Smart targeting nano-theranostics for image-guided drug delivery to pediatric brain tumors Project Summary/Abstract Pediatric brain tumors (PBTs) are the leading cause of cancer-related morbidity and mortality among children. For an improved prognosis in PBT patients, there is a critical need to develop treatment that is efficacious, avoids damage to the developing brain, and crosses the blood brain tumor barrier (BBTB). There is an also unmet need in the development of molecularly-specific imaging agents to monitor the drug distribution, tumor progression and response to treatment. The goal of this project is to develop a robust set of novel BBTB- crossing and on-demand-releasing nano-theranostics (named BONs) for image-guided drug delivery to improve the efficacy and minimize the toxicity of PBT therapies. BONs integrate unique stimuli-responsive crosslinking strategies and highly potent integrin targeting ligands (LXY30 and LXW7) into a novel multifunctional nanoporphyrin platform. The goal of Aim 1 is to synthesize a series of stimuli-responsive crosslinked BONs that can be activated by the intrinsic stimuli at the tumor microenvironment (e.g. acidic pH) to release drugs, and amplify fluorescence signal and magnetic resonance imaging (MRI) contrast. In order to enhance their capability to cross the BBTB and penetrate tumor tissue, the particle size of BONs will be varied from 8 to 71 nm while the surface of BONs will be decorated with LXY30 and/or LXW7 ligands.
In Aim 2, the spatiotemporal distribution, intratumoral delivery and drug release of BONs, will be quantitatively investigated by optical imaging and MRI in orthotopic PBT xenografts. We will also determine the best particle size and ligand for BONs to efficiently traverse BBTB and penetrate deeply in tumor tissue. The imaging results will be validated by inductively coupled plasma mass spectrometry (ICP-MS) for quantitative nanoparticle distribution in tissues, bioluminescence imaging (BLI) for quantitative tumor burden, frster resonance energy transfer (FRET) for drug release, immunohistochemistry (IHC) for integrin level and cryo- electron microscopy (Cryo- EM) for the physiologic pore size of the BBTB and the fenestration and endothelial gap size of tumors.
In Aim 3, orthotopic PBT xenografts and patient derived xenografts (PDXs) will be treated with BONs that are co-loaded with a synergistic therapeutic doublet (vincristine, a proven drug for PBTs, and ganetespib, a new heat shock protein 90 inhibitor). Tumor regression associated with response to therapy will be non-invasively monitored and quantified by molecular imaging, and correlated with real tumor burden and histology results. Successful development of the proposed theranostic nano-platform will significantly enhance the drug delivery to PBTs while sparing developing brain and other normal organs of children. It will also greatly improve the imaging sensitivity for non-invasively monitoring the therapeutic delivery process, tumor progression and response to therapy. Results from this study will be significant not only in advancing the development of a more efficacious and less toxic theranostic nano-platform against PBTs, but also in providing a new framework of using BBTB- crossing and on-demand-releasing theranostics for image-guided drug delivery in brain tumors.
The proposed novel theranostic agents are expected to improve the care of pediatric patients with brain tumors through: (i) effective treatment with minimal side effects; (ii) effectively overcoming the BBTB for the delivery of drugs to brain tumors; (iii) non-invasively monitoring tumor progression and drug distribution; and (iv) real-time evaluation of the treatment outcomes. As a result, we expect many pediatric patients with brain tumors will benefit from such novel imaging-guided therapeutic approach. This project will lead to lower morbidity and mortality among pediatric patients with brain tumors and will have a tremendous impact on quality of life of these patients.
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