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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林文澧(Win-Li Lin) | |
dc.contributor.author | Po-Chin Liang | en |
dc.contributor.author | 梁博欽 | zh_TW |
dc.date.accessioned | 2021-05-19T17:40:17Z | - |
dc.date.available | 2022-08-16 | |
dc.date.available | 2021-05-19T17:40:17Z | - |
dc.date.copyright | 2019-08-16 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-08-12 | |
dc.identifier.citation | [1]Greish K. Enhanced permeability and retention of macromolecular drugs in solid tumors: a royal gate for targeted anticancer nanomedicines. J Drug Target. 2007;15:457–464.
[2]Greish K. Enhanced permeability and retention (EPR) effect for anticancer nanomedicine drug targeting. Methods Mol Biol. 2010;624:25–37. [3]Wang X, Wang Y, Shin DM. Advances of cancer therapy by nanotechnology. Cancer Res Treat. 2009;41:1–11. [4]Byrne JD, Betancourt T, Brannon-Peppas L. Active targeting schemes for nanoparticle systems in cancer therapeutics. Adv Drug Deliv Rev. 2008;60:1615–1626. [5]Kreuter J. Nanoparticles - a historical perspective. Int J Pharm. 2007;331:1–10. [6]Maeda H, Matsumura Y. Tumoritropic and lymphotropic principles of macromolecular drugs. Crit Rev Ther Drug Carrier Syst. 1989;6:193–210. [7]Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986;46:6387–6392. [8]Stohrer M, Boucher Y, Jain RK. Oncotic pressure in solid tumors is elevated. Cancer Res. 2000;60:4251–4255. [9]Kirpotin DB, Drummond DC, Park JW. Antibody targeting of long-circulating lipidic nanoparticles does not increase tumor localization but does increase internalization in animal models. Cancer Res. 2006;66:6732–6740. [10]Bartlett DW, Su H, Davis ME. Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc Natl Acad Sci U S A. 2007;104:15549–15554. [11]Farokhzad OC, Cheng J, Langer R. Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc Natl Acad Sci U S A. 2006;103:6315–6320. [12]Alexiou C, Arnold W, Lübbe AS. Locoregional cancer treatment with magnetic drug targeting. Cancer Res. 2000;60:6641–6648. [13]Reiss G, Hutten A. Magnetic nanoparticles are useful for a wide range of applications from data storage to medicinal imaging. The large-scale preparation of FeCo nanoparticles boosts this potential. Nat Mater. 2005;4:725–726. [14]Qiao R, Jia Q, Gao M. Receptor-mediated delivery of magnetic nanoparticles across the blood–brain barrier. ACS Nano. 2012;6:3304–3310. [15]Dilnawaz F, Singh A, Sahoo SK. Dual drug loaded superparamagnetic iron oxide nanoparticles for targeted cancer therapy. Biomaterials. 2010;31:3694–3706. [16]Polyak B, Friedman G. Magnetic targeting for site-specific drug delivery: applications and clinical potential. Expert Opinion on Drug Delivery. 2009; 6 (1): 53–70. [17]Arruebo M, Fernandez-Pacheco R, Santamaria J. Magnetic nanoparticles for drug delivery. Nanotoday 2007;2(3):22-32. [18]Johannsen M, Gneveckow U, Jordan A, et al. Clinical hyperthermia of prostate cancer using magnetic nanoparticles: presentation of a new interstitial technique. Int J Hyperthermia 2005;21(7):637-47. [19]Johannsen M, Thiesen B, Loening SA, et al. Magnetic fluid hyperthermia (MFH) reduces prostate cancer growth in the orthotopic Dunning R3327 rat model. Prostate 2005;64(3):283-92. [20]Alexiou C, Jurgons R, Odenbach S, et al. Delivery of superparamagnetic nanoparticles for local chemotherapy after intraarterial infusion and magnetic drug targeting. Anticancer Res 2007;27(4A):2019-22. [21]Jurgons R, Seliger C, Alexiou C, et al. Drug loaded magnetic nanoparticles for cancer therapy. J Phys Condens Matter 2006;18(38):S2893-S902. [22]Ito A, Ino K, Honda H, et al. Novel methodology for fabrication of tissue-engineered tubular constructs using magnetite nanoparticles and magnetic force. Tissue Eng 