Development and Validation of a Targeted Treatment for Brain Tumours Using a Multi-drug Loaded, Relapse-Resistant Polymeric Theranostic

Weijing Chu, Zachary H Houston, Nicholas L Fletcher, Pie Huda, Muneer Ahamed, Ting Xiang Lim, Bryan W. Day, Mark Pinkham, Kristofer J. Thurecht

Research output: Contribution to journalArticlepeer-review

Abstract

This study aimed to develop a multifunctional polymer platform that could address the issue of treatment resistance when using conventional chemotherapeutics to treat glioblastoma (GBM). An antibody-conjugated, multi-drug loaded hyperbranched polymer was developed that provided a platform to evaluate the role of targeted nanomedicine treatments in overcoming resistant glioblastoma (GBM) by addressing the various complications with current clinically-administered formulations. The polymer was synthesized via reversible addition fragmentation chain transfer
polymerisation and included the clinical first-line alkylating agent temozolomide (TMZ) which was incorporated as a polymerisable monomer, poly (ethylene glycol) (PEG) units to impart biocompatibility and enable conjugation with αPEG-αEphA2 bispecific antibody (αEphA2 BsAb) for tumour targeting, and hydrazide moieties for attachment of a secondary drug which allows exploration of synergistic therapies. To overcome resistance to TMZ, the O6 alkylguanine DNA
alkyltransferase (AGT, DNA repair protein) inhibitor, dialdehyde O6 benzylguanine (DABG) was subsequently conjugated to the polymer via an acid labile hydrazone linker to facilitate controlled release under conditions encountered within the tumour microenvironment. The prolonged
degradation half-life (4-5 h) of the polymer conjugated TMZ in vitro, offered a potential avenue to overcome the inability to deliver these drugs in combination at therapeutic doses. Although only 20% of DABG could be released within the studied timeframe (192 h) under conditions mimicking the acidic nature of the tumour environment, cytotoxicity evaluation using cell assays confirmed
the improved therapeutic efficacy towards resistant GBM cells after attaching DABG to the
polymer delivery vehicle. Of note, when the polymeric delivery vehicle was specifically targeted to receptors (Ephrin A2) on the surface of the GBM cells using our in-house developed EphA2 specific BsAb, the dual-drug loaded polymer exhibited an improved therapeutic effect on TMZ Biomacromolecules resistant cells compared to the free drug combination. Both in vitro and in vivo targeting studies showed high uptake of the construct to GBM tumours with upregulated EphA2 receptor (T98G and U251) compared to a tumour that had low expression (U87MG), where a dual tumour xenograft model was used to demonstrate the enhanced accumulation in tumour tissue in vivo. Despite the synthetic challenges of developing systems to effectively deliver controlled doses of TMZ and DABG, these studies highlight the potential benefit of this formulation for delivering
multi-drug combinations to resistant GBM tumour cells and offer a platform for future
optimization in therapeutic studies.
Original languageEnglish
Number of pages52
JournalBiomacromolecules
DOIs
Publication statusPublished or Issued - 4 May 2023

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