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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/46545完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 謝銘鈞(Ming-Jium Shieh) | |
| dc.contributor.author | Han-Min Tsai | en |
| dc.contributor.author | 蔡翰旻 | zh_TW |
| dc.date.accessioned | 2021-06-15T05:14:48Z | - |
| dc.date.available | 2015-07-26 | |
| dc.date.copyright | 2010-07-26 | |
| dc.date.issued | 2010 | |
| dc.date.submitted | 2010-07-21 | |
| dc.identifier.citation | (1) Brannon-Peppas, L., and Blanchette, J. O. (2004) Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev. 56, 1649-1659.
(2) Gregoriadis, G. (1995) Engineering liposomes for drug delivery: progress and problems. Trends Biotechnol. 12, 527-537. (3) Peng, C. L., Lai, P. S., Lin, F. H., Wu, Y. H., and Shieh, M. J. (2009) Dual chemotherapy and photodynamic therapy in an HT-29 human colon cancer xenograft model using SN-38-loaded chlorin-core star block copolymer micelles. Biomaterials. 30, 3614-3625. (4) Koizumi, F., Kitagawa, M., Negishi, T., Onda, T., Matsumoto, S., Hamaguchi, T., and Matsumura, Y. (2006) Novel SN-38–Incorporating Polymeric Micelles, NK012, Eradicate Vascular Endothelial Growth Factor–Secreting Bulky Tumors. Cancer Res. 66, 10048-10056. (5) Vargas, A., Pegaz, B., Debefve, E., Konan-Kouakou, Y., Lange, N., Ballini, J. P., van den Bergh, H., Gurny, R., and Delie, F. (2004) Improved photodynamic activity of porphyrin loaded into nanoparticles: an in vivo evaluation using chick embryos. Int J Pharm. 286, 131–145. (6) Keyes, K. A., Mann, L., Cox, K., Treadway, P., Iversen, P., Chen, Y. F., and Teicher, B. A. (2003) Circulating angiogenic growth factor levels in mice bearing human tumors using Luminex Multiplex technology. Cancer Chemother Pharmacol. 51, 321-327. (7) Jung, Y. D., Ahmad, S. A., Akagi, Y., Takahashi, Y., Liu, W., Reinmuth, N., Shaheen, R. M., Fan, F., and Ellis, L. M. (2000) Role of the tumor microenvironment in mediating response to anti-angiogenic therapy. Cancer Metastasis Rev. 19, 147-157. (8) Dvorak, H. F., Nagy, J. A., Dvorak, J. T., and Dvorak, A. M. (1988) Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules. Am J Pathol. 133, 95-109. (9) Ferrara, N. (2004) Vascular endothelial growth factor as a target for anticancer therapy. Oncologist. 9, 1:2-10. (10) Maeda, H., Wu, J., Sawa, T., Matsumura, Y., and Hori, K. (2000) Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release. 65, 271-284. (11) Soppimath, K. S., Aminabhavi, T. M., Kulkarni, A. R., and Rudzinski, W. E. (2001) Biodegradable polymeric nanoparticles as drug delivery devices. J Control Release. 70, 1-20. (12) Park, J. H., von Maltzahn, G., Xu, M. J., Fogal, V., Kotamraju, V. R., Ruoslahti, E., Bhatia, S. N., and Sailor, M. J. (2010) Proc Natl Acad Sci U S A. 107, 981-986. (13) Kwon, I. C., Bae, Y. H., and Kim, S. W. (1991) Electrically erodible polymer gel for controlled release of drugs. Nature. 354, 291-293. (14) Kono, K., Yoshino, K., and Takagishi, T. (2002) Effect of poly(ethylene glycol) grafts on temperature-sensitivity of thermosensitive polymer-modified liposomes. J Control Release. 80, 321-332. (15) Sakaguchi, N., Kojima, C., Harada, A., and Kono, K. (2008) Preparation of pH-sensitive poly(glycidol) derivatives with varying hydrophobicities: their ability to sensitize stable liposomes to pH. Bioconjug Chem. 19, 1040-1048. (16) Wang, J., Pelletier, M., Zhang, H., Xia, H., and Zhao, Y. (2009) High-frequency ultrasound-responsive block copolymer micelle. Langmuir. 