研究生: |
許宏心 HUNG-HSIN, HSU |
---|---|
論文名稱: |
電場誘導聚己內酯奈米粒子之細胞內藥物釋放 In Vitro Drug Release from Electric-Field Responsive Polycaprolactone Nanoparticles |
指導教授: |
陳建光
Jem-Kun Chen |
口試委員: |
蔡協致
Hsieh-Chih Tsai 張棋榕 Chi-Jung Chang 陳建光 Jm-Kun Chen |
學位類別: |
碩士 Master |
系所名稱: |
工程學院 - 材料科學與工程系 Department of Materials Science and Engineering |
論文出版年: | 2019 |
畢業學年度: | 107 |
語文別: | 中文 |
論文頁數: | 101 |
中文關鍵詞: | 聚己內酯 、生物相容性高分子 、藥物載體 、乳化聚合 、電響應藥物釋放 |
外文關鍵詞: | Polycaprolactone, Biodegradagle polymer, Drug carrier, Emulsion polymerization, Electric-field responsive nanoparticle |
相關次數: | 點閱:412 下載:0 |
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本研究為設計一具電場響應之生物相容性藥物載體模型,透過交流感應電場誘導帶電奈米粒子之電泳行為,進而加速藥物之釋放。利用生物可降解之高分子聚己內酯(Polycaprolactone diol,PCL diol)為基材,經末端官能基改質為聚己內酯(Polycaprolactone diacrylate,PCLDA),由IR、NMR證實官能基成功改質。以乳化聚合法將聚己內酯(PCLDA)合成聚己內酯奈米粒子,並透過尼羅紅(Nile red)對其進行螢光標記,並利用Zeta-sizer及DLS探討不同參數下的粒徑與電位變化。由UV-vis測量得在尼羅紅200ug/ml的濃度下具有71%的藥物包覆率,並且在一個月內僅損失10%的藥物量。藉由CLSM觀察螢光包覆影像。對聚己內酯奈米粒子施加不同頻率及電壓之交流電場,利用OM觀察微觀下之變化,並藉由雷射去探討聚己內酯奈米粒子受電場響應之穿透率,其中以6V、6mHz之交流電穿透率最高。由UV-Vis觀察聚己內酯/尼羅紅奈米粒子在上述特定交流電場下之釋放率,在30分鐘釋放率可達30%。
將聚己內酯/尼羅紅奈米粒子與RAW264.7細胞共培養,再利用聚己內酯粒子之電響應特性,對其施加6V、6mHz交流電,利用CLSM觀察細胞攝取粒子情況與藥物釋放效果。本研究成功製備出具電場響應之聚己內酯奈米粒子模型,能透過交流電場誘導粒子泳動加速藥物之釋放。藉由調控粒徑與表面官能化修飾,電響應藥物遞送系統可以克服常規藥物製劑的缺點,它們能夠在特定的部位和時間以受控的方式遞送藥物,未來於癌症治療具有相當之潛力。
In this study, we prepared a biocompatible drug carrier model with electric-field response. First, we modified polycaprolactone diol’s terminal functional group to polycaprolactone diacrylate(PCLDA), which has been comfirmed by IR and NMR spectrum. Second, we used emulsion polymerization to synthesize the polycaprolactone nanoparticles with PCLDA and also labled with nile red via drug encapsulation. Using Zeta-sizer and DLS to explore particle size and potential changes under different concentration of SDS.Furthermore, a high loading efficiency 71% and high stability carrier that only loss approximately 10% drug amounts during one month nanocarrier was prepared, which is measured by UV-vis spectrum, and then we observed nanoparticles containing red fluorescence images by CLSM. Applying an alternating electric-field of different frequencies and voltages to the polycaprolactone nanoparticles, observing the change of nanoparticles under the electric-field by OM, and exploring the penetration rate of the polycaprolactone nanoparticles under the electric-field by laser, we found that the penetrationg rate is the highest under specific alternating electric-field, which is 6 volts and 6 mHz. The release rate reached 30% in 30 minutes under the alternating electric-field(6V、6mHz) was observed by UV-vis spectrum.
The polycaprolactone/Nile red nanoparticles were co-cultured with RAW264.7 cells. Owing to the characteristic of electric-field response of the polycaprolactone nanoparticles, we applied an alternating electric-field with 6 volts and 6 mHz, then using CLSM to observe the cellular uptake and drug release.
