Polyethylenimine–Bisphosphonate–Cyclodextrin Ternary Conjugates: Supramolecular Systems for the Delivery of Antineoplastic Drugs

Bisphosphonates (BPs) are bone-binding
molecules that provide targeting
capabilities to bone cancer cells when conjugated with drug-carrying
polymers. This work reports the design, synthesis, and biological
evaluation of polyethyleneimine–BP–cyclodextrin (PEI-BP-CD)
ternary conjugates with supramolecular capabilities for the loading
of antineoplastic drugs. A straightforward, modular, and versatile
strategy based on the click aza-Michael addition reaction of vinyl
sulfones (VSs) allows the grafting of BPs targeting ligands and βCD
carrier appendages to the PEI polymeric scaffold. The in vitro evaluation (cytotoxicity, cellular uptake, internalization routes,
and subcellular distribution) for the ternary conjugates and their
doxorubicin inclusion complexes in different bone-related cancer cell
lines (MC3T3-E1 osteoblasts, MG-63 sarcoma cells, and MDA-MB-231 breast
cancer cells) confirmed specificity, mitochondrial targeting, and
overall capability to mediate a targeted drug transport to those cells.
The in vivo evaluation using xenografts of MG-63
and MDA-MB-231 cells on mice also confirmed the targeting of the conjugates.