跳到主要內容

臺灣博碩士論文加值系統

(44.222.218.145) 您好!臺灣時間:2024/02/29 12:43
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

: 
twitterline
研究生:林宥欣
研究生(外文):Yu-Hsin Lin
論文名稱:新穎奈米微粒載體於口服蛋白質藥物傳遞的應用研究
論文名稱(外文):Novel Nanoparticles for Oral Delivery of Protein Drugs via Paracellular Pathways
指導教授:宋信文
指導教授(外文):Hsing-Wen Sung
學位類別:博士
校院名稱:國立清華大學
系所名稱:化學工程學系
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:英文
論文頁數:83
中文關鍵詞:nanoparticlesinsulinparacellular transporttight junctiondiabetes
相關次數:
  • 被引用被引用:0
  • 點閱點閱:480
  • 評分評分:
  • 下載下載:87
  • 收藏至我的研究室書目清單書目收藏:2
An oral route is the most convenient and comfortable means of administering protein drugs, and eliminates pain caused by an injection, the stress association with multiple daily injections and possible infections. Oral administration has a higher patient compliance rate than injections. However, oral administration of protein drugs also has certain obstacles, as drugs must overcome various significant barriers in the gastrointestinal (GI) tract prior to delivery to the blood stream. First, protein drugs are rapidly degraded by the low pH of gastric medium in the stomach. Secondly, some digestive enzymes in the stomach and small intestine may lead to degradation of protein drugs. Finally, the intestinal epithelium is a major barrier to the absorption of protein drugs, as they cannot diffuse across the cells through the lipid-bilayer cell membranes.
The study presents a novel nanoparticle (NP) delivery system which is able to provide a protection from the GI environment and enhances absorption of protein drugs in the intestinal epithelium. This novel delivery system was prepared using a simple and mild ionic-gelation method to which a poly-γ-glutamic acid (g-PGA) solution was added to a low molecular-weight chitosan (low-MW CS) solution. The particle size and the zeta potential value of the prepared NPs can be controlled under various weight ratios of CS to γ-PGA. The diameters of the prepared NPs were 110-150 nm and these NPs had a negative or positive surface charge depending on the relative concentrations of CS to g-PGA utilized. X-ray diffractograms demonstrated that the crystal structure of CS was disrupted when combined with g-PGA. The ionized CS and γ-PGA formed polyelectrolyte complexes via electrostatic interactions. The FT-IR spectra showed that CS and g-PGA were ionized at pH 2.5-6.6 and the prepared NPs remained intact in the pH range of 2.5-6.8. By TEM examinations, the proposed NPs have a matrix structure and are spherical in shape.
The ability of the prepared NPs to enhance paracellular transport was investigated in vitro in Caco-2 cell monolayers. The NPs with a positive surface charge (or shelled with CS) effectively reduced the transepithelial electrical resistance (TEER) of Caco-2 cell monolayers. After removal of the incubated nanoparticles, a gradual increase in TEER was occurred. Confocal laser scanning microscopy observations verified that the NPs transiently opened the tight junctions between Caco-2 cells and facilitated transport of the NPs via the paracellular pathways. Furthermore, orally administered NPs were co-localized with the ZO-1 proteins at cell-cell contact sites in the small intestine of rats. This suggested that these NPs were able to interact and modulate the function of ZO-1 proteins, thus allowing transport of the NPs through the intestinal epithelium.
In the protein drug (insulin) loading process, increasing the amount of insulin used led to a larger size of the NPs together with a significant increase in their insulin loading efficiency and loading content. The insulin concentration used was 84.0 mg/ml, the loading efficiency and loading content of the NPs were approximately 55% and 15%, respectively. Insulin release profiles were significantly affected by their stability at distinct pH environments. No significant conformational change was observed for insulin released from the NPs at pH 7.4, as compared with that of the standard insulin. Moreover, in vivo results clearly indicated that oral administration of insulin in NPs in diabetic rats achieved a sustained effect in decreasing the blood glucose level over at least 10 h, suggesting that the effect of the proposed NPs enhanced absorption of fully functional insulin. These experimental results indicated that the prepared NPs increased absorption of insulin in the intestine and provided a protection from the GI environment. This novel NP system, which is composed of CS and γ-PGA, may be a suitable carrier for oral insulin delivery.