2005;11(9-10):1553-61. [23]Ito A, Takizawa Y, Kobayashi T, et al. Tissue engineering using magnetite nanoparticles and magnetic force: heterotypic layers of cocultured hepatocytes and endothelial cells. Tissue Eng 2004;10(5-6):833-40. [24]Shimizu K, Ito A, Honda H, et al. Bone tissue engineering with human mesenchymal stem cell sheets constructed using magnetite nanoparticles and magnetic force. J Biomed Mater Res B Appl Biomater 2007;82(2):471-80. [25]Kumar CS. Nanomaterials for medical diagnosis and therapy. Wiley-VCH. 2007. [26]Na K, Lee ES and Bae YH. Self-organized nanogels responding to tumor extracellular pH: pH-dependent drug release and in vitro cytotoxicity against MCF-7 cells. Bioconjug Chem 2007; 18: 1568–1574. [27]Leroux J, Roux E, Drummond DC. (2001) N-Isopropylacrylamide copolymers for the preparation of pH-sensitive liposomes and polymeric micelles. J. Controlled Release 72, 71−84. [28]Cammas S, Suzuki K, Okano T. (1997) Thermo-responsive polymer nanoparticles with a core-shell micelle structure as site-specific drug carriers. J. Controlled Release 48, 157−164. [29]Na K, Lee KH, Bae YH. (2006) Biodegradable temperature-sensitive nanoparticles from poly(ethylene glycol)(PEG)/poly(L-lactic acid)(PLLA) alternating multiblock copolymer for anticancer drug delivery. Eur. J. Pharm. Sci. 27, 115−122. [30]Chung JE, Yokoyama M, and Okano T. (2000) Inner core segment design for delivery control of thermo-responsive polymeric micelles. J. Controlled Release 65, 93−103. [31]Bae Y, Nishiyama N, Kataoka K. (2005) Preparation and biological characterization of polymeric micelle drug carriers with intracellular pH-triggered drug release property: tumor permeability, controlled subcellular drug distribution, and enhanced in vivo antitumor efficacy. Bioconjugate Chem. 16, 122−130. [32](a) Bulmus V, Woodward M, Hoffman A. A new pH-responsive and glutathione-reactive, endosomal membrane-disruptive polymeric carrier for intracellular delivery of biomolecular drugs. Journal of Controlled Release. 2003;93:105–120. (b) You YZ, Zhou QH, Oupický D. Dually responsive multiblock copolymers via RAFT polymerization: Synthesis of temperature- and redox-responsive copolymers of PNIPAM and PDMAEMA. Macromolecules2007;40:8617-8624. [33]V.P. Torchilin.Multifunctional nanocarriers.Adv Drug Deliv Rev, 58 (2006), pp. 1532-1555. [34]J.M. Chan, L. Zhang, OC. Farokhzad, et al.PLGA-lecithin-PEG core-shell nanoparticles for controlled drug delivery .Biomaterials, 30 (2009), pp. 1627-1634. [35]J. Kim, J.E. Lee, T. Hyeon, et al.Designed fabrication of a multifunctional polymer nanomedical platform for simultaneous cancer-targeted imaging and magnetically guided drug delivery.Adv Mater, 20 (2008), pp. 478-483. [36]D. Peer, J.M. Karp, R. Langer.Nanocarriers as an emerging platform for cancer therapy.Nat Nanotechnol,2 (2007), pp. 751-760. [37]L. Zhang, J.M. Chan, O.C Farokhzad, et al.Self-assembled lipid–polymer hybrid nanoparticles: a robust drug delivery platform.ACS Nano, 2 (2008), pp. 1696-1702 [38]Montet X, Funovics M, Josephson L. Multivalent effects of RGD peptides obtained by nanoparticle display. J Med Chem. 2006;49:6087–93. [39]Gao J, Gu H, Xu B. Multifunctional magnetic nanoparticles: design, synthesis, and biomedical applications. Acc Chem Res. 2009;42:1097–107. [40]Pan D, Caruthers SD, Lanza GM. et al. Ligand-directed nanobialys as theranostic agent for drug delivery and manganese-based magnetic resonance imaging of vascular targets. J Am Chem Soc. 2008;130:9186–7. [41]Bae KH, Lee K, Park TG. Surface functionalized hollow manganese oxide nanoparticles for cancer targeted siRNA delivery and magnetic resonance imaging. Biomaterials. 2011;32:176–84. [42]Xiong D, He Z, Shi L, et al. Temperature-responsive multilayered micelles formed from the complexation of PNIPAM-b-P4VP block-copolymer and PS-b-PAA core–shell micelles. Polymer. 