非晶相碳酸鈣為自然界中常見的生物礦物之一，由於其無毒、高生物相容性與對 pH 值敏感等特質，對於抗癌藥物是非常具有潛力的載體。然而，由於其本身對於水的不穩定性而限制了它的應用。
在本研究中，我們嘗試添加鎂離子以穩定非晶相碳酸鈣。因鎂離子的高電荷密度會使其擁有極高的水合能，在與鈣離子沉澱時，由於水合鎂離子脫水不易，導致陽離子難與碳酸根排列為整齊的晶體結構，使得碳酸鈣可以停留在熱力學不穩定的非晶相態。此外，進一步使用有機分子包覆在含鎂非晶相碳酸鈣的表面，除了加強非晶相碳酸鈣對水的穩定性，同時也增加其在水中的分散性。在尺寸大小方面，為了符合高滲透長滯留效應 (EPR effect)，我們使用逆相微胞搭配氣體擴散法製備含鎂非晶相碳酸鈣，以物理性限制的方式，將礦物的尺寸限制在100奈米以下，以達到最好的靶向腫瘤組織效果。
本研究成功合成含鎂非晶相碳酸鈣奈米顆粒，在保有碳酸鈣本身對於 pH 值獨特的反應性的同時改善它在生理環境中的穩定性。這種能在弱酸環境下精準釋放藥物的載體，可以減少藥物的需求量與副作用，證明了它在癌症治療上有著極大的潛力。

Amorphous calcium carbonate (ACC) is one of the most important precursor phase of calcareous biominerals. ACC is nontoxic, biocompatible, and pH-sensitive. According to these properties, ACC has a high potential for being used as drug delivery systems. However, owing to its metastable character, it is hard to prepare nano-sized ACC in vitro. One possible solution is to dope some magnesium ions into calcium carbonate and form Mg-ACC because magnesium cations have higher dehydration energy barrier which could stabilize the ACC. To prepare Mg-ACC with the enhanced permeability and retention (EPR) effect for cancer treatment, we have exploited the strategy of reverse micelles to get nanoscale and very uniform particles. As a result, the size of the Mg-ACC particles are under 100 nm, which is the most suitable size in tumor targeting.

口試委員會審定書 I
誌謝 II
中文摘要 VIII
Abstract IX
縮寫表 X
目錄 XII
圖目錄 XV
表目錄 XIX
第一章 緒論 1
1.1 癌症簡介 1
1.1.1 癌症登月計畫 2
1.1.2 癌症治療方法 3
1.2 藥物載體 4
1.2.1 高滲透長滯留效應 6
1.2.2 癌細胞生理環境簡介 7
1.2.3 抗癌藥物 9
1.2.4 表面修飾奈米載體 10
1.2.5 藥物載體釋放機制 12
1.3 非晶相碳酸鈣 16
1.3.1 鎂離子影響 18
1.4 逆相微胞簡介 19
1.5 研究動機 23
第二章 實驗儀器與樣品製備 24
2.1 化學藥品 24
2.2 實驗儀器 25
2.2.1 X 光繞粉末射 (X-ray Powder Diffraction, XRD) 25
2.2.2 傅立葉轉換紅外線光譜儀 (Fourier Transform Infrared Spectroscopy, FT-IR) 26
2.2.3 掃描式電子顯微鏡 (Scanning Electron Microscope, SEM) 27
2.2.4 穿透式電子顯微鏡 (Transmission Electron Microscope, TEM) 28
2.2.5 X光能量色散光譜儀 (Energy Dispersive X-ray Spectroscopy, EDS) 29
2.2.6 固態核磁共振光譜 (Solid-State Nuclear Magnetic Resonance, ssNMR) 29
2.2.7 動態光散射粒徑分析儀 (Dynamic Light Scattering, DLS) 35
2.2.8 NSRRC X 光高解析度粉末繞射 (High-Resolution Powder X-ray Diffraction, HRXRD) 36
2.2.9 感應耦合電漿質譜儀 (Inductively coupled plasma mass spectroscopy, ICP-MS) 36
第三章 結果與討論 38
3.1 製備含鎂非晶相碳酸鈣奈米顆粒 38
3.1.1 氣體擴散法 (Vapor Diffusion Reaction) 38
3.1.2 薄膜水合法 40
3.1.3 逆相微胞搭配氣體擴散法 43
