Nanoarchitectonics and Simulation on the Molecular-Level Interactions between p-Sulfonic Acid Calix[4]arene and Langmuir Monolayers Representing Healthy and Cancerous Cell Membranes

Sep 21, 2026

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Chemotherapeutic drug carriers require detailed knowledge of how they interact with the plasma membrane so they can be internalized without disrupting membrane integrity. This study uses Langmuir monolayers modeling the outer leaflet of healthy and cancerous cells to examine interactions with p-sulfonic acid calix[4]arene (SCX4) as a potential carrier. SCX4 expands surface pressure isotherms, reduces compressional moduli, and alters morphology, with spectroscopy and simulations showing preferential binding to cancer lipid headgroups via electrostatics, while in healthy models SCX4 binds mainly to cholesterol. Multidimensional comparisons indicate composition-dependent effects without cancer selectivity, supporting biocompatibility and non-compromised membrane integrity.

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ABSTRACT

INTRODUCTION

Calixarenes and p-sulfonatocalix[n]arenes in drug delivery

This article is licensed under CC-BY 4.0 [pubs.acs.org/Langmuir](pubs.acs.org/Langmuir) Article Nanoarchitectonics and Simulation on the Molecular-Level Interactions between p-Sulfonic Acid Calix[4]arene and Langmuir Monolayers Representing Healthy and Cancerous Cell Membranes Ellen C. Wrobel, * Lucas Stori de Lara, ngelo de Fátima, and Osvaldo N. Oliveira, Jr. * Cite This: Langmuir 2024, 40, 27010−27027 Read Online | | | | | | | | --- | --- | --- | --- | --- | --- | | ACCESS | Metrics & More | | Article Recommendations | | *sı Supporting Information | ABSTRACT: The design of chemotherapeutic drug carriers requires precise information on their interaction with the plasma membrane since the carriers should be internalized by cells without disrupting or compromising the overall integrity of the membrane. In this study, we employ Langmuir monolayers mimicking the outer leaflet of plasma membranes of healthy and cancerous cells to determine the molecular-level interactions with a water-soluble calixarene derivative, p-sulfonic acid calix[4]arene (SCX4), which is promising as drug carrier. The cancer membrane models comprised either 40% 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 30% cholesterol (Chol), 20% 1,2-dipalmitoyl-snglycero-3-phosphoethanolamine (DPPE), and 10% 1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine (DPPS). The healthy membrane models were composed of 60% DPPC or DOPC, 30% Chol, and 10% DPPE. SCX4 expanded the surface pressure isotherms and decreased compressional moduli in all membrane models, altering their morphologies as seen in Brewster angle microscopy images. A combination of polarization-modulated infrared reflection absorption spectroscopy and molecular dynamics simulations revealed that SCX4 interacts preferentially with lipid headgroups in cancer membrane models through electrostatic interactions with the amine groups of DPPS and DPPE. In healthy membrane models, SCX4 interacts mostly with cholesterol through van der Waals forces. Using a multidimensional projection technique to compare data from the distinct membrane models, we observed that SCX4 effects depend on membrane composition with no preference for cancer or healthy membrane models, which is consistent with its biocompatibility. Furthermore, the interactions and close location of SCX4 to the headgroups indicate that it does not compromise membrane integrity, confirming that SCX4 may be a suitable drug carrier. ■ INTRODUCTION Calixarenes are oligomers synthesized through condensation of para-substituted phenols with formaldehyde in the presence of strong acid or alkaline catalysts. 1−3 These molecules are shaped like truncated cones with phenolic units linked by methyl bridges at the ortho position to the hydroxyl group. As representers of the third generation of supramolecular chemistry,3,4 calixarenes may have steric flexibility, hydrophobic cavities of variable sizes, biocompatibility, inertness, and nontoxicity.5 The water-soluble p-sulfonatocalix[n]arenes are notable for their thermal and chemical stability, high solubility in aqueous media, biocompatibility, nontoxicity, and lack of hemolytic activity. These features make them suitable for drug delivery vehicles,6 as inclusion complexes,7 micelles,8 hydrogels,9 liposomes, 10 and vesicles.5, 11, 12 Calixarenes have been used for anticancer drug delivery with chemotherapeutic agents such as doxorubicin, 13, 14 Temozolomide,7, 15 curcumin,16, 17 paclitaxel, 18 and camptothecin.19 Using calixarenes | Received: | October 7, 2024 | | | --- | --- | --- | | Revised: | November 27, 2024 | | | Accepted: | December 3, 2024 | | | Published: | December 12, 2024 | | © 2024 The Authors. Published by American Chemical Society 27010 [https://doi.org/10.1021/acs.langmuir.4c03948](https://doi.org/10.1021/acs.langmuir.4c03948) Langmuir 2024, 40, 27010−27027 Figure 1. (a) Molecular structures for thep-s

FAQs

Why is membrane interaction information important for chemotherapeutic drug carriers?

Carriers must be internalized without compromising the overall integrity of the plasma membrane. Preserving membrane integrity helps maintain cellular function and mitigates unwanted cytotoxicity.

How were healthy and cancerous cell membranes modeled in the study?

The work uses Langmuir monolayers mimicking the outer leaflet composition. Cancer models include DPPC or DOPC with cholesterol, DPPE, and DPPS, while healthy models contain DPPC or DOPC, cholesterol, and DPPE.

What interactions does SCX4 show in cancer versus healthy membrane models?

SCX4 preferentially interacts with lipid headgroups in cancer models through electrostatic interactions with amine groups of DPPS and DPPE. In healthy models, SCX4 interacts mostly with cholesterol via van der Waals forces.

Sep 21, 2026

Uploaded by Theodora