1 research outputs found
Simvastatin Coadministration Modulates the Electrostatically Driven Incorporation of Doxorubicin into Model Lipid and Cell Membranes
Understanding the interactions between drugs and lipid
membranes
is a prerequisite for finding the optimal way to deliver drugs into
cells. Coadministration of statins and anticancer agents has been
reported to have a positive effect on anticancer therapy. In this
study, we elucidate the mechanism by which simvastatin (SIM) improves
the efficiency of biological membrane penetration by the chemotherapeutic
agent doxorubicin (DOX) in neutral and slightly acidic solutions.
The incorporation of DOX, SIM, or a combination of them (DOX:SIM)
into selected single-component lipid membranes, zwitterionic unsaturated
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
(POPC), neutral cholesterol, and negatively charged 1,2-dimyristoyl-sn-glycero-3-phospho-l-serine (DMPS) was assessed
using the Langmuir method. The penetration of neutral lipid monolayers
by the codelivery of SIM and DOX was clearly facilitated at pH 5.5,
which resembles the pH conditions of the environment of cancer cells.
This effect was ascribed to partial neutralization of the DOX positive
charge as the result of intermolecular interactions between DOX and
SIM. On the other hand, the penetration of the negatively charged
DMPS monolayer was most efficient in the case of the positively charged
DOX. The efficiency of the drug delivery to the cell membranes was
evaluated under in vitro conditions using a panel
of cancer-derived cell lines (A172, T98G, and HeLa). MTS and trypan
blue exclusion assays were performed, followed by confocal microscopy
and spheroid culture tests. Cells were exposed to either free drugs
or drugs encapsulated in lipid carriers termed cubosomes. We demonstrated
that the viability of cancer cells exposed to DOX was significantly
impaired in the presence of SIM, and this phenomenon was greatly magnified
when DOX and SIM were coencapsulated in cubosomes. Overall, our results
confirmed the utility of the DOX:SIM combination delivery, which enhances
the interactions between neutral components of cell membranes and
positively charged chemotherapeutic agents