2008;49:2548–2552. [43]Kim SY, Shin G, Lee YM. Amphiphilic diblock copolymeric nanospheres composed of methoxy poly(ethylene glycol) and glycolide: properties, cytotoxicity and drug release behavior. Biomaterials. 1999;20:1033–1042. [44]Li JB, Shi L, Dong H, et al. Reverse micelles of star-block copolymer as nanoreactors for preparation of gold nanoparticles. Polymer. 2006;47:8480–8487. [45]Kataoka K, Matsumoto T, Kwon GS, et al. Doxorubicin-loaded poly(ethylene glycol)–poly(β-benzyl-L-aspartate) copolymer micelles: their pharmaceutical characteristics and biological significance. J Control Release. 2000;64:143–153. [46]Liu D, Zhong C. Multicompartment micelles formed from star-dendritic triblock copolymers in selective solvents: a dissipative particle dynamics study. Polymer. 2008;49:1407–1413. [47]Nasongkla N, Bey E, Gao J, et al. Multifunctional, polymeric micelles as cancer-targeted, MRI-ultrasensitive drug delivery systems. Nano Lett. 2006;6:2427–2430. [48]Yang J, Lee CH, Haam S, et al. Multifunctional magneto-polymeric nanohybrids for targeted detection and synergistic therapeutic effects on breast cancer. Angew Chem Int Ed. 2007;46:8836–8839. [49]Liong M, Lu J, I.Zink J, et al. Multifunctional inorganic nanoparticles for imaging, targeting, and drug delivery. ACS Nano. 2008;2:889–896. [50]Yang X, Grailer JJ, Gong S, et al. Multifunctional SPIO/DOX-loaded wormlike polymer vesicles for cancer therapy and MR imaging. Biomaterials. 2010;31:9065–9073. [51]Zhang HZ, Gao FP, Zhang QQ, et al. Pullulan acetate nanoparticles prepared by solvent diffusion method for epirubicin chemotherapy. Colloids Surf B Biointerfaces. 2009;71:19–26. [52]Liu Z, Jiao Y, Zhang Z, et al. Polysaccharides-based nanoparticles as drug delivery systems. Adv Drug Deliv Rev. 2008;60:1650–1662. [53]Lubbe AS, Alexiou C, Bergemann C. Clinical applications of magnetic drug targeting. J Surg Res. 2001;95:200–206. [54]Häfeli UO. Magnetically modulated therapeutic systems. Int J Pharm. 2004;277:19–24. [55]Lübbe AS, Bergemann C, Huhn D, et al. Preclinical experiences with magnetic drug targeting: tolerance and efficacy. Cancer Res. 1996;56:4694–4701. [56]Wang X, Wei F, Wang J, et al. Cancer stem cell labeling using poly(L-lysine)-modified iron oxide nanoparticles. Biomaterials. 2012;33(14):3719–3732. [57]Laurent S, Dutz S, Häfeli UO, Mahmoudi M. Magnetic fluid hyperthermia: focus on superparamagnetic iron oxide nanoparticles. Adv Colloid Interface Sci. 2011;166(1–2):8–23. [58]Alexiou C, Jurgons R, Parak F, et al. Magnetic drug targeting: biodistribution of the magnetic carrier and the chemotherapeutic agent mitoxantrone after locoregional cancer treatment. J Drug Target. 2003;11:139–149. [59]Asmatulu R, Zalich MA, Riffle J.S, et al. Synthesis, characterization and targeting of biodegradable magnetic nanocomposite particles by external magnetic fields. J Magn Magn Mater. 2005;292:108–119. [60]Ma YH, Hsu YW, Wu Tony, et al. Intra-arterial application of magnetic nanoparticles for targeted thrombolytic therapy: a rat embolic model. J Magn Magn Mater. 2007;311:34–36. [61]Liu HL, Hua MY, Wei KC., et al. Magnetic resonance monitoring of focused ultrasound/magnetic nanoparticle targeting delivery of therapeutic agents to the brain. Proc Natl Acad Sci U S A. 2010;107(34):15205–15210. [62]Lübbe AS, Bergemann C, Huhn D, et al. Clinical experiences with magnetic drug targeting: a phase I study with 4′-epidoxorubicin in 14 patients with advanced solid tumors. Cancer Res. 1996;56:4686–4693. [63]Owens DE, 3rd, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2006;307:93–102. [64]Lin JJ, Chen JS, Wang LF, et al. Folic acid-Pluronic F127 magnetic nanoparticle clusters for combined targeting, diagnosis, and therapy applications. Biomaterials. 