Advantages of Heparin as a Nano-Drug Carrier Material
Natural polysaccharides have the characteristics of high safety, good stability and degradability, and are easy to be chemically modified and modified, such as heparin, chitosan, hyaluronic acid and hydroxyethyl starch, and are widely used in nano-drug delivery systems. However, chitosan has poor water solubility and needs to be modified with polyethylene glycol; although hyaluronic acid can improve the selectivity of drugs to tumor cells, it is easy to accumulate in the liver and kidney and cause toxic side effects. Both hydroxyethyl starch and heparin have good hydrophilicity and biocompatibility, but heparin also has its unique natural advantages: 1. Inhibition of angiogenesis-mediated anti-tumor activity; 2. Anti-tumor metastasis activity; 3. Tumor targeting.
The growth and development of tumors depend on an abnormal angiogenic system. Angiogenesis is co-regulated by a variety of growth factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (βFGF) and platelet derived growth factor (PDGF). These growth factors bind to heparan sulfate proteoglycans (HSPGs) present in endothelial cells and extracellular matrix to promote endothelial cell proliferation and migration. Heparin (especially LMWH) binds to a variety of growth factors through the heparin binding domain, competitively inhibits the binding of growth factors to their endothelial receptors, thereby reducing the angiogenesis induced by βFGF and VEGF, and exerting anti-tumor activity.
Natural products such as ursolic acid (UA), gambogic acid (GA), and quercetin (Qu) have broad antiangiogenic activities, but poor water solubility and instability limit their potential. Combining heparin with these anti-angiogenic drugs through chemical coupling can produce a synergistic effect and improve the anti-angiogenic activity and tumor-inhibiting effect of the drugs.
Anti-tumor Metastatic Activity
VEGF-C and its receptor VEGFR-3 play an important role in the regulation of lymphangiogenesis. The signal cascade generated by the combination of the two can induce lymphangiogenesis, proliferation, migration and tube formation of lymphatic endothelial cells. Heparin can inhibit lymphangiogenesis by blocking the VEGFC signaling pathway, thereby reducing the incidence of tumor metastasis. In addition, heparin has good affinity with P- and L-selectin, so it can competitively inhibit the binding of selectin and related ligands, thereby inhibiting the adhesion of tumor cells and platelets mediated by selectin, and reducing the metastasis of tumor cells and invasion. Heparin can also destroy the organization of actin stress fibers in tumor cells and hinder the interaction between platelets and tumor cells, thereby hindering platelet-induced epithelial-mesenchymal transition (EMT) and inhibiting tumor metastasis.
Tumor Targeting
Heparin has a strong affinity with vascular endothelial cells and vascular growth factors abundant in tumor sites, so heparin and its derivatives have natural tumor targeting properties, which are beneficial to the enrichment of drugs in tumor sites. Existing studies have shown that mitoxantrone (MTO)-prednisolone (PLP) co-encapsulated liposomes were prepared by liposome fusion technology, and then low molecular weight heparin-deoxycholic acid conjugate (LHD) was used as targeting ligands. The results showed that LHD enhanced the tumor targeting of the drug in vivo, allowing the liposome to exhibit better tumor-suppressive effects in melanoma and colon cancer models.
Surface Modification of Heparin for Nanomedicine
Heparin is a negatively charged endogenous polysaccharide, which can be used for surface modification of nano-drugs by electrostatic adsorption or chemical bonding, so as to play the following roles: 1. Improve the water solubility of drugs; 2. Inhibit protein conditioning and reduce Phagocytosis of the reticuloendothelial system (RES), prolonging the circulation time of drugs in the body; 3. Shielding the positive charge of nanoparticles, preventing particle aggregation, improving the stability of nanoparticles and reducing toxicity; 4. Heparin has anticoagulant properties , Anti-tumor growth and metastasis activity, can synergize with a variety of therapeutic components to exert stronger anti-tumor effect.
Heparin as a Carrier Scaffold for Nanomedicine
Heparin is a water-soluble natural anionic polysaccharide with good biocompatibility and strong affinity with a variety of proteins, so it can be used as a skeleton material for the construction of drug carriers, and realizes hydrophobic drugs, proteins, genes, etc. efficient delivery of biotherapeutic molecules. In addition, there are a large number of free hydroxyl groups, carboxyl groups and sulfate groups in heparin molecules, which can be used to connect various functional molecules and enrich the functions of nanoparticles.