TABLE OF CONTENT
ABSTRACT………………………………………………………………. I
TABLE OF CONTENT………………………………………………….. III
LIST OF FIGURES AND TABLES…………………………………….. VI

Chapter 1. Introduction 1

Chapter 2. Preparation of Nanoparticles Composed of Chitosan/Poly-γ-Glutamic Acid and Evaluation of Their Permeability Through Caco-2 Cells
2-1 Materials and Methods 6
2-1-1 Materials 6
2-1-2 Depolymerization of CS by Enzymatic Hydrolysis 6
2-1-3 Production and Purification of g-PGA 7
2-1-4 Preparation of the CS–γ-PGA NPs 9
2-1-5 Characterization of the CS–γ-PGA NPs 9
2-1-6 Caco-2 Cell Cultures and TEER Measurements 10
2-1-7 fCS–γ-PGA NP Preparation and CLSM Visualization 11
2-1-8 Statistical Analysis 12
2-2 Results and Discussion 12
2-2-1 Depolymerization of CS by Enzymatic Hydrolysis 12
2-2-2 Production and Purification of g-PGA 14
2-2-3 Preparation of the CS–γ-PGA NPs 15
2-2-4 Characterization of the CS–γ-PGA NPs 17
2-2-5 TEER Measurements 20
2-2-6 CLSM Visualization 22
2-3 Conclusion 24

Chapter 3. Preparation and Characterization of Nanoparticles Shelled with Chitosan for Oral Insulin Delivery
3-1 Materials and Methods 26
3-1-1 Materials 26
3-1-2 Preparation of Low MW CS and g-PGA 26
3-1-3 Preparation of NPs 26
3-1-4 Characterization of NPs 27
3-1-5 TEER Measurements 27
3-1-6 FITC-Labeled NPs and CLSM Visualization 28
3-1-7 Visualization of Opening Tight Junctions 28
3-1-8 Insulin Loaded Capacity of NPs 29
3-1-9 In Vitro Release Study 30
3-1-10 In Vivo Release Study 30
3-1-11 Statistical Analysis 31
3-2 Results and Discussion 31
3-2-1 Preparation of NPs 31
3-2-2 Characterization of NPs at Distinct pH Values 34
3-2-3 TEER Measurements 37
3-2-4 CLSM Visualization 39
3-2-5 Insulin Loaded Capacity of NPs 42
3-2-6 In Vivo Release Study 43
3-3 Conclusion 45

Chapter 4. Novel Nanoparticles for Oral Insulin Delivery via The Paracellular Pathway for non-Invasive Diabetes Managements
4-1 Materials and Methods 47
4-1-1 Materials 47
4-1-2 Preparation of Low MW CS and g-PGA 47
4-1-3 Preparation of NPs 47
4-1-4 Caco-2 Cell Cultures and TEER Measurements 48
4-1-5 Fluorescence (FITC)-Labeled NPs and CLSM Visualization 48
4-1-6 Stability and Functionality of NPs at Distinct pH Environments
49
4-1-7 Insulin-Loaded NPs 50
4-1-8 Animal Study 51
4-1-9 Statistical Analysis 52
4-2 Results and Discussion 52
4-2-1 Preparation of NPs 53
4-2-2 Stability of NPs at Distinct pH Environments 53
4-2-3 Functionality of NPs at Distinct pH Environments 55
4-2-4 Insulin-Loaded NPs 62
4-2-5 Release of Insulin from Loaded NPs 65
4-2-6 In Vivo Studies 66
4-3 Conclusion 67

References 68


著作目錄 77
作者簡歷 83
1.Liang HF, Hong MH, Ho RM, Chung CK, Lin YH, Chen CH, Sung HW. Novel method using a temperature-sensitive polymer (methylcellulose) to thermally gel aqueous alginate as a pH-sensitive hydrogel. Biomacromolecules 2004;5:1917-1925.
2.Krauland AH, Guggi D, Bernkop-Schnürch A. Oral insulin delivery: The potential of thiolated chitosan-insulin tablets on non-diabetic rats. J Control Release 2004;95:547-555.
3.Ma Z, Lim TM, Lim LY. Pharmacological activity of peroral chitosan–insulin nanoparticles in diabetic rats. Int J Pharm 2005;293:271-280.
4.Borchard G, Lueßen HL, de Boer AG, Verhoef JC, Lehr CM, Junginger HE. The potential of mucoadhesive polymers in enhancing intestinal peptide drug absorption. III: Effects of chitosan-glutamate and carbomer on epithelial tight junctions in vitro. J Control Release 1996;39:131-138.