2009;30:5114–5124. [65]Babic M, Horák D, Syková E, et al. Poly(N, N-dimethylacrylamide)-coated maghemite nanoparticles for stem cell labeling. Bioconjug Chem. 2009;20:283–294. [66]Chen AL, Ni HC, hen JS, et al. Biodegradable amphiphilic copolymers based on poly(epsilon-caprolactone)-graft chondroitin sulfate as drug carriers. Biomacromolecules. 2008;9:2447–2457. [67]Liu X, Hu Q, Zhang B, et al. Magnetic chitosan nanocomposites: a useful recyclable tool for heavy metal ion removal. Langmuir. 2009;25:3–8. [68]Bumb A, Brechbiel M, Dobson PJ, et al. Synthesis and characterization of ultra-small superparamagnetic iron oxide nanoparticles thinly coated with silica. Nanotechnology. 2008;19:335601. [69]Chertok B, Moffat BA, Yang VC, et al. Iron oxide nanoparticles as a drug delivery vehicle for MRI monitored magnetic targeting of brain tumors. Biomaterials. 2008;29:487–496. [70]Liu CG, Desai KG, Chen XG, et al. Linolenic acid-modified chitosan for formation of self-assembled nanoparticles. J Agric Food Chem. 2005;53:437–441. [71]Imai Y, Murakami T, Nakamura H, et al. Superparamagnetic iron oxide-enhanced magnetic resonance images of hepatocellular carcinoma: correlation with histological grading. Hepatology. 2000;32:205–212. [72]Ward J, Guthrie JA, obinson PJ, et al. Hepatocellular carcinoma in the cirrhotic liver: double-contrast MR imaging for diagnosis. Radiology. 2000;216:154–162. [73]Hori M, Murakami T, Nakamura H, et al. Detection of hypervascular hepatocellular carcinoma: comparison of SPIO-enhanced MRI with dynamic helical CT. J Comput Assist Tomogr. 2002;26:701–710. [74]Lee PW, Hsu SH, Sung HW, et al. The characteristics, biodistribution, magnetic resonance imaging and biodegradability of superparamagnetic core–shell nanoparticles. Biomaterials. 2010;31:1316–1324. [75]Zhang B, Li Q, Shi D, et al. Ultrasound-triggered BSA/SPION hybrid nanoclusters for liver-specific magnetic resonance imaging. ACS Appl Mater Interfaces. 2012;4:6479–6486. [76]Zhang WQ, Shi LQ, Wu K, et al. Thermoresponsive micellization of poly(ethylene glycol)-b-poly(Nisopropylacrylamide) in water. Macromolecules 2005; 38: 5743–5747. [77]Motokawa R, Morishita K, Annaka M, et al. Thermosensitive diblock copolymer of poly(N-isopropylacrylamide) and poly(ethylene glycol) in water: polymer preparation and solution behavior. Macromolecules 2005; 38: 5748–5760. [78]Qin S, Geng Y, Yang S, et al. Temperature-controlled assembly and release from polymer vesicles of poly(ethylene oxide)-block-poly(N-isopropylacrylamide). Adv Mater 2006; 18: 2905-2909. [79]Hoogenboom R, Thij HML, Schubert U.S, et al. Tuning solution polymer properties by binary water-ethanol solvent mixtures. Soft Matter 2008; 4: 103–107. [80]Ahmed F and Discher DE. Self-porating polymersomes of PEG–PLA and PEG–PCL: hydrolysis-triggered controlled release vesicles. J Control Release 2004; 96: 37–53. [81]Lomas H, Massignani M, Battaglia G, et al. Non-cytotoxic polymer vesicles for rapid and efficient intracellular delivery. Faraday Discuss 2008; 139: 143–159. [82]Hu J, Qian Y, Liu S, et al. Drug-loaded and superparamagnetic iron oxide nanoparticle surface embedded amphiphilic block copolymer micelles for integrated chemotherapeutic drug delivery and MR imaging. Langmuir 2011; 28: 2073–2082. [83]Sanson C, Diou O, Lecommandoux S, et al. Doxorubicin loaded magnetic polymersomes: theranostic nanocarriers for MR imaging and magneto-chemotherapy. ACS Nano 2011; 5: 1122–1140. [84]Jiang JQ, Tong X, Zhao Y, et al. Toward photocontrolled release using light-dissociable block copolymer micelles. Macromolecules 2006; 39: 4633–4640. [85]Oerlemans C, Bult W, Hennink WE, et al. Polymeric micelles in anticancer therapy: targeting, Imaging and Triggered