β-Cyclodextrin Nanophotosensitizers for Redox-Sensitive Delivery of Chlorin e6

Abstract

The aim of this study is to prepare redox-sensitive nanophotosensitizers for the targeted delivery of chlorin e6 (Ce6) against cervical cancer. For this purpose, Ce6 was conjugated with β-cyclodextrin (bCD) via a disulfide bond, creating nanophotosensitizers that were fabricated for the redox-sensitive delivery of Ce6 against cancer cells. bCD was treated with succinic anhydride to synthesize succinylated bCD (bCDsu). After that, cystamine was attached to the carboxylic end of bCDsu (bCDsu-ss), and the amine end group of bCDsu-ss was conjugated with Ce6 (bCDsu-ss-Ce6). The chemical composition of bCDsu-ss-Ce6 was confirmed with 1H and 13C NMR spectra. bCDsu-ss-Ce6 nanophotosensitizers were fabricated by a dialysis procedure. They formed small particles with an average particle size of 152.0 ± 23.2 nm. The Ce6 release rate from the bCDsu-ss-Ce6 nanophotosensitizers was accelerated by the addition of glutathione (GSH), indicating that the bCDsu-ss-Ce6 nanophotosensitizers have a redox-sensitive photosensitizer delivery capacity. The bCDsu-ss-Ce6 nanophotosensitizers have a low intrinsic cytotoxicity against CCD986Sk human skin fibroblast cells as well as Ce6 alone. However, the bCDsu-ss-Ce6 nanophotosensitizers showed an improved Ce6 uptake ratio, higher reactive oxygen species (ROS) production, and phototoxicity compared to those of Ce6 alone. GSH addition resulted in a higher Ce6 uptake ratio, ROS generation, and phototoxicity than Ce6 alone, indicating that the bCDsu-ss-Ce6 nanophotosensitizers have a redox-sensitive biological activity in vitro against HeLa human cervical cancer cells. In a tumor xenograft model using HeLa cells, the bCDsu-ss-Ce6 nanophotosensitizers efficiently accumulated in the tumor rather than in normal organs. In other words, the fluorescence intensity in tumor tissues was significantly higher than that of other organs, while Ce6 alone did not specifically target tumor tissue. These results indicated a higher anticancer activity of bCDsu-ss-Ce6 nanophotosensitizers, as demonstrated by their efficient inhibition of the growth of tumors in an in vivo animal tumor xenograft study.

Comparative Analysis of the Structure and Pharmacological Properties of Some Piperidines and Host–Guest Complexes of β-Cyclodextrin

“…In our previous works [ 7 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], we reported the preparation of host–guest complexes of the above piperidines with β-CD and studied their structure ( Table 10 ). All the compounds except MEP formed inclusion complexes with a guest–host ratio of 1:2.…”

“…Cyclodextrins are widely used in the pharmaceutical industry for transporting and modification of an active substance [ 13 , 14 ]. The formation of inclusion complexes makes it possible to change the properties of the biologically active component in the desired direction, i.e., to increase the bioavailability and resistance to hydrolysis, solubility, and biodegradability of many active substances [ 15 , 16 ]. In order to improve the anesthetic effects and reduce the toxicity of the water-soluble salt forms of piperidine derivatives, we synthesized and studied [ 7 , 17 , 18 , 19 , 20 , 21 ] the host–guest complexes of some of these compounds with β-cyclodextrin.…”