Study Of Supramolecular Systems Derived From Water Soluble Pillararenes-based Host-Guest Chemistry For Drug Delivery

Cancer is one of the major diseases that threaten human health.Common therapies of cancer include chemotherapy,photodynamic therapy?PDT?,etc.However,these therapies still have some shortcomings,such as the toxic side effects of anticancer drugs,the photobleaching and dark toxicity of photosensitizers.Constructing targeted drug delivery system provides efficient method to solve those problems.As an emerging multidisciplinary interdisciplinary subject,supramolecular chemistry encompasses a wide range of research fields.The research focus of supramolecular chemistry is macrocyclic molecule,including crown ether,cyclodextrin,cucurbituril,calixarene and the like.As a new generation of macrocyclic molecule,pillararenes have attracted widespread attention in the past decade.And the host-guest chemistry based on pillararenes has also been greatly developed.Herein,in this thesis,we constructed three different kinds of supramolecular systems to solve the problems existed in PDT and chemotherapy.The main works are listed as follows:1.Supramolecular photosensitizer system based on host-guest complexation between water-soluble pillar[6]arene and methylene blue for durable photodynamic therapyA supramolecular photosensitizer system?WP6-MB?has been constructed based on water-soluble pillar[6]arene?WP6?and photosensitizer methylene blue?MB?via host-guest interaction for durable PDT.In this research,MB was selected as a model photosensitizer,which can complex with WP6 directly,obtaining WP6-MB.The complexation constant of WP6 and MB was determined to be?1.15±0.30?×10⁷ M^-1.The results showed that upon long time irradiation,both production rate and yield of singlet oxygen quantum induced by WP6-MB was remarkably higher than that produced by MB,indicating that WP6-MB can overcome the photobleaching of MB efficiently.More importantly,cellular experiments showed that benefiting from the complexation with WP6,the dark toxicity of MB,which is one of the biggest obstacles of PDT,can be efficiently reduced.Herein,we have successfully developed a supramolecular photosensitizer system for durable photodynamic therapy.This work provides an effective new method to overcome the photo-bleaching and dark toxicity of photosensitizers.2.Supramolecular hybrid system based on pillar[6]arene host-guest complex and ZIF-8 for targeted drug deliveryA supramolecular hybrid material ZIF-8@DOX@WP6@G composed of the host-guest complexation between carboxylated pillar[6]arene?WP6?and galactose derivative?G-1?,and doxorubicin?DOX?-loaded ZIF-8 has been constructed for targeted drug delivery.WP6 was synthesized and used as the solubilizing agent to assemble with ZIF-8@DOX to enhance its water dispersibility through the coordination between the carboxyl group of WP6 and metal nodes of ZIF-8@DOX,obtaining ZIF-8@DOX@WP6.G-1 was assembled with ZIF-8@DOX@WP6 through the host-guest interaction obtaining ZIF-8@DOX@WP6@G.The resulting ZIF-8@DOX@WP6@G possessed excellent water dispersibility and pH-sensitive drug release property.Furthermore,benefiting from the target function of G-1,ZIF-8@DOX@WP6@G showed improved selectivity in killing HepG2 cells.Meanwhile,the side effects on normal cells can be avoided to some extent.Therefore,this work provides a good example of rational design of supramolecular hybrid material for potential cancer therapy.3.Supramolecular vesicles based on tryptophan-modified pillar[5]arene and galactose derivatives for synergistic targeted drug deliveryA DNA interacting drug delivery system?TP5G?based on supramolecular vesicles self-assembled by the host-guest complex of tryptophan?Trp?-modified pillar[5]arene?TP5?and galactose derivative?G-2?has been developed.The host-guest complexation between TP5 and G-2 was investigated,the complexation constant of which was determined to be?3.5±0.6?×10⁵ M^-1.The results showed that TP5G can encapsulate DOX efficiently,and be used for controllable release in response to pH.In addition,TP5G possessed hepatoma-targeting ability owing to the function of G-2.Notably,DOX-loaded TP5G exhibited significantly enhanced cytotoxicity compared to free DOX towards hepatoma cells through the synergistic effect of Trp with DOX.Furthermore,DOX-loaded TP5G showed unexpected ability to restore the drug sensitivity of DOX-resistant hepatoma cells,which suggested TP5G as a potential drug delivery system for overcoming multi-drug resistance.We hope this system can broaden the scope of nano-drug delivery systems towards synergistically enhanced therapy.In summary,the above-mentioned three drug delivery systems,based on the host-guest chemistry of pillararenes,have been constructed to overcome the photobleaching and dark toxicity of photosensitizers as well as the toxic side effects of anti-cancer drugs respectively,which can enhance the therapeutic effect to some extent.We hope these researches can provide new ideas for durable PDT and targeted chemotherapy.