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A Facile Synthesis and Application of Protein-Shelled Microbubbles as Temperature-Responsive Drug Carriers with the Aid of a Poly(N-isopropylacrylamide)-block-(acrylic acid) Shell Open Access


Other title
Type of item
Degree grantor
University of Alberta
Author or creator
Ma, Xiaochen
Supervisor and department
Liu, Qingxia (Chemical Engineering)
Examining committee member and department
Hao Zhang (Chemical Engineering)
Phillip Choi (Chemical Engineering)
Liu, Qingxia (Chemical Engineering)
Yang Liu (Civil Engineering)
Department of Chemical and Materials Engineering
Chemical Engineering
Date accepted
Graduation date
2017-06:Spring 2017
Master of Science
Degree level
In this study, a novel synthesis of proteinaceous microbubbles (MBs) was introduced in an effort to substantially lengthen the short lifetime of the sonochemically-synthesized microbubbles using surface-treated proteins. Bovine serum albumin (BSA) as a representative protein, was treated with 2-iminothiolane hydrochloride (the Traut’s reagent) to convert surface amines to thiols before the synthesis of microbubbles. At a moderate high molar excess of the Traut’s reagent, a roughly bimodal size distribution of MBs was shown, concentrated at 0.5 and 2.5 µm. The 0.5 µm portion quickly vanished while the 2.5 µm portion gradually shrank to ~850 nm in ~3 days, stabilized at this size at 4 °C for several months. The 20 times molar excess of the Traut’s reagent to BSA was determined to be the optimal reaction ratio because of the largest long-lived portion and the greatest shell thickness of the produced MBs. Characterizations of MBs by Fourier transform infrared (FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS) showed the presence of free amines and thiols remaining on the surface of MBs. The reactivities of these functional groups were demonstrated by either electrostatically interacting with the alumina and the silica surfaces or chemically bonding with the gold surface in quartz crystal microbalance with dissipation monitoring (QCM-D) measurements. To demonstrate the potential of being utilized as drug carriers, MBs were used to load a demo drug, doxorubicin (Dox) electrostatically. To optimize the loadings of Dox onto MBs, their loading efficiencies were systematically compared using UV/Vis and fluorescence spectrophotometer, by varying the presence of the pre-coated gold nanoparticles (AuNPs), pH, dosages of MBs, temperature, and time. A temperature-sensitive polymer, poly(N-isopropylacrylamide-block-acrylic acid) (poly(NIPAM-b-AAc), was used to encapsulate the Dox-loaded MBs to prevent any premature release of the loaded Dox. With a fine-tuned lower critical solution temperature (LCST) of 39 °C, the Dox-loaded MBs with a poly(NIPAM-b-AAc) shell exhibited a temperature-responsive switch that initiated the release of Dox from ~20% to ~90% when the temperature was elevated 37 to 39 °C in in-vitro release testing (IVRT). On the other hand, the shell-free carriers, such as Dox-loaded MBs, Dox-loaded AuNPs-coated MBs, did not show such a temperature response. The further kinetic study of the Dox-loaded MBs with a poly(NIPAM-b-AAc) shell revealed that the release of Dox followed the Korsmeyer-Peppas model, governed by the Fickian diffusion and the conformational change of the polymer shell.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Ma, X., Bussonniere, A., & Liu, Q. (2017). A facile sonochemical synthesis of shell-stabilized reactive microbubbles using surface-thiolated bovine serum albumin with the Traut’s reagent. Ultrasonics Sonochemistry, 36, 454-465Ma, X., Liu, Q. Preparation of poly(N-isopropylacrylamide)-block-(acrylic acid)-encapsulated proteinaceous microbubbles for delivery of doxorubicin.Colloids and Surfaces B: Biointerfaces. In Press.

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