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“Advanced, Multifunctional Imaging and Therapy of Lymphoma by Molecularly Tailored Nanoparticles” We have rationally designed and created a tunable, synthetic delivery platform that is based on cyclodextrin-containing polymers (CDPs). When combined with therapeutic and imaging agents, the polymer delivery platform creates multifunctional nanoparticles. Through experimentation, we have demonstrated that targeted particles of 50 nm in diameter are the most appropriate for systemic use. These nanoparticles show excellent systemic biocompatibility and efficacious anti-tumor behavior when carrying either small molecule chemotherapeutic agents or short interfering RNAs (siRNA) and administered intravenous in rodent models. One variant of this platform is schedule to begin human clinical trials this year. Here, we propose efforts that involve research groups at Caltech where the polymer platform was invented and the Lymphoma Specialized Program of Research Excellence (SPORE) at the City of Hope to develop an effective nanotechnology platform for the systemic imaging and treatment of lymphoma. We propose to evaluate the hypothesis that properly designed and engineered, synthetic CDP-based nanoparticles that are ca. 50 nm in diameter can effectively provide targeted therapeutics and imaging agents for lymphoma. Specific Aims: 1. 2. 3. 4. Create targeted nanoparticles ca. 50 nm diameter for the effective MRI imaging of lymphoma that have sizes and surface properties (including surface presentation of protein targeting ligands) that are analogous to those used with the targeted therapeutics so that the imaging and therapeutic agents have the same biodistribution in mammals. Create targeted nanoparticles with the same surface properties as those prepared in Specific Aim 1 that also contain payloads that are able to provide intracellular, molecular-level readouts of therapeutic targets. Create targeted nanoparticles of ca. 50 nm diameter using CDPs with small molecule chemotherapeutic agents and protein targeting ligands, and test their ability to target and treat lymphoma in rodent animal models. Create targeted nanoparticles of ca. 50 nm diameter using CDPs with siRNAs and protein targeting ligands, and test their ability to target and treat lymphoma in rodent animal models. Significance: The development of an effective, targeted, synthetic platform for imaging and treating patients in a systemic manner would provide new therapeutic methods for treating lymphoma and metastatic cancer in general. Long-term Goals: The potential for providing new disease treatments for metastatic cancer has been restricted by limitations in the safe and effective delivery of therapeutic agents. The long-term objective of our work is to design and engineer a generalized, synthetic platform for ultimately providing targeted therapies for metastatic cancer. While lymphoma is used here as the cancer type for proof of concept experiments, the concepts investigated and anticipated outcomes will be readily generalizable to other forms of cancer.