Nearly 50,000 new cases of glioblastoma (GBM) are diagnosed in the United States each year, with a dismal median survival of 14.6 months. Currently available therapeutics are largely ineffective due to the genetic, epigenetic, and signaling heterogeneity within the GBM tumor. Non-coding small RNAs such as short interfering RNA and micro-RNA are emerging as potent epigenetic regulators of cell fate and oncogenesis, and represent a promising tailored therapeutic strategy to counter tumor cell heterogeneity. However, clinical translation of small RNAs has been limited by significant knowledge gaps regarding their safe and effective delivery to GBM cells. The overall objective of this study is to use high-throughput screening approaches to optimize poly(beta-amino ester) (PBAE) polymeric nanoparticles for therapeutic small RNA delivery to treat GBM. Our preliminary data have shown that 1st generation PBAE materials enabled small RNA delivery to inhibit GBM proliferative phenotype in vitro and significantly slowed GBM tumor growth in GBM xenografts in vivo. However, these nanoparticles need to be optimized in delivery efficiency, biomaterial-mediated tumor targeting, long-term nanoparticle colloidal stability, and permeation throughout the tumor bulk to further their clinical translatability. To develop optimized 2nd generation PBAE nanoparticle formulations, the proposed work will utilize novel high-throughput approaches to generate polymer structural diversity and screen hundreds of unique polymer structures in parallel to identify delivery materials of improved potency and cancer targeting.
In Aim 1, innovative in vitro assays examining nanoparticle performance in overcoming critical intracellular delivery barriers such as nanoparticle uptake and endosomal escape will be performed in primary patient- derived GBM cell models to better predict nanoparticle performance in vivo. Furthermore, these assays will yield important structure-functional relationships on how biomaterial structures can be altered to control their interactions with cells in a cancer-selective manner.
In Aim 2, nanoparticle surface engineering techniques will be employed to enhance nanoparticle stability and tumor penetration capabilities. Orthotopic GBM tumor bearing mice will be treated with optimized nanoparticle formulations to characterize nanoparticle diffusion throughout the tumor bulk. This is critical in achieving uniform nanoparticle delivery as well as in reaching infiltrative GBM cells at the tumor periphery, which are primarily responsible for tumor recurrence after treatment. Finally, in Aim 3, nanoparticles carrying two GBM-inhibiting micro-RNAs will be evaluated for their ability to reduce GBM proliferation and self-renewal. State of the art primary human GBM cell models will be used to assess nanoparticle-induced phenotypic changes in vitro, and nanoparticles will also be infused into tumor-bearing mice to assess therapeutic delivery in the 3D tumor environment in vivo. These findings will have substantial positive impact on developing a scalable, bio-degradable small RNA delivery system to treat brain cancer.
Small non-coding RNAs have emerged as a promising, tailored therapeutic strategy to treat glioblastoma (GBM). However, their clinical application is limited by the lack of safe, effective, and tumor-targeted small RNA delivery technologies. This project will utilize high-throughput screening methods to identify bio- degradable polymeric nanoparticles with potent and tumor-targeted small RNA delivery efficiency to inhibit GBM proliferation and self-renewal.
