二甲雙胍(Metformin)為一種治療第二型糖尿病的口服藥物，近年來有研究指出其具有抑制癌症的能力，但二甲雙胍(Metformin)強烈的親水特性，使之誘導癌細胞凋亡需使用更高的劑量且不易包埋入載體中。厚朴酚(Magnolol)為天然之中草藥萃取物，已知其具有良好的抗癌和抑制發炎功效，但厚朴酚(Magnolol)不易懸浮與分散性不佳之問題，在臨床應用性受到諸多限制。本研究選用生物相容性和生物可降解性高的聚乳酸-甘醇酸(PLGA)、聚縮酮(PCADK)搭配牛血清白蛋白(Bovine serum albumin)、海藻酸鈉(Sodium Alginate)，嘗試調整不同參數以雙重乳化法製備包埋二甲雙胍(Metformin)和厚朴酚(Magnolol)的高分子載體，並希望藉由MTT assay、Caspase-3 Elisa kit、TNF- Elisa kit來驗證不同組合的包藥顆粒與包藥顆粒搭配純藥的抗癌與抗發炎之療效。
研究結果顯示，經由將外層水相加入飽和的Metformin藥物溶液後，使用雙重乳化法能成功製備出同時包埋Metformin與Magnolol之PLGA 顆粒，且和傳統的雙重乳化法相比，有效提升15.63倍的Metformin藥物包埋率與9.96倍的Metformin藥物搭載量。另一方面，本實驗製備之blank PLGA NPs在高劑量(1000 g/ml)對癌細胞仍不具備毒性，有效改善blank BSA-PLGA NPs在180 g/ml的劑量下，即毒殺72.26 %癌細胞之情形。

Metformin is a common used first line oral drug for type two diabetes and it is recently been reported to inhibit cancer. Because of its strong hydrophilicity, it's hard to be encapsulated into carrier and it only induce cell apoptosis when it reach high concentration. Magnolol, a kind of traditional herbal medicines extracted from the bark of the Magnolia. It's known to have anti-cancer and anti-inflammation ability. However, the poor solubility and suspension capacity under physiological conditions have hindered its bioavailability and clinical efficacy. In the present study, we prepared and optimized the magnolol and metformin loaded particles which is used by boicompatible and biodegradable materials such as PLGA, PCADK, bovine serum albumin and sodium alginate as drug carriers. Further, we used different groups of metformin and magnolol loaded particles and magnolol loaded particles with metformin to do the anti-cancer and anti-inflammation experiment. MTT assay and Caspase-3 ELISA kit were used to evaluate the anti-cancer efficacy. TNF- Elisa kit was used to evaluate the anti-inflammation efficacy.
The result showed that the metformin and magnolol loaded particles were successfully prepared. And its encapsulation efficacy of metformin and drug loading of metformin are much higher than metformin particles which was used by normal double emulsion. On the other hand, the blank PLGA nanoparticles didn't occur cytotoxicity effect in cacer cells which improve the cytotoxicity of blank BSA-PLGA nanoparticles.

1. Jemal, A., et al., Global cancer statistics. CA Cancer J Clin, 2011. 61(2): p. 69-90.
2. Su, C.-C., et al., Chronic exposure to heavy metals and risk of oral cancer in Taiwanese males. Oral Oncology, 2010. 46(8): p. 586-590.
3. 101年癌症登記年報. 行政院衛生福利部國民健康署, 2015.
4. Colotta, F., et al., Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis, 2009. 30(7): p. 1073-81.
5. Demaria, S., et al., Cancer and inflammation: promise for biologic therapy. J Immunother, 2010. 33(4): p. 335-51.
6. Evans, J.M.M., et al., Metformin and reduced risk of cancer in diabetic patients. BMJ : British Medical Journal, 2005. 330(7503): p. 1304-1305.
7. Algire, C., et al., Metformin attenuates the stimulatory effect of a high-energy diet on in vivo LLC1 carcinoma growth. Endocr Relat Cancer, 2008. 15(3): p. 833-9.
