Asialoglycoprotein receptor mediated hepatocyte targeting - strategies and applications.

Patients treated with conventional cancer chemotherapy suffer from side effects of the drugs due to non-selective action of chemotherapeutic drugs to normal cells. Active targeting nanoparticles that are conjugated to targeting ligands on the surface of nanoparticles play an important role in improving drug selectivity to the cancer cell. Several chemotherapeutic drugs and traditional/herbal medicines reported for anticancer activities have been investigated for their selective delivery to cancer cells by active targeting nanoparticles. This systematic review summarizes reports on this application. Literature search was conducted through PubMed database search up to March 2017 using the terms nanoparticle, chemotherapy, traditional medicine, herbal medicine, natural medicine, natural compound, cancer treatment, and active targeting. Out of 695 published articles, 61 articles were included in the analysis based on the predefined inclusion and exclusion criteria. The targeting ligands included proteins/peptides, hyaluronic acid, folic acid, antibodies/antibody fragments, aptamer, and carbohydrates/polysaccharides. In vitro and in vivo studies suggest that active targeting nanoparticles increase selectivity in cellular uptake and/or cytotoxicity over the conventional chemotherapeutic drugs and non-targeted nanoparticle platform, particularly enhancement of drug efficacy and safety. However, clinical studies are required to confirm these findings.

/pdf/application-of-active-targeting-nanoparticle-delivery-system-1idyav39pw.pdf

Application of active targeting nanoparticle delivery system for chemotherapeutic drugs and traditional/herbal medicines in cancer therapy: a systematic review.

Polysaccharide based nanogels in the drug delivery system: Application as the carrier of pharmaceutical agents

Nanoparticulate drug/gene carriers have gained much attention in the past decades because of their versatile and tunable properties. However, efficacy of the therapeutic agents can be further enhanced using naturally occurring materials-based nanoparticles. Polysaccharides are an emerging class of biopolymers; therefore, they are generally considered to be safe, non-toxic, biocompatible and biodegradable. Considering that the target of nanoparticle-based therapeutic strategies is localization of biomedical agents in subcellular compartments, a detailed understanding of the cellular mechanism involved in the uptake of polysaccharide-based nanoparticles is essential for safe and efficient therapeutic applications. Uptake of the nanoparticles by the cellular systems occurs with a process known as endocytosis and is influenced by the physicochemical characteristics of nanoparticles such as size, shape and surface chemistry as well as the employed experimental conditions. In this study, we highlight the main endocytosis mechanisms responsible for the cellular uptake of polysaccharide nanoparticles containing drug/gene.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jcmm.13110

Overviews on the cellular uptake mechanism of polysaccharide colloidal nanoparticles.

Pectin, a complex class of plant polysaccharides, is composed of a galacturonan backbone and neutral sugar side chains. Natural pectin is reported to prevent colon cancer as a dietary fiber (DF). To enhance its bioavailability and bioactivity, pectin was modified into bioavailable modified pectin fragments (MPs) with low molecular mass. Also, MPs had low degrees of esterification (DE) which is reported to inhibit tumor growth, induce apoptosis, suppress metastasis, and modulate immunological responses. Antitumor activity of MPs chiefly arises from intervention in ligand recognition by galectin-3 (Gal-3). In addition, pectin is a suitable vehicle for anti-cancer drug delivery systems, due to its abundant modifiable functional groups and special physicochemical properties. Here, we summarize the structural features, bio-absorption and antitumor mechanisms and the structure-activity relationship of MPs. We also offer prospects and challenges for developing pectin into nutraceuticals or drugs.

Pectin in cancer therapy: A review

The fabrication and evaluation of a natural pectin-based drug delivery system are reported in this study. The drug delivery system displays specific active targeting ability to hepatocellular carcinoma due to the presence of excess galactose residues in the polymer structure as the natural targeting ligands. The system was prepared under very mild conditions in an aqueous medium containing Ca(2+) and CO3(2-) ions, generating uniform pectin-based nanoparticles with an average diameter of 300 nm, and the drug-loading content of anticancer drug 5-fluorouracil (5-FU) is around 24.8%. Cytotoxicity study of the 5-FU-loaded nanoparticles (5-FU-NPs) in HepG2 and A549 cell lines demonstrated their greater potency in killing cancer cells with overexpressed asialoglycoprotein receptor (ASGPR) on the cell surface, compared to that of the free drug. Pharmacokinetics study using Sprague-Dawley (SD) rats further confirmed that the drug-loaded nanoparticles showed a much longer half-life in the circulation fluids than the free drug. Tissue distribution was investigated on Kunming mice, and the results also demonstrated that the 5-FU-NPs has a long circulation effect. Taken together, the pectin-based drug delivery systems exhibit size-induced prolonged circulation as well as ASGP receptor-mediated targeting ability to cancer cell lines; therefore, it is a promising platform for the treatment of hepatocellular carcinoma.

