Novel diagnostic and therapeutic tools that can enable earlier and more specific detection, as well as enhance efficacy are critically needed to improve patient outcomes, in particular in melanoma and malignant brain tumors studied in this Center. For example, such tools should enable the operating surgeon to directly visualize tumor margins and metastatic disease spread to lymph nodes, while identifying adjacent vital neurovascular structures. Such structures may be difficult to visualize, thus putting them at risk for injury. Unfortunately, while nanoparticles have a number of desirable features permitting the addition of new functionalities to create a more potent, tumor-directed imaging and/or therapeutic platform, such molecularly targeted, multimodality particles that can improve diagnostic accuracy and/or triage patients to appropriate treatment arms, have been slow to advance to the clinical trial stage. The vision of the MSKCC-Cornell Center for Translation of Cancer Nanomedicines (MC2TCN) is to advance, translate, and disseminate a suite of ultrasmall (<10 nm) multimodality (PET/optical) silica-organic hybrid nanoparticles with tunable size, brightness, and geometry that, as a result of their proven favorable pharmacokinetics, clearance profiles and tumor-to-background ratios in human patients, have the potential to overcome these limitations and dramatically impact the way we diagnose and treat cancer patients. This includes the development and implementation of intraoperative optical detection tools to improve cancer localization, staging, and treatment, as well as the development of optimized therapeutic platforms that enhance delivery and therapeutic index relative to existing technologies. The proposed Center is focused on initial development efforts of diagnostic particle probes, fluorescent core-shell silica nanoparticles referred to as Cornell dots or C dots,which have already received FDA investigational new drug (IND) approvals for first in-human clinical trials. This successful work, for the first time in human patients, has validated the "taret or clear" approach of <10 nm nanoparticles pursued in this Center, opening the door to transformative research and development of new clinically promising classes of nanoparticles and their applications in cancer diagnostics and therapeutics. Transitioning to water-based synthetic approaches proposed here will enable cost-effective creation of novel diagnostic and therapeutic particle platforms with sizes <10 nm. These ultrasmall particle platforms will exhibit high brightness for maximum detection sensitivity by altering particle core composition, lead to particle geometries (rings vs. spheres) with increased surface area for maximizing drug loading capacity, and address the effects of particle size and surface chemistry heterogeneity on PK, clearance profiles and target-to-background ratios - key issues in the use of nanomaterials in nanomedicine. Informed by the encouraging results of the first-in-human clinical trials with first generation multimodal C dots, built on many years of collaborative research between investigators of the proposed multi-institutional, multi-disciplinary team, we envision that the proposed work defined by the framework of this Center and by the use of same-sized particle platforms exhibiting improved and significantly enhanced capabilities has a realistic chance to change the paradigm of cancer care applications pursued herein.