8. Shen, J.-L., et al., Honokiol and Magnolol as Multifunctional Antioxidative Molecules for Dermatologic Disorders. Molecules, 2010. 15(9): p. 6452-6465.
9. Yu-Chiang, L., et al., Magnolol and honokiol isolated from magnolia officinalis protect rat heart mitochondria against lipid peroxidation. Biochemical Pharmacology, 1994. 47(3): p. 549-553.
10. Tsai, Y.-C., et al., Beneficial effects of magnolol in a rodent model of endotoxin shock. European Journal of Pharmacology, 2010. 641(1): p. 67-73.
11. Balasubramaniam, J., et al., Sodium alginate microspheres of metformin HCl: formulation and in vitro evaluation. Curr Drug Deliv, 2007. 4(3): p. 249-56.
12. Chen, F., et al., The emerging role of RUNX3 in cancer metastasis (Review). Oncol Rep, 2016. 35(3): p. 1227-36.
13. 103年國人死因統計結果. 行政院衛生福利部國民健康署, 2015.
14. G.O.Kruger, Textbook of oral and maxillofacial surgery. 5th Ed. St Louis, MO. The C.V. Mosby Company. 1979.
15. Jensen, K.E., et al., Chlamydia trachomatis and risk of cervical intraepithelial neoplasia grade 3 or worse in women with persistent human papillomavirus infection: a cohort study. Sex Transm Infect, 2014. 90(7): p. 550-5.
16. 癌症防治組, 子宮頸癌防治. 行政院衛生福利部國民健康署, 2013.
17. Balkwill, F. and A. Mantovani, Inflammation and cancer: back to Virchow? Lancet, 2001. 357(9255): p. 539-45.
18. Mantovani, A., Cancer: Inflaming metastasis. Nature, 2009. 457(7225): p. 36-7.
19. Hussain, S.P. and C.C. Harris, Inflammation and cancer: an ancient link with novel potentials. Int J Cancer, 2007. 121(11): p. 2373-80.
20. Itzkowitz, S.H. and X. Yio, Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol, 2004. 287(1): p. G7-17.
21. Macarthur, M., G.L. Hold, and E.M. El-Omar, Inflammation and Cancer II. Role of chronic inflammation and cytokine gene polymorphisms in the pathogenesis of gastrointestinal malignancy. Am J Physiol Gastrointest Liver Physiol, 2004. 286(4): p. G515-20.
22. Berasain, C., et al., Inflammation and liver cancer: new molecular links. Ann N Y Acad Sci, 2009. 1155: p. 206-21.
23. Ohnishi, S., et al., DNA damage in inflammation-related carcinogenesis and cancer stem cells. Oxid Med Cell Longev, 2013. 2013: p. 387014.
24. Hussain, S.P., L.J. Hofseth, and C.C. Harris, Radical causes of cancer. Nat Rev Cancer, 2003. 3(4): p. 276-85.
25. Harada, K., et al., Metformin in combination with 5-fluorouracil suppresses tumor growth by inhibiting the Warburg effect in human oral squamous cell carcinoma. Int J Oncol, 2016. 49(1): p. 276-84.
26. Peng, M., et al., Metformin and gefitinib cooperate to inhibit bladder cancer growth via both AMPK and EGFR pathways joining at Akt and Erk. Sci Rep, 2016. 6: p. 28611.
27. Tousoulis, D., et al., Combined effects of atorvastatin and metformin on glucose-induced variations of inflammatory process in patients with diabetes mellitus. Int J Cardiol, 2011. 149(1): p. 46-9.
28. Chen, M.C., et al., Supplementation of Magnolol Attenuates Skeletal Muscle Atrophy in Bladder Cancer-Bearing Mice Undergoing Chemotherapy via Suppression of FoxO3 Activation and Induction of IGF-1. PLoS One, 2015. 10(11): p. e0143594.
29. Yue, Y., et al., Synergistic inhibitory effects of naproxen in combination with magnolol on TPA-induced skin inflammation in mice. Rsc Advances, 2016. 6(44): p. 38092-38099.
