Nanoparticles Drug Carriers Based On Lipids And Polymers

Chemotherapy is one of the most effective methods for cancer treatment. However, chemotherapy is a kind of systemic treatments with poor specificity, and it will produce serious toxic and side effects to normal tissues and organs when killing the cancer cells. Nanocarriers can protect the pharmacological activity of drug, increase its stability and solubility, prolong its cycle time in the body and accumulate drug in tumorous tissue by EPR effect. The traditional nanocarriers release drugs slowly through the degradation of carriers or the diffusion of small molecule drugs. It will lead to a low concentration of the drugs in the lesion site due to the slow or the incomplete release of drugs, drugs cannot exert therapeutic effects in time even lead to cell resistance. Targeting drug-delivery system (TDDS) integrated passive and active targeting ability, which can improve the specificity of drug delivery, reduce the toxic and side effects of drugs and increase the utilization of drugs. The reduction sensitive nanocarriers burst release encapsulated drugs due to the cleavage of disulfide bonds under the action of reducing agent after entering the tumor cells, leading to the increase of drug concentration in real time and the chemotherapy efficacy can be significantly enhanced. In this dissertation, we designed and prepared a series of functional nanocarriers for cancer therapy. The main research work includes:Chapter 1 summarized the current situation of cancer treatment as well as the classification and research progress of nanocarriers, mainly introduced the application of the functional nanocarriers in cancer treatment, especially active targeting liposomes and reduction-sensitive nanoparticles.In chapter 2, an amphiphilic polymer acetyl glycyrrhetinic acid-poly (ethylene glycol)-stearic acid (AGA-PEG-ST) was designed and synthesized for the preparation of liver targeted liposomes to reduce the adverse effects of drugs and enhance the anti-tumor activity. The AGA modified liposomes was used for targeted delivery of cisplation (CDDP), in which AGA acts as liver targeting ligand, PEG donates the liposome stealth character, and ST helps the molecule to assemble by anchoring itself into the lipid double molecular layer. In vitro results demonstrated that the introduction of hepatic targeting group AGA in liposomes significantly enhanced the affinity to HepG2 cells with approximately a 4-5 fold higher cytotoxicity in comparison to non-hepatic targeting liposomes. The in vivo biodistribution results displayed that AGA modified liposomes accumulated particularly in the mice liver, which was different from the liposomes without AGA with high accumulation in the mice lung. The results suggested a potential application of AGA containing liposome as effective carriers for hepatic targeting delivery of cisplatin. It was proved that AGA modified liposomes can be effectively used in liver targeted delivery of anticancer drug cisplatin.In chapter 3, an amphiphilic polymer ST-PEG-TPP containing triphenylphosphonium cation (TPP) was synthesized to construct mitochondrial targeted liposomes for targeted delivery of cisplatin (CDDP). In addition, the fluorescent labeled cholesterol (CHO-FITC) was synthesized to prepare fluorescent labeled liposomes, and the liposomes were used to observe the co-localization of the targeting liposomes into the mitochondria to track the TPP modified liposomes. The co-localization results displayed that the TPP-modified fluorescent-labeled liposomes were more concentrated in mitochondria than liposomes without TPP. In vitro results demonstrated that the uptake of TPP modified liposomes by MCF-7 cells was 4-5 times higher than that of liposomes without TPP. Flow cytometry results displayed that compared with cisplatin loaded liposomes without TPP, cisplatin loaded TPP modified liposomes can better improve cells apoptosis. All the results proved that TPP modified liposome has a function of mitochondria targeting, which can effectively transport cisplatin to the mitochondria of tumor cells and promote cells apoptosisIn chapter 4, a polymer C16-S-S-PEG-AGA was designed and synthesized to construct AGA-SS-LPNPs for targeted delivery and intracellular reduction triggered release of doxorubicin (DOX). In vitro drug release results showed that DOX release from DOX/AGA-SS-LPNPs significantly faster than DOX/LPNPs and DOX/AGA-CC-LPNPs in the presence of DTT. In vitro assay demonstrated that compared with DOX/LPNPs and DOX/AGA-CC-LPNPs, DOX/AGA-SS-LPNPs not only have a better affinity to HepG2 cells but also can fast release DOX after entering into cancer cells.In chapter 5, an amphiphilic polymer DLPE-S-S-MPEG was synthesized and employed to prepare two-component reduction-sensitive lipid-polymer hybrid nanoparticles (SLPNPs) for reduction triggered intracellular delivery of DOX. Unlike traditional LPNPs, lecithin is no longer necessary in this system. DOX-loaded SLPNPs rapidly released DOX under reduction conditions, efficiently delivered DOX to the cell nuclei, and displayed higher cytotoxicity against HeLa cells and HepG2 cells than DOX/ILPNPs. Both DOX/SLPNPs and DOX/ILPNPs entered cells mainly through the clathrin-mediated endocytosis pathway, and the different behaviors between DOX/SLPNPs and DOX/ILPNPs may occurred after the LPNPs were internalized into the cells. Further in vivo biological evaluation confirmed that the introduction of disulfide bond in LPNPs can significantly enhance tumor cells growth inhibition ability, improve tumor cells apoptosis and in vivo antitumor efficacy. Combining the simple composition, easy preparation process, excellent antitumor efficacy and low side effect in vivo, two-component reduction-sensitive SLPNPs would be a promising responsive nanocarrier for cancer therapy.In chapter 6, to explore the effect of PEG density on the surface of nanoparticles on the antitumor efficacy, a series of DOX/LPNPs with different PEG contents, including DOX/SLPNPs 15%, DOX/SLPNPs 35%, DOX/SLPNPs 50% and DOX/SLPNPs 100%, were designed and prepared. The four kinds of nanoparticles have homogeneous spherical structure with a size of about 100 nm. The difference of PEG content on nanoparticles had little effect on drug release. The in vitro studies indicated that the nanoparticles with a higher surface PEG content had a lower cellular internalization in tumor cells. Further in vivo biological evaluation confirmed that the in vivo retention time of nanoparticles increased along with the increase of PEG content, subsequently giving rise to the better cumulative effect in tumor, leading to enhanced anti-tumor activity.