Open AccessMechanically interlocked molecular architectures of valinomycin as cancer targeted prodrugs
Author(s) -
Tachihara Yoshihiro,
Nakagawa Yasuhiro,
Miyazaki Takuya,
Anraku Yasutaka,
Cabral Horacio
Publication year - 2022
Publication title -
nano select
Language(s) - English
Resource type - Journals
ISSN - 2688-4011
DOI - 10.1002/nano.202100368
Subject(s) - prodrug , chemistry , ethylene glycol , cytotoxicity , isothiocyanate , hydrazone , combinatorial chemistry , valinomycin , small molecule , hydrazide , in vitro , stereochemistry , biochemistry , organic chemistry , membrane
Macrocyclic drugs are promising agents for treating a variety of diseases. However, these compounds usually present delivery limitations, such as low tissue selectivity and poor cellular uptake, which may impair efficacy and clinical translation. Here, we propose a molecular machine approach for delivering macrocyclic drugs based on their assembly into bioactive rotaxanes. To prove this concept, we use the extremely toxic macrocycle valinomycin (Val) as the host molecule, and identify dihydralazine (Dihyd) as a guest molecule after screening several guest compounds. The Val‐Dihyd complex is mechanically interlocked by capping one hydrazide group in Dihyd with fluorescein isothiocyanate (FITC) and the other with a Y‐shape branched poly(ethylene glycol) (PEG) via a pH‐sensitive hydrazone bond. Thus, the Val‐loaded rotaxanes (Vrot) are stable at physiological pH, but release Val at mild acidic conditions mimicking intratumoral and endosomal environments. In vitro studies revealed Vrot is less cytotoxic than free Val in pancreatic cancer cells, while modifying Vrot with cyclic arginine‐glycine‐aspartic acid (cRGD) peptides promotes the cytotoxicity by enhancing cellular uptake. These results indicate the potential of rotaxanes of macrocyclic drugs for generating cancer targeted prodrugs.