5.Sullivan CO, Birkinshaw C. In vitro degradation of insulin-loaded poly(n-butylcyanoacrylate) nanoparticles. Biomaterials 2004;25:4375-4382.
6.Kidron M, Bar-On H, Berry EM, Ziv E. The adsorption of insulin from various regions of the rat intestine. Life Sci 1982;31:2837-2841.
7.Kotzé AF, Lueßen HL, de Leeuw BJ, de Boer (A)BG, Verhoef JC, Junginger HE. Comparison of the effect of different chitosan salts and N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (Caco-2). J Control Release 1998;51:35-46.
8.Ballard ST, Hunter JH, Taylor AE. Regulation of tight-junction permeability during nutrient absorption across the intestinal epithelium. Annu Rev Nutr 1995;15:35-55.
9.Thanou M, Verhoef JC, Junginger HE. Chitosan and its derivatives as intestinal absorption enhancers. Adv Drug Deliv Rev 2001;50:S91-S101.
10.Lin YH, Liang HF, Chung CK, Chen MC, Sung HW. Physically crosslinked alginate/N,O-carboxymethyl chitosan hydrogels with calcium for oral delivery of protein drugs. Biomaterials 2005;26:2105-2113.
11.Chen SC, Wu YC, Mi FL, Lin YH, Yu LC, Sung HW. A novel pH-sensitive hydrogel composed of N,O-carboxymethyl chitosan and alginate cross-linked by genipin for protein drug delivery. J Control Release 2004;96:285-300.
12.Jin J, Song M, Hourston DJ. Novel chitosan-based films cross-linked by genipin with improved physical properties. Biomacromolecules 2004;5:162-168.
13.Iwasaki N, Yamane ST, Majima T, Kasahara Y, Minami A, Harada K, Nonaka S, Maekawa N, Tamura H, Tokura S, Shiono M, Monde K, Nishimura SI. Feasibility of Polysaccharide Hybrid Materials for Scaffolds in Cartilage Tissue Engineering: Evaluation of Chondrocyte Adhesion to Polyion Complex Fibers Prepared from Alginate and Chitosan. Biomacromolecules 2004;5:828-833.
14.Artursson P, Lindmark T, Davis SS, Illum L. Effect of chitosan on the permeability of monolayers of intestinal epithelial cells (Caco-2). Pharm Res 1994;11:1358-1361.
15.Niederhofer A, Müller BW. A method for direct preparation of chitosan with low molecular weight from fungi. Eur J Pharm Biopharm 2004;57:101-105.
16.Richard A, Margaritis A. Poly(glutamic acid) for biomedical Applications. Crit Rev Biotechnol 2001;21:219-232.
17.Li C. Poly(l-glutamic acid)–anticancer drug conjugates. Adv Drug Deliver Rev 2002;54:695-713.
18.Li C, Yu DF, Newman A, Cabral F, Stephens C, Hunter N, Milas L, Wallace S. Complete regression of well-established tumors using a novel water-soluble poly(L-glutamic acid)-paclitaxel conjugate. Cancer Res 1998;58:2404-2409.
19.Hashida M, Akamatsu K, Nishikawa M, Yamashita F, Takakura Y. Design of polymeric prodrugs of prostaglandin E1 having galactose residue for hepatocyte targeting. J Control Release 1999;62:253-262.
20.World Health Organization. Diabetes: the cost of diabetes (2002).
21.Smyth S, Heron A. Diabetes and obesity: the twin epidemics. Nature Med 2005;12:75-80.
22.American Diabetes Association. National Diabetes Fact Sheet (2005).
23.Morçöl T, Nagappan P, Nerenbaum L, Mitchell A, Bell SJD. Calcium phosphate-PEG-insulin-casein (CAPIC) particles as oral delivery systems for insulin. Int J Pharm 2004;277:91-97.
24.Krauland AH, Guggi D, Bernkop-Schnürch A. Oral insulin delivery: The potential of thiolated chitosan-insulin tablets on non-diabetic rats. J Control Release 2004;95:547-555.
25.Hu Y, Jiang X, Ding Y, Ge H, Yuan Y, Yang C. Synthesis and characterization of chitosan-poly(acrylic acid) nanoparticles. Biomaterials 2002;23:3193-3201.