30. Bailey, C.J. and R.C. Turner, Metformin. New England Journal of Medicine, 1996. 334(9): p. 574-579.
31. Jose, P., et al., Metformin-Loaded BSA Nanoparticles in Cancer Therapy: A New Perspective for an Old Antidiabetic Drug. Cell Biochemistry and Biophysics, 2014. 71(2): p. 627-636.
32. Garrett, C.R., et al., Survival advantage observed with the use of metformin in patients with type II diabetes and colorectal cancer. Br J Cancer, 2012. 106(8): p. 1374-1378.
33. Chen, T.-M., et al., Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation. Journal of Gastroenterology and Hepatology, 2011. 26(5): p. 858-865.
34. Nenu, I., et al., Metformin associated with photodynamic therapy – A novel oncological direction. Journal of Photochemistry and Photobiology B: Biology, 2014. 138: p. 80-91.
35. Lee, Y.J., et al., Response of Breast Cancer Cells and Cancer Stem Cells to Metformin and Hyperthermia Alone or Combined. PLoS ONE, 2014. 9(2): p. e87979.
36. Sahra, I.B., et al., The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene, 2008. 27(25): p. 3576-3586.
37. Romero, I.L., et al., Relationship of Type II Diabetes and Metformin Use to Ovarian Cancer Progression, Survival, and Chemosensitivity. Obstetrics and gynecology, 2012. 119(1): p. 61-67.
38. Liou, W.-S., et al., Herbal product silibinin-induced programmed cell death is enhanced by metformin in cervical cancer cells at the dose without influence on nonmalignant cells. Journal of Applied Biomedicine, 2015. 13(2): p. 113-121.
39. Dowling, R.J., P.J. Goodwin, and V. Stambolic, Understanding the benefit of metformin use in cancer treatment. BMC Med, 2011. 9: p. 33.
40. Aldea, M., et al., Repositioning metformin in cancer: genetics, drug targets, and new ways of delivery. Tumor Biology, 2014. 35(6): p. 5101-5110.
41. 沈孟翰, 探討添加二甲雙胍對提升厚朴酚載體對抑制人類口腔癌細胞之效果. 國立台灣科技大學 醫學工程研究所, 2015.
42. Dsilva, L.C., et al., Effect of food on the absorption of metformin from sustained release metformin hydrochloride formulations in healthy Indian volunteers. Asian Journal of Pharmaceutical and Clinical Research, 2013. 6(1): p. 95-99.
43. Gundogdu, N. and M. Cetin, Chitosan-poly (lactide-co-glycolide) (CS-PLGA) nanoparticles containing metformin HCl: Preparation and in vitro evaluation. Pakistan Journal of Pharmaceutical Sciences, 2014. 27(6): p. 1923-1929.
44. Corti, G., et al., Sustained-release matrix tablets of metformin hydrochloride in combination with triacetyl-beta-cyclodextrin. European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2008. 68(2): p. 303-309.
45. Cusi, K., A. Consoli, and R.A. DeFronzo, Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. Journal of Clinical Endocrinology & Metabolism, 1996. 81(11): p. 4059-4067.
46. Witters, L.A., The blooming of the French lilac. Journal of Clinical Investigation, 2001. 108(8): p. 1105-1107.
47. Belfiore, A. and F. Frasca, IGF and insulin receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia, 2008. 13(4): p. 381-406.
48. Frasca, F., et al., The role of insulin receptors and IGF-I receptors in cancer and other diseases. Arch Physiol Biochem, 2008. 114(1): p. 23-37.
49. Mulligan, A.M., et al., Insulin receptor is an independent predictor of a favorable outcome in early stage breast cancer. Breast Cancer Res Treat, 2007. 106(1): p. 39-47.
50. Basen-Engquist, K. and M. Chang, Obesity and cancer risk: recent review and evidence. Curr Oncol Rep, 2011. 13(1): p. 71-6.
51. Decensi, A., et al., Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila), 2010. 3(11): p. 1451-61.
52. Goodwin, P.J., et al., Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol, 2002. 20(1): p. 42-51.
53. Ish-Shalom, D., et al., Mitogenic properties of insulin and insulin analogues mediated by the insulin receptor. Diabetologia, 1997. 40 Suppl 2: p. S25-31.