3.1.4 製備 DOX@Mg-ACC 奈米顆粒 44
3.2 逆相微胞鑑定 45
3.3 測試氣體擴散反應時間 46
3.4 含鎂非晶相碳酸鈣構型與成分鑑定 48
3.5 含鎂非晶相碳酸鈣結構鑑定 51
3.6 界面活性劑殘留鑑定 52
3.7 含鎂非晶相碳酸鈣的分散性與尺寸 54
3.8 含鎂非晶相碳酸鈣於水中不穩定 56
3.9 磷脂質包覆 Mg-ACC 增強對水穩定性 59
第四章 結論與未來展望 68
參考文獻 70
附錄 77
附錄 A 77
A.1 以 AOT 製備逆相微胞系統 77
A.2 以95% PC 製備逆向微胞系統 79
附錄 B 82
附錄 C 86
附錄 D 88
附錄 E 94
E.1 使用聚丙烯酸 (Polyacrylic Acid) 包覆 Mg-ACC 94
E.2 使用磷酸鈉包覆 Mg-ACC 98
E.3 使用 m-PEG4-膦酸包覆 Mg-ACC 101

(1) What Is Cancer? https://www.cancer.gov/about-cancer/understanding/what-is-cancer (accessed May 29, 2019).
(2) Klein, C. A. The Metastasis Cascade. Science 2008, 321 (5897), 1785–1787. https://doi.org/10.1126/science.1164853.
(3) Jemal, A.; Bray, F.; Center, M. M.; Ferlay, J.; Ward, E.; Forman, D. Global Cancer Statistics. CA. Cancer J. Clin. 2011, 61 (2), 69–90. https://doi.org/10.3322/caac.20107.
(4) Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R. L.; Torre, L. A.; Jemal, A. Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA. Cancer J. Clin. 2018, 68 (6), 394–424. https://doi.org/10.3322/caac.21492.
(5) 衛生福利部 https://www.mohw.gov.tw/mp-1.html (accessed Jun 19, 2019).
(6) Collins, F. S.; Varmus, H. A New Initiative on Precision Medicine. N. Engl. J. Med. 2015, 372 (9), 793–795. https://doi.org/10.1056/NEJMp1500523.
(7) 台灣癌症登月計畫 https://leavenoonebehind.com.tw/zh/article.php?unit=454&content=132532 (accessed Jun 20, 2019).
(8) Urruticoechea, A.; Alemany, R.; Balart, J.; Villanueva, A.; Capella, F. V. and G. Recent Advances in Cancer Therapy: An Overview http://www.eurekaselect.com/70602/article (accessed Jun 21, 2019).
(9) Sun, T.; Zhang, Y. S.; Pang, B.; Hyun, D. C.; Yang, M.; Xia, Y. Engineered Nanoparticles for Drug Delivery in Cancer Therapy. Angew. Chem. Int. Ed. 2014, 53 (46), 12320–12364. https://doi.org/10.1002/anie.201403036.
(10) Cancer Treatment Options | Houston Methodist https://www.houstonmethodist.org/cancer/treatment-options/ (accessed Jun 21, 2019).
(11) Cytotoxic chemotherapy: clinical aspectsClinicalKey 臨床醫學資料庫 https://www.clinicalkey.com/#!/content/playContent/1-s2.0-S1357303907003490?returnurl=https:%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1357303907003490%3Fshowall%3Dtrue&referrer=https:%2F%2Fzh.wikipedia.org%2F (accessed Jun 24, 2019).
(12) julia. 從實驗到上市，一款藥物的開發可以耗費多少青春與成本？ https://www.thenewslens.com/article/95507 (accessed Jun 25, 2019).
