Addressing Drug Resistance in Cancer with Macromolecular Chemotherapeutic Agents

Drug resistance to
chemotherapeutics is a recurrent issue plaguing
many cancer treatment regimens. To circumvent resistance issues, we
have designed a new class of macromolecules as self-contained chemotherapeutic
agents. The macromolecular chemotherapeutic agents readily self-assemble
into well-defined nanoparticles and show excellent activity in vitro against multiple cancer cell lines. These cationic
polymers function by selectively binding and lysing cancer cell membranes.
As a consequence of this mechanism, they exhibit significant potency
against drug-resistant cancer cells and cancer stem cells, prevent
cancer cell migration, and do not induce resistance onset following
multiple treatment passages. Concurrent experiments with the small-molecule
chemotherapeutic, doxorubicin, show aggressive resistance onset in
cancer cells, a lack of efficacy against drug-resistant cancer cell
lines, and a failure to prevent cancer cell migration. Additionally,
the polymers showed anticancer efficacy in a hepatocellular carcinoma
patient derived xenograft mouse model. Overall, these results demonstrate
a new approach to designing anticancer therapeutics utilizing macromolecular
compounds.