Optimized synthesis of glycyrrhetinic acid-modified chitosan 5-fluorouracil nanoparticles and their characteristics

Abstract

The nanoparticle drug delivery system, which uses natural or synthetic polymeric material as a carrier to deliver drugs to targeted tissues, has a broad prospect for clinical application for its targeting, slow-release, and biodegradable properties. Here, we used chitosan (CTS) and hepatoma cell-specific binding molecule glycyrrhetinic acid to synthesize glycyrrhetinic acid-modified chitosan (GA-CTS). The synthetic product was confirmed by infrared (IR) spectra and hydrogen-1 nuclear magnetic resonance. The GA-CTS/5-fluorouracil (5-FU) nanoparticles were synthesized by combining GA-CTS and 5-FU and conjugating 5-FU onto the GA-CTS nanomaterial. The central composite design was performed to optimize the preparation process as CTS:tripolyphosphate sodium (TPP) weight ratio =5:1, 5-FU:CTS weight ratio =1:1, TPP concentration =0.05% (w/v), and cross-link time =50 minutes. GA-CTS/5-FU nanoparticles had a mean particle size of 193.7 nm, a polydispersity index of 0.003, a zeta potential of +27.4 mV, and a drug loading of 1.56%. The GA-CTS/5-FU nanoparticle had a protective effect on the drug against plasma degrading enzyme, and provided a sustained release system comprising three distinct phases of quick, steady, and slow release. Our study showed that the peak time, half-life time, mean residence time and area under the curve of GA-CTS/5-FU were longer or more than those of the 5-FU group, but the maximum concentration (C max ) was lower. We demonstrated that the nanoparticles accumulated in the liver and have significantly inhibited tumor growth in an orthotropic liver cancer mouse model.

Effect of co-administration of Bee honey and some chemotherapeutic drugs on dissemination of hepatocellular carcinoma in rats

“…While, treatment with both honey and 5-FU showed improvement in cell structure with deficient collagen deposition. Our findings are in accordance with Abdel-Hamid et al [76], Cheng et al [125].…”

Current understanding of interactions between nanoparticles and the immune system

“…Liposomes were shown to reduce the antigenicity of recombinant coagulation factor FVIII and to protect encapsulated protein from the antibodies formed in response to the traditional formulation of this therapeutic protein (Ramani et al, 2008). Other success stories demonstrating the reduction of immunotoxicity by reformulation of a traditional drug using nanotechnology-based carriers include the encapsulation of therapeutic antisense oligonucleotides into liposomes to prevent activation of the complement system (Klimuk et al, 2000) and to reduce cytokine-mediated toxicities (Yu et al, 2013), as well as the reformulation of the small-molecule oncology drug 5-fluorouracil, using chitosan nanoparticles to decrease its hematotoxicity (Giacalone et al, 2013; Cheng et al, 2014). …”

Pre-clinical immunotoxicity studies of nanotechnology-formulated drugs: Challenges, considerations and strategy

“…Likewise, the therapeutic protein tumor necrosis factor alpha (TNFα) failed in clinical studies due to the systemic immunostimulation, but after reformulation using polyethylene glycol (PEG) coated colloidal gold nanoparticles it has successfully passed through Phase I trials [9]. Pre-clinical success stories demonstrating the reduction of immunotoxicity by reformulating a traditional drug using nanotechnology carriers include the formulation of 5-fluorouracil (5-FU) using chitosan nanoparticles to decrease the hematotoxicity of the drug [10, 11] and the encapsulation of therapeutic antisense oligonucleotides into liposomes to prevent activation of the complement [12] and to reduce cytokine-mediated toxicities [13]. While reformulation using nanoparticles offers the potential to reduce immunotoxicity, ignorance of the immunological properties of a nanotechnology carrier may lead to exaggeration of the drug’s immunotoxicity.…”