Nanotechnology holds promise for new treatments for disease in man. Nanoparticle-based approachesoffer the possibility of significant advances over current clinical methods accommodating multipletherapeutic, imaging, targeting or other effector functions within each nanoplatform. while improving thepharmacological properties of imaging agents and drugs The multifunctional nature of nanoplatforms istherefore well-suited for the diagnosis and treatment of complex diseases involving multiple physiologicalcompartments, such as cancer. The overall objective of project 3 is to characterize the impact of vasculartargeting on the accumulation of new programmable 'smart' nanoplatforms (SNaPs) within tumors.
AIM 1 will examine the characterize how targeting nanoplatforms to oncofetal integrin receptors - expressed ontumors and tumor vasculature - leads to accumulation within these sites. These studies will focus onunderstanding the impact of affinity and avidity on the ultimate accumulation of nanoparticle within the targetsite.
In AIM 2. we will assess targeting of nanoplatforms which undergo spontaneous self-assembly on a'honeycomb' core, based on host-guest chemical interactions. Assembly is dependent upon integration ofpolyethyleneglycol polymer (PEG)-conjugated molecular guests. The distal terminus of the PEG polymersare pre-conjugated to 'programmable' elements, such as targeting or imaging agents. The targeting andstability of the SNaPs will be tested against conventional nanoparticles.
Both AIMS 1 & 2 will employ MRI ofavian tumor models and the dorsal window preparation of optically imaged mice with dual reporter (optical &Gd) bearing nanoparticles.
AIM 3. The capacity to incorporate multiple targeting elements into the SNaPs bysimple ratiometric combination of the host platform and the guest-anchored moieties will be used to evaluatewhether combinatorial approaches at targeting - using ligands for two different receptors on the target cell -offers any increase in specificity over singly targeted. Finally, in AIM 4. we will extend the studies fromsimply imaging accumulation at particle sites to testing whether multifunctional, imagable nanoparticles candetect nascent tumors in genetic preclinical models of disease. The studies will employ Optical and MRimaging of mouse models of subcutaneous tumor growth and metastasis, and spontaneous murine modelsof tumor development. We believe that these studies should lay the groundwork for a new generation ofeasily programmed, multifunctional nanoplatforms, amenable to the imaging and possibly treatment ofmalignancy in human patients. Such particles represent an important first step towards the development of'on site' programmable and personalized, but mass-producible, diagnostic/therapeutic products.
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