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 beta CD 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.

Automated summary

Bisphosphonate molecules, when conjugated with drug-carrying polymers, can target bone cancer cells. A polyethyleneimine-BP-cyclodextrin ternary conjugate was designed and tested for its ability to load antineoplastic drugs and target specific cancer cells. The conjugates showed specificity and capability for targeted drug transport in both in vitro and in vivo evaluations.