Release. Pharm Res 2010; 27: 2569–2589. [86]Chen J, Qiu X, Xing M.Q, et al. pH and reduction dual-sensitive copolymeric micelles for intracellular Doxorubicin delivery. Biomacromolecules 2011; 12: 3601–3611. [87]Zhang J, Wu L, Zhong Z, et al. pH and reduction dual-bioresponsive polymersomes for efficient intracellular protein delivery. Langmuir 2011; 28: 2056–2065. [88]Wei C, Guo J, Wang C. Dual stimuli-responsive polymeric micelles exhibiting “AND” logic gate for controlled release of Adriamycin. Macromol Rapid Commun 2011; 32: 451–455. [89]Xiong Z, Peng B, Hu Y, et al. Dual-stimuli responsive behaviors of diblock polyampholyte PDMAEMA-b-PAA in aqueous solution. J Colloid Interface Sci 2011; 356: 557–565. [90]Han D, Tong X, Zhao Y. Block copolymer micelles with a dual-stimuli-responsive core for fast or slow degradation. Langmuir 2012; 28: 2327–2331. [91]Klaikherd A, Nagamani C, Thayumanavan S. Multi-stimuli sensitive amphiphilic block copolymer assemblies. J Am Chem Soc 2009; 131: 4830–4838. [92]Morimoto N, Qiu XP, Winnik FM, et al. Dual stimuli-responsive nanogels by self-assembly of polysaccharides lightly grafted with thiol-terminated poly(Nisopropylacrylamide) chains. Macromolecules 2008; 41: 5985–5987. [93]De Las Heras Alarcon C, Pennadam S and Alexander C. Stimuli responsive polymers for biomedical applications. Chem Soc Rev 2005; 34: 276–85. [94]Xiong W, Wang W, Yang X, et al. Dual temperature/pH-sensitive drug delivery of poly(N- isopropylacrylamide-co-acrylic acid) nanogels conjugated with Doxorubicin for potential application in tumor hyperthermia therapy. Colloids and Surfaces B: Biointerfaces 2011; 84: 447-453. [95]Yu MK, Kim D, Jon S, et al. Image-guided prostate cancer therapy using aptamer-functionalized thermally cross-linked superparamagnetic iron oxide nanoparticles. Small 2011; 7: 2241–2249. [96]Lim EK, Huh YM, Haam S, et al. pH-Triggered drug-releasing magnetic nanoparticles for cancer therapy guided by molecular imaging by MRI. Adv Mater 2011; 23: 2436–2342. [97]Yu MK, Jeong YY, Jon S, et al. Drug-loaded superparamagnetic iron oxide nanoparticles for combined cancer imaging and therapy in vivo. Angew Chem Int Ed Engl 2008; 47: 5362–5365. [98]Srinivas M, Aarntzen EH, Figdor CG, et al. Imaging of cellular therapies. Adv Drug Deliv Rev 2010; 62: 1080–1093. [99]Tacar O, Sriamornsak P, Dass CR. Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. Journal of Pharmacy and Pharmacology 2013; 65: 157–170. [100]Pedchenko V, Zent R, Hudson BG. αvβ3 and αvβ5 integrins bind both the proximal RGD site and non-RGD motifs within noncollagenous (NC1) domain of the α3 chain of type IV collagen: implication for the mechanism of endothelial cell adhesion. J Biol Chem 2004; 279: 2772–2780. [101]Zhang C, Jugold M, Kiessling F, et al. Specific targeting of tumor angiogenesis by RGD-conjugated ultrasmall superparamagnetic iron oxide particles using a clinical 1.5-T magnetic resonance scanner. Cancer Res 2007;67: 1555-1562. [102]Murphy EA, Majeti BK, Cheresh DA, et al. Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis. Proc Natl Acad Sci USA 2008; 105: 9343-9348. [103] Tsai MH, Peng CL, Shieh MJ, et al. Photothermal, Targeting, Theranostic Near-Infrared Nanoagent with SN38 against Colorectal Cancer for Chemothermal Therapy. Mol Pharm. 2017 Aug 7;14(8):2766-2780. [104]Sugahara KN, Teesalu T, Ruoslahti E, et al. Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell 2009; 16: 510-520. [105]Stevens KR, Miller JS, Bhatia SN, et al. Degradable hydrogels derived from PEG-diacrylamide for hepatic tissue engineering. J Biomed Mater Res A 2005; 103: 3331–3338. [106]Petcharoen K, Sirivat A. Synthesis and characterization of magnetite nanoparticles via the chemical co-precipitation method. Materials Science and Engineering: B 2012; 177: 421-427. [107]Koning GA, Eggermont AM, Lindner LH, et al. Hyperthermia and thermosensitive liposomes for improved delivery of chemotherapeutic drugs to solid tumors. Pharm Res 2010; 27: 1750–1754. [108]Chen YC, Min CN, Hsieh WY, et al. In vitro evaluation of the L-peptide modified magnetic lipid nanoparticles as targeted magnetic resonance imaging contrast agent for the nasopharyngeal cancer. Journal of Biomaterials Applications 2012; 28: 580–594. [109]Tian Y, Bromberg L, Tam KC, et al. Complexation and release of Doxorubicin from its complexes with pluronic P85-b-poly (acrylic acid) block copolymers. Journal of Controlled Release 2007; 121: 137-145. [110]Chiang WH, Ho VT, Chern CS, et al. Dual stimuli-responsive polymeric hollow nanogels designed as carriers for intracellular triggered drug release. Langmuir 2012; 28: 15056-15064. [111]Nie X, Zhang J, Wu Yan, et al. Targeting peptide iRGD-conjugated amphiphilic chitosan-co-PLA/DPPE drug delivery system for enhanced tumor therapy. J Mater Chem B 2014; 2: 3232-3242. [112]Allen TM. Ligand-Targeted Therapeutics in Anticancer Therapy. Nat Rev Cancer 2002; 2: 750–763 | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/7215 | - |
dc.description.abstract | 癌症是台灣最常見的死因,根據台灣衛生福利部公布的資料,2017年癌症奪走4萬8037條人命,再創歷史新高,蟬聯36年十大死因之首。化學治療是治療癌症的主要方法之一,然而傳統的化療藥物在體內非特定地分佈,它們同時影響癌症和健康細胞,導致劑量相關的副作用和到達腫瘤的藥物濃度不足。多功能奈米粒子能靶向和控制向腫瘤細胞釋放化療藥劑,從而減少藥物誘發的全身性副作用,並提高局部腫瘤治療效果。
在我們的第一項研究中,我們開發了多功能磁性奈米顆粒SPIO-PEG-D,它是由超順磁性氧化鐵 (SPIO) 磁性核心和親水性聚乙烯乙二醇 (PEG) 外殼組成,之後再鍵結Doxorubicin (Dox) 而形成SPIO-PEG-D,它同時具有腫瘤磁振成像(MRI)和腫瘤化學治療的功用。SPIO奈米粒子的大小大約10nm,可以由穿透式電子顯微鏡觀察。而由振動樣品磁力計生成的遲滯曲線,可以發現SPIO-PEG-D仍具有超順磁性,其磁性與SPIO-PEG沒有顯著差別,表示不會因為鍵結Doxorubicin 而影響其磁性。SPIO-PEG-D 的橫向鬆弛度 (r2) 明顯高於縱向鬆弛度 (r1) (r2/r1 = 9),因此我們可以由磁振T2加權影像來觀察SPIO-PEG-D的分佈。經由將Doxorubicin結合在SPIO-PEG的表面,因為PEG的隱藏效應,可以減少Doxorubicin的降解,因此延長了Doxorubicin在血液循環中的半衰期。在體外實驗中發現,SPIO-PEG-D可導致HT-29癌細胞DNA交聯更嚴重,使其DNA表現降低,細胞凋亡升高。在普魯士藍染色研究中發現,在外加磁場中用SPIO-PEG-D治療的腫瘤,其腫瘤內鐵密度遠遠高於單獨使用SPIO-PEG-D治療的腫瘤。在體內MRI研究中發現,有外加磁場用SPIO-PEG-D治療的腫瘤,其T2加權信號比沒有外加磁場單獨使用SPIO-PEG-D治療的腫瘤更強,顯示外加磁場可以吸引更多SPIO-PEG-D累積在腫瘤組織中。在SPIO-PEG-D的抗癌效率研究中顯示,有外加磁場組比沒有外加磁場組的腫瘤明顯縮小。在體內實驗中還發現,SPIO-PEG-D這種藥物輸送系統結合局部外加磁場可以減少心毒性和肝毒性的副作用。我們的第一項研究結果顯示,我們研製的多功能磁性奈米顆粒SPIO-PEG-D,在MRI監測及外加磁場增強腫瘤化療效果具有相當大的潛力。 在我們的第二項研究中,我們開發了多功能磁性奈米凝膠顆粒iMNP-D ,它是由iRGD鍵結溫度/pH雙敏感的磁性奈米凝膠顆粒(MNP-D),而此凝膠顆粒中裝有超順磁性氧化鐵奈米顆粒和Doxorubicin。溫度/pH雙敏感聚合物(丙烯酸-共聚(乙二醇)二丙烯醯胺-共聚-N-異丙烯醯胺(Poly(AA-CO-PEGDA-CO-NIPAM))奈米凝膠,是通過自由基聚合而成。正電荷的Doxorubicin ,在pH7.4的環境下,經由靜電相互作用,而引入帶負電荷的奈米凝膠中。SPION 和 Doxorubicin 均封裝在奈米凝膠中,以合成溫度/pH 雙敏感磁性奈米凝膠顆粒 (MNP-D),然後將iRGD結合在 MNP-D 表面形成 iMNP-D,iMNP-D因為與iRGD結合,因而提高其腫瘤靶向和穿透效率。因為iRGD可以與腫瘤的 intergrin 與 neuropilin-1的受體結合,而被內化進入腫瘤細胞。另外由於iMNP-D具有溫度/pH雙敏感特性,所以可以利用周圍環境溫度/pH值的變化,來改變其大小和親水/疏水性,從而控制藥物釋放。Doxorubicin 在酸性及高溫的環境下容易從 iMNP-D中釋放出來。而腫瘤的酸性環境正好有利於Doxorubicin的釋放。另外,我們可以利用短時間的局部高溫,來啟動Doxorubicin從 iMNP-D中釋放出來。我們對iMNP-D進行了增強HT-29結腸癌化療和MR成像的評估。體外和體內研究證明iRGD的存在提高了Doxorubicin對結腸癌細胞/腫瘤的細胞毒性效率,並顯示iMNP-D可以專門將Doxorubicin輸送到結腸癌。此外經由短時間局部高熱來控制藥物釋放因而促進抗腫瘤療效。 總體實驗結果顯示,這種高腫瘤穿透性,高癌細胞靶向的iMNP-D,是結腸癌的高潛力診斷與治療兼具的多功能磁性奈米凝膠載體。 | zh_TW |
dc.description.abstract | Cancer is the most common cause of death in Taiwan, with 48,037 people killed in 2017, a record high and the top 10 causes of death in 36 years, according to data released by Taiwan's Ministry of Health and Welfare. Chemotherapy is one of the main ways to treat cancer, while conventional cancer chemotherapeutic drugs are distributed nonspecifically in the body and hence they affect both cancerous and healthy cells, resulting in dose-related side effects and inadequate drug concentrations reaching the tumor. Multifunctional nanoparticles can target and control releasing chemotherapy agent to tumor cells, thus it can reduce drug induced systemic side effects and improve local tumor treatment results.