(13) Markolin, P. Dynamic undocking, a structure guided tool for virtual drug discovery https://medium.com/advances-in-biological-science/dynamic-undocking-a-structure-guided-tool-for-virtual-drug-discovery-bd380ff30435 (accessed Jun 26, 2019).
(14) Tiwari, G.; Tiwari, R.; Sriwastawa, B.; Bhati, L.; Pandey, S.; Pandey, P.; Bannerjee, S. K. Drug Delivery Systems: An Updated Review. Int. J. Pharm. Investig. 2012, 2 (1), 2. https://doi.org/10.4103/2230-973X.96920.
(15) 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 (12 Part 1), 6387–6392.
(16) 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 (1), 189–207. https://doi.org/10.1016/S0065-2571(00)00013-3.
(17) Gratton, S. E. A.; Ropp, P. A.; Pohlhaus, P. D.; Luft, J. C.; Madden, V. J.; Napier, M. E.; DeSimone, J. M. The Effect of Particle Design on Cellular Internalization Pathways. Proc. Natl. Acad. Sci. 2008, 105 (33), 11613–11618. https://doi.org/10.1073/pnas.0801763105.
(18) Wang, M.; Thanou, M. Targeting Nanoparticles to Cancer. Pharmacol. Res. 2010, 62 (2), 90–99. https://doi.org/10.1016/j.phrs.2010.03.005.
(19) Role of Particle Size in Phagocytosis of Polymeric Microspheres | SpringerLink https://link.springer.com/article/10.1007%2Fs11095-008-9562-y (accessed Jun 25, 2019).
(20) Perrault, S. D.; Walkey, C.; Jennings, T.; Fischer, H. C.; Chan, W. C. W. Mediating Tumor Targeting Efficiency of Nanoparticles Through Design. Nano Lett. 2009, 9 (5), 1909–1915. https://doi.org/10.1021/nl900031y.
(21) Wang, A. Z.; Langer, R.; Farokhzad, O. C. Nanoparticle Delivery of Cancer Drugs. Annu. Rev. Med. 2012, 63 (1), 185–198. https://doi.org/10.1146/annurev-med-040210-162544.
(22) Haag, R.; Kratz, F. Polymere Therapeutika: Konzepte und Anwendungen. Angew. Chem. 2006, 118 (8), 1218–1237. https://doi.org/10.1002/ange.200502113.
(23) Gatenby, R. A.; Gillies, R. J. Why Do Cancers Have High Aerobic Glycolysis? Nat. Rev. Cancer 2004, 4 (11), 891. https://doi.org/10.1038/nrc1478.
(24) Fung, D. J. The Paradox of Cancer’s Warburg Effect - Dr. Jason Fung https://medium.com/@drjasonfung/the-paradox-of-cancers-warburg-effect-7fb572364b81 (accessed Jun 26, 2019).
(25) Owen, S. C.; Doak, A. K.; Wassam, P.; Shoichet, M. S.; Shoichet, B. K. Colloidal Aggregation Affects the Efficacy of Anticancer Drugs in Cell Culture. ACS Chem. Biol. 2012, 7 (8), 1429–1435. https://doi.org/10.1021/cb300189b.
(26) Huh, K. M.; Lee, S. C.; Cho, Y. W.; Lee, J.; Jeong, J. H.; Park, K. Hydrotropic Polymer Micelle System for Delivery of Paclitaxel. J. Controlled Release 2005, 101 (1), 59–68. https://doi.org/10.1016/j.jconrel.2004.07.003.
(27) Torchilin, V. P.; Lukyanov, A. N.; Gao, Z.; Papahadjopoulos-Sternberg, B. Immunomicelles: Targeted Pharmaceutical Carriers for Poorly Soluble Drugs. Proc. Natl. Acad. Sci. 2003, 100 (10), 6039–6044. https://doi.org/10.1073/pnas.0931428100.