25, 13201-13205. (17) Schild, H. G. (1992) Poly (N-isopropylacrylamide)-experiment, theory and application. Prog Polym Sci. 17, 163-249. (18) Nordgren, N., and Rutland, M. W. (2009) Tunable nanolubrication between dual-responsive polyionic grafts. Nano Lett. 9, 2984-2990. (19) Yancheva, E., Paneva, D., Maximova, V., Mespouille, L., Dubois, P., Manolova, N., Rashkov, I. (2007) Polyelectrolyte complexes between (cross-linked) N-carboxyethylchitosan and (quaternized) poly[2-(dimethylamino)ethyl methacrylate]: preparation, characterization, and antibacterial properties. Biomacromolecules. 8, 976-984. (20) Huang, J., Murata, H., Koepsel, R.R., Russell, A.J., Matyjaszewski, K. (2007) Antibacterial polypropylene via surface-initiated atom transfer radical polymerization. Biomacromolecules. 8, 1396-1399. (21) Zhang, J., Chen, H., Xu, L., and Gu, Y. (2008) The targeted behavior of thermally responsive nanohydrogel evaluated by NIR system in mouse model. J Control Release. 131, 34-40. (22) Liao, S. H., Weng, C. C., Yen, C. Y., Hsiao, M. C., Ma, C. C., Tsai, M. C., Su, A., Yen, M. Y., Lin, Y. F., and Liu, P. L. (2010) Preparation and properties of functionalized multiwalled carbon nanotubes/polypropylene nanocomposite bipolar plates for polymer electrolyte membrane fuel cells. J. Power Sources 195, 263–270. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/46545 | - |
| dc.description.abstract | 本篇碩士論文利用異丙基丙烯酰胺(N-isoproprlacrylamide)與二甲氨基甲基丙烯酸乙酯((2-dimethylamino) ethyl methacrylate)以自由基聚合法製備具有熱敏型(thermo-sensitive)與陽離子型(cationic)奈米粒子。其粒子直徑與介面電位(zeta potential)分別為140 nm與13.02 mV. 熱敏感性聚異丙基丙烯酰胺-二甲氨基甲基丙烯酸乙酯共聚合物奈米粒子(poly(N-isoproprlacrylamide-co-((2-dimethylamino) ethyl methacrylate)) nanoparticle) 具有體積相轉移溫度(lower critical solution temperature, LCST)在41℃，當溫度高於LCST，奈米粒子會因自體與水分子間的氫鍵(hydrogen bond)受熱裂解而產生體積相轉移(volume phase transition)，造成粒子皺縮現象(shrinkage)。由動態光散射測量法(Dynamic Light Scattering)得知，奈米粒子粒徑隨溫度升高而變化，在25℃ (below LCST)時，Dp,25℃=140 nm，當溫度高達42℃(above LCST)，Dp,42℃=100 nm，利用體積相變化將藥物釋放出來。
本研究將奈米粒子包覆大腸直腸癌化療藥物，7-ethyl-10-hydroxycamptothecin (SN-38)，且在藥物對高分子重量比1/10時，包覆率(encapsulation efficiency)與負載量(loading content)分別為80% 與6.293%。由人類大腸腺癌細胞(HT-29)毒性之評估可知，具有包覆SN-38的熱敏感性奈米粒子其細胞毒殺能力皆優於目前臨床大腸直腸癌化療藥物，Irinotecan®(CPT-11)；另由體外藥物釋放曲線結果得知，藥物在模擬人體溫度(37℃)環境下釋放24小時候，瞬間加溫至熱治療(hyperthermia)溫度(42℃)後，藥物釋放速率可在短時間內有效地大量提升。因此，我們可藉由熱治療的導入來產生熱能(heat)，達到藥物控制釋放(controlled release)的效果。在老鼠大腸直腸癌(CT-26)抗腫瘤評估發現，具有包覆SN-38的奈米粒子結合熱治療相較於其他治療顯示出良好抑制腫瘤成長的效果 因此，利用具熱敏感性聚異丙基丙烯酰胺-二甲氨基甲基丙烯酸乙酯共聚合物奈米粒子包覆抗癌藥物，可藉由患部熱治療(local hyperthermia)使藥物載體產生體積相變化來達成局部區域的藥物控制釋放。而此具有高潛力的功能性奈米粒子，對於生物醫學領域又邁進一大步，並希望有朝一日能使用於人類臨床癌症治療。 | zh_TW |
| dc.description.abstract | A thermoresponsive and cationic nanoparticles based on poly(N-isopropylacrylamide-co-((2-dimethylamino)ethylmethacrylate)) copolymers (poly(NIPA-co-DMAEMA)) was fabricated by the free radical polymerization. The diameter and zeta potential of the prepared nanoparticles was about 140 nm, and 13.02 mV at 25℃, respectively. The lower critical solution temperature (LCST) of the synthesized nanoparticles was about 41℃ and higher than the human body temperature. These nanoparticles would undergo the volume phase transition when the temperature raising above the LCST. On account of the volume phase