Abstract:
An efficient synthetic framework was assembled (G8-FKE-FADox),
consisting of a lysosome-targeting octaguanidine molecular
transporter with a cathepsin B (cath B)-specific peptide
substrate, folic acid, and the potent chemotherapeutic drug
doxorubicin (Dox). Because the folate receptor (FR) and cath B
are overexpressed in malignant cells, this transporter conjugate
successfully executed lysosome-mediated transport of Dox to
FR-positive tumor cells, illustrating this framework as an excellent
targeted drug delivery system (TDDS). G8-FKE-FA-Dox was
shown to exhibit selective toxicity toward FR-overexpressing
cancer cells, with an IC50 value superior to that of the USFDAapproved
LipodoxTM and proportional to that of free Dox via
selective induction of apoptosis by the activation of caspases
8, 9, and 3. This TDDS was observed to be nontoxic to red
blood cells and lymphocytes at neutral pH. Furthermore the
tumor-targeting dissemination pattern of this system was revealed
by monitoring the in vivo biodistribution of the carrier
(G8-FKE-FA-FL) in normal and FR-overexpressing tumor-bearing
mice.