(28) McConnell, E. L.; Fadda, H. M.; Basit, A. W. Gut Instincts: Explorations in Intestinal Physiology and Drug Delivery. Int. J. Pharm. 2008, 364 (2), 213–226. https://doi.org/10.1016/j.ijpharm.2008.05.012.
(29) Suk, J. S.; Xu, Q.; Kim, N.; Hanes, J.; Ensign, L. M. PEGylation as a Strategy for Improving Nanoparticle-Based Drug and Gene Delivery. Adv. Drug Deliv. Rev. 2016, 99 (Pt A), 28–51. https://doi.org/10.1016/j.addr.2015.09.012.
(30) Abuchowski, A.; McCoy, J. R.; Palczuk, N. C.; Es, T. van; Davis, F. F. Effect of Covalent Attachment of Polyethylene Glycol on Immunogenicity and Circulating Life of Bovine Liver Catalase. J. Biol. Chem. 1977, 252 (11), 3582–3586.
(31) Duncan, R. The Dawning Era of Polymer Therapeutics. Nat. Rev. Drug Discov. 2003, 2 (5), 347. https://doi.org/10.1038/nrd1088.
(32) Duncan, R. Polymer Conjugates as Anticancer Nanomedicines. Nat. Rev. Cancer 2006, 6 (9), 688. https://doi.org/10.1038/nrc1958.
(33) Göpferich, A. Mechanisms of Polymer Degradation and Erosion. Biomaterials 1996, 17 (2), 103–114. https://doi.org/10.1016/0142-9612(96)85755-3.
(34) Arifin, D. Y.; Lee, L. Y.; Wang, C.-H. Mathematical Modeling and Simulation of Drug Release from Microspheres: Implications to Drug Delivery Systems. Adv. Drug Deliv. Rev. 2006, 58 (12), 1274–1325. https://doi.org/10.1016/j.addr.2006.09.007.
(35) Robitzki, A. A.; Kurz, R. Biosensing and Drug Delivery at the Microscale. In Drug Delivery; Schäfer-Korting, M., Ed.; Handbook of Experimental Pharmacology; Springer Berlin Heidelberg: Berlin, Heidelberg, 2010; pp 87–112. https://doi.org/10.1007/978-3-642-00477-3_3.
(36) Kim, H.-J.; Matsuda, H.; Zhou, H.; Honma, I. Ultrasound-Triggered Smart Drug Release from a Poly(Dimethylsiloxane)– Mesoporous Silica Composite. Adv. Mater. 2006, 18 (23), 3083–3088. https://doi.org/10.1002/adma.200600387.
(37) Felber, A. E.; Dufresne, M.-H.; Leroux, J.-C. PH-Sensitive Vesicles, Polymeric Micelles, and Nanospheres Prepared with Polycarboxylates. Adv. Drug Deliv. Rev. 2012, 64 (11), 979–992. https://doi.org/10.1016/j.addr.2011.09.006.
(38) Mo, R.; Jiang, T.; DiSanto, R.; Tai, W.; Gu, Z. ATP-Triggered Anticancer Drug Delivery. Nat. Commun. 2014, 5, 3364. https://doi.org/10.1038/ncomms4364.
(39) Mura, S.; Nicolas, J.; Couvreur, P. Stimuli-Responsive Nanocarriers for Drug Delivery. Nat. Mater. 2013, 12 (11), 991–1003. https://doi.org/10.1038/nmat3776.
(40) Cheng, R.; Meng, F.; Deng, C.; Klok, H.-A.; Zhong, Z. Dual and Multi-Stimuli Responsive Polymeric Nanoparticles for Programmed Site-Specific Drug Delivery. Biomaterials 2013, 34 (14), 3647–3657. https://doi.org/10.1016/j.biomaterials.2013.01.084.
(41) Sirsi, S. R.; Borden, M. A. State-of-the-Art Materials for Ultrasound-Triggered Drug Delivery. Adv. Drug Deliv. Rev. 2014, 72, 3–14. https://doi.org/10.1016/j.addr.2013.12.010.
