RESUMEN
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 ßCD 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.
Asunto(s)
Antineoplásicos/uso terapéutico , Ciclodextrinas/química , Difosfonatos/química , Portadores de Fármacos/química , Neoplasias/tratamiento farmacológico , Polietileneimina/análogos & derivados , Animales , Línea Celular Tumoral , Ciclodextrinas/síntesis química , Ciclodextrinas/toxicidad , Difosfonatos/síntesis química , Difosfonatos/toxicidad , Doxorrubicina/uso terapéutico , Portadores de Fármacos/síntesis química , Portadores de Fármacos/toxicidad , Diseño de Fármacos , Femenino , Humanos , Ratones , Polietileneimina/síntesis química , Polietileneimina/toxicidad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We report the application of the click Michael-type addition reaction to vinyl sulfone or vinyl sulfonate groups in the synthesis of rotaxanes through the threading-and-capping method. This methodology has proven to be efficient and versatile as it allowed the preparation of rotaxanes using template approaches based on different noncovalent interactions (i.e., donor-acceptor π-π interactions or hydrogen bonding) in yields of generally 60-80 % and up to 91 % aided by the mild conditions required (room temperature or 0 °C and a mild base such as Et3 N or 4-(N,N-dimethylamino)pyridine (DMAP)). Furthermore, the use of vinyl sulfonate moieties, which are suitable motifs for coupling-and-decoupling (CAD) chemistry, implies another advantage because it allows the controlled chemical disassembly of the rotaxanes into their components through nucleophilic substitution of the sulfonates resulting from the capping step with a thiol under mild conditions (Cs2 CO3 and room temperature).
