# Targeted drug delivery system to overcome blood-brain barrier and therapeutic resistance to current standard of care in Glioblastoma

> **NIH CA R01** · WAYNE STATE UNIVERSITY · 2026 · $517,352

## Abstract

Project Summary/Abstract: The uniform lethality of glioblastoma (GBM) with a survival of less than 2
years despite best available therapy is attributed to treatment resistance due to DNA repair mechanisms that
drive disease relapse and tumor heterogeneity. One prognostic factor identified as a reliable biomarker for GBM
sensitivity to temozolomide (TMZ) and radiotherapy (RT) is the overexpression of O6-methylguanine-methyl-
transferase (MGMT) enzyme. Patients with active MGMT were found to receive little benefit from TMZ and RT
and represent a group of great unmet need with no treatment options that significantly improve survival. Recently,
several preclinical and clinical studies suggest that alcohol aversion drug, disulfiram (DSF), inhibited MGMT and
improved the efficacy of TMZ in GBM when combined with copper (Cu). However, phase II trial showed that
there was no survival benefit from oral Cu/DSF. Nevertheless, the major limitation of oral Cu/DSF has been
delivery of fragile DSF within the in vivo system.
 We have developed 2-hydroxypropyl beta cyclodextrin (HPßCD) encapsulating Cu complex of DSF metabolite,
diethyldithiocarbamic acid (DDC), Cu(DDC)2 delivery system that addresses major drawbacks of the Cu(DDC)2:
easy degradation in the blood and non-specific interactions with cells and serum proteins and lack of tissue
specific delivery. HPßCD providing stability of Cu(DDC)2 is identified. In vitro cell culture study revealed that
HPßCD-Cu(DDC)2 inhibited MGMT through the ubiquitin-proteasome pathway. Inhibition of MGMT activity in cell
cultures vastly increased the alkylation-induced DNA double-strand breaks, cytotoxicity, and the levels of
apoptotic markers like -H2AX, JNK-P and cleavage of PARP-1. Preliminary intravenous delivery of HPßCD-
Cu(DDC)2 in combination with TMZ in an MGMT-positive patient derived orthotopic xenograft (PDOX) model
demonstrated tumor size regression with prolonged survival. HPßCD-Cu(DDC)2 targets MGMT-145-cysteine
and its unique cy

## Key facts

- **NIH application ID:** 11360642
- **Project number:** 5R01CA269607-05
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Meser M. Ali
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $517,352
- **Award type:** 5
- **Project period:** 2023-04-01T00:00:00 → 2028-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11360642

## Citation

> US National Institutes of Health, RePORTER application 11360642, Targeted drug delivery system to overcome blood-brain barrier and therapeutic resistance to current standard of care in Glioblastoma (5R01CA269607-05). Retrieved via AI Analytics 2026-07-05 from https://api.ai-analytics.org/grant/nih/11360642. Licensed CC0.

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