Coordination Polymer Nanoparticles For PH-Responsive Drug Delivery System

Coordination polymers (CPs) are a class of burgeoning materials created from thelimitless choice of metals and organic building blocks, which have been attracted muchattention because of their potential applications in gas adsorption, catalysis, ion exchange,magnetism, and sensing. Recently, efforts have been focused on the preparation ofcoordination polymer nanoparticles (CPNs) for the applications in bioimaging and drugdelivery. However, few attempts have been made towards the stimuli-responsive deliverysystem. Stimuli-responsive drug delivery systems have attracted much attention in recentyears, which can release the drug in a controlled manner on arrival at the target site. Ofthe stimuli-responsive system, the pH-responsive delivery system is of special interest.The extracellular pH of tumors is more acidic (pH=5.7-7.8) than normal tissues and thebloodstream, and the pH values in endosomes and lysosomes reach values as low as5.5and4.5, respectively.For state-of-the-art pH-responsive systems, driving forces commonly changes in theelectrostatic state, polarity, hydrophobicity, or conformation of the pH-sensitive polymers,surfactants, or anchored functional groups, as a result of hydrolysis or a change inionization under different pH conditions. However, a finely responsive system that wouldrelease guest molecules by small pH variations has been pursued for a long time andremains a challenge. Herein, a pH responsive drug delivery system based on thecoordination bonds has been developed and its universality has been investigated indetail. Depending on the coordination ability of the drug molecules, the“ligand-metal” and “host-metal-ligand” architectures, core-shell CPNs containing a drug reservoir core and pH-responsive CPs shell and another CPs coated MSNsloading drugs have been designed and fabricated, respectively. The breakage ofcoordination bonds in coordination polymers, gives rise to a significant release ofguest molecules in response to pH variations.Chapter1. Background and significance of this research subject. The “smart” drugdelivery system, especially the pH-responsive delivery system, and the application ofcoordination polymers in drug delivery were introduced. The significance and researchcontents of this dissertation were summarized.Chapter2. Coordination polymer nanoparticles for pH-responsive delivery system.Firstly, the pH sensitivity of various coordination bonds between different metal ions andkinds of ligands has been evaluated. The formation, cleavage, and pH sensitivity of thecoordination bonds between kinds of metal ions and ligands have been tested by UV-Visspectroscopy. The formation and cleavage of the coordination bonds are sensitive to thechange in external pH, which gives rise to the formation of nanoparticles and release ofthe guest molecules at designated pH of the medium. Secondly, the “ligand-metal” and“host-metal-ligand” architectures have been designed and fabricated, which exhibited afine pH-responsiveness. The states of drug molecules in the dissolution medium wereinvestigated by UV-Vis spectroscopy. The stronger the dissolution medium was acidic,the more ligands were in free state.Chapter3. Core-shell CPNs containing a drug reservoir core and pH-responsive CPsshell composed of “drug-metal” and “ligand-metal” coordination bond for pH-responsivedelivery system. Firstly, core CPNs (drug-metal) were synthetized by poor solventprecipitation method, which are unstable and release drug molecules under physiologicalcondition, and then grown of CPs shell with BIX and Zn coordination bond (BIX-Zn)around the “drug-metal” CPNs cores, generating “drug-metal” core and “BIX-Zn” shell(drug-metal@BIX-Zn) CPNs. The breakage of coordination bond in the shell, triggered by a reduction in external pH, leads to the ablation of shells and the exposure of“drug-metal” CPNs cores into the surrounding environment and subsequent release ofdrug from the cores. Free CHG, MTX and BIX-Zn have no obvious effect on cell viability,while a high cytotoxic activity of core-shell CPNs against HeLa cells was demonstratedby in vitro cell assays.Chapter4. CPs coated MSNs loading drugs for pH-responsive drug delivery system.Mesoporous silica nanoparticles with two-dimensional hexagonal p6mm mesostructurewere firstly synthetized by self-assembling of hexadecyltrimethylammonium bromide(CTAB) and tetraethyl orthosilicate (TEOS) under basic condition in the presence ofPluronic F127as a dispersant; And then the surfaces of as-made MSNs werefunctionalized with amino groups by grafting3-aminopropyltriethoxysilane (APES);After removal of the template by extraction, the amino group surface-functionalizedMSNs with void pores can be harnessed as reservoirs to encapsulate the anticancer drugs(TPT) into the pores, which are unstable and release drug molecules under physiologicalcondition; Finally, the TPT-loaded MSN-NH2(MSN-NH2-TPT) was then capped by theCPs of zinc and1,4-bis (imidazol-1-ylmethyl) benzene (BIX) grown on the MSNssurfaces, giving rise to MSN-NH2-TPT@BIX-Zn architecture. The breakage ofcoordination bond in the coating layer, triggered by a reduction in external pH, leads tothe ablation of nanolayers and the exposure of MSN-NH2-TPT into the surroundingenvironment and subsequent release of drug from the MSNs. Free TPT, MSN-NH2andMSN-NH2@BIX-Zn have no obvious effect on cell viability, while a high cytotoxicactivity of CPs coated MSNs loading drugs against HeLa cells was demonstrated by invitro cell assays. The CLSM and TEM images results confrmed that CPs coated MSNswere more readily internalized by HeLa cells through endocytosis mechanism, thebreakage of coordination bond in the nanolayers, triggered by a reduction in endosomeand lysosome compartments, leads to the collapse of nanolayers and the exposure of MSN-NH2-TPT into the acidic organelles and subsequent release of drug from the MSNs.Chapter5. The conclusions for this research were summarized and the future workfor the continuous development of this field were given.