54. Goodwin, P.J., et al., Insulin-lowering effects of metformin in women with early breast cancer. Clin Breast Cancer, 2008. 8(6): p. 501-5.
55. Dowling, R.J., et al., Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res, 2007. 67(22): p. 10804-12.
56. Inoki, K., T. Zhu, and K.L. Guan, TSC2 mediates cellular energy response to control cell growth and survival. Cell, 2003. 115(5): p. 577-90.
57. Lee, J.W., et al., PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene, 2005. 24(8): p. 1477-80.
58. Markman, B., et al., Status of PI3K inhibition and biomarker development in cancer therapeutics. Ann Oncol, 2010. 21(4): p. 683-91.
59. Alimova, I.N., et al., Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle, 2009. 8(6): p. 909-15.
60. Gotlieb, W.H., et al., In vitro metformin anti-neoplastic activity in epithelial ovarian cancer. Gynecol Oncol, 2008. 110(2): p. 246-50.
61. Zakikhani, M., et al., Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res, 2006. 66(21): p. 10269-73.
62. Foretz, M., et al., Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest, 2010. 120(7): p. 2355-69.
63. Kalender, A., et al., Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab, 2010. 11(5): p. 390-401.
64. Watanabe, K., et al., Pharmacological properties of magnolol and honokiol extracted from Magnolia officinalis: central depressant effects. Planta Med, 1983. 49(2): p. 103-8.
65. Clark, A.M., F.S. El-Feraly, and W.S. Li, Antimicrobial activity of phenolic constituents of Magnolia grandiflora L. J Pharm Sci, 1981. 70(8): p. 951-2.
66. Chen, H.H., S.C. Lin, and M.H. Chan, Protective and restorative effects of magnolol on neurotoxicity in mice with 6-hydroxydopamine-induced hemiparkinsonism. Neurodegener Dis, 2011. 8(5): p. 364-74.
67. Lee, Y.-J., et al., Therapeutic applications of compounds in the Magnolia family. Pharmacology & Therapeutics, 2011. 130(2): p. 157-176.
68. Tsai, T.-H., et al., Pharmacokinetics of honokiol after intravenous administration in rats assessed using high performance liquid chromatography. Journal of Chromatography B: Biomedical Sciences and Applications, 1994. 655(1): p. 41-45.
69. Tsai, T.H., C.J. Chou, and C.F. Chen, Pharmacokinetics and Brain Distribution of Magnolol in the Rat after Intravenous Bolus Injection. Journal of Pharmacy and Pharmacology, 1996. 48(1): p. 57-59.
70. Lin, S.P., et al., Pharmacokinetics, bioavailability, and tissue distribution of magnolol following single and repeated dosing of magnolol to rats. Planta Med, 2011. 77(16): p. 1800-5.
71. Tsai, T.H., et al., Pharmacokinetic and Pharmacodynamic Studies of Magnolol after Oral Administration in Rats. Pharmacy and Pharmacology Communications, 1996. 2(4): p. 191-193.
72. Ma, T., Magnolol, a natural compound, induces apoptosis of SGC-7901 human gastric adenocarcinoma cells via the mitochondrial and PI3K/Akt signaling pathways. International Journal of Oncology, 2011.
73. Kuo, D.-H., et al., Inhibitory Effect of Magnolol on TPA-Induced Skin Inflammation and Tumor Promotion in Mice. Journal of Agricultural and Food Chemistry, 2010. 58(9): p. 5777-5783.
74. Yang, S.-E., et al., Effector mechanism of magnolol-induced apoptosis in human lung squamous carcinoma CH27 cells. British Journal of Pharmacology, 2003. 138(1): p. 193-201.
75. Lee, S.-K., et al., Obovatol inhibits colorectal cancer growth by inhibiting tumor cell proliferation and inducing apoptosis. Bioorganic & Medicinal Chemistry, 2008. 16(18): p. 8397-8402.