In the first study, we developed multifunctional magnetic nanoparticle superparamagnetic iron oxide – polyethylene glycol- Doxorubicin (SPIO-PEG-D), consisting of a superparamagnetic iron oxide (SPIO) magnetic core and a shell of aqueous stable polyethylene glycol (PEG) conjugated with doxorubicin (Dox), for tumor magnetic resonance imaging (MRI) and chemotherapy. The size of SPIO nanoparticles was ~10 nm, which was visualized by transmission electron microscope (TEM). The hysteresis curve, generated with vibrating-sample magnetometer, showed that SPIO-PEG-D was superparamagnetic with an insignificant difference as compared to superparamagnetic iron oxide – polyethylene glycol (SPIO-PEG). The transverse relaxivity (r2) for SPIO-PEG-D was significantly higher than the longitudinal relaxivity (r1) (r2/r1 = 9), so we can observe the distribution of SPIO-PEG-D by MRI T2WI. The half-life of Dox in blood circulation was prolonged by conjugating Dox on the surface of SPIO with PEG to reduce its degradation, by stealth shielding effect of PEG. The in vitro experiment showed that SPIO-PEG-D could cause DNA crosslink more serious, resulting in a lower DNA expression and a higher cell apoptosis for HT-29 cancer cells. The Prussian blue staining study showed that the tumors treated with SPIO-PEG-D under a magnetic field had a much higher intratumoral iron density than the tumors treated with SPIO-PEG-D alone. The in vivo MRI study showed that the T2-weighted signal was stronger for the group under a magnetic field, indicating that it had a better accumulation of SPIO-PEG-D in tumor tissues. In the anticancer efficiency study for SPIO-PEG-D, the results showed that there was a significantly smaller tumor size for the group with a magnetic field than the group without. The in vivo experiments also showed that this drug delivery system SPIO-PEG-D combined with a local magnetic field could reduce the side effects of cardiotoxicity and hepatotoxicity. The results showed that our developed multifunctional magnetic nanoparticle SPIO-PEG-D owns a great potential for MRI-monitoring and magnet-enhancing tumor chemotherapy. In the second study, we developed multifunctional magnetic nanogel particle iMNP-D (iRGD-conjugated magnetic nanogel particles – Doxorubicin) , which was made of iRGD (internalized Arginine–glycine–aspartic acid) conjugated temperature/pH dually sensitive magnetic nanogel particles (MNP-D), which was loaded with superparamagnetic iron oxide nanoparticles and doxorubicin. Temperature/pH dually sensitive poly(acrylic aicd-co-poly (ethylene glycol) di-acrylamide-co-N-isopropylacrylamide (poly(AA-co-PEGDA-co-NIPAM)) nanogels were synthesized by free radical polymerization. Positively charged Dox was introduced into the negatively charged nanogels by electrostatic interaction at pH 7.4. Both Superparamagnetic iron oxide nanoparticles (SPIONs) and Dox were encapsulated in nanogels to develop temperature/pH dually sensitive magnetic nanogel particles (MNP-D), followed by conjugating the peptide iRGD on the MNP-D surface to form iMNP-D, and iMNP-D could enhance its tumor targeting and penetrating efficiency by the conjugation of iRGD. Because iRGD could be internalized into tumor cells by intergrin and neuropilin-1 receptor. Besides, the iMNP-D maintains temperature/pH dually sensitive properties and it can change its size and hydrophilic/hydrophobic properties by changing environment temperature/pH, thus achieving controlled drug release. Dox could be released from iMNP-D at a low pH and/or a high temperature. And the acid environment of tumor could trigger the release of Dox from iMNP-D. In addition, we can apply short-time local hyperthermia to trigger Dox releasing from iMNP-D. We evaluated iMNP-D for both enhancing HT-29 colon cancer chemotherapy and MR imaging. In-vitro and in-vivo studies proved that the presence of iRGD enhanced the cytotoxic efficiency of Dox to colon cancer cells/tumors and indicated that iMNP-D can deliver Dox specifically to colon cancer and can control drug release with a short-time local hyperthermia to promote anti-tumor efficacy. The overall experimental results indicate that this high tumor-penetrating, high cancer cell-targeting iMNP-D is a highly potential theranostic multifunctional magnetic nanogel carrier for the monitoring and treatment of colon cancer. | en |
dc.description.provenance | Made available in DSpace on 2021-05-19T17:40:17Z (GMT). No. of bitstreams: 1 ntu-108-D00548003-1.pdf: 2446382 bytes, checksum: f2301d70b811bf392187ebd122dd50cb (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | 中文摘要 i