26.Qin C, Zhou B, Zeng L, Zhang Z, Liu Y, Du Y, Xiao L. The physicochemical properties and antitumor activity of cellulase-treated chitosan. Food Chem 2004;84:107-115.
27.Yoon SH, Do JH, Lee SY, Chang HN. Production of poly-g-glutamic acid by fed-batch culture of Bacillus licheniformis. Biotechnol Lett 2000;22:585-588.
28.Kuno T, Naito S, Ito H, Ohta M, Kido N, Kato N. Staining of the O-specific polysaccharide chains of lipopolysaccharides with alkaline bismuth. Microbiol Immunol 1986;30:1207-1211.
29.Chacón M, Molpeceres J, Berges L, Guzmán M, Aberturas MR. Stability and freeze-drying of cyclosporine loaded poly(D,L-lactideglycolide) carriers. Eur J Pharm Sci 1999;8:99-107.
30.Kotzé AF, Lueßen HL, de Leeuw BJ, de Boer (A)BG, Verhoef JC, Junginger HE. Comparison of the effect of different chitosan salts and N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (Caco-2). J Control Release 1998;51:35-46.
31.Ward PD, Tippin TK, Thakker DR. Enhancing paracellular permeability by modulating epithelial tight junctions. Pharm Sci Technol Today 2000;3:346-358.
32.Yamashita S, Furubayashi T, Kataoka M, Sakane T, Sezaki H, Kokuda H. Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells. Eur J Pharm Sci 2000;10:195-204.
33.Kamm W, Jonczyk A, Jung T, Luckenbach G, Raddatz P, Kissel T. Evaluation of absorption enhancement for a potent cyclopeptidic alpha(nu)beta(3)-antagonist in a human intestinal cell line (Caco-2). Eur J Pharm Sci 2000;10:205-214.
34.Ma Z, Lim LY. Uptake of chitosan and associated insulin in Caco-2 cell monolayers: A comparison between chitosan molecules and chitosan nanoparticles. Pharm Res 2003;20:1812–1819.
35.Richardson SCW, Kolbe HJV, Duncan R. Potential of low molecular mass chitosan as a DNA delivery system: Biocompatibility, body distribution and ability to complex and protect DNA. Int J Pharm 1999; 178:231-243.
36.Hayashi K, Ito M. Antidiabetic action of low molecular weight chitosan in genetically obese diabetic KK-Ay mice. Biol Pharm Bull 2002;25:188-192.
37.Vårum KM, Holme HK, Izume M, Stokke BT, Smidsrød O. Determination of enzymatic hydrolysis specificity of partially N-acetylated chitosans. Biochim Biophys Acta 1996;1291:5-15.
38.Shin-ya Y, Lee MO, Hinode H, Kajiuchi T. Effects of N-acetylation degree on N-acetylated chitosan hydrolysis with commercially available and modified pectinases. Biochem Eng J 2001;7:85-88.
39.Pantaleone D, Yalpani M, Scollar M. Unusual susceptibility of chitosan to enzymic hydrolysis. Carbohydr Res 1992;237:325-332.
40.Hu Y. Jiang X, Ding Y, Ge H, Yuan Y, Yang C. Synthesis and characterization of chitosan poly(acrylic acid) nanoparticles. Biomaterials 2002;23:3193-3201.
41.Xu Y, Du Y. Effect of molecular structure of chitosan on protein delivery properties of chitosan nanoparticles. Int J Pharm 2003;250: 215-226.
42.Schatz C, Lucas JM, Viton C, Domard A, Pichot C, Delair T. Formation and properties of positively charged colloids based on polyelectrolyte complexes of biopolymers. Langmuir 2004;20: 7766-7778.
43.Borchard G, Lueben HL, de Boer AG, Verhoef JC, Lehr CM, Junginger HE. The potential of mucoadhesive polymers in enhancing intestinal peptide drug absorption. III: Effects of chitosan-glutamate and carbomer on epithelial tight junctions in vitro. J Control Release 1996;39:131-138.
44.van der Merwe SM, Verhoef JC, Verheijden JHM, Kotzé AF, Junginger HE. Trimethylated chitosan as polymeric absorption enhancer for improved peroral delivery of peptide drugs. Eur J Pharm Biopharm 2004;58:225-235.
45.Smitha JM, Dornishb M, Woodc EJ. Involvement of protein kinase C in chitosan glutamate-mediated tight junction disruption. Biomaterials 2005;26:3269-3276.
