Title: A “STICK” theranostic nanoplatform for image-guided drug delivery to brain malignancies Project Summary/Abstract Our long-term goal is to engineer a new and generalizable drug delivery platform to improve the delivery of various payloads to a series of brain malignancies and neurological disorders. The payloads can be imaging agents, chemotherapeutics, molecularly targeted drugs and immunotherapeutics. We identified the following major barriers for successful treatment of brain malignancies: 1) the blood-brain barrier/blood-brain tumor barrier (BBB/BBTB), 2) severe destabilizing effect in blood circulation that leads to a poor central nervous system (CNS) pharmacokinetics (PK) and 3) inability for agents to penetrate tumor tissue, and 4) lack of specificity for tumor cell delivery; resulting in poor treatment efficacy and off-target toxicity. To this end, we propose an integrated approach to mitigate these physiological barriers and mediate drug delivery to ensure disease targeting specificity. The goal of this revised R01 renewal application is to develop a new Sequential Targeting In CrosslinKing (STICK) nano-delivery platform to improve the drug delivery to brain malignancies. The characteristics of the proposed STICK nanoparticle (STICK NP) allow it to overcome the multiple barriers to penetrate deeply in brain malignancies. In Aim1, we will engineer new STICK NPs by designing new types of boronate crosslinkages to improve their CNS PK to maximize the time window to enhance the glucose transporter (GLUT1)-mediated transcytosis across the BBB/BBTB. The new crosslinkages also enhance the pH-responsive size transformation for improved tumor tissue penetration and sialic acid-targeting selectivity for enhanced tumor cell specificity. Our previous R01 grant focused on low grade brain tumors and as a logical but distinctive extension in this research topic, the target of our current project is diffuse midline glioma (DMG, previously called Diffuse Intrinsic Pontine Glioma (DIPG)), a high grade and the most aggressive form of pediatric glioma. DMG is the second most common type of primary, high grade brain tumor occurring in children with a median survival <1 year from diagnosis and the five-year survival rate of DMG is only around 2%. Discovery of the characteristic Histone 3-Lysine- 27-Methionine (H3K27M) mutation offers opportunity for development of targeted epigenetic therapies for this deadly disease. In Aim2, we will quantitatively determine the spatiotemporal distribution of the newly engineered STICK NPs in orthotopic DMG patient-derived xenograft (PDX) models and elucidate their delivery mechanisms by optical imaging, magnetic resonance imaging, liquid chromatography-mass spectrometry (LC- MS), and a series of biophysical approaches. In Aim3, two promising epigenetic drugs (panobinostat and ONC201) will be specifically delivered to DMG by encapsulations within selected STICK NPs for epigenetic therapy. The efficacy, toxicity, and mo...