Targeting phosphatidylserine in tumor cell membranes with a zinc-containing molecule to efficiently combat tumor metastasis

Metal drugs, such as platinum drugs, are widely used in tumor treatment. However, most traditional tumor treatments face the risk of failure due to the ineffective control over drug resistance and tumor metastasis. Targeting the cell membrane and disrupting its function to combat drug resistance and metastasis is a promising strategy. Nevertheless, membranolytic drugs always cause significant cytotoxicity. In this study, we developed a zinc-containing molecule to selectively kill tumor cells by targeting phosphatidylserine in the tumor cell membrane, which is commonly distributed in the outer cell membrane of tumor cells. Herein, a structurally optimized amphiphilic zinc-containing molecule, 2aZn, was developed by screening the appropriate hydrophobic tail and linker. This functional molecule can disrupt the tumor cell membrane to kill various types of tumor cells with minimal damage to normal tissue. After repeated stimulation, no obvious drug resistance was observed. Importantly, 2aZn could successfully combat tumor metastasis by destroying the cell membrane and reducing the capacity of cells to invade. As a result, zinc-containing molecules have the potential to overcome drug resistance and tumor metastasis in the treatment of tumors, providing a new perspective for the design of effective antitumour medications.