A Novel Charge Reversal Anticancer Drug Delivery Nanoparticles Based On Chitosan-G-PHB Grafted Polymer

Chitosan is a kind of widespread polysaccharide in the biosphere. Due to the biocompatibility, biodegradability and non-toxicity, chitosan has already been widely used as the biological material in the field of food, pharmaceutical and oral drug delivery. Poly-β-butyrolactone (PHB) is a natural polymer produced by the microorganism under unbalanced growth conditions. Due to the excellent biocompatibility and biodegradability, researches about PHB are mainly focused on the application in the field of drug delivery and tissue engineering.In this paper, alkoxide potassium, potassium naphthalene/18-crown-6, zinc lactate and dibutylmagnesium were used as initiators to prepare poly-P-hydroxybutyrate (PHB) by ring opening polymerization of β-butyrolactone. FT-IR, NMR, DSC were used to characterize the structure of the products. It proved that PHB can be prepared by all of these initiators even thourgh there existed differences in both catalytic efficiency and structure of the products. PHB initiated by potassium naphthalene/18-crown-6and dibutylmagnesium repectively was used to prepare the chitosan-g-PHB grafted polymer.The hydrophobic chitosan was obtained through the modification of chitosan with sodium dodecyl sulfate (SDS). The chitosan-g-PHB was obtained via the conjunction of PHB and SDS modified chitosan with the existence of1,6-hexamethylene diisocyanate (HDI). Then the amphiphilic chitosan-g-PHB was prepared by removal of the SDS groups. The pH responsive grafted polymer was prepare by introducing acylamides as well as β-carboxyl-groups into chitosan segments through proper reaction between succinic anhydride and the amino-groups in the chitosan chain. The acrylamides could hydrolyze and reproduce amino-groups along with the change of pH, which triggers the change-conversion on the polymer surface. This kind of charge-converse polymers can be used as a drug delivery system to strength the interaction between the drugs and the cell membrane and endocytosis. At the same time, with pH responsive property it can targetedly delivery toxic anti-cancer drugs into tumor, which has a relatively acid environment than normal tissue, herein increase the drug accumulation in tumor and reduce the damage to normal tissues and cells.1H NMR,13C NMR and FT-IR were used to characterize the structure of different products.Finally, the chitosan-g-PHB grafted polymer based nanoparticles were firstly prepared through layer-by-layer self-assembly technique. The effects of the concentration of polymer solution, pH and other external situation on the morphology of nanoparticles were dicussed in this paper. SEM and TEM were used to characterize the morphology and size of nanoparticles. It proved that chitosan-g-PHB based spherical nanoparticles with regular appearance and narrow size distribution were successfully prepared. DLS was used to measure the particle size of succinic anhydride acylated chitosan-g-PHB based nanoparticles in neutral and acidic conditions. Placing in the acidic solution for1h, the diameter of the nanoparticles increased from about200nm to450nm. It proved that, due to the hydrolyzation of the amide group in acidic solution, the chitosan shell of the nanoparticles gradually dissolved which resulted in the increase of particle diameter. Such changes are conducive to the exposure of PHB based nucleus of the nanoparticles and the release of drug in acidic environment of cancer cells.