Beta-Cyclodextrin modified Pt(II) metallacycle-based supramolecular hyperbranched polymer assemblies for DOX delivery to liver cancer cells
Menée à l'aide d'une lignée cellulaire de cancer hépatique d'origine humaine, cette étude met en évidence l'intérêt thérapeutique d'un polymère supramoléculaire capable de pénétrer dans les cellules cancéreuses et de délivrer, sous l'action d'espèces réactives de l'oxygène et du monoxyde d'azote, des anticancéreux
The development of chemotherapeutic drugs for cancer treatment has been limited by problems such as adverse side effects and inefficient performance of the drugs. To deliver multiple anticancer drugs for accurate and synergistic liver cancer treatment, a Pt(II) metallacycle-based drug delivery system, with endogenous redox and nitric oxide stimuli responsiveness and two chemotherapeutic agents is designed via the orthogonal self-assembly strategy. In vitro studies demonstrate that this system has good ability to deliver hydrophobic anticancer drug doxorubicin to HepG2 liver cancer cells. It also efficiently inhibits tumor cell growth for enhanced liver cancer treatment. This study provides an opportunity for the further design of metallacycle-based drug delivery systems for cancer therapy.Despite the widespread clinical application of chemotherapeutic anticancer drugs, their adverse side effects and inefficient performances remain ongoing issues. A drug delivery system (DDS) designed for a specific cancer may therefore overcome the drawbacks of single chemotherapeutic drugs and provide precise and synergistical cancer treatment by introducing exclusive stimulus responsiveness and combined chemotherapy properties. Herein, we report the design and synthesis of a supramolecular drug delivery assembly 1 constructed by orthogonal self-assembly technique in aqueous media specifically for application in liver cancer therapy. Complex 1 incorporates the β-cyclodextrin host molecule-functionalized organoplatinum(II) metallacycle 2 with two specific stimulus-responsive motifs to the signaling molecule nitric oxide (NO), in addition to the three-armed polyethylene glycol (PEG) functionalized ferrocene 3 with redox responsiveness. With this molecular design, the particularly low critical aggregation concentration (CAC) of assembly 1 allowed encapsulation of the commercial anticancer drug doxorubicin (DOX). Controlled drug release was also achieved by morphological transfer via a sensitive response to the endogenous redox and NO stimuli, which are specifically related to the microenvironment of liver tumor cells. Upon combination of these properties with the anticancer ability from the platinum acceptor, in vitro studies demonstrated that DOX-loaded 1 is able to codeliver anticancer drugs and exhibit therapeutic effectiveness to liver tumor sites via a synergistic effect, thereby revealing a potential DDS platform for precise liver cancer therapeutics.The details of the synthesis, characterization, and biological experiments are given in SI Appendix.