Design of self-assembled zein-based nanoparticles as an effective drug carrier and transporter
Description
TitleDesign of self-assembled zein-based nanoparticles as an effective drug carrier and transporter
Date Created2019
Other Date2019-01 (degree)
Extent1 online resource (132 pages) : illustrations
DescriptionCancer is the second leading cause of death in the world. General characteristics of tumors include abnormal blood vessels and lack of lymphatic system. Due to large sizes, drug-loaded delivery systems cannot diffuse out the tumor blood vessels, as a result of progressive accumulation: the EPR effect. That’s the main reason to utilize nanoparticles in cancer therapy. Besides, the size, shape, surface chemistry and targeting groups of nanoparticles are important in controlling biodistribution and cellular internalization of engineered nanoparticles.
Zein specifically acts as reservoirs for lipophilic bioactive substances or drugs due to the strong hydrogen bond and hydrophobic interaction between nutraceutical and proteins. Zein nanoparticles (NPs) are commonly prepared via phase separation method. Although it is a relatively easy technique, the resultant zein colloidal dispersion usually form poorly redispersable aggregates and sediments after drying. Also, individual zein NPs exhibited a burst drug release profile at physiological conditions due to the swelling of the zein NPs and the drug cannot tightly bind to zein particles. Therefore, we aim to design novel zein-based NPs to enhance the stability and sustained release of individual zein NPs. At the meantime, the cellular uptake and bioefficacy of the encapsulated drug were also discussed in this work.
In the first part of this work, hydrophilic carboxymethyl konjac glucomannan and calcium ion crosslinking were used to modify the surface of zein nanoparticles, therefore zein- carboxymethyl konjac glucomannan-calcium (ZCC) NPs were assembled. As a result, ZCC NPs showed good stabilities in cell culture medium at 37 °C, and enhanced pH stability at a range from 5.0 to 8.5 and lower surface hydrophobicity. The endocytic pathway of ZCC NPs is cell-line dependent, and ZCC NPs enhanced the cellular uptake through dynamin- mediated endocytosis can be assigned to clathrin-mediated endocytosis in HT29 cells. And the stability and cellular uptake were enhanced compared to individual zein NPs.
Because of the anti-inflammation and anti-cancer properties, andrographolide (AG) and its derivatives, which are labdane diterpenoid compounds extracted from Andrographis paniculata Nees, are often used as herbal drugs in Asian countries. AG sparingly soluble in water (3.29μg/ml at 25 °C), which restricts its therapeutic use due to low bioavailability by oral administration. ZCC NPs was used as a drug carrier for AG to enhance the water solubility and the bioefficacy. Importantly, ZCC NPs loaded AG were shown effectively decreasing the cancer cell population and resulting cell death. The efficacy of AG to regulate the in vitro NF-κB expression was notably enhanced by the ZCC nanoparticle delivery system due to enhanced dose efficiency resulting from better solubility, transportability and reduced toxicity. In these preliminary studies, ZCC NPs were proved to be appealing delivery systems for hydrophobic bioactive compounds.
Efficient pH-sensitive delivery systems sensitively response to subtle pH variations in the tumor microenvironment. In this paper, we utilized the acid-sensitive bonds between metal ions and dihydromyricetin (DMY) and designed a pH-sensitive zein-based delivery system. The self-assembled zein NPs were coated with a DMY-Zn2+ coordinated bonding layer. Z-DMY/ZnII NPs not only acted as an efficient drug carrier, but also a highly pH-responsive drug release system. Therefore, Z-DMY/ZnII NPs had a better sustained release compared with individual zein NPs. Moreover, Z-DMY/ZnII NPs demonstrated excellent cellular uptake by HeLa cells. Z-DMY/ZnII NPs effectively inhibited the cancer cell growth and exhibited an efficient anti-cancer activity toward HeLa cells. As a result, Z-DMY/ZnII NPs acts as a promising pH-responsive food-grade colloidal delivery system encapsulating hydrophobic nutraceuticals in cancer therapy.
NotePh.D.
NoteIncludes bibliographical references
Noteby Xunan Zhu
Genretheses, ETD doctoral
Languageeng
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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