Nanoparticle treatment of glioblastoma

Glioblastoma is a devastating malignant primary brain tumor with poor survival despite availability of aggressive treatments. These therapies ultimately fail for most patients because of the highly resistant infiltrative nature of glioblastoma, wide intratumoral heterogeneity and complex suppressive microenvironment. An important factor contributing to recurrence of glioblastoma is high chemoradioresistance of intrinsic cancer stem cells. Therefore, the Veronesi Lab sees a critical need to develop novel drug therapies that specifically target and eliminate the glioblastoma cancer stem cell population. Paramount to both targeting of therapeutics to the cancer and site-specific delivery of multiple drugs that reduce off-site side effects using smarter drug delivery systems. Nanoparticles (NPs) represent an important emerging technology that can serve all of these functions. Polymeric NPs are made of organic materials that can become multifunctional because of further conjugation after NPs formation. Micelle NPs are amphiphilic surfactant molecules that spontaneously aggregate into spherical NPs. Hybrid polymer-micellar NPs combine many of the advantages of individual polymer NPs or micelle NPs while potentially avoiding some of their respective disadvantages. For instance, the polymer component provides structural stability while the micelle component allows decreased size. NPs can be surface tagged following addition of functional chemical groups with a radiotracer for in vivo biodistribution studies. The same  can also simultaneously allow tagging of a targeting molecule such as an antibody or aptamer that selectively binds to antigens on the tumor surface. NP development spans the bench to bedside by studying a well-designed process for characterizing their absorption, distribution, metabolism and excretion (ADMET) in vitro and in vivo. 
  • Publications

    Veronesi MC, Zamora M, Bhuiyan M, Obrien-Penney B, Chen CT, Vannier MW. Use of a clinical PET/CT scanner for whole body biodistribution of intranasal nanoparticles. Apr 2017. arXiv:1704.00691.

    Smiley SB, Targetable multi-drug therapies for treatment of glioblastoma with neuroimaging assessment. Master’s thesis dissertation, Indiana University, 2020. https://scholarworks.iupui.edu/bitstream/handle/1805/22683/Shelby%20Smiley%20Masters%20Thesis%20.pdf?sequence=1

    Smiley SB, Yun Y, Ayyagari P, Shannon HE, Pollok KE, Vannier MW, Das SK, Veronesi MC. Development of CD133 Targeting Multi-Drug Polymer Micellar Nanoparticles for Glioblastoma - In Vitro Evaluation in Glioblastoma Stem Cells. Pharm Res. 2021 Jun;38(6):1067-1079. PMID: 34100216.

The making of a biodegradable polymer nanoparticle

The drug agent is encapsulated in the inner core during nanoparticle (NP) polymerization (1). An MRI agent such as gadolinium or iron oxide can also be encapsualted in the shell during polymerization for MRI visualization (2). Polyethylene glycol can then be added to the outer surface of the NP for increased hydrophilicity and stealth immune evasion (3). In the next step, a radionuclide (4) or fluorescence molecule (5) can be covalently tagged to functional groups on the surface of the NP for in vivo imaging imaging detection. Finally, the surface can be covalently bonded with targeting agents such as receptor ligands, antibodies or aptamers (6).