of the nanoplatform, as recurring and metastatic disease accounts for themajority of disease morbidity. These studies will lay the groundwork for a new generation of easilyprogrammed, multifunctional nanoplatforms, amenable to the treatment of malignancy in human patients.
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