Poster Presentation 30th Lorne Cancer Conference 2018

Using cucurbiturils to deliver chemotherapeutics to metastases via the EPR effect (#214)

Ruqaya Maliki 1 2 , Shyam K Konda 3 , Alex Spurling 1 , Sean McGrath 1 , Alison Cheong 1 , Tina Robinson 1 , Belinda S Parker 1 , Peter Lock 1 , Paul J Pigram 2 , J Grant Collins 3 , Suzanne M Cutts 1
  1. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Sciences, La Trobe University, Melbourne, VIC 3086, Australia
  2. Centre for Materials and Surface Science & Department of Physics and Chemistry, La Trobe University, Melbourne, VIC 3086, Australia
  3. School of Physical, Environmental and Mathematical Sciences, University of New South Wales, Australian Defence Force Academy, Canberra, ACT 2600, AUS

Metastasis is the leading cause of death in cancer patients. Triple negative breast cancer (TNBC) is a highly metastatic breast cancer that has a poor survival rate. Chemotherapy is a major treatment modality for TNBC as it lacks receptors for targeted treatments. While chemotherapies such as doxorubicin and mitoxantrone have found clinical success in the treatment of breast cancer, patients with recurring cancers often cannot be treated as they are at risk of cardiovascular complications after receiving a cumulative dose of 450 mg/m2 of doxorubicin or 250 mg/m2 mitoxantrone. Recent studies have shown that targeting chemotherapies directly to the tumour sites can reduce the risk of dose-dependent toxicities. One such targeting mechanism involves the encapsulation of the chemotherapy agents in a nanoparticle (NP) vehicle to indirectly target tumour sites through the enhanced permeability and retention (EPR) effect, where NPs are thought to leak into the tumour microenvironment through fenestrations in the surrounding veins. We have shown previously that encapsulating mitoxantrone in cucurbit[8]uril (mito-Q[8]), a novel NP, protects from toxicity in vivo, and increases survival rate in mice with a highly metastatic breast cancer in a primary treatment setting.1 Following the success of this study, we examined the efficacy of mito-Q[8] in a neoadjuvant treatment setting to determine the targeting effects of the NP to metastases. Through luminescent imaging, real-time PCR and immunohistochemistry experiments it was found that mito-Q[8] offered no benefit over mitoxantrone in targeting the sites of metastases. This signifies that the mechanism of NP uptake may vary at different tumour sites, likely due to the variant structure of angiogenic vessels on newly-developed metastases vs the primary tumour. To examine this theory, we are working on a novel Time-of-Flight Secondary Ion Mass Spectrometry technique to localise the NPs in both the primary tumour and metastases. Overall, our current findings suggest a combinatorial treatment of varying NP sizes may be required to target tumours at their different developmental stages.

  1. [1] - S.K. Konda, R. Maliki, S. McGrath, B.S. Parker, T. Robinson, A. Spurling, A. Cheong, P. Lock, P.J. Pigram, D.R. Phillips, L. Wallace, A.I. Day, J.G. Collins and S.M. Cutts, “Encapsulation of Mitoxantrone within Cucurbit[8]uril Decreases Toxicity and Enhances Survival in a Mouse Model of Cancer.“, ACS Med. Chem. Lett., vol. 8, no. 5, pp. 538-542, 2017.