Chemotherapeutics Co-delivery Carriers Through Pulmonary Delivery For Anti-tumor Study

Cancer, also called malignancy, is one of the major threats to human health andlife nowadays. Lung cancer ranks the first of the mortality rate among all kinds ofcancers since of2013. There are many causes of lung cancer. On the one hand,because of the serious air pollution, a large number of carcinogenic substances areinhaled into the lungs ofhumans that could induce cancer. and smoking is alsoaimportant factor for lung cancer. In particular, with the rapid development ofindustrial as well as the rapid changes of the way of human life, the morbidity andmortality of lung cancer has increased trend.The tumor in the lung tissue can not be completely removed by conventionaltherapy of surgery, chemotherapy or radiation therapy, meanwhile, the damage tothe body, the side effects, the defects such as recurrence rate were very serious. Forinstance, it is difficult to achieve good long-term efficacy especially for patientswith metastasis. A key factor in lung cancer treatment is to carry therapeutic genesor drugs into the lungs, for instance, carrying drugs or genes into the lungs byintravenous administration through the body circulation is the traditional method,however, there are several disadvantages by intravenous injection, such as hightoxicity, lower concentration of drugs or genes during circulation, easilybiodegradable of drugs or genes, difficult to reach the target organ and so on.Compared with intravenous administration, pulmonary administration has its uniqueadvantages, the route of administration can lead to a high concentration level ofdrugs or genes in lung tumor tissue quickly and reduce the distribution in othernormal tissues, and it is possible to achieve quantitative and low toxicity to normal tissues. In addition, lung tissue has a relatively large surface area that can absorb thegene or drug retention in the lungs and avoid primary metabolic degradation.The main purpose of this paper is to prepare polymer drug and drug co-deliverycarriers with low cytotoxicity and high transfection efficiency, which is suitable forspray administration trachea and lungs in vivo, and provides a new treatment forlung metastasis treatment.Based on the polyglutamic acid cationic carrier, we prepared simple structure,easy, effective and practical polymer nanoparticle carrier. The carriers are poly(ethylene glycol)-b-poly(L-glutamicacid)(mPEG-b-PLG) and poly(ethyleneglycol)-polyethyleneimine-poly(L-glutamicacid)(PEG-OEI-PLG). Chemotherapydrugscan be complexed to carriers, and then composite particles are prepared. Thecomposite nanoparticles can be sprayed by a syringe through the trachea, and theninjected directly into the lungs. Subsequently, the Doxorubicin (DOX) andcis-platinum (CDDP) can be released into the nucleus of tumor cells in the form ofconnotation at a low pH. The carrier dissociates and metabolismout to the body andthe drugs inhibit the metastasis and treatment.Through the research above, this paperdraw the concrete points are as follow:(1) Using mPEG-NH2as the macroinitiator, triggered BLG-NCA ring openingpolymerization, abtained mPEG-b-PBLG, at last prepared mPEG-b-PLG afterdeprotection. The chemotherapy drugs (DOX and CDDP) can be complexed tomPEG-b-PLGcarrier, respectively. And the carriers are: mPEG-b-PLG-DOX,mPEG-b-PLG-CDDP and mPEG-b-PLG-DOX-CDDP. The results showed that, theDOX and CDDP from mPEG-b-PLG-DOX-CDDP could be released largely underacidic conditions, while the DOX and CDDP from mPEG-b-PLG-DOX-CDDPcould be released less in acidic or neutral conditions. Moreover, the results ofconfocal laser experiments validated the consistent results of acid-sensitiveproperties of mPEG-b-PLG-DOX-CDDP, as well as the phenomenon that the DOXfracture and play efficacy continuously in tumor tissues. MTT results showed that,the cell survival rate in the co-delivery system was significantly lower than that inthe single-delivery system, which indicated that a common carrier system can significantly inhibit the growth of tumor cells in the former group. The anti-tumorexperiments in vivo showed that the co-delivery system could significantly inhibittumor growth compared with the single-delivery system, and H&E staining resultsalso showed that this system was harmless to organs, which indicated thatpulmonary administration can effectively improve drug concentration, and reducetoxicity. The distribution results in vivo showed that pulmonary administration canimprove the deposition of co-delivery systems in the lungs and prolong the releasingtime compared with intravenous administration. The gathering appearance of DOXshowed that the drugs and genes gathered more at the tumor site than that in thenormal tissue after pulmonary administration, which indicated that the drugs andgenes play a good role at the tumor site without side effects to normal tissues.(2) According to the molar ratio ofmPEG-NHS and OEI60(1:1), we triggeredBLG-NCA ring opening polymerization using mPEG-NH2as the macroinitiator,abtained mPEG-OEI-PBLG, at last prepared mPEG-OEI-PLG after deprotection.The chemotherapy drugs (DOX and CDDP) can be complexed tomPEG-OEI-PLGcarrier, respectively. The release results in vitro showed that atdifferent pH, DOX from mPEG-OEI-PLG released more especially under acidicconditions. The confocal laser experiments showed that DOX from mPEG-OEI-PLGentered the cells by endocytosis, which is different free DOX. So the accumulationtime could be prolonged. The inhibitory effect of the co-delivery system on thetumor cells were determined, and the results indicated that the co-delivery systemgroup contained a significantly reduced tumor numbers or even absent tumors, andthe lung weights of the co-delivery system group were significantly lower than thatof the PBS group. H&E staining results further indicated the advantages of theco-delivery system, and H&E staining showed no injury to other organs. And thebody weight curves showed no difference for each treatment group, indicating thatthe safety of the drug and the mode of pulmonary administration. The results ofDOX and CDDP distribution in vivo showed that, after intravenous administration,the majority of drug distributed in the liver and kidney, only a small amount of drugsdistributed in lungs, even most of the drugs were released after24h; by contrast, after the pulmonary administration, the large part of the drugs could deposit in lungs,and continuously play efficacy, and it is still possible to detect visible fluorescencesignal in lungs after seven days. The gathering appearance of drugs and genes inlungs indicated that the majority of drugs and genes gathered around the tumortissue instead of the normal tissue, and this may be related to the EPR effect.