76. Hwang, E.-S. and K.-K. Park, Magnolol Suppresses Metastasis via Inhibition of Invasion, Migration, and Matrix Metalloproteinase-2/-9 Activities in PC-3 Human Prostate Carcinoma Cells. Bioscience, Biotechnology, and Biochemistry, 2010. 74(5): p. 961-967.
77. Ledgerwood, E.C. and I.M. Morison, Targeting the apoptosome for cancer therapy. Clinical cancer research : an official journal of the American Association for Cancer Research, 2009. 15(2): p. 420-424.
78. Chen, X.r., et al., Honokiol: a promising small molecular weight natural agent for the growth inhibition of oral squamous cell carcinoma cells. International Journal of Oral Science, 2011. 3(1): p. 34-42.
79. Rasul, A., et al., Magnolol, a natural compound, induces apoptosis of SGC-7901 human gastric adenocarcinoma cells via the mitochondrial and PI3K/Akt signaling pathways. Int J Oncol, 2012. 40(4): p. 1153-61.
80. 薛敬和, 生命科學與工程. 2nd ed. 百晴文化科寄出版股份有限公司, 2012.
81. Hoffman, A.S., CHAPTER II.5.16 - Drug Delivery Systems, in Biomaterials Science (Third Edition), B.D.R.S.H.J.S.E. Lemons, Editor. 2013, Academic Press. p. 1024-1027.
82. Steve I. Shen, B.R.J., and Xiaoling Li, Design Of Controlled-release Drug Delivery Systems. New York: McGraw-Hill, 2006.
83. Allen, T.M., Drug Delivery Systems: Entering the Mainstream. Science, 2004. 303(5665): p. 1818-1822.
84. Das, S., et al., Nanotechnology in oncology: Characterization and in vitro release kinetics of cisplatin-loaded albumin nanoparticles: Implications in anticancer drug delivery. Indian J Pharmacol, 2011. 43(4): p. 409-13.
85. Wang, X., et al., Advances of Cancer Therapy by Nanotechnology. Cancer Res Treat, 2009. 41(1): p. 1-11.
86. Sun, T., et al., Engineered Nanoparticles for Drug Delivery in Cancer Therapy. Angewandte Chemie International Edition, 2014: p. n/a-n/a.
87. Acharya, S. and S.K. Sahoo, PLGA nanoparticles containing various anticancer agents and tumour delivery by EPR effect. Advanced Drug Delivery Reviews, 2011. 63(3): p. 170-183.
88. Koziara, J.M., et al., In-vivo efficacy of novel paclitaxel nanoparticles in paclitaxel-resistant human colorectal tumors. Journal of Controlled Release, 2006. 112(3): p. 312-319.
89. Panyam, J. and V. Labhasetwar, Sustained Cytoplasmic Delivery of Drugs with Intracellular Receptors Using Biodegradable Nanoparticles. Molecular Pharmaceutics, 2004. 1(1): p. 77-84.
90. Furst, W. and A. Banerjee, Release of glutaraldehyde from an albumin-glutaraldehyde tissue adhesive causes significant in vitro and in vivo toxicity. Ann Thorac Surg, 2005. 79(5): p. 1522-8; discussion 1529.
91. Gough, J.E., C.A. Scotchford, and S. Downes, Cytotoxicity of glutaraldehyde crosslinked collagen/poly(vinyl alcohol) films is by the mechanism of apoptosis. J Biomed Mater Res, 2002. 61(1): p. 121-30.
92. Sun, H.W., R.J. Feigal, and H.H. Messer, Cytotoxicity of glutaraldehyde and formaldehyde in relation to time of exposure and concentration. Pediatr Dent, 1990. 12(5): p. 303-7.
93. Kohane, D.S., et al., Biodegradable polymeric microspheres and nanospheres for drug delivery in the peritoneum. Journal of Biomedical Materials Research Part A, 2006. 77A(2): p. 351-361.
94. Kohane, D.S., Microparticles and nanoparticles for drug delivery. Biotechnology and Bioengineering, 2007. 96(2): p. 203-209.
