The DDS Of Palitaxel To The Lung-chitosan Modified PLGA Nanoparticles

The incidence rate of lung cancer increased greatly in the nearly decades. So far the lung cancer has been the most common cause of death from cancer, with an annual toll of 1.18 million deaths. Lung cancer became an urgent mission among the long topic of curing cancer for.the human being. Presently, the eutherapeutic chemotherapeutic medicine is considerable, but the shorting of valid and safe DDS decreased their curative effect. Therefore, the development of safe and effective lung targeting DDS has became the imperative work.In the present studies, the chitosan coated PLGA nanoparticles were prepared successfully. In addition, the first line drug against non-small lung cancer—paclitaxel has been encapsulated in the nanoparticles. The particle size, encapsulation efficiency, drug content, in vitro release and so on factor were examined. The shapes of nanoparticles were observed using the scanning microscope and transmission electron microscope. The X-ray diffraction experiment was used to detect the crystal form of drug in the nanoparticles.The therapeutic effect of paclitaxel loaded nanoparticles was pre-evaluated by in vitro cytotoxicity experiments. In addition, the mechanism of cancer endocytosis was approached. Three mechanisms were proposed to illuminate the reason that the greatly cellular uptake efficiency of chitosan coated PLGA nanoparticles.The following in vivo pharmacokinetics and biodistribution experiments were performed to certify the therapeutic effect more exactly. The sustained-release result was observed in vivo pharmacokinetics experiments. The most important phenomenon was the chitosan-coated PLGA nanoparticles could accumulate in the lung significantly. The mechanism was as follows:positively charged nanoparticles formed loose aggregation with negatively charged protein in the blood in vivo. The micro-size aggregation could be trapped in the lung. In addition, the aggregation was verified transient and loose in vitro which was the difference with permanent microparticles. This character avoided the drawbacks of microparticles such as arterial embolism.In biodistribution experiment, the lung cancer model was built to confirm above results in normal mice more precisely. The lung cancer mice were built by injection CT-26 cell line (the dog colon cancer lines) from tail vein. In results, apart from the same conclusion got from the normal mice, an interesting phenomenon was observed in lung caner mice:comparing normal tissue, the chitosan coated PLGA nanoparticles could target to the tumor. A novel mechanism was proposed:the tumor site is more acidic in physiology conditions than the normal tissue. On the other hand, the chitosan coated nanoparticles were more positively charged in lower pH environment. In the same time, the tumor tissue was more negatively charged in vivo than normal tissue. The two factors contributed the high affinity of chitosan coated nanoparticles to the tumor tissue. The in vitro cell experiment simulated the environment in vivo and confirmed the novel mechanism. The novel mechanism gives another light to the DDS of tumor targeting.Finally, pharmacodynamic test in vivo was done to check the curative effect in lung cancer mice. After the experiment, the chitosan coated nanoparticles were indeed diminished the number of nodules in the lung tumor tissues. In addition, the chitosan coated paclitaxel loaded PLGA nanoparticles increased the survive rate and longer the survival time of lung cancer mice. The body weight of mice increased after therapeutic.In sum, the in vitro prepare method, in vitro cytotoxicity, in vivo pharmacokinetics, in vivo biodistribution, in vivo pharmacodynamic experiments were all studied.The novel point of present studies:1. Mechanism about chitosan coated nanoparticles target to the tumor tissue was proposed firstly which give light to the tumor targeting DDS.2. Paclitaxel (the first line antitumor drug of non-small lung cancer) was encapsulated in the chitosan coated nanoparticles firstly.3. The phenomenon of lung accumulation of chitosan coated nanoparticles was observed firstly and mechanism was proposed to clarify it.