Supramolecular self-associating amphiphiles (SSAs) as novel enhancers of cancer treatment

Drug resistance is a significant barrier in cancer treatment, leading to relapse and poor patient outcomes despite initial therapeutic success. In ovarian cancer, resistance to first line platinum therapies such as cisplatin is a major clinical challenge. In bladder cancer, treatment efficacy of intravesically delivered mitomycin C is often limited by poor cellular uptake and drug resistance. Hence, there is a need for novel treatment strategies to overcome drug resistance and improve treatment outcomes.

Supramolecular self-associating amphiphiles (SSAs) are a new class of compounds developed by Prof Jennifer Hiscock and colleagues that are characterised by their self-assembly properties and ability to adopt numerous material forms through different hydrogen bonding modes. Initially investigated for antimicrobial activity, SSAs have also demonstrated potential to modulate drug activity in cancer cells. This thesis investigates the anion binding and recognition capabilities of a new generation of carboxylate SSAs and their potential as novel anticancer agents and adjuvants to existing chemotherapeutics in ovarian cancer, with a focus on overcoming drug resistance. This thesis also explores the activity of a panel of SSAs in bladder cancer to understand their potential to improve mitomycin C efficacy.

SSAs were evaluated as single agents and showed growth-inhibitory activity against the A2780 human ovarian cancer cell line, its cisplatin-resistant subline (A2780 CisR), the T24 human bladder cancer cell line, and a non-transformed control cell line (RPE-1). The inclusion of RPE-1 allowed assessment of selectivity, to compare growth inhibition across cancerous and non-cancerous cell lines. Combination studies revealed dose-dependent synergistic enhancement of cisplatin activity in ovarian cancer and enhancement of mitomycin C activity in bladder cancer, suggesting their potential to improve treatment efficacy. To understand the mechanisms underlying SSA biological activity, the phospholipid compositions of A2780 and A2780 CisR cell lines were analysed, revealing an enhancement of anionic phospholipids in the drug-resistant cell line. Mechanism of action studies showed enhanced DNA damage and apoptosis induction by SSAs alone and in combination with cisplatin in A2780 CisR cells.

In conclusion, this thesis provides novel insights into the potential application of SSAs as single agents and in combination with established chemotherapeutic agents in ovarian and bladder cancer. The findings demonstrate that SSAs have the potential to help overcome drug resistance, enhance chemotherapeutic efficacy, promote DNA damage and apoptosis in cancer cells and provide a promising new avenue for therapeutic development. Further studies investigating the mechanistic basis of SSA activity and their translational potential in clinically relevant models can enable the development of effective combination therapies to improve outcomes and overall survival of patients with drug-resistant cancers.