Despite immense resources dedicated to its treatment, cancer remains one of the most common causes of death worldwide. A key problem with chemotherapy, the most common form of treatment, is that it does not discriminate between normal and cancerous cells, causing serious side effects. A promising strategy to overcome this issue is to utilize a synthetic material that can activate a chemotherapy pre-drug at the site of the tumor—in this way, the drug will remain inactive until it reaches the desired site in the body and result in fewer side effects. What kind of material could achieve this function? We take inspiration from enzymes, which are specialized proteins that act as highly active and selective catalysts in cells. A key contributor to their performance is the precise folding of polypeptide chains around the enzyme’s active site. Possible conformations of the polypeptide chains are fundamentally determined by the primary structure of the polypeptide, the sequence of amino acids. In our research, we are interested in exploiting amphiphilic polymers with pendant “sticky” hydrogen bonding moieties and catalytic centers for targeted drug delivery therapies. When these polymers are dissolved in dilute aqueous solutions, individual chains fold to form single chain polymer nanoparticles (SCPNs), resembling “synthetic enzymes.” However, in contrast to the well-defined structure of natural enzymes, current SCPNs exhibit open, elliptical structures. We proposed that this lack of high-order structure is due to current SCPNs having random sequences and theorized that the activity of SCPNs could be enhanced by optimizing the sequence.
The primary objective of this project was to develop new fundamental chemistry to control the high order structure of SCPNs. We sought to design SCPNs with reversible connections so that the sequence could be “shuffled” in conjunction with the dynamic aggregation of the “sticky” pendant units to “molecularly evolve” the SCPN primary structure. This strategy allows for individual SCPNs to thermodynamically optimize their structure to achieve a lower energy state, leading to a better defined core for performing catalytic reactions. We have developed new chemistry that allows us to “shuffle” the sequences of SCPNs and track the changes of this process by nuclear magnetic resonance spectroscopy. Additionally, in response to challenges in achieving later project milestones, we pursued an alternative line of research to improve SCPN folding. We investigated “stickier” aggregation units, envisioning that they could be used to more efficiently fold SCPNs, and discovered a new class of “stickier” units that form one-dimensional stacks. Remarkably, these stacks change their helicity as a function of temperature, and we ultimately discovered that these transitions are caused by water molecules binding to the stacks. A manuscript that describes these discoveries was recently accepted for publication in Nature and give researchers better insight into fundamentals of hydrophobic effects. We believe that this technology will be key in developing SCPNs with better folding and temperature responsiveness.
