Abstract: The problem: Most cancers kill patients because of metastatic disease, which requires systemic therapy. However, systemic therapy approaches suffer from dosing limitations ? due to reaching unacceptable cytotoxic side effects before complete tumor death. To address this deficiency, nanoparticles are particularly promising ? to deliver more drug to tumor cells while sparing non-tumor cells from drug exposure. An ?ideal? nanoparticle carrier would (i) be a clinically approved agent able to carry clinically approved drugs for facile clinical translation, (ii) deliver drugs preferentially to tumors to attain highly efficacious concentrations without systemic toxicity, (iii) have a drug release mechanism for controlled release, and (iv) provide confirmation of drug delivery so physicians will know if efficacious quantities of drug were delivered, e.g. to adapt dosing or predict response. Yet, more often than not, particles are not clinically approved; drugs are covalently coupled to particles and require cleavage for release (altering approved formulations of both); there is no defined release mechanism; or there is no way to monitor actual drug release and thus delivery of active drug in patients. Proposed solution: We have developed a drug delivery method with potential ?ideal? delivery features. This method is based on clinically approved nanoparticles and is characterized by improved therapy efficacy, a release mechanism triggered by the tumor, and the ability to self-report the release of the drug in the tumor through magnetic resonance imaging (MRI). Our nanocarriers are the clinically approved iron oxide nanoparticle Feraheme and clinically used high molecular weight dextran. Both retain small hydrophobic drugs through electrostatic interactions (i.e. without change in compositions) and release them in a tumor environment. Our hypothesis is that the nanocarriers will deliver higher amounts of drugs selectively to tumors as compared to free-drug and that imaging will be effective at monitoring drug delivery and release. In addition to MRI multiplexed PET (mPET) will allow us to simultaneously image and quantify radiolabeled drug and radiolabeled nanocarrier. In Aim 1, we will use mPET/MRI to quantitatively monitor delivery, release and fate of drug and nanocarrier within orthotopic tumor models. In Aim 2, we will apply mPET/MRI to evaluate if targeted therapy results in higher drug delivery compared to passive, non-targeted delivery, and in Aim 3, we will explore if MRI of drug release can predict the therapy response by probing the tumors microenvironment and receptiveness for nanocarrier-mediated therapy, tailoring nanocarrier-based therapy personally to each patient. This approach will provide valuable insight into the in vivo kinetics of nanocarrier and drug that cannot be obtained otherwise. We will obtain essential data for in vivo drug delivery and therapy response with high potential to improve cancer therapy. This work can be easily translated into clinic. Patients undergoing cancer therapy could be in the near future imaged with drug-loaded nanocarrier to evaluate if their tumors will be suitable for such a therapy - essentially to realize much of the promise provided by nanoparticles.