Metastatic melanoma has a very poor prognosis, with a median survival of less than 1 year. There are no satisfactory treatments for most patients; therapies are largely palliative and yield short-term benefit. Significant advances in the rapidly growing field of nanomedicine have the potential to profoundly impact cancer diagnosis and treatment. Multifunctional particle platforms that combine and deliver several functionalities to tumors offer distinct advantages over individual molecules, and are poised to move into clinical practice. By attaching tumor-selective peptides and therapeutic moieties to particle surfaces to create such platforms, cancers may be selectively targeted and treated. Fluorescent core-shell silica nanoparticles are clinically-promising non- toxic "lab-on-a-particle platforms" that demonstrate exceptional per particle brightness and stability, and have successfully integrated multiple functionalities for cancer diagnostics and radiotherapeutics. Tuned to sizes for renal clearance, the particle shows increased receptor binding potency and favorable targeting kinetics after small peptide ligands and radiolabels are attached to its surface to create a combined PET-optical probe. As such, it represents the only renally excretable, inorganic, PET-optical probe that simultaneously targets tumors in vivo without attendant toxicity issues. In addition to size considerations, optimal in vivo performance dictates that particle surface chemistry be well-controlled and reproducible. This requires collectively tailoring the number of peptide ligands and polyethylene glycol (PEG) chain lengths and grafting densities on particle surfaces to achieve favorable targeting and clearance profiles. For inorganic nanoparticles, it is not known how surface chemistry variations modulate biological properties. The long-term objective of this proposal is to develop and implement good surface designs for our FDA IND approved ~7-nm diameter core-shell silica nanoparticle architectures for detection, staging, and therapy planning of human metastatic melanoma. This proposal aims to: (1) determine the optimal tunable surface chemistry for targeted silica nanoparticles to achieve favorable melanoma receptor binding using variable numbers of cyclic arginine-glycine-aspartic acid-tyrosine (cRGDY) peptides, PEG chain lengths, and grafting densities; (2) investigate whether optimally formulated chemistries established for cRGDY-bound probes can be extended to alternative probes bearing melanoma-specific peptides (1-MSH); (3) assess in vivo tumor-selective accumulations of 124I-cRGDY-PEG- and 124I-1MSH-PEG-dots and feasibility of targeted radionuclide therapy; and (4) perform targeted radiotherapy and 18FDG PET response monitoring of tumors and normal tissues by attaching therapeutic radiolabels. The success of this study will enable the generation of investigational new drug applications for conducting future Phase I/II clinical trials in metastatic melanoma patients, offering the potential for wider application to other receptor-bearing malignancies. The efficiency of probe translation to the clinic may additionally be improved based upon the establishment of generalized templates for small ligand targeting platforms.