Nanostructure of doxorubicin-loaded promelittin lipid
derivative–reduced graphene oxide (Dox/PL-rGO) nanosheets and a schematic depiction
of the hypothesized mechanism underlying their action. A) The
promelittin lipid derivative, PL, containing a fibroblast activation protein
(FAP)–cleavable sequence, was anchored onto rGO nanosheets. The resulting PL-rGO was
further loaded with Dox, yielding Dox/PL-rGO. B) Schematic depiction of
the presumed mechanism of Dox/PL-rGO. Activation of the promelittin moiety of PL-rGO
by FAP overexpressed on cancer-associated fibroblasts releases melittin. Diffusion
of melittin to surrounding tumor cells and cells in the tumor microenvironment
promotes formation of pores in the membrane, increasing the cellular uptake of
Dox-loaded rGO nanosheets and enhancing anticancer efficacy. CAFs =
cancer-associated fibroblasts; Dox = doxorubicin; FAP = fibroblast activation
protein; PL = promelittin lipid derivative; rGO = reduced graphene
oxide.