ORCID ID
Graduation Date
Summer 8-14-2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Pharmaceutical Sciences
First Advisor
Ram Mahato
Second Advisor
Donald Coulter
Third Advisor
Jered Garrison
Fourth Advisor
Don Ronning
Abstract
This thesis aims to design a nanoparticle-based formulation decorated with a targeting peptide to deliver drugs along with radiation therapy and to study their pharmacokinetics. We evaluated in vitro and in vivo efficacy using xenograft and orthotopic mouse models. In Chapter 1, we describe medulloblastoma, different subgroups of medulloblastoma, and various strategies that are employed to overcome the BBB hurdle to deliver therapeutic cargo to the brain.
In Chapter 2, we addressed concerns regarding craniospinal irradiation (CSI) therapy. CSI has long been a cornerstone in the treatment of MB, especially for patients with high-risk or metastatic disease. However, it often leads to long-term neurocognitive deficits, including learning disabilities and growth abnormalities, especially in children. In this study, we aimed to decrease the dose of irradiation and the proliferation of MB by using volasertib (VSB), a Polo-like kinase 1 (PLK1)-specific inhibitor. We encapsulated VSB in lipid nanoparticles functionalized with COG133, an apolipoprotein E (ApoE)-mimetic peptide (COG133-LNPs), to improve drug delivery across the blood–brain barrier (BBB). We observed that COG133-LNPs loaded with VSB increased the brain biodistribution of VSB by three-fold compared with non-targeted LNPs. Furthermore, COG133-LNPs combined with irradiation significantly decreased tumor burden compared with VSB or radiation alone. Overall, COG133-LNPs displayed high potency in killing MB cells and sensitizing them to radiation therapy.
Chapter 3 covers the pharmacokinetics and biodistribution of JW475A, a dual MDM2/XIAP dual inhibitor and BRD4/PI3K dual inhibitor MDP5. In this study, we investigated the pharmacokinetics (PK) and biodistribution parameters of MDP5 and JW475A in preclinical mouse models. MDP5 and JW475A depicted short half-life, fast clearance, and high volume of distribution. Therefore, we encapsulated these drugs in m-PEG [113]-p-[Asp-BLA]-p-g[Asp-DA] polymer to improve their circulation time and total drug exposure in mice. Hence, we observed that these polymeric NPs depicted a higher Cmax and AUC. Further, we decorated these NPs with RVG peptide to improve the targeting to the brain. We observed that our RVG-targeted NPs showed higher brain biodistribution as compared to non-targeted and free drugs. Also, the drug accumulation was found to be more at the tumor site as compared to the normal site in the brain, showing that the nanocarriers can reduce the off-target effects of these drugs.
Finally, Chapter 4 summarizes the results of this thesis and gives suggestions for future research.
Rights
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Recommended Citation
Gupta, Aditya, "Targeted Nanomedicine Strategies for Enhanced Drug Delivery and Therapeutic Efficacy in Medulloblastoma" (2026). Theses & Dissertations. 1087.
https://digitalcommons.unmc.edu/etd/1087