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Construction And Application Of Supramolecular Drug Delivery Systems Based On Water-soluble Pillar[n]arenes

Posted on:2018-10-28Degree:DoctorType:Dissertation
Country:ChinaCandidate:X LiuFull Text:PDF
GTID:1311330542966487Subject:Chemistry
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Stimuli-responsive drug delivery systems(DDSs)self-assembled from amphiphiles have received tremendous attentions in cancer therapy due to various advantages,such as enhanced bioavailability,prolonged blood circulation,improved stability and so on.Pillar[n]arenes,an emerging type of macrocyclic hosts,have received great attentions due to their symmetrical pillar and unique rigid architectures,easy functionalization,and excellent abilities to selectively bind with various kinds of guest molecules.Numerous pillar[n]arene-based dynamic host-guest recognition motifs have been built and further applied in the fabrication of a variety of functional materials,including mechanically interlocked molecules,chemosensors,artificial transmembrane channels,and drug delivery systems.In this dissertation,we have constructed three kinds of smart stimuli-reponsive supramolecular nanocarriers based on water-soluble pillar[n]arenes.The detailed research mainly includes the following three parts:In the first part,we designed and synthesized two types of supramolecular nanocarriers based on novel biocompatible water-soluble phosphate-based pillar[5]arene(WP5P)or pillar[6]arene(WP6P)with alkyl chain modified pyridinium bromide guest G1 for the selective anticancer drug delivery.Solid supramolecular micelles could be obtained by formation amphiphilic host-guest inclusion complex at alkyl chain motifs formed from WP5P and G1,whereas hollow supramolecular vesicles were acquired from WP6P and G1 by host-guest interactions at pyridinium sites.Both of them showed pH-and Zn2+-responsiveness.Furthermore,the resulting solid micelles were able to encapsulate hydrophobic anticancer drug doxorubicin(DOX)to achieve DOX-loaded micelles,while hydrophilic anticancer drug mitoxantrone(MTZ)could be successfully loaded into the hollow vesicles.And the encapsulated anticancer drugs could be efficiently released at pH=5 environment or with the introduction of Zn2+.More importantly,cytotoxicity experiments indicated that these water-soluble phosphate-based pillar[5,6]arenes showed excellent biocompatibility,and the drug-loaded nanoparticles exhibited comparable therapeutic effect for cancer cells as free anticancer drugs and remarkably reduced damage for normal cells as well.Cellular uptake and intracellular localization experiments further confirmed that these two types of nanocarriers,taken up by cancer cells via endocytosis,could lead to efficient drug accumulation in cancer cells.Therefore,this novel strategy of controllable construction of different types of stimuli-responsive supramolecular nanocarriers based on biocompatible phosphate-based pillar[5,6]arenes have great potential applications in the field of cotrolled drug delivery.In the second part,a pH and GSH(glutathione)dual-responsive bola-type supramolecular amphiphile was successfully fabricated by the complexation between a water-soluble pillar[5]arene(WP5)and a bolaform naphthalimide guest(G2)in water.The resulting bola-type amphiphile further self-assembled into supramolecular binary vesicles,which could encapsulated hydrophobic anticancer drug DOX into the Stern region and generated the DOX-loaded vesicles.Moreover,the obtained DOX-loaded vesicles displayed efficient and rapid DOX release at a simulated tumor microenvironment with low-pH and/or excess GSH conditions.Significantly,cytotoxicity experiments revealed that the DOX-loaded supramolecular vesicles could obviously improve the anticancer efficiency of free DOX for tumor cells,while remarkably reduce its side effects for normal cells.In vitro cellular uptaking and subcellular localization assays further proved that these smart drug nanovehicles,entering cancer cells mainly via endocytosis,could cause excellent drug accumulation in cancer cells.The present study provides a successfully example to rational design an effective bola-type stimuli-responsive supramolecular nanocarrier,which might have wide potential applications in constructing various controlled drug delivery systems.In the third part,a smart ?-D-galactose installed supramolecular prodrug nanoparticle GalP5(?)G3 with GSH-responsiveness and active targeting abilities was successfully developed by the novel host-guest complexation between a?-D-galactose functionalized water-soluble pillar[5]arene(GalP5)and a camptothecin prodrug(G3)containing disulfide linkage in water.The obtained supramolecular prodrug nanoparticles were stable under physiological conditions,whereas efficient drug release behavior were triggered by disulfide-bonds cleavage via GSH.In vitro studies revealed that these supramolecular prodrug nanoparticles preferentially entered asialoglycoprotein receptor over-expressing hepatocellular carcinoma cells due to the active targeting of galactose units and accumulated in cancer cells.Importantly,cytotoxicity experiments suggested that GalP5(?)G3 prodrug nanoparticles not only could efficiently inhibit the proliferation to cancer cells but also reduce the side effects to the normal cells.This present study offers insights to construct targeted supramolecular prodrug nanoparticles with stimuli-responsiveness,which have great potential applications in the fields of targeted drug delivery.In summary,three kinds of stimuli-responsive supramolecular drug delivery systems were constructed on the basis of molecular recognition and assembly of water-soluble pillar[n]arenes in this dissertation.Moreover,researches from structure synthesis to functions and applications are attempted.We hope these works will provide some benefits and references in drug delivery and biomedical fields based on pillar[n]arenes.
Keywords/Search Tags:supramolecular chemistry, self-assembly, nanocarriers, stimuli-responsive, pillar[n]arenes, drug delivery systems
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