In this study, a polycaprolactone nanoparticle model with electric field response was successfully prepared. By controlling particle size and particle’s surface functionalization, the electric-field responsive drug delivery system can overcome the disadvantages of conventional pharmaceutical preparations. They are capable of delivering drugs in a controlled manner at specific sites and times, and have considerable potential for cancer treatments in the future.
Liang Zhaoa,1, Arjun Setha,1, Nani Wibowoa, Chun-Xia Zhaoa, Neena Mitterb, Chengzhong Yua, Anton P.J. Middelberga, Nanoparticle vaccines, Vaccine, 2014, 3, 27~337.
Guanying Chen, Indrajit Roy, Chunhui Yang, and Paras N. Prasad, Nanochemistry and Nanomedicine for Nanoparticle-based Diagnostics and Therapy, Chem. Rev., 2016, 116, 2826~2885.
Simona Mura, Julien Nicolas and Patrick Couvreur, Stimuli-responsive nanocarriers for drug delivery, NATURE MATERIALS, 2013, Vol. 12, 991~1003.
Ghosh Chaudhuri R, Paria S. Core/shell nanoparticles: classes, properties, synthesis mechanisms, characterization, and applications, Chem. Rev., 2012, 112, 2373-2433.
Erem Bilensoy, Can Sarisozen, Günes¸ Esendaglı, A. Lale Dogan, Yesim Aktas, Murat Sen, N. Aydın Mungan, Intravesical cationic nanoparticles of chitosan and polycaprolactone for the delivery of Mitomycin C to bladder tumors, International Journal of Pharmaceutics, 2009, 170–176.
Ying Zhang, Ren-xi Zhuo, Synthesis and in vitro drug release behavior of amphiphilictriblock copolymer nanoparticles based on poly (ethylene glycol) and polycaprolactone, Biomaterials, 2005, 6736–6742.
MATTEO CONTI, VALERIA TAZZARI, CESARE BACCINI, GIANNI PERTICI, LORENZO PIO SERINO AND UGO DE GIORGI, Anticancer Drug Delivery with Nanoparticles, in vivo, 2006, 20, 697-702.
Sarwar Hossen, M. Khalid Hossain, M.K. Basher, M.N.H. Mia, M.T. Rahman, M. Jalal Uddin. Smart nanocarrier-based drug delivery systems for cancer therapy and toxicity studies: A review, Journal of Advanced Research, 2018.
Arsalan Ahmed, Sen Liu, Yutong Pan, Shanmei Yuan, Jian He, and Yong Hu, Multicomponent Polymeric Nanoparticles Enhancing Intracellular Drug Release in Cancer Cells, ACS Appl. Mater. Interfaces, 2014, 6, 21316~21324.
Muhammad Sajid Hamid Akash, Kanwal Rehman & Shuqing Chen, Natural and Synthetic Polymers as Drug Carriers for Delivery of Therapeutic Proteins, Polymer Reviews, 2015, 55:3, 371~406.
Ge J, Neofytou E, Cahill TJ, Beygui RE, Zare RN. Drug release from electric-field-responsive nanoparticles. ACS Nano, 2012;6:227–33.
Han-Min Kim, Hak-Ryul Kim, Ching T. Hou, Beom Soo Kim, Biodegradable Photo-Crosslinked Thin Polymer Networks Based on Vegetable Oil Hydroxy Fatty Acids, J Am Oil Chem Soc, 2010, 87:1451–1459.
Klaus Strebhardt and Axel Ullrich, Paul Ehrlich’s magic bullet concept: 100 years of progress, Nature Rev. Cancer, 2008, 8, 473~480
Jorg Kreuter, Nanoparticles—a historical perspective, International Journal of Pharmaceutics, 2007, 331, 1~10.
Gurny, R., Peppas, N.A., Harrington, D.D., Banker, G.S., Development of biodegradable and injectable lattices for controlled release of potent drugs., Drug Dev. Ind. Pharm., 1981, 7, 1–25.
Birrenbach, G., Speiser, P.P., Polymerized micelles and their use as adjuvants in immunology., J. Pharm. Sci., 1976, 65, 1763–1766.
Khanna, S.C., Jecklin, T., Speiser, P., Bead polymerisation technique for sustained release dosage form., J. Pharm. Sci., 1970, 59, 614–618.
Perrault, S. D.; Chan, W. C. W., Synthesis and Surface Modification of Highly Monodispersed, Spherical Gold Nanoparticles of 50−200 nm, J. Am. Chem. Soc., 2009, 131 (47), 17042~17043.
