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Design, Synthesis and Loading Potential of a New Family of Nonionic Amphiphilic Dendro-Calix[4]arene

Author: Khalid Khan
Tutor: ZhengYanSong
School: Huazhong University of Science and Technology
Course: Organic Chemistry
Keywords: Calix[4]arene derivatives Self-assembly Micelles Transport Potential Naproxen Ibuprofen Morphological Changes
CLC: TQ460.1
Type: PhD thesis
Year: 2012
Downloads: 2
Quote: 0
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Abstract


During the treatment of specific diseases certain drugs are facing serious problems i.e. limited (water/membrane) solubility, low chemical stability, slow serum clearance, dissolution and release rate, degradation of drug before reaching the target site, and cytotoxicity. To minimize these factors, and enhance the bioavailability and potency of these drugs have been a challenging area in the field of medicine and biopharmaceutical. Different nano-structures such as micelles, vesicles, solid lipid nanoparticles (SLNs) have been applied as drugs carriers. This thesis mainly deals with the synthesis of a new family of amphiphilic dendro-calix[4]arene, their self-assemble into nano-vehicles (micelles) and their potential as drug solubility enhancer.It is quite evident from the first chapter of this thesis that the functionalized calix[n]arenes have shown strong potential to carry drug molecules in four ways i.e.(1) in the form of inclusion complexes (2) in the cavity of the micelles and vesicles (3) encapsulated in SLNs based on calix[n]arenes scaffold (4) calix[n]arene bearing pharmacophore. In the case of inclusion complexes, the inclusion environment around the drugs molecules is originated by both ionic and nonionic calix[n]arene derivatives.The second chapter deals with the design, synthesis and characterization of amphiphiles11a-c and monomeric analogue15. Transmission electron micrscopy (TEM), Dynamic light scattering (DLS) and molecular modeling proved the micellar nature of all amphiphiles lla-c. Fluorescence assay investigated the critical micelle concentrations (CMC) of calix[4]arene derivatives lla-c. Further the effect of variation in alkyl chain length on the CMC, morphology of nanoparticles and solubility of11a-c in water were studied.The third chapter provides the detail discussion about the comparative studies of the loading potential of11a-c and monomeric analogue15. UV-analysis showed that all amphiphiles11a-c tremendously enhance the water solubility of AY. It was also found that the loading potential of11a-c is a function of alkyl chain length and the intrinsic cyclic nature of calix[n]arene framework.1H NMR assays and UV titration were further carried out to verify the role of intrinsic cyclic nature of calix[n]arene and the alkyl chain length in the loading potential. In addition, by varying pH, no AY molecules were released from11a-c nanoparticles due the populated hydrophilic portion at the upper rim of calix[4]arene.The fourth chapter focuses on the ability of11a-c as drug solubility enhancer and the effect of drugs on the morphology of micelles. It was acquired that all amphiphiles11a-c significantly increased the solubility of the hydrophobic drugs NAP and IBP in water. Fluorescence analyses proved the interactions between11a-c and drug molecules. The solubility of NAP and IBP in the aqueous solution of11a-c is a function of alkyl chain length and cyclic core of calix[4]arene scaffold. DLS and TEM analyses also confirmed the encapsulation of drug molecules in11a-c micelles but it was quite obvious from TEM images that drug molecule is included in the upper branched substituents of11a-c instead of micelle cavity. Molecular modeling study also supported the above assumption. Furthermore, upon addition of drugs the morphology of micelles changed from solid into hollow micelles or linear ones by reversing the direction of tribranched3,4,5-TMEEE benzamide substituent of11a-c from folded to stretched state. Hydrogen bonding and π-π stacking were responsible for the inclusion complexes. Finally, fifth chapter is about total summary of the work and future perspectives.

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