Doxorubicin Loaded BSA-dextran Nanoparticles With Tumor Target Functions

Chemotherapy is the main treatment for advanced cancer. However, none of anti-cancer drugs are strictly tumor-cell specific, leading to some damage to healthy tissues and organs. Moreover, the complicacy of tumor tissues and metastasis has posed challenges during cancer diagnostics. Therefore, developing proper nanomaterials, which associate anti-cancer drugs with diagnosis agents for early diagnosis, timely detection, and prognosis tracking, is required.Albumin-based drug carries have been well studied owing to their biodegradable, biocompatible, and nontoxic properties. Bovine serum albumin (BSA) has been widely used in drug delivery systems in virtue of the abundance, ease of purification, low cost, and their high binding capacity of various drugs. In addition, by modulating the surface properties, BSA nanoparticles can prevent the drug from binding to blood proteins, escape the absorption of the reticuloendothelial system (RES), and enhance the passive targeting function. Therefore, it is important to develop a simple, green, effective, and safe approach to produce multifunctional albumin-based drug carriers by self-assembly technique.In this thesis, we prepared BSA-dextran conjugates (BSA-DEX) by Maillard reaction. Doxorubicin (DOX) loaded BSA-DEX nanoparticles were fabricated by changing the pH and temperature of the mixture. In order to enhance the tumor targeting ability and antitumor activity, the drug carriers with folic acid (FA) was prepared. Furthermore, DOX/Fe3O4/BSA-DEX-FA nanoparticles were produced to combine therapy and imaging reagents together and enable the nanoparticles to have double targeting functions.This thesis contains three parts as following:In the first part, BSA-DEX conjugates were produced with different molecular weights of dextran and different molar ratios of BSA to dextran via Maillard reaction. The nanoparticles with 5000 and 10000 dextran have a size about 60 nm and higher conjugation degree, whereas the nanoparticles with 62000 dextran have a size about 200 nm and lower conjugation degree. Cell viability investigation revealed that BSA-DEX conjugates have excellent biocompatibility. Compared with free doxorubicin, the doxorubicin loaded nanoparticles can enhance the cellular internalization but show lower activity at lower doxorubicin concentrations because of the sustained release of doxorubicin. The nanoparticles composed of 5000 dextran show better cellular internalization and better activity due to their smaller size, denser dextran brush surface, certain free doxorubicin concentration, and faster release rate of the loaded doxorubicin than the nanoparticles with 62000 and 10000 dextran.In the second part, DOX/BSA-DEX-FA nanoparticles was prepared from BSA-DEX-FA conjugate and doxorubicin via a pH adjustment and heating process. The nanoparticles have a size about 90 nm and excellent dispersibility at pH 7.4 aqueous solution. The doxorubicin loading efficiency and loading amount of the nanoparticles are larger than 90% and 14%, respectively. In vitro cell viability demonstrated that DOX/BSA-DEX-FA nanoparticles can improve the cellular internalization of the loaded doxorubicin owing to the folate receptor-mediated endocytosis process. The antitumor activity of DOX/BSA-DEX-FA nanoparticles was evaluated via H22 tumor bearing mice. At a doxorubicin dose of 10 mg/kg, the nanoparticles can achieve 88.9%of the tumor inhibition rate that is the same as the free doxorubicin at the dose of 5 mg/kg. Importantly, the nanoparticles can decrease the toxicity of doxorubicin that results in a significant increase of the average life time in comparison with the free doxorubicin as well as the nanoparticles without FA.In the last part, we prepared DOX/Fe3O4/BSA-DEX-FA nanoparticles, which have a size about 110 nm. The doxorubicin loading efficiency and loading amount of the nanoparticles are larger than 88% and 14%, respectively. The cellular uptake and toxicity of the nanoparticles can be significantly enhanced by an external magnetic field. The anti-tumor activity of DOX/Fe3O4/BSA-DEX-FA nanoparticles was also evaluated by H22 tumor bearing mice. At a doxorubicin dose of 8 mg/kg, the tumor inhibition rate of the nanoparticles under an external magnet is better than that of free doxorubicin at a dose of 5 mg/kg, and the toxicity of doxorubicin can be decreased and the average life time of the mice can be prolonged. In addition, DOX/Fe3O4/BSA-DEX-FA nanoparticles have r2 relaxation rate of 396.6 mM-1s-1. The MRI images of tumor cells and nude mice demonstrate that DOX/Fe3O4/BSA-DEX-FA nanoparticles are an effective MRI contrast and the imaging ability can be enhanced by an external magnet, which may benefit the early tumor diagnosis.