MASSACHUSETTS INSTITUTE OF TECHNOLOGY
The main approach outlined in the original application was to enhance the specificity of tumor targeting by designing mechanisms to amplify the targeting. We believe that this is still an approach unique to us in the nanobiotechnology research arena. This project has been highly successful. We have successfully created targeting systems for nanoparticles that incorporate both specific targeting and amplified accumulation of the nanoparticles in tumor tissue. Our research is now more focused on demonstrating efficacy in animal models and we have more targeting systems we have shown to be active in tumor imaging and/or treatment is mice than we originally envisioned. Optimizing these systems and comparing their efficacy is generating more peptide synthesis and animal experiments exploring diagnostic MRI and various treatment options, each of which is expensive, but still within the scope of our original specific aims. The Specific Aims originally approved are: Specific Aim 1. Synthesis and Characterization of Magnetic Nanoparticles Specific Aim 2. Targeting Magnetic Nanoparticles to Tumors In Vivo Specific Aim 3. Amplification of Targeting by Self-Assembly in Tumors Specific Aim 4. Controlled Delivery of Model Drugs Specific Aim 5. Treatment of Tumors by Engineered Multifunctional Nanoparticles. This supplemental request primarily relates to the original Specific Aims 1, 4, and 5, and Specific Aim 1. Aim 1. Develop alternative nanoparticle synthesis methods. To accomplish this, we are working on scale-up based on high temperature decomposition of organometallic precursors. This method is known to yield gram-scale, monodisperse, and highly crystalline nanoparticles. This work will require a full FTE in the Sailor laboratory to characterize the nanoparticles in comparison to the first synthesis process that was utilized for the program until now. This work falls within the scope of Aim 1 but is required to accelerate the tempo of our work towards preclinical therapeutic comparisons in mice. Aims 4 and 5. We have reported several potential drug delivering nanoparticle formulations under this grant, including unique ones the potency of which is enhanced by amplified homing to tumors. It will now be important to select the best formulations for the applications proposed in the original application, such as the delivery of chemotherapeutic drugs, including pro-apoptotic peptides, and siRNA. We have seen remarkably enhanced anti-tumor activity by the pro-apoptotic peptide (KLAKLAK2) when coated onto nanoparticles. This multivalent presentation could greatly enhance the (previously narrow) therapeutic window of this compound. We will target these particles to tumors to determine whether this enhanced activity can be translated into improved efficacy of tumor treatment. Again, our the potency of our delivery systems bodes well for the selectivity of the delivery, but it will not be possible to compare the potential delivery systems, and at the same exploit the tumor homing by combining it with effective delivery to the cytoplasm, which is required for the activity of intracellularly acting drugs and is a sine non qua for siRNA. Supplemental funding would allow us to combine our amplified tumor-targeting systems, novel tumor-penetrating peptides from the Ruoslahti laboratory and existing intracellular delivery technologies. Our technology has significant potential to improve the efficacy and specificity of conventional cancer therapeutics.