95. Sun, T., et al., Engineered nanoparticles for drug delivery in cancer therapy. Angew Chem Int Ed Engl, 2014. 53(46): p. 12320-64.
96. D.M. Parkin, F.B., J. Ferlay, P. Pisani, Global cancer statistics. CA Cancer
J. Clin. 55, 2002.
97. Peer, D., et al., Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol, 2007. 2(12): p. 751-60.
98. Lee, D.-E., et al., Multifunctional nanoparticles for multimodal imaging and theragnosis. Chemical Society Reviews, 2012. 41(7): p. 2656-2672.
99. Perez-Herrero, E. and A. Fernandez-Medarde, Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy. Eur J Pharm Biopharm, 2015. 93: p. 52-79.
100. Jeong, K., et al., Development of highly efficient nanocarrier-mediated delivery approaches for cancer therapy. Cancer Letters, 2016. 374(1): p. 31-43.
101. Banerjee, D., R. Harfouche, and S. Sengupta, Nanotechnology-mediated targeting of tumor angiogenesis. Vasc Cell, 2011. 3(1): p. 3.
102. Vangara, K.K., J.L. Liu, and S. Palakurthi, Hyaluronic Acid-decorated PLGA-PEG Nanoparticles for Targeted Delivery of SN-38 to Ovarian Cancer. Anticancer Research, 2013. 33(6): p. 2425-2434.
103. Park, J.H., et al., Targeted delivery of low molecular drugs using chitosan and its derivatives. Advanced Drug Delivery Reviews, 2010. 62(1): p. 28-41.
104. Gabizon, A., et al., Targeting folate receptor with folate linked to extremities of poly(ethylene glycol)-grafted liposomes: In vitro studies. Bioconjugate Chemistry, 1999. 10(2): p. 289-298.
105. Lee, R.J. and P.S. Low, FOLATE-MEDIATED TUMOR-CELL TARGETING OF LIPOSOME-ENTRAPPED DOXORUBICIN IN-VITRO. Biochimica Et Biophysica Acta-Biomembranes, 1995. 1233(2): p. 134-144.
106. Lu, Y.J. and P.S. Low, Folate-mediated delivery of macromolecular anticancer therapeutic agents. Advanced Drug Delivery Reviews, 2002. 54(5): p. 675-693.
107. Yuan, Z., et al., Enhanced antitumor efficacy of 5-fluorouracil loaded methoxy poly(ethylene glycol)-poly(lactide) nanoparticles for efficient therapy against breast cancer. Colloids and Surfaces B-Biointerfaces, 2015. 128: p. 489-497.
108. Xiong, W., et al., Surface modification of MPEG-b-PCL-based nanoparticles via oxidative self-polymerization of dopamine for malignant melanoma therapy. International Journal of Nanomedicine, 2015. 10: p. 2985-2996.
109. Park, S., et al., Amphiphilized poly(ethyleneimine) nanoparticles: a versatile multi-cargo carrier with enhanced tumor-homing efficiency and biocompatibility. Journal of Materials Chemistry B, 2015. 3(2): p. 198-206.
110. Qi, X., et al., Amphiphilic oligomer-based micelles as cisplatin nanocarriers for cancer therapy. Nanoscale, 2013. 5(19): p. 8925-8929.
111. Lee, Y.-D., et al., Directed molecular assembly into a biocompatible photosensitizing nanocomplex for locoregional photodynamic therapy. Journal of Controlled Release, 2015. 209: p. 12-19.
112. Taratula, O., et al., Nanostructured lipid carriers as multifunctional nanomedicine platform for pulmonary co-delivery of anticancer drugs and siRNA. Journal of Controlled Release, 2013. 171(3): p. 349-357.
113. Gasser, O. and J.A. Schifferli, Activated polymorphonuclear neutrophils disseminate anti-inflammatory microparticles by ectocytosis. Blood, 2004. 104(8): p. 2543-8.
114. Sadallah, S., C. Eken, and J.A. Schifferli, Erythrocyte-derived ectosomes have immunosuppressive properties. J Leukoc Biol, 2008. 84(5): p. 1316-25.
