Superparamagnetic Fe <sub> 3 </ Sub> O <sub> 4 </ Sub> Nanoparticles Of Anticancer Drugs Targeting The Release Of The System Design

Cancer is a common disease which threatens human health. Chemotherapy is the important treatment for cancer disease. The main problem of chemotherapy is how to decrease side effects, to reduce the total amount of drug administered as well as limit circulation of the drug throughout the body, while still achieving an efficacious concentration at the desired site in the body. Superparamagnetic iron oxide nanoparticles (SPION) is a kind of excellent biocompatible material and exhibits superparamagnetic and quantum size effects, which have got great and wide attentions in the field of biomedical, especially in the cancer treatment. As a carrier of anticancer drug, nanoparticles are easier to penetrate cell member than microparticles, therefore, SPION could enhance the pharmacodynamic than the other microparticles. However, SPION without surface modification often suffered from the aggregation problem in aqueous system. As an anticancer drug carrier, it is very important to modify SPION surface with the aim to enhance its stability, biocompatibility and drug loading efficient. Chitosan (CS) is the exclusive natural alkaline polysaccharide. It is a well-known low-toxicity, biocompatible and biodegradable biomaterial. The active amino and hydroxyl groups on CS provide many opportunities to synthesize its derivatives. Modification of SPION with CS and its derivatives not only increases the suspension stability but also endows SPION with the bioactivities.According to molecular design principle, several water-soluble chitosan derivatives were synthesized in this paper, such as N-succinyl-chitosan (NSCS), O-carboxymethylchitosan (OCMCS) and N-succinyl-O-carboxymethyl-chitosan (NSOCMCS). The physicochemical and biological properties of these derivatives including biocompatibilityies, the interactions with protein and biocompatibility with physiological environment were investigated. Then, the loading and controlled release of camptothecin (CPT), a well-known anticancer drug, from the derivatives were studied. The synthesis of well-dispersed SPION modified with CS and its derivatives was investigated in detail. The physicochemical properties of suspension of surface modified SPION were discussed and the suspension stabilization mechanisms were given. Lastly, the loading and delivery of CPT from polysaccharide modified SPION together with the inhibition rate against cancer cells were studied in this paper.Interactions between NSCS and bovine serum albumin (BSA) was investigated by circular dichroism (CD), isothermal titration calorimetric (ITC), ultraviolet (UV) spectroscopy, fluorescence spectroscopy and transmission electron microscopy (TEM) techniques. The results showed that H-bond and hydrophobic associations were the main interactions between NSCS and BSA. The conformation of BSA did not change significantly during the chain entanglement of BSA and NSCS, which suggesting that NSCS was a kind of biocompatible chitosan derivative.The loading and release of CPT from NSOCMCS aggregates were examined by TEM, fluorescence spectroscopy and in vitro drug release. The results showed that size of NSOCMCS aggregates increased significantly after loading CPT, the solubility of CPT in NSOCMCS increased 2-3 times compared to that in water, and CPT release behavior was sustained. It could be concluded that NSOCMCS was a perfect candidate for the anticancer drug carrier.Fe₃O₄ nanoparticles were successfully synthesized by chemical co-precipitation method. The well-dispersed SPION suspension was obtained by surface modification with CS, OCMCS and NSOCMCS. The obtained suspension properties were studied by several techniques, such as FTIR, TEM, X-ray diffraction (XRD) and dynamic light scattering (DLS). The results indicated that the electrostatic interaction was the driving force for chemisorption of CS onto SPION and coordination interaction was the main driving force for chemisorption of OCMCS and NSOCMCS onto SPION. The suspension stabilization mechanisms were found to be steric hindrance and electrostatic repulsion.The loading and delivery of CPT from polysaccharide surface modified SPION nanoparticles were discussed by TEM, DLS and fluorescence spectroscopy. In vitro drug release and cytotoxicity against 7721 liver cancer cells and MKN-45 stomach cancer cells activity of CPT-loaded SPION were also studied. It could be concluded that the CPT loading, in vitro release behavior were influenced significantly by polysaccharide character; CPT/CS/Fe₃O₄ was not stabile under physiological environment, thus cannot be used in cytotoxicity experiment; CPT/OCMCS/Fe₃O₄ and CPT/NSOCMCS/Fe₃O₄ systems changed the cancer cell morphology; the inhibition rate against cancer cells for CPT-loaded polysaccharide surface modified SPION increased greatly comparison with that of CPT free drug.In a word, CS and its derivatives were the ideal modifiers to produce well-dispersed suspension of SPION. Polysaccharide modified SPION was found to be biocompatible and could load CPT efficiently. The in vitro drug release from these polysaccharide modified nanoparticles exhibited a steady sustained-release profile. Cytotoxicity test against 7721 liver cancer cells and MKN-45 stomach cancer cells showed that these drug-loaded surface modified Fe₃O₄ nanoparticles had better in vitro cancer cell inhibition activity than CPT free drug. The possible reason was believed to be the synergetic effects of magnetic nanoparticles and amphiphilic polysaccharide property. The present study indicated that these nanoparticles might become a promising high-performance targeted delivery material for CPT.