transition, the nanoparticle diameter collapsed from 140 nm to 100 nm and the size shrinkage could result in expulsion of encapsulated anticancer drugs. In this study, we successfully used the nanoparticles based on poly(NIPA-co-DMAEMA) copolymers as a drug carrier to encapsulate 7-ethyl-10-hydroxycamptothecin (SN-38). The drug encapsulation efficiency and drug loading content of SN-38/ poly(NIPA-co-DMAEMA) (D/P=1/10) nanoparticles were about 80% and 6.293%, respectively. However, the cytotoxcity of SN-38/poly(NIPA-co-DMAEMA) nanoparticles were investigated by human colon cancer cells (HT-29). The cytotoxicity effect of SN-38/poly(NIPA-co-DMAEMA) nanoparticles was elevated in HT-29 cells compared with Irinotecan® (CPT-11). In addition, the results of the drug release profile revealed that the release rate at 42℃ (above LCST) was higher than that at 37℃ (below LCST) during different periods, and the release of SN-38 molecules could be controlled by increasing the temperature. The antitumor efficacy was also evaluated in CT-26 mouse colon cancer xenograft model, indicating that the SN-38 loaded nanoparticles with hyperthermia exhibited a efficient suppression on tumor growth as compared with other treatments. Therefore, the nanoparticles based on poly(NIPA-co-DMAEMA) copolymers exhibited better temperature sensitivity and it would be an ideal carrier for drug delivery system. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T05:14:48Z (GMT). No. of bitstreams: 1 ntu-99-R97548034-1.pdf: 771991 bytes, checksum: 6e8c605c07a5e8c6d503f5773d778719 (MD5) Previous issue date: 2010 | en |
| dc.description.tableofcontents | 中文摘要……………………………………………………………Ⅰ
英文摘要 ………………………………………………………………Ⅲ 1. INTRODUCTION………………………………………………………1 2. EXPERIMENTAL PROCEDURES …………………………………………4 2.1 Materials ……………………………………………………4 2.2 Synthesis …………………………………… 4 2.3 Characterization of nanoparticles ………………… 6 2.4 Encapsulation analysis ………………………………… 7 2.5 Stability test of nanoparticles …………………………… 8 2.6 In vitro release profiles …………………………………… 8 2.7 In vitro intracellular uptake ……………………………… 9 2.8 In vitro cytotoxicity ………………………………………… 9 2.9 Anti-tumor effect of SN-38 loaded nanoparticles ………11 2.10 Statistical analysis ……………………………………… 12 3. RESULTS AND DISCUSSION ............................... 13 3.1 Characterization of nanoparticles ……………………… 13 3.2 Stability of nanoparticles ………………………………… 18 3.3 In vitro release profiles ………………………………… 19 3.4 In vitro intracellular uptake …………………………… 19 3.5 In vitro cytotoxicity ……………………………………… 20 3.6 Anti-tumor effect of SN-38 loaded nanoparticles …… 22 4. CONCLUSIONS …………………………………………………… 24 5. LITERATURE CITED ..................................... 25 6. TABLE ……………………………………………………………… 29 Table 1. The z-average diameter, zeta-potential, encapsulation efficiency (E.E.) and loading content of SN-38 in the poly(NIPA-co-DMAEMA) nanoparticles, which were prepared in various conditions ………………………………… 29 7. SCHEME …………………………………………………………… 30 Scheme 1(A). The illustration of preparation of thermo-sensitive poly(NIPA-co-DMAEMA) nanoparticles by the free radical polymerization. (B) The formation of preparation of thermo-sensitive poly(NIPA-co-DMAEMA) nanoparticles by the cross-linked reaction and dialysis of purification....... 30 8. FIGURE …………………………………………………………… 31 Figure 1. The absorbance curve of poly(NIPA-co-DMAEMA) nanoparticle solution at the wavelength of 500 nm as a function of temperature…………………………………………… 31 Figure 2. 