posted on 2024-04-23, 15:08authored byLina Zhao, Yanjiao Wang, Yi Zhang, Hao Chen, Fude Sun
The lipid raft subdomains in cancer cell membranes play
a key role
in signal transduction, biomolecule recruitment, and drug transmembrane
transport. Augmented membrane rigidity due to the formation of a lipid
raft is unfavorable for the entry of drugs, a limiting factor in clinical
oncology. The short-chain ceramide (CER) has been reported to promote
drug entry into membranes and disrupt lipid raft formation, but the
underlying mechanism is not well understood. We recently explored
the carrier-membrane fusion dynamics of PEG-DPPE micelles in delivering
doxorubicin (DOX). Based on the phase-segregated membrane model composed
of DPPC/DIPC/CHOL/GM1/PIP2, we aim to explore the dynamic mechanism
of the PEG-DPPE micelle-encapsulating DOXs in association with the
raft-included cell membrane modulated by C8 acyl tail CERs. The results
show that the lipid raft remains integrated and DOX-resistant subjected
to free DOXs and the micelle-encapsulating ones. Addition of CERs
disorganizes the lipid raft by pushing CHOL aside from DPPC. It subsequently
allows for a good permeability for PEG-DPPE micelle-encapsulated DOXs,
which penetrate deeper as CER concentration increases. GM1 is significant
in guiding drugs’ redistributing between bilayer phases, and
the anionic PIP2 further helps DOXs attain the inner bilayer surface.
These results elaborate on the perturbing effect of CERs on lipid
raft stability, which provides a new comprehensive approach for further
design of drug delivery systems.