Polymer theranostics for recurrent brain tumours

This project is lead by:

Ms. Weijing Chu

Thesis Title: TBD

PhD Student – Thurecht Group, University of Queensland

Profile

Summary

As the most malignant of brain cancers, the median survival time of glioblastoma (GBM) patients is less than 15 months from the time of diagnosis. Glioblastoma cancer cells invade extensively into surrounding brain tissue and have a high rate of proliferation. Medical intervention includes surgery combined with chemo- (Temozolomide, TMZ) and radiotherapy. However, some patients show drug resistance to TMZ clinically because of the expression of DNA repair protein O6-alkylguanine DNA alkyltransferase (AGT), which can restore part of the gene adducts triggered by alkylation agent and induce tumour recurrence.1 As an AGT inhibitor, O6-Benzyl Guanine (O6-BG) has shown an improved therapeutic effect of alkylation drug on resistant glioma cell lines and tumour bearing animal model.2,3 However, in clinical trials the therapeutic effect of TMZ with O6-BG has not performed as well as expected, mainly due to the reduced dosage of the alkylation. The dosage down regulation was caused by severe side effects of this combination treatment due to off-target toxicity.4 Hence, an effective drug delivery system which can improve the targeted release of TMZ and O6-BG at the tumour site and maintain the dosage of TMZ in treatment could increase the therapeutic effect of this drug combination to TMZ-resistant patients.

The aim of this research is to generate an effective theranostic platform by using TMZ and O6-BG linked to hyperbranched polymeric (HBP) backbone together with bispecific antibodies (BsAbs) that increase tumour accumulation through targeting the tumour-associated antigen, EphA2. (Figure 1.) This hybrid platform will facilitate targeted drug delivery using a covalent bond used to link TMZ and acid sensitive bond for site-selective O6-BG release. Bispecific antibodies (PEG-EphA2) will also be utilised to increase the specific accumulation of drug in glioblastoma nidus, leading to increased therapeutic efficacy. In addition, the engineered system will include a dye (Cy5) and a radioisotope (89Zr), for convenient monitoring of the drug delivery system both in vitro and in vivo, forming a ‘theranostic’ platform for glioblastoma treatment.

People

This project is a PhD project for Weijing Chu, for which I am a co-supervisor. This project is a result from my initial work in preparing nanomaterials for the treatment of brain cancer. People other than Weijing and myself who are involved in the project are listed below with their roles and affiliations (see affiliations by superscript below).

  • Muneer Ahamed1,2,4 – Co-supervisor, organic and radiochemist
  • Kristofer J. Thurecht1,2,3,4 – Primary supervisor

Affiliations

  1. Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD 4072, Australia.
  2. Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia.
  3. ARC Centre of Excellence in Convergent BioNano Science and Technology, The University of Queensland, St Lucia, QLD 4072, Australia
  4. ARC Training Centre for Innovation in Biomedical Imaging Technology, The University of Queensland, St Lucia, QLD 4072, Australia