本研究利用腫瘤組織的獨特生理特徵，開發ㄧ具還原與酸鹼應答之高分子奈米微胞，並以具備良好的生物相容性、低免疫反應性及標靶癌細胞表面標記物CD44的玻尿酸(Hyaluronic acid)當作奈米載體的主體，並修飾上天然的胺基酸使奈米載體具備選擇性釋放藥物及可在細胞內特定位置釋放藥物。第一種胺基酸為半胱胺酸(L-Cysteine)，在氧化交聯後形成雙硫鍵促使奈米微胞的結構更加穩固，在血液循環及正常組織中不易釋放藥物，只可在高濃度穀胱甘肽(Glutathione)的腫瘤微環境中使雙硫鍵還原，使奈米微胞具有選擇性的釋放藥物之能力。此外，當奈米微胞被內吞形成核內體後，因第二種胺基酸為組胺酸(L-Histidine)的imidazole ring pka 值約在6.5，當pH 低於6.5 時會使其質子化，進而使奈米微胞產生膨潤的現象，加速藥物釋放效率，並其引發質子海綿效應 (proton sponge effect)，導致核內體破裂讓藥物逃脫，達到有效釋放藥物進而誘導癌細胞凋亡。研究中成功合成出具還原與酸鹼應答之高分子Hyaluronic acid30k-Cysteine-Histidine (C2H2)，以此高分子攜載奧沙利鉑前驅物DACHPt，並且成功製備出高分子奈米微胞 (C2H2-D4)。進一步，藉由體外試驗探討腫微環境中pH 與GSH對於奈米微胞變化的情形，由粒徑變化與藥物釋放的實驗數據得知奈米載體在腫瘤環境下具有選擇性的應答能力。除此之外，在細胞實驗中，C2H2-D4 奈米微胞具備標靶CD44 並有效毒殺大腸癌細胞，並對正常細胞小鼠纖維母細胞的毒性較小。因此，在此研究中，成功開發一具標靶與雙重應答之高分子奈米微胞可有效地應用於大腸癌治療。

Hyaluronic acid (HA) has some great ability such as biocompatible, biodegradable and non-immunogenic. Especially, HA can regulate cell proliferation and movement through CD44, a receptor specific to HA. This property makes HA an attractive material for hydrogel-based drug delivery. In this study, Hyaluronic acid30k-Cysteine-Histidine (C2H2) dual-sensitive polymers were conjugated with L-histidine and L-cysteine. The micelles were then prepared through dialysis to conjugate an anti-cancer drug dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt) which is the oxaliplatin parent complex. The properties of micelles exhibited targeting and controlled-release abilities. The particles size of the DACHPt-loaded C2H2 micelles was around 200 nm. The ICP-MS showed the successful conjugation of DACHPt to HA via a carboxylic group. The drug content of DACHPt in the micelles was approximately 38 w.t. %. The results of drug release demonstrated that the DACHPt-loaded C2H2 micelles exhibited the sensitivity of GSH and pH; the rate of drug release at the high concentration of GSH and pH 5.0 was faster than that at pH 7.4. In addition, the results of cytotoxicity indicated that the DACHPt-loaded C2H2 micelles had greater bioactivity in colon cancer cells than mouse fibroblast cells. The datas of flow cytometry assay confirmed that DACHPt-loaded C2H2 micelles were uptaken via CD44 receptors. Therefore, the Hyaluronic acid based Pt-loaded micelles have great potential for colon cancer therapy.

