Improving Intracellular Doxorubicin Delivery Through Nanoliposomes Equipped with Selective Tumor Cell Membrane Permeabilizing Short-Chain Sphingolipids

Abstract

C₈-GluCer or C₈-GalCer incorporated in DoxNL selectively improved intracellular drug delivery upon transfer to tumor cell membranes by local enhancement of cell membrane permeability.

Plasma membrane targeting by short chain sphingolipids inserted in liposomes improves anti-tumor activity of mitoxantrone in an orthotopic breast carcinoma xenograft model

“…Studies toward the mechanism described rapid SCS delivery from the liposomal to the tumor cell membrane independent of liposomal uptake, which preceded enhanced liposomal drug influx [14,21]. Previous studies demonstrated that C 8 -GluCer or C 8 -GalCer by themselves is innocuous to cells, as empty SCS-liposomes did not cause cell cytotoxicity [21]. In our formulations the antitumor activity is merely related to co-formulated drug (MTO).…”

“…SCS upon their insertion into cell membranes exerts drug transport enhancing properties to amphiphilic drugs such as Doxorubicin (Dox) and MTO [14,[19][20][21][22]33]. SCS preferentially exerts these properties toward tumor cell membranes, a phenomenon which is likely related to an aberrant makeup of these membranes in comparison with those of normal cells [14,21,22]. A tumor cell selectivity has been observed for the drug uptake enhancing effect of SCS [21,34].…”

“…SCS preferentially exerts these properties toward tumor cell membranes, a phenomenon which is likely related to an aberrant makeup of these membranes in comparison with those of normal cells [14,21,22]. A tumor cell selectivity has been observed for the drug uptake enhancing effect of SCS [21,34]. Studies toward the mechanism described rapid SCS delivery from the liposomal to the tumor cell membrane independent of liposomal uptake, which preceded enhanced liposomal drug influx [14,21].…”

“…A tumor cell selectivity has been observed for the drug uptake enhancing effect of SCS [21,34]. Studies toward the mechanism described rapid SCS delivery from the liposomal to the tumor cell membrane independent of liposomal uptake, which preceded enhanced liposomal drug influx [14,21]. Previous studies demonstrated that C 8 -GluCer or C 8 -GalCer by themselves is innocuous to cells, as empty SCS-liposomes did not cause cell cytotoxicity [21].…”

“…Whereas liposomal encapsulation prolongs systemic circulation and decreases drug toxicity, it is less beneficial for effective delivery of bioavailable drug into tumor cells limiting therapeutic efficacy [18]. However, inserting SCS, such as C 8 -Glucosylceramide (C 8 -GluCer) or C 8 -Galactosylceramide (C 8 -GalCer) in the liposomal bilayer improves drug co-delivery to tumor cells through membrane permeabilization [19][20][21][22]. This approach combines reduced toxicity through liposomal encapsulation with the advantage of enhanced intracellular drug delivery by SCS-mediated tumor cell membrane traversal.…”