<p>Dual-Ligand Functionalized Core-Shell Chitosan-Based Nanocarrier for Hepatocellular Carcinoma-Targeted Drug Delivery</p>

Abstract

Introduction: Hepatocellular carcinoma represents a major health problem with the related death numbers still increasing. Active targeting is considered an attractive choice for the development of selective therapeutics with limited side effects and improved efficiency. In this study, we report the design, development and evaluation of a novel dual-ligand functionalized core-shell chitosan-based nanocarrier for the selective delivery of doxorubicin (DOX) for treatment of hepatocellular carcinoma (HCC). Methods: Following factorial design experiments, DOX was initially complexed with negatively charged carboxymethyl chitosan-g-poly(acrylate) and then the complex was coated with a positively charged dual-ligand (lactobionic acid and glycyrrhetinic acid)conjugated chitosan. The developed active targeting system was then tested in vitro on Hep-G2 cells using flow cytometry and fluorescence imaging. Results: The obtained results proved the ability of the dual-ligand system to enhance the intracellular uptake of the drug by 4-fold and 8-fold after 4 hrs and 24 hrs of incubation, respectively. The efficiency of the dual-ligand functionalized nanoparticles was also tested in vivo on Wistar rats with induced liver tumors. Testing of serum biomarkers (albumin, creatinine, urea, alpha fetoprotein, ALT, AST and ALP) in addition to histopathological microscopic examination of liver, kidney and heart tissues confirmed the enhanced safety of the developed targeted nanocarrier system compared to the conventional DOX. Discussion: The developed targeted system showed improved intracellular drug delivery and uptake as well as enhanced safety profile. The nanoparticles were formed based on electrostatic interactions providing the flexibility that allows their use as a model for delivery of other drugs and other targets.

Morus nigra L. extract prolongs survival of rats with hepatocellular carcinoma

“…Therefore, it is reasonable to expect that MNE does not raise blood glucose in HCC rats. In the present work, no significant changes were observed in urea and creatinine levels of HCC rats, which were also reported by some other researchers (Hefnawy, Khalil, Arafa, Emara, & El-Sherbiny, 2020;Kumar, Vijayalakshmi, & Saravanan, 2019).…”

Glycyrrhizic Acid and Its Hydrolyzed Metabolite 18β-Glycyrrhetinic Acid as Specific Ligands for Targeting Nanosystems in the Treatment of Liver Cancer

“…Another way is the conjugation of GA with CS by a click reaction, by the activation of GA through the formation of the O-acylisourea ester and its stabilization with the addition of N-hydroxysuccinimide, and then favoring the formation of amine in the presence of CS [87]. The conjugation was confirmed by 1 H-NMR and FTIR analyses.…”

“…In addition to the determination of average particle size performed by dynamic light scattering (DLS) and transmittance electronic microscopy (TEM), other techniques have also been used in order to confirm the synthesis of ligands with different types of nanosystems. In studies with GL and GA, nuclear magnetic resonance (NMR) [80][81][82][83][84][85] and Fourier transform infrared spectroscopy (FTIR) [81,82,[86][87][88] were commonly used.…”

Chitosan Nanoparticles at the Biological Interface: Implications for Drug Delivery

“…Kai Jiang et al utilized the pH-sensitive nature of chitosan polymers to deliver a hydrophobic drug, namely ursolic acid, into endosomes (pH < 5.5) and reported the suppression of cancer cell growth [72]. The derivatization of chitosan polymers broadens opportunities such as dual-ligand functionalization [73], co-polymerization to develop amphoteric block co-polymers [11], co-delivery of drug molecules and oligonucleotides [68], and improving solubility [70]. Zhu et al reported that chitosan derivative N-succinyl-N -octyl chitosan self-assembles to form micelles due to its amphipathic nature, and conjugation with folic acid imparts a targeting nature to the micelles [74].…”