Evaluation of Chitosan Derivative Microparticles Encapsulating Superparamagnetic Iron Oxide and Doxorubicin as a pH-Sensitive Delivery Carrier in Hepatic Carcinoma Treatment: An in vitro Comparison Study

Abstract

We developed a novel, pH-sensitive drug delivery microparticle based on N-palmitoyl chitosan (NPCS) to transport the superparamagnetic iron oxide (SPIO) and anticancer drug doxorubicin (DOX). The characteristics of NPCS were characterized through nuclear magnetic resonance. Our results based on testing of volume swelling in multiple pH aqueous solutions revealed that the modified chitosan had a pH-sensitive property. The morphology and size of the DOX-SPIO/NPCS microparticles were investigated using transmission electron microscopy and scanning electron microscopy. The statistical result of microparticles had diameter of 185 ± 87 nm. Surface chemical moieties of DOX-SPIO/NPCS microparticles were confirmed using attenuated total reflection Fourier transform infrared spectroscopy and indicated the existence of mostly hydrophilic groups such as -OH, -C=O, and -C-O-C-. Transmission electron microscopy revealed the dark contrast of SPIO dots encapsulated in the NPCS matrix. Nuclear magnetic resonance T2-weighted magnetic resonance imaging confirmed that the produced DOX-SPIO/NPCS microparticles still exhibited T2 relaxation durations as short as 37.68 ± 8.69 ms (under administration of 2.5 μg/mL), which is comparable to the clinically required dosage. In the drug release profile, the DOX-SPIO/NPCS drug delivery microparticle was accelerated in an acidic environment (pH 6.5) compared with that in a basic environment. Microparticles in a cytotoxicity assay (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay) revealed that DOX-SPIO/NPCS microparticles had better antitumor ability than did free-form of DOX. Additionally, microparticles loaded with 0.5–5 μg/mL DOX in an acidic environment (pH 6.5) demonstrated higher efficacy against Hep G2 cell growth, possibly because of the swelling effect of NPCS, resulting in volume expansion and easy drug release. Accordingly, these large DOX-SPIO/NPCS microparticles showed potential for application as a pH-sensitive drug delivery system and as chemoembolization particles for hepatic carcinoma therapy.

Engineering and Functionalization of Gelatin Biomaterials: From Cell Culture to Medical Applications

“…Other commonly used materials in generating microparticles include inorganic polymers (hydroxyapatite, calcium phosphate), 142,143 organic polymers (poly-lactic-co-glycolic acid, poly-lactic acid, and poly-ethylene glycol), [144][145][146] natural proteins (collagen, ECM, and gelatin), 95,147,148 and polysaccharides (alginate, chitosan). [148][149][150] The use of these materials for the generation of microparticles have their own advantages and drawbacks. For instance, hydroxyapatite-based microparticles have been widely used for bone regeneration for its natural osteoinductive capacity.…”

Progress in the Development of Chitosan-Based Biomaterials for Tissue Engineering and Regenerative Medicine

“…Controlled anticancer drug release [142] Tumor targeted therapy [143] N-octyl-O-sulfate chitosan Self-assembled polymeric micelles Absorption enhancement of anticancer drug [144,145] Tumor targeted therapy [146][147][148] Increasing stability of drug loaded liposomes [149] 2-[phenylhydrazine (or hydrazine)-thiosemicarbazone]-chitosan Powder Pharmaceutical and food industries [150] (Ser-Ile-Lys-Val-Ala-Val) peptide-modified chitosan Hydrogel Skin substitutes for wound closure in mice [53,151] Galactosylated chitosan (GC) NPs Tumor targeted therapy [152][153][154][155] siRNA delivery [156,157] N-palmitoyl chitosan (NPCS) MPs and micelles Tumor targeted therapy [158,159] O-palmitoyl chitosan (OPC) Liposomes Intestinal drug delivery [160] Hydroxyapatite/CS NPs Drug delivery [161][162][163][164] CS loaded with antioxidant NPs Hydrogel Drug release [165] PEGylated CS NPs Tumor targeted therapy [166][167][168] Chitosan-based vaccine Polyelectrolyte, NPs Intranasal CS-DNA vaccine [169,170] 4. Conclusions CS, as a natural polymer, is actively used in tissue engineering and regenerative medicine as a biomaterial alone, as well as in combination with other polymers.…”

Effects of Chitosan Oligosaccharides on Human Blood Components

“…The great research interest on this oligomer results not only from its physical-chemical properties such as better water solubility and cationic nature at neutral pH, but also from its biological activities, e.g., anti-tumor, anti-inflammatory, anti-oxidant, anti-bacterial activity, biological recognition, and immune enhancing effects (Liu et al, 2009; Lu et al, 2014, 2015; Zhang et al, 2014, 2018; Huang et al, 2016; Kunanusornchai et al, 2016; Mattaveewong et al, 2016; Ding et al, 2017; Kalagatur et al, 2018). These unique properties and activities continuously attract many research interests in drug, food, cosmetics, biomaterials and tissue engineering fields (Swiatkiewicz et al, 2015; Lee et al, 2017; Bai et al, 2018; El-Sayed et al, 2018; Nan et al, 2018).…”