Because the same imaging methodology can be applied to clinical routines, the mechanistic information determined from this preclinical study holds the potential to inform on the optimal timing of nanomedicine administration in a clinical setting in relapse treatment, and therefore the therapeutic potential of this methodology is of significant interest for future work both preclinically and clinically. physicochemical properties (size and surface functionality) and established a relationship between structure and tissue accumulation as a function of a new parameter that measures BBB leakiness; this offers significant advancements in our ability to relate tumor accumulation of nanomedicines to more physiologically relevant parameters. Our data show that accumulation of nanomedicines in brain tumor tissue is better correlated with the of the BBB than actual tumor formed brain tumors which inherently have initially intact BBB has not been tested, nor have the physicochemical properties of the nanoparticles been directly correlated to the leakiness of these tumors longitudinally. In PTC-209 this work we describe a modular approach to building custom designed nanomedicines for the purpose of interrogating their ability to cross the BBB and retain in the brain tumor. The nanomaterials used in this study have no therapeutic component, but for the sake PTC-209 of clarity in the context for which they hold the potential to be used, we refer to them as a nanomedicine. We define a nanomedicine as any nanoparticle-based carrier with the ability to have a therapeutic payload, a reporter or probe functionality (dye or radiopharmaceutical), and a targeting vector within the one particle. Specifically, we investigated two major factors that dictate a nanomaterials biodistribution, tumor accumulation, and tissue penetration: size and active targeting. By longitudinally assessing the increased potential for nanomedicines to cross the progressively more porous BBB and retain in the tumor tissue as a consequence of disease progression, we can relate a component of the tumor physiology to the physicochemical properties of model nanoparticles with respect to disease state progression. We developed this approach utilizing a mouse model that forms endogenous and PTC-209 spontaneous brain tumors, and a combination of complementary information gained from high-resolution magnetic resonance imaging (MRI) and positron emission tomography (PET) techniques based on clinically relevant methods.11?13 To assess the effect of nanoparticle size, two PEGylated spherical nanoparticles (20 and 100 nm) were chosen for this study. Both particles have been previously characterized and evaluated results but also an ideal methodology for investigating the influence of physiological changes in the tumor microenvironment on the accumulation and retention of nanoparticles with well-defined characteristics. The nanomedicines were labeled with a radioisotope (64Cu) to quantitatively assess their ability to cross the BBB and be retained in the tumor tissue at different stages of the tumor progression using PET. By correlating these quantitative data with a method for predicting leakiness of the tumors, we could directly compare the ability of a particular nanomedicine PTC-209 to cross the BBB and correlate this to disease state progression. This provides unique insight into whether a particular nanomedicine would be effective against a tumor at a certain stage in its development and contributes toward personalization of therapies for cancer patients. Herein, we propose that the leakiness of a tumor is Goat polyclonal to IgG (H+L) more indicative of the ability for a nanomedicine to cross the BBB and accumulate in the tumor, rather than size of the tumor alone. We also propose that there is a particle size dependence on this ability that can be correlated to the degree of leakiness associated with the tumor. This unique mechanistic insight offers the potential to better develop nanomedicine therapeutics for treating brain tumors in a patient-specific manner. While leaky vasculature is determined by a number of biological factors, in this work the term is defined as the overall cumulative increase in permeability of the tumor space with respect to increased blood flow surrounding the tumor. The uptake and accumulation of nanomedicines in tumors is dependent on not only particle size but also their composition (stealth material and targeting), shape (linear, globular, branched), rigidity (flexible, firm, spongelike), and architecture (coreCshell, micelle, polymeric).17?21.