Smart Nano-Systems Based On Polymeric Lipid Vesicles And Their Applications In Tumor Diagnosis And Therapy

Nanoparticles, have emerged as one of the most fascinating drug delivery systems for the controlled delivery of antitumor drugs to improve therapeutic efficacy and reduce systemic toxicity. The design and development of “smart” nanoparticles seek to expand upon the benefits. In this dissertation, amphiphilic modified dextran and its derivatives were synthesized successfully. Based on these polymers, a smart responsive polymeric lipid vesicle(PLV) system was successfully fabricated. It can be used as a multi-functional platform for tumor diagnosis and therapy. The details are as follows:1. The synthesis of the amphiphilic modified dextran and its derivatives. The FTIR and 1H NMR results show that the amphiphilic modified dextran and its derivatives were synthesized successfully. PEG chains with pH-sensitive hydrazone bonds, hydrophobic chains with reduction-sensitive disulfide bonds were connected to the dextran main chain. The hydrazone bonds and disulfide bonds can be broken in the specific environments. Furthermore, the critical aggregation concentration of amphiphilic modified dextran was determined as about 38.19 mg/L, which indicate that the synthesized amphiphilic modified dextran could easily self-assemble to form vesicles in aqueous medium.2. The preparation of smart polymeric lipid vesicles(PLVs) and their application in drug delivery. The results show that the PLVs were well dispersed as individual particles with a well-defined spherical structure and homogeneously distributed at around 50 nm in diameter. The nano-sized FPPLVs were modified with PEG on the surface, so they had the potential to accumulate in the tumor by the EPR effect. Once the PLVs reach tumor sites, they will lose their PEG coating by hydrolysis of hydrazone bonds under acidic tumor environments. Then the exposed ligands or positive charge could realize enhanced tumor cellular internalization. After the PLVs are internalized by tumor cells, the PLVs would disintegrate and release encapsulated DOX rapidly due to the cleavage of disulfide bonds in the reduction environment.3. The preparation of magnetic PLVs(SPIO&DOX-PPLVs) and their applications in tumor magnetic resonance imaging(MRI) diagnosis and therapy. The results show that the PLVs were well dispersed in water with spherical structures and distributed at around 80 nm in diameter. The SPIO-PPLVs show high saturation magnetization(27.5 emu/g) and high transverse relaxivity(213.82 mM-1 s-1). The assembled SPIO&DOX-PPLVs had magnetic superparamagnetic iron-oxide(SPIO) cores and PEG shells, so they had the potential to accumulate in tumor by passive targeting and active magnetic targeting. Then they can realize a real-time diagnosis by MRI. Once the SPIO&DOX-PPLVs enter tumor cells, their structures would disintegrate in the reduction environment of tumor cells. Therefore the encapsulated drugs would rapidly released and kill tumor cells.4. The preparation of smart pH-responsive upconversion nanoparticles(RB-UPPLVs) and their application in near-infrared(NIR) light-triggered photodynamic therapy. The results show that these nanocarriers exhibit a nanosized structure and low cytotoxicity. Under 980 nm NIR light excitation, the green upconversion emission from the UCNs can effectively activate the RB molecules to produce cytotoxic singlet oxygen. The RB-UPPLVs with pH 5.0 treatment have a much better photodynamic effect in the tumor cells than the RB-UPPLVs with pH 7.4 treatment.5. The preparation of smart upconversion nanocarriers and their application in combination tumor treatment. These nanocarriers can realize a pH-triggered DOX release and can generate cytotoxic singlet oxygen successfully under the irradiation of NIR light. In vitro and in vivo combination treatments evidenced the high antitumor effects of the nanocarriers under NIR light irradiation.All of the results suggest that the PLVs can be used as a kind of platform technology to develop different nano-systems, may be promising nanocarriers for tumor diagnosis and therapy applications.