<i>In Situ</i> Heparan Sulfate-Induced Peptide\nSelf-Assembly to Overcome the Cell Surface Glycocalyx Barrier for\nCancer Treatment

Heparan sulfate (HS) is a major component of cell surface\nglycocalyx\nwith extensive negative charges and plays a protective role by preventing\ntoxins, including small molecule drugs and anticancer cationic lytic\npeptides (ACLPs), from cells. However, this effect may compromise\nthe treatment efficiency of anticancer drugs. To overcome the impedance\nof cancer cell glycocalyx, an HS-targeting ACLP PTP-7z was designed\nby fusion of an ACLP and a Zn<sup>2+</sup>-binding HS-targeting peptide.\nUpon Zn<sup>2+</sup> ion binding, PTP-7z could self-assemble into\nuniform nanoparticles and show improved serum stability and reduced\nhemolysis, which enable it to self-deliver to tumor sites. The peptide\nPTP-7z showed a pH- and Zn<sup>2+</sup> ion-dependent HS-binding ability,\nwhich triggers the HS-induced <i>in situ</i> self-assembling\non the cancer cell surface in the acidic tumor microenvironment (TME).\nThe self-assembled PTP-7z can overcome the impedance of cell glycocalyx\nby either disrupting cell membranes or translocating into cells through\nendocytosis and inducing cell apoptosis. Moreover, PTP-7z can also\ninhibit cancer cell migration. These results proved that HS-responsive <i>in situ</i> self-assembling is a practical strategy to overcome\nthe cancer cell glycocalyx barrier for ACLPs and could be extended\nto the design of other peptide drugs to promote their <i>in vivo</i> application.