115. Dalli, J., et al., Annexin 1 mediates the rapid anti-inflammatory effects of neutrophil-derived microparticles. Blood, 2008. 112(6): p. 2512-9.
116. Dalli, J., et al., CFTR inhibition provokes an inflammatory response associated with an imbalance of the annexin A1 pathway. Am J Pathol, 2010. 177(1): p. 176-86.
117. Masloub, S.M., et al., Comparative evaluation of PLGA nanoparticle delivery system for 5-fluorouracil and curcumin on squamous cell carcinoma. Arch Oral Biol, 2016. 64: p. 1-10.
118. Makadia, H.K. and S.J. Siegel, Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier. Polymers, 2011. 3(3): p. 1377-1397.
119. Commandeur, S., H.M. van Beusekom, and W.J. van der Giessen, Polymers, drug release, and drug-eluting stents. J Interv Cardiol, 2006. 19(6): p. 500-6.
120. Danhier, F., et al., PLGA-based nanoparticles: an overview of biomedical applications. J Control Release, 2012. 161(2): p. 505-22.
121. Sy, J.C., et al., Sustained release of a p38 inhibitor from non-inflammatory microspheres inhibits cardiac dysfunction. Nat Mater, 2008. 7(11): p. 863-8.
122. Yang, S.C., et al., Polyketal copolymers: a new acid-sensitive delivery vehicle for treating acute inflammatory diseases. Bioconjug Chem, 2008. 19(6): p. 1164-9.
123. Lee, S., et al., Solid polymeric microparticles enhance the delivery of siRNA to macrophages in vivo. Nucleic Acids Res, 2009. 37(22): p. e145.
124. Lee, S., et al., Polyketal microparticles: a new delivery vehicle for superoxide dismutase. Bioconjug Chem, 2007. 18(1): p. 4-7.
125. Fiore, V.F., et al., Polyketal microparticles for therapeutic delivery to the lung. Biomaterials, 2010. 31(5): p. 810-7.
126. Fattal, E. and A. Bochota, State of the art and perspectives for the delivery of antisense oligonucleotides and siRNA by polymeric nanocarriers. International Journal of Pharmaceutics, 2008. 364(2): p. 237-248.
127. Vrignaud, S., J.P. Benoit, and P. Saulnier, Strategies for the nanoencapsulation of hydrophilic molecules in polymer-based nanoparticles. Biomaterials, 2011. 32(33): p. 8593-604.
128. Tardi, P.G., et al., Drug ratio-dependent antitumor activity of irinotecan and cisplatin combinations in vitro and in vivo. Mol Cancer Ther, 2009. 8(8): p. 2266-75.
129. Zhang, Y., W.Y. Kim, and L. Huang, Systemic delivery of gemcitabine triphosphate via LCP nanoparticles for NSCLC and pancreatic cancer therapy. Biomaterials, 2013. 34(13): p. 3447-58.
130. Li, J., Y. Yang, and L. Huang, Calcium phosphate nanoparticles with an asymmetric lipid bilayer coating for siRNA delivery to the tumor. J Control Release, 2012. 158(1): p. 108-14.
131. Hu, Y., et al., A highly efficient synthetic vector: nonhydrodynamic delivery of DNA to hepatocyte nuclei in vivo. ACS Nano, 2013. 7(6): p. 5376-84.
132. Xu, Z., et al., Multifunctional nanoparticles co-delivering Trp2 peptide and CpG adjuvant induce potent cytotoxic T-lymphocyte response against melanoma and its lung metastasis. J Control Release, 2013. 172(1): p. 259-65.
133. Miao, L., et al., Nanoparticles with Precise Ratiometric Co-Loading and Co-Delivery of Gemcitabine Monophosphate and Cisplatin for Treatment of Bladder Cancer. Advanced Functional Materials, 2014. 24(42): p. 6601-6611.
134. Guo, S., et al., Co-delivery of Cisplatin and Rapamycin for Enhanced Anticancer Therapy through Synergistic Effects and Microenvironment Modulation. Acs Nano, 2014. 8(5): p. 4996-5009.
