The Construction Of Stimuli-responsive Supramolecular Drug Delivery System Based On Water Soluble Pillar[6]arene

Supramolecular chemistry is a discipline based on non-covalent interaction, since the 1987 Nobel Prize in chemistry was awarded to Pederson, Cram and Lehn, the research of supramolecular chemistry became more and more thorough. Pillararene, as the fifth generation of supramolecular macrocyclic host molecules, was widely researched and applied because of its excellent properties. Water soluble pillar[6]arene(WP6) was first synthesized in 2012, its solubility in water can be controlled by adjusting the p H value of the solution, and it has strong binding effect with various guest molecules. Therefore, we choose WP6 as the host to construct p H-responsive supramolecular system. According to the previous studies, nanoparticles usually show a longer retention time in the blood stream than free small-molecule drugs, and the multidrug resistance(MDR) of tumor cells can be overcome efficiently. Therefore, nanocarrier has great prospect of application in drug delivery and cancer therapy. Our research mainly includes the following two parts:In the first part, to solve the problem of the inefficient drug release rate of polymeric nanocarriers in tumor cells, and achieve a suf?cient intracellular drug concentration for cancer therapy, we designed a supramolecular drug delivery system which can release drug much faster. The host molecule we used is WP6, which will precipitate from water after acidification of the solution. We synthesized two kinds of guest molecules G1 and G2, where DOX was conjugated to the guest molecule via acid-responsive hydrazone bond, which may induce faster release of DOX in an acidic environment than under neutral conditions. WP6 and G1 or G2 can form supramolecular amphiphiles in aqueous solution via host-guest interaction, and then the formed supramolecular amphiphiles WP6éG1 and WP6éG2 could further self-assemble into nanoparticles. The properties of the host-guest interaction were confirmed via 1H NMR. Transmission electron microscopy(TEM) and dynamic light scattering(DLS) tests proved its nano structure. In addition, we also investigated the DOX release properties of the obtained supramolecular nanoparticles in PBS buffer with different p H value through HPLC, and found that they are stable under physiological conditions; whereas the cumulative release of DOX is approximate to 100 % within 30 min at p H 5.5. Finally, intracellular localization experiments demonstrated that these two nanoparticles, taken up by cancer cells via endocytosis, can lead to efficient DOX accumulation in SKOV3 cancer cells.In the second part, combined two kinds of stimuli responses p H and light stimuli together, we synthesized the guest molecule G3, where anticancer drug chlorambucil was conjugate with another anticancer drug betulinic acid via ester bond. WP6 could form supramolecular complex WP6éG3 with chlorambucil via host-guest interaction. In addition, G3 also contains “phototrigger” acridin-9-ylmethyl chromophore. WP6 and G3 could form supramolecular amphiphiles in aqueous solution, and the formed supramolecular amphiphiles could further self-assemble into nanoparticles. Two kinds of drugs could be released through the p H and light stimuli. Transmission electron microscopy(TEM) and dynamic light scattering(DLS) tests confirmed its nano structure. We also performed fluorescence test to characterize the release properties of drugs after different irradiation time using an irradiation wavelength of ≥410 nm. Further evaluations of the anti-cancer effect of the obtained supramolecular nanoparticles are ongoing.