ORCID ID
Graduation Date
Spring 5-9-2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Immunology, Pathology & Infectious Disease
First Advisor
Svetlana G. Romanova
Abstract
This dissertation presents two complementary investigations: (1) androgen receptor (AR)-directed therapy in glioblastoma (GBM) and (2) therapeutic and nanoparticle-based strategies for cisplatin-induced acute kidney injury (AKI).
The first study identifies AR as a therapeutically actionable target in GBM. Multi-platform analyses revealed elevated AR expression across transcriptional subtypes that correlated with AR protein abundance. Pharmacologic evaluation demonstrated that enzalutamide exhibited stronger tumor-suppressive activity in GBM cell lines (U87MG, U138MG) and primary patient-derived cultures than bicalutamide, evidenced by reduced viability, increased apoptosis, altered cell-cycle distribution, and suppressed clonogenic growth. These effects were more pronounced in glioma models than in non-malignant central nervous system (CNS) comparators, indicating in vitro selectivity. Beyond conventional GBM agents, therapies with non-overlapping mechanisms remain of interest. In this context, cinobufagin, a bufadienolide cardiac glycoside, exhibited marked antiglioma activity with concentration- and time-dependent cytotoxicity. In orthotopic models, bicalutamide and cinobufagin demonstrated in vivo antitumor efficacy, with cinobufagin providing a dose-dependent survival benefit.
The second study focuses on cisplatin-induced AKI and evaluates both small-molecule nephroprotective candidates and nanoparticle delivery platforms. Specifically, the study examines suberoylanilide hydroxamic acid (SAHA; vorinostat), pifithrin-α, mitoquinone (MQ), and olaparib, along with lipid nanoparticles (LNPs) for nucleic acid delivery and dexamethasone-loaded, Cy5-labeled mesoporous silica nanoparticles (MSNs-Dex) for kidney-directed therapy. While small-molecule combinations (SAHA plus pifithrin-α and MQ plus olaparib) provided limited or transient protection in proximal tubule cell models, nanoparticle engineering enabled development of an LNP-based nucleic acid formulation and MSNs-Dex for kidney-directed delivery. The LNP platform enabled GFP mRNA delivery with detectable renal signal, benchmarking kidney-directed nucleic acid delivery. In parallel, MSNs-Dex showed preferential renal accumulation in injured kidneys, with sustained kidney-associated signal and limited off-target accumulation. Flow-cytometric analyses in HK-2 proximal tubule epithelial cells confirmed that MSNs-Dex preserved mitochondrial function, reduced injury-associated cellular stress, and improved cell viability. In vivo, MSNs-Dex administration preserved body weight trajectories relative to AKI plus saline controls and did not produce an additional hematologic burden. Overall, this dissertation establishes AR as a viable therapeutic target for GBM, identifies LNPs as a benchmark platform for kidney-directed nucleic acid delivery, and supports MSNs-Dex as a promising kidney-directed platform for nephroprotection.
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Recommended Citation
Das, Ashish, "Therapeutic Strategies in Glioblastoma and Acute Kidney Injury: Androgen Receptor-Directed Therapy for High-Grade Glioma and Nanoparticle-Based Therapeutic Strategies for Cisplatin-Induced Nephrotoxicity" (2026). Theses & Dissertations. 1041.
https://digitalcommons.unmc.edu/etd/1041
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