In Vitro and in Vivo Evaluation of Pectin-Based Nanoparticles for Hepatocellular Carcinoma Drug Chemotherapy

A novel type of macromolecular prodrug delivery system is reported in this research. The N-galactosylated-chitosan-5-fluorouracil acetic acid conjugate (GC-FUA) based nanoparticle delivery system was evaluated in vitro and in vivo. Biocompatibility of GC-FUA-NPs was screened by BSA adsorption test and hemolysis activity examination in vitro. Cytotoxicity and cellular uptake study in HepG2 and A549 cells demonstrated that compared to free 5-Fu, the GC-FUA-NPs play great function in killing cancer cells for the cell endocytosis mediated by asialoglycoprotein receptor (ASGPR), which overexpresses on the cell surface. Pharmacokinetics study further illustrated that the drug-loaded nanoparticles has a much longer half-time than free 5-Fu in blood circulation in Sprague-Dawley (SD) rats. Tissue distribution was investigated in Kunming mice, and the result showed that the GC-FUA-NPs have a long circulation effect. The obtained data suggested that GC-FUA-NP is a very promising drug delivery system for efficient treatment of hepatocellular carcinoma.

https://tandfonline.com/doi/pdf/10.1080/10717544.2016.1264499

In vitro and in vivo evaluation of macromolecular prodrug GC-FUA based nanoparticle for hepatocellular carcinoma chemotherapy.

In this study, a novel type of macromolecular prodrug, N-galactosylated chitosan (GC)−5-fluorouracil acetic acid (FUA) conjugate based nanoparticles, was designed and synthesized as a carrier for hepatocellular carcinoma drug delivery. The GC–FUA nanoparticles were produced by an ionic crosslinking method based on the modified ionic gelation of tripolyphosphate with GC–FUA. The structure of the as-prepared GC–FUA was characterized by Fourier transform infrared and 1H-NMR analyses. The average particle size of the GC–FUA nanoparticles was 160.1 nm, and their drug-loading content was 21.22 ± 2.7% (n = 3). In comparison with that of the freshly prepared nanoparticles, this value became larger after 7 days because of the aggregation of the GC–FUA nanoparticles. An in vitro drug-release study showed that the GC–FUA nanoparticles displayed a sustained-release profile compared to 5-fluorouracil-loaded GC nanoparticles. All of the results suggest that the GC–FUA nanoparticles may have great potential for anti-liver-cancer applications. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 42625.

Fabrication of galactosylated chitosan–5‐fluorouracil acetic acid based nanoparticles for controlled drug delivery

The development of slow release nano-sized carriers for efficient antineoplastic drug delivery with a biocompatible and biodegradable pectin-based macromolecular pro-drug for tumor therapy has been reported in this study. Pectin-doxorubicin conjugates (PDC), a macromolecular pro-drug, were prepared via an amide condensation reaction, and a novel amphiphilic core-shell micell based on a PDC macromolecular pro-drug (PDC-M) was self-assembled in situ, with pectin as the hydrophilic shell and doxorubicin (DOX) as the hydrophobic core. Then the chemical structure of the PDC macromolecular pro-drug was identified by both Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy ((1)H-NMR), and proved that doxorubicin combined well with the pectin and formed macromolecular pro-drug. The PDC-M were observed to have an unregularly spherical shape and were uniform in size by scanning electron microscopy (SEM). The average particle size of PDC-M, further measured by a Zetasizer nanoparticle analyzer (Nano ZS, Malvern Instruments), was about 140 nm. The encapsulation efficiency and drug loading were 57.82% ± 3.7% (n = 3) and 23.852% ±2.3% (n = 3), respectively. The in vitro drug release behaviors of the resulting PDC-M were studied in a simulated tumor environment (pH 5.0), blood (pH 7.4) and a lysosome media (pH 6.8), and showed a prolonged slow release profile. Assays for antiproliferative effects and flow cytometry of the resulting PDC-M in HepG2 cell lines demonstrated greater properties of delayed and slow release as compared to free DOX. A cell viability study against endothelial cells further revealed that the resulting PDC-M possesses excellent cell compatibilities and low cytotoxicities in comparison with that of the free DOX. Hemolysis activity was investigated in rabbits, and the results also demonstrated that the PDC-M has greater compatibility in comparison with free DOX. This shows that the resulting PDC-M can ameliorate the hydrophobicity of free DOX. This work proposes a novel strategy for in-situ one-step synthesis of macromolecular pro-drugs and fabrication of a core-shell micelle, demonstrating great potential for cancer chemotherapy.

The In-Situ One-Step Synthesis of a PDC Macromolecular Pro-Drug and the Fabrication of a Novel Core-Shell Micell.

Targeted Delivery Systems Based on Polymeric Nanoparticles for Biomedical Applications

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