Headgroup-driven binding selectivity of alkylphospholipids to anionic lipid bilayers
Abebual Molla1, Tun Naw Sut1, Bo Kyeong Yoon2
1School of Chemical Engineering and Translational Nanobioscience Research Center, Sungkyunkwan University, Suwon 16419, Republic of Korea.
Colloids and Surfaces. B, Biointerfaces
|July 22, 2025
Summary
Alkylphospholipids (APLs) bind selectively to cancer cell membranes via headgroup chemistry. Miltefosine and edelfosine show strong binding due to flexible headgroups, unlike perifosine, informing drug design.
Area of Science:
- Biochemistry
- Materials Science
- Pharmacology
Background:
- Alkylphospholipids (APLs) are amphiphiles with anticancer properties and membrane-targeting capabilities.
- Engineered APLs have varied headgroup chemistries, but their impact on membrane interactions is not well understood.
Purpose of the Study:
- Investigate how three representative APLs (miltefosine, edelfosine, perifosine) interact with supported lipid bilayers (SLBs).
- Elucidate interaction principles based on headgroup sterics, chain length, binding strength, selectivity, and aggregation.
Main Methods:
- Utilized quartz crystal microbalance-dissipation (QCM-D) technique.
- Employed SLB platforms mimicking cancer cell membrane lipid compositions, particularly high phosphatidylserine (PS) content.
Main Results:
- Miltefosine (MIL) and edelfosine (EDE) showed strong binding to anionic PS-enriched membranes, suppressed by divalent cations.
- Perifosine (PER) exhibited weaker binding due to a sterically hindered headgroup.
- MIL and EDE binding is electrostatic-mediated, distinct from hydrophobic surfactant mechanisms.
Conclusions:
- APL headgroup chemistry, specifically conformational flexibility, is crucial for selective PS lipid binding and cancer cell targeting.
- Findings provide a molecular framework for rational APL design and colloidal delivery strategies.
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