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

Author :Khalid Khan

Tutor:ZhengYanSong
School :Huazhong University of Science and Technology
CLC :TQ460.1
TYPE :PhD thesis
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Year:2012
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 - stacking were responsible for the inclusion complexes. Finally, fifth
chapter is about total summary of the work and future perspectives.