Cytotoxic drugs (i.e. molecules that damage and kill cells) are therapeutic agents with a long history in clinical application. These compounds cause structural damage to cell membranes, being useful as antitumoral and antimicrobial agents due to their tumor-lytic and antimicrobial effects, respectively. However, cytotoxic agents are generally unspecific in action, and they can cause severe toxicity to patients due to indiscriminate killing of host cells. Thus, to unlock the full therapeutic potential of cytotoxic drugs, strategies to control and direct their activity are needed.
Nanomaterials have been widely explored as carriers for the targeted delivery of cytotoxic agents. Capitalising on certain pathological markers, these nanovehicles can release in situ the active cell-damaging molecules they carry, thus minimising off-target interactions and preventing toxicity to the host. Despite decades of development, poor reproducibility in nanomaterial formulation and activity still hampers their widespread application in clinic. Alternatives to these nanocarriers are required as innovative mechanisms to control the selectivity of cytotoxic drugs.
This project aims to tune the cytotoxic effects of a model drug in response to acidic microenvironments, which are characteristic of certain pathologies like cancer and infection. In this design, a cytotoxic peptide has been chemically modified to mask the chemical groups responsible for its membrane-lytic effects. At acidic pH, the masking groups are removed, causing the peptide to aggregate into polyion complexes -PIC for short- and thus accumulate at acidic environments. Thus, PIC peptide aggregates surrounding the tumour or bacteria niches are activated and can exert their toxic effects locally without indiscriminate damage to healthy host tissues buffered at neutral pH.
The innovative aspect of this project is the activation mechanism of the cytotoxic drug, which occurs at a molecular level, not requiring of any nanocarrier to adapt its activity. Addressing this serious healthcare challenge is key to society’s welfare and global economy. The development of new advanced strategies to tackle infection and cancer is critical to address the associated biomedical and economic burden. The concepts developed during this project will resonate across other biomedical fields, making our discoveries translatable to other conditions and target cells based on their modular design, tailoring molecular structure and pH-responsive masking for each application.
