Polyethylenimine-Bisphosphonate-Cyclodextrin Ternary Conjugates: Supramolecular Systems for the Delivery of Antineoplastic Drugs
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Plesselova, Simona; García Cerezo, Pablo; Blanco Suárez, Víctor; Reche Pérez, Francisco José; Hernández Mateo, Fernando; Santoyo González, Francisco; Girón González, María Dolores; Salto González, RafaelEditorial
American Chemical Society
Date
2021-08-09Referencia bibliográfica
J. Med. Chem. 2021, 64, 12245−12260. [https://doi.org/10.1021/acs.jmedchem.1c00887]
Sponsorship
Ministry of Science and Innovation, Spain (MICINN) Spanish Government CTQ2014-55474-C2-2-R CTQ2017-86125-P; European Commission; Fundacion Marcelino BotinAbstract
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.