(42) Schmaljohann, D. Thermo- and PH-Responsive Polymers in Drug Delivery. Adv. Drug Deliv. Rev. 2006, 58 (15), 1655–1670. https://doi.org/10.1016/j.addr.2006.09.020.
(43) Xiong, M.-H.; Bao, Y.; Yang, X.-Z.; Wang, Y.-C.; Sun, B.; Wang, J. Lipase-Sensitive Polymeric Triple-Layered Nanogel for “On-Demand” Drug Delivery. J. Am. Chem. Soc. 2012, 134 (9), 4355–4362. https://doi.org/10.1021/ja211279u.
(44) Minelli, C.; Lowe, S. B.; Stevens, M. M. Engineering Nanocomposite Materials for Cancer Therapy. Small 2010, 6 (21), 2336–2357. https://doi.org/10.1002/smll.201000523.
(45) Zhao, Y.; Luo, Z.; Li, M.; Qu, Q.; Ma, X.; Yu, S.-H.; Zhao, Y. A Preloaded Amorphous Calcium Carbonate/Doxorubicin@Silica Nanoreactor for PH-Responsive Delivery of an Anticancer Drug. Angew. Chem. Int. Ed. 2015, 54 (3), 919–922. https://doi.org/10.1002/anie.201408510.
(46) Cölfen, H.; Mann, S. Higher-Order Organization by Mesoscale Self-Assembly and Transformation of Hybrid Nanostructures. Angew. Chem. Int. Ed. 2003, 42 (21), 2350–2365. https://doi.org/10.1002/anie.200200562.
(47) Murai, K.; Kinoshita, T.; Nagata, K.; Higuchi, M. Mineralization of Calcium Carbonate on Multifunctional Peptide Assembly Acting as Mineral Source Supplier and Template. Langmuir 2016, 32 (36), 9351–9359. https://doi.org/10.1021/acs.langmuir.6b02439.
(48) Helman, Y.; Natale, F.; Sherrell, R. M.; LaVigne, M.; Starovoytov, V.; Gorbunov, M. Y.; Falkowski, P. G. Extracellular Matrix Production and Calcium Carbonate Precipitation by Coral Cells in Vitro. Proc. Natl. Acad. Sci. 2008, 105 (1), 54–58. https://doi.org/10.1073/pnas.0710604105.
(49) Wolf, S. E.; Leiterer, J.; Pipich, V.; Barrea, R.; Emmerling, F.; Tremel, W. Strong Stabilization of Amorphous Calcium Carbonate Emulsion by Ovalbumin: Gaining Insight into the Mechanism of ‘Polymer-Induced Liquid Precursor’ Processes. J. Am. Chem. Soc. 2011, 133 (32), 12642–12649. https://doi.org/10.1021/ja202622g.
(50) Wolf, S. L. P.; Jähme, K.; Gebauer, D. Synergy of Mg2+ and Poly(Aspartic Acid) in Additive-Controlled Calcium Carbonate Precipitation. CrystEngComm 2015, 17 (36), 6857–6862. https://doi.org/10.1039/C5CE00452G.
(51) Politi, Y.; Batchelor, D. R.; Zaslansky, P.; Chmelka, B. F.; Weaver, J. C.; Sagi, I.; Weiner, S.; Addadi, L. Role of Magnesium Ion in the Stabilization of Biogenic Amorphous Calcium Carbonate: A Structure−Function Investigation. Chem. Mater. 2010, 22 (1), 161–166. https://doi.org/10.1021/cm902674h.
(52) Long, X.; Ma, Y.; Qi, L. In Vitro Synthesis of High Mg Calcite under Ambient Conditions and Its Implication for Biomineralization Process. Cryst. Growth Des. 2011, 11 (7), 2866–2873. https://doi.org/10.1021/cg200028x.
(53) Zhang, J.; Zhou, X.; Dong, C.; Sun, Y.; Yu, J. Investigation of Amorphous Calcium Carbonate’s Formation under High Concentration of Magnesium: The Prenucleation Cluster Pathway. J. Cryst. Growth 2018, 494, 8–16. https://doi.org/10.1016/j.jcrysgro.2018.05.001.