46.Kotzé AF, Lueßen HL, de Leeuw BJ, de Boer (A)BG, Verhoef JC, Junginger HE. N-trimethyl chitosan chloride as a potential absorption enhancer across mucosal surface: In vitro evaluation in intestinal epithelial cells (Caco-2). Pharm Res 1997;14:1197-1202.
47.Lin YH, Chung CK, Chen CT, Liang HF, Chen SC, Sung HW. Preparation of nanoparticles composed of chitosan/poly-g-glutamic acid and evaluation of their permeability through Caco-2 cells. Biomacromolecules 2005;6:1104-1112.
48.Qu X, Wirsén A, Albertsson AC. Novel pH-sensitive chitosan hydrogels: Swelling behavior and states of water. Polymer 2000;41:4589-4598.
49.Shu XZ, Zhu KJ, Song W. Novel pH-sensitive citrate cross-linked chitosan film for drug controlled release. Int J Pharm 2001;212:19-28.
50.Joshi AB, Rus E, Kirsch LE. The degradation pathways of glucagon in acidic solutions. Int J Pharm 2000;203:115-125.
51.He X, Sugawara M, Takekuma Y, Miyazaki K. Absorption of ester prodrugs in Caco-2 and rat intestine models. Antimicrob Agents Chemother 2004;48:2604-2609.
52.Kim B, Peppas NA. In vitro release behavior and stability of insulin in complexation hydrogels as oral drug delivery carriers. Int J Pharm 2003;266:29-37.
53.Grenha A, Seijo B, Remuñán-López C. Microencapsulated chitosan nanoparticles for lung protein delivery. Eur J Pharm Sci 2005;25:427-437.
54.Ma Z, Yeoh HH, Lim LY. Formulation pH modulates the interaction of insulin with chitosan nanoparticles. J Pharm Sci 2002;91:1396-1404.
55.Quaglia F, De Rosa G, Granata E, Ungaro F, Fattal E, Immacolata La Rotonda M. Feeding liquid, non-ionic surfactant and cyclodextrin affect the properties of insulin-loaded poly(lactide-co-glycolide) microspheres prepared by spray-drying. J Control Release 2003;86:267-278.
56.Ma Z, Lim TM, Lim LY. Pharmacological activity of peroral chitosan–insulin nanoparticles in diabetic rats. Int J Pharm 2005;293:271-280.
57.Pan Y, Li YJ, Zhao HY, Zheng JM, Xu H, Wei G, Hao JS, Cui FD. Bioadhesive polysaccharide in protein delivery system: Chitosan nanoparticles improve the intestinal absorption of insulin in vivo. Int J Pharm 2002;249:139-147.
58.van der Lubben IM, Verhoef JC, Borchard G, Junginger HE. Chitosan and its derivatives in mucosal drug and vaccine delivery. Eur J Pharm Sci 2001;14:201-207.
59.Evans DF, Pye G, Bramley R, Clark AG, Dyson TJ, Hardcastle JD. Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut 1988;29:1035-1041.
60.Thouzeau C, Peters G, Le Bohec C, Le Maho Y. Adjustments of gastric pH, motility and temperature during long-term preservation of stomach contents in free-ranging incubating king penguins. J Exp Biol 2004;207:2715-2724.
61.Eaimtrakarn S, Itoh Y, Kishimoto JI, Yoshikawa Y, Shibata N, Takada K. Retention and transit of intestinal mucoadhesive films in rat small intestine. Int J Pharm 2001;224:61-67.
62.Shargel L, Yu A. Applied Biopharmaceutics and Pharmacokinetics 4th ed. New York: McGraw-Hill, 1999 (Chapter 5).
63.Hidalgo IJ, Raub TJ, Borchardt RT. Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology 1989;96:736-749.
64.Rakieten N, Rakieten ML, Nadkarni MV. Studies on the diabetogenic action of streptozotocin. Cancer Chemother Rep 1963;29:91-98.
65.Liang HF, Yang TF, Huang CT, Chen MC, Sung HW. Preparation of nanoparticles composed of poly(g-glutamic acid)-poly(lactide) block copolymers and evaluation of their uptake by HepG2 cells. J Controlled Release 2005;105:213–225.
