Atherosclerosis
remains one of the leading causes of morbidity
and mortality globally. Recently, reconstituted high-density lipoprotein
(rHDL), the synthetic form of endogenous plasma HDL, has been utilized
as a therapeutic delivery system for statins, a class of lipid-lowering
drugs, to treat atherosclerosis. Accumulating evidence suggests that
ganglioside GM1 modification can induce an increased stability, a
prolonged circulation time, and a decreased reticuloendothelial system
uptake of liposomes. Therefore, we hypothesized that GM1 modification
probably has similar effects on statin-loaded rHDL and finally enhances
its inhibitory effect on atherogenesis. To test this hypothesis, we
prepared GM1-modified lovastatin (LT)-loaded rHDL (LT-GM1-rHDL), as
well as LT-loaded rHDL (LT-rHDL) and LT-loaded nanostructured lipid
carriers (LT-NLC) for comparison, via thin film dispersion followed
by physicochemical characterization, in vitro LT release assay, and
in vitro cellular experiments. Subsequently, the pharmacokinetic behavior,
tissue distribution, and in vivo antiatherosclerotic effect of all
LT-loaded nanocarriers were evaluated by using ApoE–/– mice fed with a high-fat diet. We found that LT-GM1-rHDL has a more
efficient LT sustained-release, a longer circulation time, a lower
liver uptake, a better atherosclerotic plaque targeting efficiency,
and a stronger inhibitory effect on atherogenesis compared with LT-NLC
and LT-rHDL. The data verified our hypothesis that GM1 modification
of statin-loaded rHDL can induce an enhanced inhibitory effect on
atherogenesis and imply that statin-GM1-rHDL can potentially be recruited
as a promising drug delivery system for the treatment of atherosclerosis.
Background: Cell-bound membrane vesicles (CBMVs) are a type of membrane vesicles different from the wellknown extracellular vesicles (EVs). In recent years, the applications of EVs as drug delivery systems have been studied widely. A question may arise whether isolated CBMVs also have the possibility of being recruited as a drug delivery system or nanocarrier? Methods: To test the possibility, CBMVs were isolated/purified from the surfaces of cultured endothelial cells, loaded with a putative antitumor drug doxorubicin (Dox), and characterized. Subsequently, cellular experiments and animal experiments using mouse models were performed to determine the in vitro and in vivo antitumor effects of Doxloaded CBMVs (Dox-CBMVs or Dox@CBMVs), respectively. Results: Both Dox-free and Dox-loaded CBMVs were globular-shaped and nanometer-sized with an average diameter of ~ 300-400 nm. Dox-CBMVs could be internalized by cells and could kill multiple types of cancer cells. The in vivo antitumor ability of Dox-CBMVs also was confirmed. Moreover, Quantifications of blood cells (white blood cells and platelets) and specific enzymes (aspartate aminotransferase and creatine kinase isoenzymes) showed that Dox-CBMVs had lower side effects compared with free Dox. Conclusions: The data show that the CBMV-entrapped Doxorubicin has the antitumor efficacy with lower side effects. This study provides evidence supporting the possibility of isolated cell-bound membrane vesicles as a novel drug nanocarrier.
In contrast to the released/circulating membrane vesicles (extracellular vesicles), cell-bound membrane vesicles are poorly identified and characterized. In this study, cell-bound membrane vesicles on human umbilical vein endothelial cells (HUVECs) and human hepatoma HepG-2 cells were investigated. We identified that cell-bound membrane vesicles are not co-localized with the major markers for extracellular vesicles (e.g. phosphatidylserine, CD63, CD107α, CD31, and DNA fragments for the three well-known types of extracellular vesicles) and for intracellular organelles with similar sizes (e.g. MitoTracker and LAMP1/LAMP3 for mitochondria and multivesicular bodies or lysosomes, respectively). The data imply that cell-bound membrane vesicles are neither the precursors of extracellular vesicles nor a false structure pushed up by an intracellular organelle but probably a novel unknown structure in the plasma membrane. Moreover, we revealed that cell-bound membrane vesicles are resistant to various detergents including but probably not limited to Triton X-100, SDS, and saponin. We further characterized that these unique vesicles are soluble in organic solvents (e.g. chloroform-methanol mixture and ethanol) which can be prevented by a lipid-stabilizing fixative (e.g. OsO) and that they are co-localized with, but do not monopolize, the major markers (e.g. caveolin-1 and GM1) for lipid rafts (a nano-sized detergent-resistant domains in the plasma membrane). The data imply that cell-bound membrane vesicles contain the lipid component and lipid rafts. Involvement of other specific unknown components might explain the detergent resistance of cell-bound membrane vesicles. Further research will mainly depend on the establishment of an effective approach for isolation/purification of these vesicles from the plasma membrane.
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