Supramolecular self-associating amphiphiles (SSAs) as nanoscale enhancers of cisplatin anticancer activity.

Nova O Dora,Jessica E Boles,Edith Blackburn,George T Williams,Michelle D Garrett,Daniel P Mulvihill,Trevor Askwith,J Daniel Hothersall,Jack A Doolan,Lisa J White,Scarlett E G Turner,Jennifer R Hiscock

doi:10.1039/d1ra02281d

Abstract

Many chemotherapeutic drugs have a narrow therapeutic window due to inefficient tumour cell permeation. Supramolecular self-associating amphiphilic salts (SSAs) are a unique class of small molecules that offer potential as next generation cancer drugs and/or therapeutic enhancement agents. Herein, we demonstrate the cytotoxicity of seven SSAs towards both ovarian and glioblastoma cancer cells. We also utilize the intrinsic fluorescent properties of one of these lead SSAs to provide evidence for this class of compound to both bind to the exterior cancer cell surface and permeate the cell membrane, to become internalized. Furthermore, we demonstrate synergistic effects of two lead SSAs on cisplatin-mediated cytotoxicity of ovarian cancer cells and show that this correlates with increased DNA damage and apoptosis versus either agent alone. This work provides the first evidence that SSAs interact with and permeate cancer cell membranes and enhance the cytotoxic activity of a chemotherapeutic drug in human cancer cells.

Highlights

Cancer is a major global health problem; it is the second highest cause of death worldwide, resulting in almost 9.9 million deaths in 2020.1 Owing to the challenges inherent in designing diseased cell speci c treatments, many marketed drugs cause toxicity towards healthy cells.[2]
We demonstrate synergistic effects of two lead self-associating amphiphilic salts (SSAs) on cisplatin-mediated cytotoxicity of ovarian cancer cells and show that this correlates with increased DNA damage and apoptosis versus either agent alone
The development of agents to selectively enhance the efficacy of these cytotoxic chemotherapies and overcome cellular resistance mechanisms, lowering the effective doses of a chemotherapy to be administered is of the utmost importance

Summary

Introduction

Cancer is a major global health problem; it is the second highest cause of death worldwide, resulting in almost 9.9 million deaths in 2020.1 Owing to the challenges inherent in designing diseased cell speci c treatments, many marketed drugs cause toxicity towards healthy cells.[2]. Supramolecular self-associating amphiphiles (SSAs) as nanoscale enhancers of cisplatin anticancer activity† Supramolecular self-associating amphiphilic salts (SSAs) are a unique class of small molecules that offer potential as generation cancer drugs and/or therapeutic enhancement agents.

Results

Conclusion