Functional Polysaccharide Nanomaterials (PS-NMs) for the reduction of elevated serum cholesterol & progressive diet-induced obesity (DIO): A 'novel' application of PS-NMs.
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Date
2022-04-28
Authors
Islam, Muhammad Shahidul
Journal Title
Journal ISSN
Volume Title
Publisher
University of Waterloo
Abstract
High plasma cholesterol (hypercholesterolemia) is a potential consequence of obesity that is becoming a major public health challenge. Excess caloric intake without a corresponding increase in energy expenditure is believed to be the major contributing factor to weight gain among Canadians leading to hypercholesterolemia. This ‘silent killer’, hypercholesterolemia is characterized by increased low-density lipoprotein cholesterol (LDL–C) that increases the risk of cardiovascular diseases which are still the leading cause of death and disability worldwide. Bile acid sequestrants (BAS), such as cholestyramine are positively charged indigestible resins that have been widely used for the treatment of hypercholesterolemia. However, it has many side effects, such as increasing the triglycerides level, constipation, flatulence, and abdominal pain all of which are due to its hydrophobic nature and large dose required for treatment.
Biopolymers are naturally occurring polymers and the polysaccharides (PS) is one of the subclasses, including cellulose, hemicellulose, starch, lignin, and chitin chitosan, gums etc. Among the PSs, cellulose is the most abundant and chitin the second. The amorphous regions of cellulose and chitin can be dissociated by acid hydrolysis, yielding high aspect-ratio rigid rod-like nanocrystals called cellulose nanocrystals (CNC) and chitin nanowhiskers (Cht.NWs). Moreover, chitosan (CS), which has a myriad of biomedical applications reported over the past centuries, can also be derived from chitin. All these nanoparticles (NPs) are proven to be excellent candidates for various applications as they possess S.M.A.R.T.© characteristics, which are sustainable, modifiable (due to the abundant surface primary hydroxyl groups), active (highly dispersible in water and shows physicochemical activity) renewable (easy surface modification making them renewable), and non-toxic (being natural, they are biocompatible). Thus, there is a significant motivation to modify these NPs with different cationic functional groups or polymers providing a platform to develop more efficacious natural polysaccharide nanomaterial (PS-NM) as BASs.
In this Ph.D. study, PS-NMs based biocompatible BASs were synthesized via the grafting of compounds with different quaternary ammonium groups (QAGs) (e.g. glycidyl trimethylammonium chloride i.e. GTMAC) or amino polymers (e.g. poly[2-(dimethylamino) ethyl methacrylate] i.e. PDMAEMA) onto CNCs, Cht.NWs and/or CS yielding quaternized/cationic NPs (Q-NP/C-NPs) with varying degrees of surface charge densities. The syntheses suggested that the (CNC/Cht.NW):(QAG containing compounds) of 1:10 yielded the largest surface charges. After purification, these Q-NPs were then characterized and evaluated using FTIR, dynamic and static light scattering (for structure confirmation, size, and zeta potential), potentiometric titration (for QAG or tertiary amino groups content, binding capacity), transmission electron microscopy (for the morphology of NPs), and UV-Vis spectroscopy. Most of the synthesized NPs possessed good aqueous dispersibility with diameters (DH) within the nano range (< 1µm), and the zetapotential (ZP) to be within the colloidally stable range (≥ ± 25 mV). The quaternary ammonium groups (QAGs) validated their high ZP values and the QAGs were from 0.8 mmol/g to 2.9 mmol/g.
The PS based NMs were strongly cationic, and they could be used to sequester negatively charged ligands (eg., anionic dyes or impurities, the bile salts from human GI systems, etc.) from aqueous samples in effluent treatment or reduced the LDL–C levels. Initially, the batch adsorption tests (BATs) with all these NMs were conducted using methyl orange (MO), a negatively charged dye as a model compound due to the lack of available techniques to quantify bile salts. The Qmax determined from the Langmuir Isotherm fitting model (~ 200 mg/g) strongly suggested that the nano-systems were excellent sequestrants for anionic compounds. Their scavenging performance for bile salt were evaluated using sodium cholate (SC or Na-Ch), one of the bile salts/acids (BS/BA) in the human body. The Qmax values were higher (Qmax for most of the NMs were > 300 mg/g) than MO, suggesting that the scavenging effects for SC were higher due to the combination of all three binding mechanisms, namely electrostatic, hydrophobic, and hydrogen bonding.
An electrochemical-based sensor for detecting SC was developed to quantify free or unbound BA/BSs in aqueous solutions. The Qmax data obtained from the BAT using this sensor showed promising binding of NMs with SC that further reinforced that all the NMs developed in this study were active bile acid sequestrants. In addition, from the carbon dioxide evolution analysis using Baker’s yeast, the PS-NM developed in this doctoral research displayed toxicity below that of cholestyramine, the widely used BAS in the market. Binding kinetics experiments showed the adsorption of SC onto these NPs was faster than cholestyramine, which suggested that the PS-NMs could be the BASs of choice and in vivo animal studies should be pursued.
Description
Keywords
Bile acid sequestrants, Cholesterol reduction, Biopolymer, Sustainable nanomaterials, LDL-C, Cellulose nanocrystals, Chitin nanowhiskers/nanofibers, Chitosan, SMART Nanomaterials, Diet Induced Obesity (DIO)