135. Chavanpatil, M.D., et al., Polymer-surfactant nanoparticles for sustained release of water-soluble drugs. J Pharm Sci, 2007. 96(12): p. 3379-89.
136. Rajaonarivony, M., et al., Development of a new drug carrier made from alginate. J Pharm Sci, 1993. 82(9): p. 912-7.
137. Yi, Y.M., T.Y. Yang, and W.M. Pan, Preparation and distribution of 5-fluorouracil (125)I sodium alginate-bovine serum albumin nanoparticles. World J Gastroenterol, 1999. 5(1): p. 57-60.
138. Chavanpatil, M.D., A. Khdair, and J. Panyam, Surfactant-polymer nanoparticles: a novel platform for sustained and enhanced cellular delivery of water-soluble molecules. Pharm Res, 2007. 24(4): p. 803-10.
139. Nayak, A., S.K. Jain, and R.S. Pandey, Controlling release of metformin HCl through incorporation into stomach specific floating alginate beads. Mol Pharm, 2011. 8(6): p. 2273-81.
140. Jain, R.A., The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices. Biomaterials, 2000. 21(23): p. 2475-90.
141. Shive, M.S. and J.M. Anderson, Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv Drug Deliv Rev, 1997. 28(1): p. 5-24.
142. Li, J.K., N. Wang, and X.S. Wu, A novel biodegradable system based on gelatin nanoparticles and poly(lactic-co-glycolic acid) microspheres for protein and peptide drug delivery. J Pharm Sci, 1997. 86(8): p. 891-5.
143. Geng, Y., et al., Formulating erythropoietin-loaded sustained-release PLGA microspheres without protein aggregation. J Control Release, 2008. 130(3): p. 259-65.
144. Zhai, P., X.B. Chen, and D.J. Schreyer, PLGA/alginate composite microspheres for hydrophilic protein delivery. Mater Sci Eng C Mater Biol Appl, 2015. 56: p. 251-9.
145. Lim, M.P.A., et al., One-step fabrication of core-shell structured alginate-PLGA/PLLA microparticles as a novel drug delivery system for water soluble drugs. Biomaterials Science, 2013. 1(5): p. 486-493.
146. Moreno, D., et al., Characterization of cisplatin cytotoxicity delivered from PLGA-systems. European Journal of Pharmaceutics and Biopharmaceutics, 2008. 68(3): p. 503-512.
147. Avgoustakis, K., et al., PLGA-mPEG nanoparticles of cisplatin: In vitro nanoparticle degradation, in vitro drug release and in vivo drug residence in blood properties. Journal of Controlled Release, 2002. 79(1-3): p. 123-135.
148. García-Contreras, L., K. Abu-Izza, and D.R. Lu, Biodegradable cisplatin microspheres for direct brain injection: Preparation and characterization. Pharmaceutical Development and Technology, 1997. 2(1): p. 53-65.
149. Gundogdu, N. and M. Cetin, Chitosan-poly (lactide-co-glycolide) (CS-PLGA) nanoparticles containing metformin HCl: preparation and in vitro evaluation. Pak J Pharm Sci, 2014. 27(6): p. 1923-9.
150. Azizi, M., et al., Fabrication of protein-loaded PLGA nanoparticles: effect of selected formulation variables on particle size and release profile. Journal of Polymer Research, 2013. 20(4): p. 1-14.
151. Kalaria, D.R., et al., Design of biodegradable nanoparticles for oral delivery of doxorubicin: in vivo pharmacokinetics and toxicity studies in rats. Pharm Res, 2009. 26(3): p. 492-501.
152. Makadia, H.K. and S.J. Siegel, Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier. Polymers (Basel), 2011. 3(3): p. 1377-1397.
153. Maeda, H., The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv Enzyme Regul, 2001. 41: p. 189-207.
154. Maeda, H., H. Nakamura, and J. Fang, The EPR effect for macromolecular drug delivery to solid tumors: Improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv Drug Deliv Rev, 2013. 65(1): p. 71-9.
155. Albanese, A., P.S. Tang, and W.C. Chan, The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu Rev Biomed Eng, 2012. 14: p. 1-16.