The Construction And Application Of Supramolecular Nanocarriers Based On Water-Soluble Pillararenes

As a new type of macrocyclic compounds,pillararenes with unique symmetrical structure provided a useful platform for the construction of various supramolecular systems,which shows considerable application prospects.Recently,scientists have paid more attention to functional supramolecular systems based on pillar[n]arenes,which are involved in material science,life science and so on.These researches greatly promote the development of pillararene chemistry.The successful synthesis of water-soluble pillar[n]arene has further widened the applications of pillararenes.In this dissertation,we have successfully achieved the controllable construction of tumor-targeting nanocarriers based on host-guest interaction between a pillar[5]arene-based prodrug and a RGD-sulfonate guest.Furthermore,we have further designed glucose-responsive supramolecular vesicles based on water-soluble pillar[5]arene and pyridylboronic acid derivative for controlled insulin delivery.This main content consists of the following two parts:In the first part,we successfully constructed a supramolecular amphiphile WP5-DOX(?)RGD-SG based on the host-guest recognition between a novel pillar[5]arene-based prodrug WP5-DOX and a RGD-sulfonate guest RGD-SG.The amphiphilic WPS-DOX(?)RGD-SG complex with a molar ratio of 5:1 self-assembles into vesicles,whereas micelles are surprisingly obtained by changing the molar ratio to 1:3.To the best of our knowledge,this is the first example of controllable construction of stimuli-responsive supramolecular prodrug nanovehicles with different morphologies based on the same host-guest interactions by using different host-guest ratios.In vitro studies reveal that both these nanocarriers could selectively deliver their cargo,the anticancer drug doxorubicin(DOX),to RGD receptor-overexpressing cancer cells.After internalization via endocytosis,the acidic endo-lysosomal environment results in the rapid release and efficient DOX accumulation specifically in cancer cells.Furthermore,in vivo experiments show that these prodrug nanocarriers could lead to longer blood retention time,enhanced antitumor efficacy,and reduced systematic toxicity in murine tumor model compared to DOX,suggesting their potential application for targeted drug delivery.In the second part we have designed a glucose-responsive supramolecular vesicles constructed by the host-guest interaction between a water-soluble pillar[5]arene and a pyridylboronic acid derivative(G)for insulin delivery and controlled release at physiological conditions.The drug loading and in vitro drug release experiments demonstrated that large molecular weight insulin could be successfully encapsulated into the constructed vesicles with high loading efficiency,which to the best of our knowledge,is the first example of small-sized supramolecular vesicles with excellent encapsulation capacity of large protein molecule.Moreover,FITC-labeled insulin was used to evaluate the release behavior of insulin,and it was demonstrated that high glucose concentration could facilitate the quick release of insulin,suggesting a smart drug delivery system(DDS)for the potential application in controlled insulin release only under hyperglycemic conditions.Finally,we demonstrated that these supramolecular nanocarriers have good cytocompatibility,which is essential for their further biomedical applications.The present study provides a novel strategy for the construction of glucose-responsive smart supramolecular drug delivery system,which has potential applications for the treatment of diabetes mellitus.In summary,two kinds of novel stimuli-responsive supramolecular nanocarriers have been successfully constructed in this dissertation.Moreover,researches from structure synthesis to functions and applications are performed.We hope these works will provide some benefits and references for nanocarriers based on pillar[n]arenes.