Abstract iii Abbreviation and Acronyms …………………………………………………………..vi Contents vii List of Figures xi List of Tables xviii Chapter 1. Background & Objectives 1 1.1. Unmet need of cancer chemotherapy 1 1.2. Cancer nanomedicine 1 1.3. Targeting drug delivery systems of nanomedicine 1 1.3.1. Passive targeting drug delivery system 2 1.3.2. Active targeting drug delivery system 2 1.4. Magnetic-targeted nanoparticles 3 1.5. Control releasing (pH/temperature dually responsive systems) 4 1.6. Multifunctional nanoparticles for targeted imaging and therapy 5 1.7. Objectives 5 Chapter 2. (My study Part I) Doxorubicin-eluting magnetic nanoparticles as a drug delivery system for magnetic resonance imaging-monitoring magnet-enhancing tumor chemotherapy 9 2.1. Introduction 9 2.2. Methods and materials 12 2.2.1. Materials 12 2.2.2. Synthesis of HOOC-PEG-triethoxysilane (HOOC-PEG silane) 12 2.2.3. Synthesis of magnetite nanoparticles with IO 13 2.2.4. Synthesis of SPIO-PEG 13 2.2.5. Synthesis of SPIO-PEG-D 14 2.2.6. Analysis of particle properties 14 2.2.7. MRI analysis of nanoparticles in cancer cells 15 2.2.8. Qualitative and quantitative studies of cellular uptake 16 2.2.9. Degradation test for free Dox and SPIO-PEG-D 17 2.2.10. DNA interstrand crosslink 17 2.2.11. Cell MTT cytotoxicity 17 2.2.12. In vivo MR image and detection of iron 18 2.2.13. In vivo antitumor activity 19 2.2.14. Apoptosis detection for tumor cells 20 2.3. Results and discussion 20 2.3.1. Synthesis of HOOC-PEG-triethoxysilane (HOOC-PEG silane) and thermal properties of nanoparticles 20 2.3.2. Characterization of nanoparticles 20 2.3.3. Qualification and quantification of SPIO-PEG-D 21 2.3.4. Structural analysis and magnetic properties of SPIO-PEG and SPIO-PEG-D 22 2.3.5. Relaxivity 22 2.3.6. In vitro qualitative and quantitative studies of cellular uptake 23 2.3.7. In vitro degradation and anticancer cell efficiency test 24 2.3.8. In vivo MR imaging and detection of iron 25 2.3.9. In vivo antitumor study 26 2.4. Conclusion 28 Chapter 3. (My study Part II) Temperature/pH sensitive magnetic nanogel particles loaded with doxorubicin and conjugated with iRGD for enhancing colon cancer tumor chemotherapy and MR imaging 43 3.1. Introduction 43 3.2. Methods and materials 45 3.2.1. Materials 45 3.2.2. Preparation of poly (ethylene glycol) di-acrylamide (PEGDA) 46 3.2.3. Synthesis of magnetite nanoparticles with oleic acid (IO-OA) 46 3.2.4. Synthesis of magnetite nanoparticles with citric acid (IO-CA) 47 3.2.5. Synthesis of magnetic nanogel particles (MNP) and iRGD-conjugated MNP (iMNP), and loaded with doxorubicin (MNP-D or iMNP-D) 47 3.2.6. Characterizations of MNP-D and iMNP-D 48 3.2.7. In vitro drug release 49 3.2.8. MRI analysis of cellular internalization of MNP-D, iMNP-D, and i+iMNP-D 49 3.2.9. Qualitative and quantitative studies of cellular uptake 50 3.2.10. Cell MTT cytotoxicity 51 3.2.11. In vivo MR image and detection of iron 51 3.2.12. In vivo antitumor activity 52 3.2.13. In vivo Dox accumulation 53 3.2.14. Apoptosis detection for tumor cells 54 3.3. Results and discussion 54 3.3.1. Characterization of poly(ethylene glycol) di-acrylamide and conjugation ratio of iRGD 54 3.3.2. Characterization of MNP-D and iMNP-D 54 3.3.3. In vitro Dox release 56 3.3.4. In vitro qualitative and quantitative studies of cellular uptake 57 3.3.5. In vitro cytotoxicity of MNP-D and iMNP-D against HT-29 cancer cells 58 3.3.6. In vivo MR imaging and detection of iron 59 3.3.7. In vivo antitumor activity 60 3.3.8. Dox accumulation analysis for tumors 61 3.3.9. Apoptosis detection for tumor cells 62 3.4. Conclusion 62 Chapter 4. Summary and future work 78 Acknowledgement 82 References 83 | |
dc.language.iso | en | |
dc.title | 用於癌症治療與診斷的多功能奈米粒子 | zh_TW |
dc.title | Multifunctional Nanoparticles for Cancer Theranostics | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 謝銘鈞,黃凱文,翁昭旼,李伯皇,王嘉齊 | |
dc.subject.keyword | 癌症,化療,阿黴素,內化精胺酸-甘胺酸-天門冬胺酸,磁體增強,磁振造影成像,磁振造影監測,奈米凝膠,聚乙烯乙二醇,超順磁性氧化鐵,溫度/酸鹼敏感,腫瘤, | zh_TW |
dc.subject.keyword | cancer,chemotherapy,Doxorubicin(Dox),iRGD,magnet enhancing,MR imaging,MRI monitoring,nanogel,polyethylene glycol,superparamagnetic iron oxide,temperature/pH sensitive,tumor, | en |
dc.relation.page | 95 | |
dc.identifier.doi | 10.6342/NTU201902917 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2019-08-12 | |
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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