1H NMR spectra of poly(NIPA) (A) and poly(NIPA-co-DMAEMA) nanoparticle (B) in D2O solution …………………… 32 Figure 3. TGA curves of poly(NIPA-co-DMAEMA) nanoparticles …… 34 Figure 4. The z-average diameter and polydispersion index (PDI) of poly(NIPA-co-DMAEMA) nanoparticles as a function of temperature……… 35 Figure 5. Photos from TEM for the poly(NIPA-co-DMAEMA) nanoparticles with or without SN-38 loaded. The scale bar in the picture is 200 nm……………… 36 Figure 6. The z-average diameter of SN-38 loaded poly(NIPA-co-DMAEMA) nanoparticles prepared at different D/P ratios as a function of temperature…..... 37 Figure 7. The z-average diameter of SN-38 loaded nanoparticles with D/P ratio of 1/10 at the temperature of 25℃ and 45℃ (A), and the relative content of SN-38 in the nanoparticles (B) as a function of time…………………38 Figure 8. In vitro release profiles of SN-38 from poly(NIPA-co-DMAEMA) nanoparticles at the temperature of 37℃ (A). Extreme drug release profile was exhibited after increasing the temperature to 42oC (B). Red arrows showed the time points for heating at 42oC for 30 min.……………………… 39 Figure 9. The relative fluorescent intensity of SN-38 in HT-29 cells when fed with the prepared free SN-38 and SN-38 loaded nanoparticles for 1, 3, 6, 12, 24, 48 and 72 hours. **: p < 0.01, and *: p < 0.05 based on ANOVA……………… 40 Figure 10. (A) The cytotoxicity of HT-29 cells when fed with free SN-38 (◆), SN-38 loaded nanoparticles (◇), free CPT-11(▲), and poly(NIPA-co-DMAEMA) nanoparticles (△) for 72 hours. (B) The cytotoxicity of HT-29 cells when fed with free SN-38 (◇) and SN-38 loaded nanoparticles (△) for 24 hours, and then heated at 42oC for 30 min (solid symbols) or not (hollow symbols).………………………………………… 42 Figure 11. (A) Antitumor efficacy of free CPT-11, and SN-38 loaded nanoparticles with or without hyperthermia were determined in the CT-26 mouse colon cancer xenograft model. (B) Body weight change (%) as an index of toxicity was also determined. **: p < 0.01, and *: p < 0.05 based on ANOVA, as compared with SN-38 loaded nanoparticles without hyperthermia…………… 44 | |
| dc.language.iso | en | |
| dc.subject | 癌症 | zh_TW |
| dc.subject | 聚異丙基丙烯酰 | zh_TW |
| dc.subject | 胺 | zh_TW |
| dc.subject | 溫度敏感 | zh_TW |
| dc.subject | 藥物控制釋放 | zh_TW |
| dc.subject | poly(N-isopropylacrylamide) | en |
| dc.subject | cancer | en |
| dc.subject | controlled release | en |
| dc.subject | thermo-sensitive | en |
| dc.title | 製備熱敏感性聚異丙基丙烯酰胺-二甲氨基甲基丙烯酸乙酯共聚合物奈米粒子於藥物控制釋放系統 | zh_TW |
| dc.title | Synthesis of thermo-sensitive nanoparticles based on poly(N-isopropylacrylamide-co-((2-dimethylamino) ethyl methacrylate)) copolymer for drug controlled release | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 98-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 楊台鴻(Tai-Horng Young),羅彩月(Tsai-Yueh Luo),賴秉杉(Ping-Shan Lai) | |
| dc.subject.keyword | 聚異丙基丙烯酰,胺,溫度敏感,藥物控制釋放,癌症, | zh_TW |
| dc.subject.keyword | poly(N-isopropylacrylamide),thermo-sensitive,controlled release,cancer, | en |
| dc.relation.page | 44 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2010-07-22 | |
| dc.contributor.author-college | 工學院 | zh_TW |
| dc.contributor.author-dept | 醫學工程學研究所 | zh_TW |
| 顯示於系所單位： | 醫學工程學研究所 | |
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