With advances in nanotechnology, it is now possible to develop highly selective and effective cancer therapeutics by combining specialized biomaterials with currently available chemotherapeutic agents. The aim of project 1 of this U54 proposal is to develop technologies for in vivo targeted delivery of cytotoxic drug encapsulated controlled release polymer nanoparticles to cancer cells. This could allow for a large amount of drug to be delivered to cancer cells and make it possible to reach a steady state cytotoxic drug concentration at the tumor site over an extended period of time. The combination of targeted delivery and controlled release could also decrease the likelihood of significant systemic toxicity since the drug is encapsulated and biologically unavailable during transit in systemic circulation. We will build upon our previous research on long circulating nanoparticles as published in Science and engineer biocompatible and biodegradable nanoparticles and optimize these for targeted drug delivery to cancer cells. By using high throughput combinatorial methods, we will develop a library of more than 3000 targeted nanoparticle formulations and optimize multiple parameters including, size, chemical structure and charge of nanoparticles;and density of targeting molecules on the nanoparticle surface for targeted delivery. As a model targeting molecule, we will use nuclease resistant RNA ligands that bind to tumor-antigens on the surface of prostate cancer cells. By isolating a panel of RNA ligands that bind to prostate tumor epitopes, we propose to develop polyvalent targeted nanoparticles that may overcome tumor heterogeneity which in some cases has hindered the clinical translation of previous targeted approaches. We believe this project has broad significance, since the successful development of this technology may result in the development of the next generation of nanoscale cancer therapeutic modalities.