Supramolecular Hydrogels from Cisplatin-Loaded Block Copolymer Nanoparticles and α-Cyclodextrins with a Stepwise Delivery Property

摘要

A stepwise anticancer drug delivery system based on an injectable supramolecular hydrogel was presented. In this system, poly(ethylene glycol)-b-poly(acrylic acid) (PEG-b-PAA) block copolymer nanoparticles containing cisplatin were released by erosion of the hydrogels and then the cisplatin was released from the nanoparticles by exchanging with chloride ions. By mixing α-cyclodextrins (α-CDs) and the PEG-b-PAA micelles with their PAA cores loaded with the cisplatin in water, the novel supramolecular hydrogels were generated by threading α-CDs onto the PEG segments and forming physical cross-links of molecular necklaces. The gelation properties could be tuned by changing concentrations of the polymers and cisplatin, their feeds, and by adding PEG homopolymers or Pluronic copolymers as additives. Structures and properties of the supramolecular hydrogels containing cisplatin were studied by wide-angle X-ray diffraction (XRD) and rheology measurements, respectively. The thixotropic effect of the hydrogels and their reversible sol—gel transition were confirmed. In vitro hydrogel erosion experiments were conducted and cisplatin release in saline and pure water was quantified. Hydrogel erosion produced discrete nanoparticles from which cisplatin was released completely in saline. In contrast, the hydrogels were eroded into nanoparticles in pure water, but no cisplatin could be released. In vitro cytotoxicity studies showed that the cisplatin-loaded hydrogels inhibited the growth of human bladder carcinoma EJ cells with a similar potency as that of the free cisplatin, whereas the hydrogels without cisplatin showed no cytotoxicity. These results suggested that the cisplatin-coordinated PEG-b-PAA/α-CD supramolecular hydrogels hold great potential as an injectable system for sustained delivery of cisplatin in cancer therapy.