Nanoarchitectonics\nand Simulation on the Molecular-Level\nInteractions between <i>p-</i>Sulfonic Acid Calix[4]arene\nand Langmuir Monolayers Representing Healthy and Cancerous Cell Membranes

The design of chemotherapeutic drug carriers requires\nprecise information\non their interaction with the plasma membrane since the carriers should\nbe internalized by cells without disrupting or compromising the overall\nintegrity of the membrane. In this study, we employ Langmuir monolayers\nmimicking the outer leaflet of plasma membranes of healthy and cancerous\ncells to determine the molecular-level interactions with a water-soluble\ncalixarene derivative, <i>p</i>-sulfonic acid calix[4]arene\n(SCX4), which is promising as drug carrier. The cancer membrane models\ncomprised either 40% 1,2-dipalmitoyl-<i>sn</i>-glycero-3-phosphocholine\n(DPPC) or 1,2-dioleoyl-<i>sn</i>-glycero-3-phosphocholine\n(DOPC), 30% cholesterol (Chol), 20% 1,2-dipalmitoyl-<i>sn</i>-glycero-3-phosphoethanolamine (DPPE), and 10% 1,2-dipalmitoyl-<i>sn</i>-glycero-3-phospho-l-serine (DPPS). The healthy\nmembrane models were composed of 60% DPPC or DOPC, 30% Chol, and 10%\nDPPE. SCX4 expanded the surface pressure isotherms and decreased compressional\nmoduli in all membrane models, altering their morphologies as seen\nin Brewster angle microscopy images. A combination of polarization-modulated\ninfrared reflection absorption spectroscopy and molecular dynamics\nsimulations revealed that SCX4 interacts preferentially with lipid\nheadgroups in cancer membrane models through electrostatic interactions\nwith the amine groups of DPPS and DPPE. In healthy membrane models,\nSCX4 interacts mostly with cholesterol through van der Waals forces.\nUsing a multidimensional projection technique to compare data from\nthe distinct membrane models, we observed that SCX4 effects depend\non membrane composition with no preference for cancer or healthy membrane\nmodels, which is consistent with its biocompatibility. Furthermore,\nthe interactions and close location of SCX4 to the headgroups indicate\nthat it does not compromise membrane integrity, confirming that SCX4\nmay be a suitable drug carrier.