66.Yazar A, Polat G, Un I, Levent A, Kaygusuz A, Buyukafsar K, Camdeviren H. Effects of glibenclamide, metformin and insulin on the incidence and latency of death by oubain-induced arrhythmias in mice. Pharm Res 2002;45:183–187.
67.Morishita M, Goto T, Nakamura K, Lowman AM, Takayama K, Peppas NA. Novel oral insulin delivery systems based on complexation polymer hydrogels: Single and multiple administration studies in type 1 and 2 diabetic rats. J Controlled Release 2006;110: 587–594.
68.Schipper NG, Varum KM, Stenberg P, Ocklind G, Lennernas H, Artursson P. Chitosans as absorption enhancers of poorly absorbable drugs 3: Influence of mucus on absorption enhancement. Eur J Pharm Sci 1999;8:335-343.
69.Schipper NG, Olsson S, Hoogstraate JA, deBoer AG, Varum KM, Artursson P. Chitosans as absorption enhancers of poorly absorbable drugs 2: Mechanism of absorption enhancement. Pharm Res 1997;14: 923-929.
70.Ponchel G, Montisci MJ, Dembri A, Durrer C, Duchêne D. Mucoadhesion of colloidal particulate systems in the gastro-intestinal tract. Eur J Pharm Biopharm 1997;44:25-31.
71.Takeuchi H, Yamamoto H, Kawashima Y. Mucoadhesive nanoparticulate systems for peptide drug delivery. Adv Drug Deliv Rev 2001;47:39–54.
72.Kajihara M, Sugie T, Hojo T, Maeda H, Sano A, Fujioka K, Sugawara S, Urabe Y. Development of a new drug delivery system for protein drugs using silicone (II). J Control Release 2001;73:279-291.
73.De Smedt SC, Demeester J, Hennink WE. Cationic polymer based gene delivery systems. Pharm Res 2000;17:113-126.
74.Yamamoto T, Harada N, Kano K, Taya S, Canaani E, Matsuura Y, Mizoguchi A, Ide C, Kaibuchi K. The ras target AF-6 interacts with ZO-1 and serves as a peripheral component of tight junctions in epithelial cells. J Cell Biol 1997;139:785-795.
75.Furuse M, Itoh M, Hirase T, Nagafuchi A, Yonemura S, Tsukita S. Direct association of occludin with ZO-1 and its possible involvement in the localization of occluding at tight junctions. J Cell Biol 1994;127: 1617-1626.
76.Emdin SO, Dodson GG, Cutfield JM, Cutfield SM. Role of zinc in insulin biosynthesis. Some possible zinc-insulin interactions in the pancreatic B-cell. Diabetologia 1980;119:174-182.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關論文
 
1. 以高密度大腸桿菌培養製程量產重組PenicillinAcylase
2. 多功能奈米微粒做為GCSF蛋白質藥物之口服釋放載體的研發
3. 口服奈米藥物載體---幾丁聚醣於促進腸道細胞間Tight Junctions通透性之分子機制探討
4. Chitosan 打開細胞Tight junction 所活化之受體蛋白及其訊息傳遞路徑的探討
5. Novel pH-Sensitive Chitosan Nanoparticles for Oral Insulin Delivery: Mechanism, Biodistribution, Toxicological, Pharmacodynamic and Pharmacokinetic Evaluations
6. 利用腸衣包覆膠囊技術於Chitosan/γ-PGA奈米微粒載體在口服胰島素藥物傳遞的應用研究
7. 口服幾丁聚醣奈米微粒載體包覆超短效與短效胰島素之藥物動力學研究
8. 探討三甲基幾丁聚醣(TrimethylChitosan)與聚麩胺酸(γ-poly-glutamic-acid)製備離子鍵結型奈米微粒於小腸環境下的穩定性分析
9. 口服奈米載體投遞生物巨分子以調控糖尿病血糖的研發
10. Oral co-administration of insulin and exendin-4 loaded nanoparticles to treat type 2 diabetes in a rat model
11. 幾丁聚醣包覆肝素之奈米微粒做為口服途徑傳遞肝素之可行性評估
12. 以共軛焦顯微鏡觀察bFGF或GinsenosideRg1於體內誘導血管新生的情形
13. 天然細胞外間質於術後抗沾黏及心肌組織再生上的應用
14. 幾丁聚醣衍生物奈米粒子於光熱治療及疫苗接種之應用評估
15. 以具有pH應答性的奈米粒子產生細菌聚集及局部光熱效應於感染治療之評估