Nikoobakht, B.; El-Sayed, M. A. Preparation and growth mechanism of gold nanorods (NRs) using seed-mediated growth method. Chem. Mater. 2003, 15 (10), 1957~1962.
Cui, Y.; Wei, Q. Q.; Park, H. K.; Lieber, C. M. Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species. Science, 2001, 293 (5533), 1289~1292.
Altintas, O.; Vogt, A. P.; Barner-Kowollik, C.; Tunca, U., Constructing Star Polymers via Modular Ligation Strategies. Polym. Chem., 2012, 3, 34−45.
Prasad, P. N. Nanophotonics; Wiley-Interscience: Hoboken, NJ, 2004.
Burda, C.; Chen, X. B.; Narayanan, R.; El-Sayed, M. A. Chemistry and properties of nanocrystals of different shapes. Chem. Rev., 2005, 105 (4), 1025−1102.
Riehemann, K.; Schneider, S. W.; Luger, T. A.; Godin, B.; Ferrari, M.; Fuchs, H. Nanomedicine-Challenge and Perspectives., Angew. Chem., Int. Ed. 2009, 48 (5), 872−897.
Allen, T. M.; Cullis, P. R. Drug delivery systems: Entering the mainstream. Science, 2004, 303 (5665), 1818−1822.
Muller, R. H.; Mader, K.; Gohla, S. Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art. Eur. J. Pharm. Biopharm. 2000, 50 (1), 161−177.
Nicolas, J.; Mura, S.; Brambilla, D.; Mackiewicz, N.; Couvreur, P. Design, functionalization strategies and biomedical applications of targeted biodegradable/biocompatible polymer-based nanocarriers for drug delivery., Chem. Soc. Rev., 2013, 42 (3), 1147−1235.
McCarthy, J. R.; Weissleder, R. Multifunctional magnetic nanoparticles for targeted imaging and therapy. Adv. Drug Delivery Rev. 2008, 60 (11), 1241−1251.
Guanying Chen, Indrajit Roy, Chunhui Yang, and Paras N. Prasad, Nanochemistry and Nanomedicine for Nanoparticle-based Diagnostics and Therapy, Chem. Rev., 2016, 116, 2826~2885. [2]
João Conniot, Joana M. Silva, Joana G. Fernandes, Liana C. Silva, Rogério Gaspar, Steve Brocchini, Helena F. Florindo and Teresa S. Barata., Cancer immunotherapy: nanodelivery approaches for immune cell targeting and tracking., Frontiers in Chemistry, 2014, Vol. 2, Article 105., 1~27
Uhrich, K. E.; Cannizzaro, S. M.; Langer, R. S.; Shakesheff, K. M., Polymeric systems for controlled drug release., Chem. Rev., 1999, 99 (11), 3181~3198.
Yasuhiro Matsumura and Hiroshi Maeda, A New Concept for Macromolecular Therapeutics in Cancer Chemotherapy: Mechanism of Tumoritropic Accumulation of Proteins and the Antitumor Agent Smancs, cancer research, 1986, 46, 6387~6392
Guanying Chen, Indrajit Roy, Chunhui Yang, and Paras N. Prasad, Nanochemistry and Nanomedicine for Nanoparticle-based Diagnostics and Therapy, Chem. Rev., 2016, 116, 2826~2885.
Saina Yang, Feiyan Zhu, Qian Wang, Fuxin Liang, Xiaozhong Qu, Zhihua Gan and Zhenzhong Yang, Combinatorial targeting polymeric micelles for anti-tumor drug delivery, Journal of Materials Chemistry B, 2015, 3(19), 4043–4051.
Ruth Duncan, The dawning era of polymer therapeutics, Nature Reviews Drug discovery, 2003, Vol. 2., 347~360
LEIBLER, Ludwik; ORLAND, Henri; WHEELER, John C. Theory of critical micelle concentration for solutions of block copolymers. The Journal of chemical physics, 1983, 79(7), 3550~3557.
Ling Mei, Yayuan Liu, HuaJin Zhang, Zhirong Zhang, Huile Gao, and Qin He, Antitumor and Antimetastasis Activities of Heparin-based Micelle Served As Both Carrier and Drug, ACS Appl. Mater. Interfaces, 2016, 8, 9577~9589
SINGH, Jasvinder, et al. Diphtheria toxoid loaded poly-(ε-caprolactone) nanoparticles as mucosal vaccine delivery systems. Methods, 2006, 38.2: 96-105.
