High grade gliomas (GBM) are the most aggressive primary tumors within the central nervous system. Patient prognosis remains poor even following surgery, chemotherapy and radiotherapy. GBMs almost always recur, causing the death of the patients. In addition, GBM stem cells are thought to initiate tumor recurrence, thus i is critical to examine response to experimental therapies in models which use GBM stem cells, both in vitro and in vivo. A main challenge in achieving therapeutic efficacy in brain tumor patients is the low brain permeability to chemotherapeutic drugs, due to the presence of the blood brain barrier. Ongoing research shows that nanoparticles (NPs) hold promise to meet the need for targeted therapeutics and combined therapeutic and imaging agents (theranostics) in solid tumors. However, few NPs have met regulatory approval for clinical translation. In this proposal, we aim to develop synthetic high density lipoprotein (sHDL) NPs to effectively deliver chemotherapeutic agents to GBM in preclinical models. sHDL are endocytosed by the cell surface receptor, scavenger receptor class B-1 (SR-B1); they present an innovative, potentially transformative approach to improve treatment of GBM. HDL is a naturally occurring NP which unlike many engineered NPs, naturally circulates for long periods of time (t1/2 ~ 3-4 days). HDL transports cholesterol and other materials, i.e., vitamin E, steroid hormones, signaling lipids, an micro RNAs, it also naturally binds paclitaxel and other hydrophobic drugs. Several synthetic ApoA-I peptide-based HDL particles, which are more economical and easier to produce at a large scale, have been administered safely to humans in Phase I/II studies. The experiments we propose will enable us to assess experimentally if sHDL NPs will target GBM in vitro and in vivo and if NP loaded with chemotherapeutic agents will induce GBM regression and long term survival of tumor bearing animals. In this respect, several GBM cell lines and human GBM stem cells express SR-B1; also we can incorporate near-infrared fluorescent dyes and chemotherapeutic drugs as payloads into sHDL, enabling molecular imaging of invasive GBM and targeted drug delivery. In addition, our preliminary data, using fluorescently labeled sHDL have further confirmed that they are specifically targeted to the tumor and are not distributed throughout the normal brain parenchyma. In summary, this proposal will test the hypothesis that HDL-NP loaded with chemotherapeutic drugs will elicit GBM regression. Our previous experience in the translation of basic science advances into early phase clinical trials for the treatment of GBM patients (FDA IND-14574) and HDL nanoparticles to Phase I/II clinical studies backs our assertion that, should the experiments support our hypothesis, we will translate such results into Phase I trials for GBM.

Public Health Relevance

High grade gliomas (GBMs) are highly invasive malignant brain tumors for which there is no cure; current standard of care include surgery, radiotherapy and chemotherapy. Due to the presence of the blood brain barrier (BBB), chemotherapeutic agents are not effective for GBM; thus using HDL NP loaded with chemotherapeutic drugs, we aim to deliver these BBB- impermeably anti-cancer agents to brain tumors, to elicit tumor regression and long term survival in experimental animal models. This therapeutic strategy has the potential to be further developed for the treatment of patients with GBM, and its implementation in early phase clinical trials.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Fountain, Jane W
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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