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1、Combination of doxorubicin-based chemotherapy and polyethylenimine/p53 gene therapy for the treatment of lung cancer using porous PLGA microparticlesXiaozheng Shi a,c, Chunjie Li a,c, Sai Gao a,c, Lingfei Zhang a,c, Haobo Han a,c, Jianxu Zhang a,c, Wei Shi a,b,c,*, Quanshun Li a,b,c,*a Key Laborator
2、y for Molecular Enzymology and Engineering, the Ministry of Education, Jilin University, Changchun 130012, Chinab National Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun 130012, Chinac School of Life Sciences, Jilin University, Changchun 130012, China*Corresponding author. Tel.
3、: +86-431-85155216; Fax: +86-431-85155200. E-mail address: (Q. Li); (W. Shi). Abstract In this study, porous PLGA microparticles for the co-delivery of doxorubicin and PEI25K/p53 were successfully prepared by the water-oil-water emulsion solvent evaporation method, using ammonium bicarbonate as a
4、porogen. The porous microparticles were obtained with a mean diameter of 22.911.8 m as determined by laser scattering particle size analysis. The particles surface porous morphology and distributions of doxorubicin and p53 were systematically characterized by scanning electron microscopy, flow cytom
5、etry, fluorescence microscopy and confocal laser scanning microscopy, revealing that doxorubicin and the plasmid were successfully co-encapsulated. Encapsulation efficiencies of 88.21.7% and 36.57.5% were achieved for doxorubicin and the plasmid, respectively, demonstrating that the porous structure
6、 did not adversely affect payload encapsulation. Microparticles harboring both doxorubicin and PEI25K/p53 exhibited enhanced tumor growth inhibition and apoptosis induction compared to those loaded with either agent alone in A549 human lung adenocarcinoma cells. Overall, the porous PLGA microparticl
7、es provide a promising anticancer delivery system for combined chemotherapy and gene therapy, and have great potential as a tool for sustained local drug delivery by inhalation. Keywords: Porous microparticles; PLGA; Co-delivery; Doxorubicin; p53 gene1. IntroductionLung cancer is a leading cause of
8、malignancy-related death in both developing and developed countries 1,2. The primary treatment choices for patients with lung cancer are conventional modalities such as chemotherapy and radiotherapy, individually or in combination 3. However, these traditional strategies can cause significant toxici
9、ties and undesirable side effects because the anticancer agents act on both normal and tumor cells. The agents are usually administered intravenously and thus have low therapy efficiencies due to their dilution in systemic circulation 4. The development of novel therapeutic strategies and delivery s
10、ystems could therefore greatly improve chemotherapy outcomes in lung cancer by increasing therapeutic efficiencies and patient survival. In contrast to radiotherapy and chemotherapy, gene therapy could potentially directly alleviate abnormalities arising from mutation or changes in gene expression.
11、It therefore has great potential in the treatment of chronic diseases, immunodeficiency disorders, genetic disorders, and cancers 5-7. One of the most important tumor suppressor genes is p53, which plays key roles in cell cycle regulation and controlling apoptosis 8,9. Almost 50% of human tumors con
12、tain mutations in the p53 gene, thus it is regarded as a very important target in anticancer gene therapy. It has been reported that enhancing the activity of wild-type p53 can have a variety of anti-proliferative effects (e.g., activation of apoptotic cell death), so using gene therapy to induce th
13、e expression of wild-type p53 could be a very effective way of treating cancers 10. Moreover, p53-based gene therapy could potentially overcome poor tumor responses to cytotoxic drugs: previous studies have shown that the simultaneous delivery of the wild-type p53 gene and doxorubicin using polymeri
14、c carriers can promote the inhibition of tumor growth and extend survival times 11-14. However, these delivery systems exhibited a limited application in the treatment of lung cancers, such as complicated production process (e.g., double-walled microspheres 14) or unfavorable administration route, e
15、specially for local delivery. The co-delivery of genetic and small molecule agents via nanocarriers appears to have synergistic effects 15,16, indicating that it may be possible to improve overall treatment outcomes by combining gene therapy with chemotherapy. Another issue to be addressed in the tr
16、eatment of lung cancers is the low delivery efficiency of intravenously-administered agents to the lungs. This could potentially be dealt with by directly delivering agents to the lungs via inhalation, which would be an attractive alternative to conventional intravenous administration 17,18. Inhalatory delivery systems have the further advantage that they need not produce high systemic levels of t