FLORINDO, H. F., et al. New approach on the development of a mucosal vaccine against strangles: systemic and mucosal immune responses in a mouse model. Vaccine, 2009, 27.8: 1230-1241.
FLORINDO, H. F., et al. The enhancement of the immune response against S. equi antigens through the intranasal administration of poly-ɛ-caprolactone-based nanoparticles. Biomaterials, 2009, 30.5: 879-891.
EMOTO, Kazunori; NAGASAKI, Yukio; KATAOKA, Kazunori. A Core− Shell Structured Hydrogel Thin Layer on Surfaces by Lamination of a Poly (ethylene glycol)-b-poly (d, l-lactide) Micelle and Polyallylamine. Langmuir, 2000, 16.13: 5738-5742.
RÖSLER, Annette; VANDERMEULEN, Guido WM; KLOK, Harm-Anton. Advanced drug delivery devices via self-assembly of amphiphilic block copolymers. Advanced drug delivery reviews, 2012, 64: 270-279.
Stephanie Tran1, Peter Joseph DeGiovanni1, Brandon Piel and Prakash Rai. Cancer nanomedicine: a review of recent success in drug delivery, Clin Trans Med, 2017 6:44.
Rizvi, S.A.A., Saleh, A.M., Applications of Nanoparticle Systems in Drug Delivery Technology, Saudi Pharmaceutical Journal, 2017
Ying-Jie Zhu and Feng, pH-Responsive Drug-Delivery, Chemistry - An Asian Journal,2014 , 284–305.
Elizabeth R. Gillies and Jean M. J. Fre´chet, pH-Responsive Copolymer Assemblies for Controlled Release of Doxorubicin, Bioconjugate Chem, 2005, 16, 361−368.
Ge J, Neofytou E, Cahill TJ, Beygui RE, Zare RN. Drug release from electric-field-responsive nanoparticles. ACS Nano, 2012;6:227–33.
Ge J, Neofytou E, Cahill TJ, Beygui RE, Zare RN. Drug release from electric-field-responsive nanoparticles. ACS Nano, 2012;6:227–33.
S. Ponsart, J. Coudane, and M. Vert, A Novel Route to Poly(E-caprolactone)-Based Copolymers via Anionic Derivatization, Biomacromolecules, 2000, 1, 275~281
A.G.A. Coombes, S.C. Rizzi, M. Williamson, J.E. Barralet, S. Downes, W.A. Wallace, Precipitation casting of polycaprolactone for applications in tissue engineering and drug delivery, Biomaterials, 2004, 25, 315~325.
Julien Nicolas, Simona Mura, Davide Brambilla, Nicolas Mackiewicz and Patrick Couvreur, Design, functionalization strategies and biomedical applications of targeted biodegradable/biocompatible polymer-based nanocarriers for drug delivery, Chem. Soc. Rev., 2013, 42, 1147
Fatemeh Bahadori, Aydan Dag, Hakan Durmaz, Nese Cakir, Hayat Onyuksel, Umit Tunca, Gulacti Topcu and Gurkan Hizal, Synthesis and Characterization of Biodegradable Amphiphilic Star and Y-Shaped Block Copolymers as Potential Carriers for Vinorelbine, Polymers, 2014, 6, 214~242.
Jorg Kreuter, Nanoparticles—a historical perspective, International Journal of Pharmaceutics, 2007, 331, 1~10.
Robert M. Fitch, Michael B. Prenosil, Karen J. Sprick, The mechanism of particle formation in polymer hydrosols. I. Kinetics of Aqueous Polymerization of Methyl Methacrylate, Journal of Polymer Science Part C: Polymer Symposia, Wiley Online Library, 1969, pp.95-118.
William D. Harkins, A General Theory of the Mechanism of Emulsion Polymerization, Journal of the American Chemical Society, 1947, 1428-1444.
H. Fessi, F. Puisieux, J.Ph. Devissaguet, N. Ammoury and S. Benita, Nanocapsule formation by interfacial polymer deposition following solvent displacement, International Journal of Pharmaceutics, 1989,55 R1-R4.
Miladi K., Sfar S., Fessi H., Elaissari A. Nanoprecipitation Process: From Particle Preparation to In Vivo Applications. In: Polymer Nanoparticles for Nanomedicines: A Guide for their Design, Preparation and Development (Vauthier C., Ponchel G. ed.). Springer International Publishing. 2016; pp 17–53.
Jong Min Sung. Dielectrophoresis and Optoelectronic Tweezers for Nanomanipulation. 2007.