(54) Nezhad, E. H.; Ghorbani, M.; Zeinalkhani, M.; Heidari, A. DNA Encapsulation in an Anionic Reverse Micellar Solution of Dioctyl Sodium Sulfosuccinate. Phys. Chem. 2013, 3 (1), 7–10.
(55) Matzke, S. F.; Creagh, A. L.; Haynes, C. A.; Prausnitz, J. M.; Blanch, H. W. Mechanisms of Protein Solubilization in Reverse Micelles. Biotechnol. Bioeng. 1992, 40 (1), 91–102. https://doi.org/10.1002/bit.260400114.
(56) Lemyre, J.-L.; Lamarre, S.; Beaupré, A.; Ritcey, A. M. A New Approach for the Characterization of Reverse Micellar Systems by Dynamic Light Scattering. Langmuir 2010, 26 (13), 10524–10531. https://doi.org/10.1021/la100541m.
(57) Bragg condition for the constructive interference of waves https://www.didaktik.physik.uni-muenchen.de/elektronenbahnen/en/elektronenbeugung/einfuehrung/bragg-bedingung.php (accessed Jun 30, 2019).
(58) Addadi, L.; Raz, S.; Weiner, S. Taking Advantage of Disorder: Amorphous Calcium Carbonate and Its Roles in Biomineralization. Adv. Mater. 2003, 15 (12), 959–970. https://doi.org/10.1002/adma.200300381.
(59) Williams, D. B.; Carter, C. B. Transmission Electron Microscopy: A Textbook for Materials Science, 2nd ed.; Springer US, 2009.
(60) Lowe, I. J. Free Induction Decays of Rotating Solids. Phys. Rev. Lett. 1959, 2 (7), 285–287. https://doi.org/10.1103/PhysRevLett.2.285.
(61) Andrew, E. R.; Bradbury, A.; Eades, R. G. Nuclear Magnetic Resonance Spectra from a Crystal Rotated at High Speed. Nature 1958, 182 (4650), 1659. https://doi.org/10.1038/1821659a0.
(62) Facey, G. University of Ottawa NMR Facility Blog: Magic Angle Spinning. University of Ottawa NMR Facility Blog, 2007.
(63) Pines, A.; Gibby, M. G.; Waugh, J. S. Proton‐enhanced NMR of Dilute Spins in Solids. J. Chem. Phys. 1973, 59 (2), 569–590. https://doi.org/10.1063/1.1680061.
(64) Hartmann, S. R.; Hahn, E. L. Nuclear Double Resonance in the Rotating Frame. Phys. Rev. 1962, 128 (5), 2042–2053. https://doi.org/10.1103/PhysRev.128.2042.
(65) Chu, B. Laser Light Scattering. Annu. Rev. Phys. Chem. 1970, 21 (1), 145–174. https://doi.org/10.1146/annurev.pc.21.100170.001045.
(66) nsrrcpxrdmailin https://nsrrcpxrd.wixsite.com/nsrrcpxrdmailin (accessed Jul 8, 2019).
(67) Wang, C.; Chen, S.; Yu, Q.; Hu, F.; Yuan, H. Taking Advantage of the Disadvantage: Employing the High Aqueous Instability of Amorphous Calcium Carbonate to Realize Burst Drug Release within Cancer Cells. J. Mater. Chem. B 2017, 5 (11), 2068–2073. https://doi.org/10.1039/C6TB02826H.
(68) Bots, P.; Benning, L. G.; Rodriguez-Blanco, J.-D.; Roncal-Herrero, T.; Shaw, S. Mechanistic Insights into the Crystallization of Amorphous Calcium Carbonate (ACC). Cryst. Growth Des. 2012, 12 (7), 3806–3814. https://doi.org/10.1021/cg300676b.
(69) Yang, S.-Y.; Chang, H.-H.; Lin, C.-J.; Huang, S.-J.; Chan, J. C. C. Is Mg-Stabilized Amorphous Calcium Carbonate a Homogeneous Mixture of Amorphous Magnesium Carbonate and Amorphous Calcium Carbonate? Chem. Commun. 2016, 52 (77), 11527–11530. https://doi.org/10.1039/C6CC04522G.
(70) Chen, S.-F.; Cölfen, H.; Antonietti, M.; Yu, S.-H. Ethanol Assisted Synthesis of Pure and Stable Amorphous Calcium Carbonate Nanoparticles. Chem. Commun. 2013, 49 (83), 9564–9566. https://doi.org/10.1039/C3CC45427D.
(71) Blasco, J.; Hampel, M.; Moreno-Garrido, I. Chapter 7 Toxicity of Surfactants. In Comprehensive Analytical Chemistry; Analysis and Fate of Surfactants and the Aquatic Environment; Elsevier, 2003; Vol. 40, pp 827–925. https://doi.org/10.1016/S0166-526X(03)40010-X.
(72) Wang, C.; Liu, X.; Chen, S.; Hu, F.; Sun, J.; Yuan, H. Facile Preparation of Phospholipid–Amorphous Calcium Carbonate Hybrid Nanoparticles: Toward Controllable Burst Drug Release and Enhanced Tumor Penetration. Chem. Commun. 2018, 54 (93), 13080–13083. https://doi.org/10.1039/C8CC07694D.
(73) Soy PC (95%) https://avantilipids.com/ (accessed Jul 10, 2019).
(74) Tamamushi, B.; Watanabe, N. The Formation of Molecular Aggregation Structures in Ternary System: Aerosol OT/Water/Iso-Octane. Colloid Polym. Sci. 1980, 258 (2), 174–178. https://doi.org/10.1007/BF01498277.
(75) Angelico, R.; Ceglie, A.; Olsson, U.; Palazzo, G. Phase Diagram and Phase Properties of the System Lecithin−Water−Cyclohexane. Langmuir 2000, 16 (5), 2124–2132. https://doi.org/10.1021/la9909190.
(76) Martiel, I.; Sagalowicz, L.; Mezzenga, R. Viscoelasticity and Interface Bending Properties of Lecithin Reverse Wormlike Micelles Studied by Diffusive Wave Spectroscopy in Hydrophobic Environment. Langmuir 2014, 30 (35), 10751–10759. https://doi.org/10.1021/la502748e.
(77) Fletcher, P. D. I.; Howe, A. M.; Robinson, B. H. The Kinetics of Solubilisate Exchange between Water Droplets of a Water-in-Oil Microemulsion. J. Chem. Soc. Faraday Trans. 1 Phys. Chem. Condens. Phases 1987, 83 (4), 985–1006. https://doi.org/10.1039/F19878300985.
(78) Xu, X.; Han, J. T.; Cho, K. Formation of Amorphous Calcium Carbonate Thin Films and Their Role in Biomineralization. Chem. Mater. 2004, 16 (9), 1740–1746. https://doi.org/10.1021/cm035183d.
(79) Phase transition of a poly(acrylic acid) gel induced by polymer complexation: The Journal of Chemical Physics: Vol 97, No 10 https://aip.scitation.org/doi/10.1063/1.463449 (accessed Jul 15, 2019).
(80) Charman, W. N.; Christy, D. P.; Geunin, E. P.; Monkhouse, D. C. Interaction between Calcium, a Model Divalent Cation, and a Range of Poly (Acrylic Acid) Resins as a Function of Solution PH. Drug Dev. Ind. Pharm. 1991, 17 (2), 271–280. https://doi.org/10.3109/03639049109043824.
(81) Lu, C.; Bhatt, L. R.; Jun, H. Y.; Park, S. H.; Chai, K. Y. Carboxyl–Polyethylene Glycol–Phosphoric Acid: A Ligand for Highly Stabilized Iron Oxide Nanoparticles. J. Mater. Chem. 2012, 22 (37), 19806–19811. https://doi.org/10.1039/C2JM34327D.