目錄
致謝-----i
摘要-----ii
Abstract-----iv
目錄-----v
圖目錄-----x
表目錄-----xiv
第一章 研究動機與目的-----1
第二章 文獻探討-----3
2.1 奈米藥物載體的發展與應用-----3
2.2 腫瘤微環境-----8
2.3 GSH應答材料-----13
2.4 酸鹼應答材料-----14
2.5 CD44於癌症的表現-----16
2.6 玻尿酸與CD44-----19
2.7 玻尿酸藥物載體於癌症治療應用 -----20
2.8 鉑類藥物的發展-----23
2.9 鉑類藥物機制與限制-----25
2.10 抗癌藥物：奧沙利鉑前驅物DACHPT-----28
第三章 材料與方法-----31
3.1 實驗藥品-----31
3.2 實驗儀器與裝置-----34
3.3 具還原與酸鹼應答高分子之製備-----36
3.3.1 Hyaluronic acid30k-L-Cys ( HA30k-C )之合成與鑑定-----36
3.3.2 Hyaluronic acid30k-L-His ( HA30k-H ) 之合成與鑑定-----37
3.3.3 Hyaluronic acid30k-L-Cys, L-His ( HA30k-CH ) 之合成與鑑定-----37
3.3.4 Hyaluronic acid30k-L-Cys-L-His ( HA30k-C-H ) 之合成與鑑定-----38
3.3.5 奧沙利鉑前驅物DACHPt 之改質-----39
3.3.6 高分子之界面電位分析-----40
3.3.7 HA30k-C2H2高分子(C2H2)之氧化量測試-----40
3.4 高分子奈米微胞之製備-----41
3.5 高分子奈米微胞之基本性質分析-----41
3.5.1 奈米微胞之粒徑分析-----41
3.5.2 奈米微胞之微觀型態分析-----42
3.5.3 DACHPt 之載藥率與有效包覆效率分析-----42
3.5.4 奈米微胞之穩定度測試-----42
3.5.5 奈米微胞之界面電位分析-----43
3.6 高分子奈米微胞之GSH與酸鹼應答測試-----43
3.6.1 奈米微胞之粒徑變化分析-----43
3.6.2 奈米微胞之形態變化分析-----43
3.6.3 奈米微胞之藥物釋放分析-----44
3.6.4 應答後C2H2之紅血球溶血測定-----44
3.7 高分子奈米微胞之生物體外試驗-----45
3.7.1 細胞與培養液製備-----45
3.7.2 細胞培養與繼代-----46
3.7.3 細胞計數-----46
3.7.4 高分子奈米微胞細胞毒性測試-----47
3.8 高分子奈米微胞細胞吞噬情形-----48
3.8.1 攜帶FITC之高分子奈米微胞製備-----48
3.8.2 細胞攝取觀察-----49
3.8.3 高分子奈米微胞對細胞週期影響-----49
3.8.4 高分子奈米微胞逃脫核內體( endosome )情形與ROS之影響-----50
第四章 結果與討論-----52
4.1 具還原與酸鹼應答高分子-----52
4.1.1 Hyaluronic acid30k-L-Cys (C2) 之合成與鑑定-----53
4.1.2 Hyaluronic acid30k-L-His (H2) 之合成與鑑定-----55
4.1.3 Hyaluronic acid30k-L-Cys-L-His (C2-H2) 之合成與鑑定-----56
4.1.4 Hyaluronic acid30k-L-Cys 1, L-His 1 (C1H1) 之合成與鑑定-----58
4.1.5 Hyaluronic acid30k-L-Cys 2, L-His 2 (C2H2) 之合成與鑑定-----60
4.1.6 Hyaluronic acid30k-L-Cys 3, L-His 3 (C3H3) 之合成與鑑定-----62
4.1.7 高分子之界面電位與酸鹼應答行為-----64
4.1.8 HA30k-C2H2高分子(C2H2)之氧化量測試-----65
4.2 高分子奈米微胞之基本性質分析-----66
4.2.1 高分子奈米微胞之粒徑、界面電位、有效包覆率與載藥率-----66
4.2.2 奈米微胞之穩定性、GSH與酸鹼應答測試-----68
4.2.3 奈米微胞之型態分析-----72
4.2.4 奈米微胞之藥物釋放分析-----74
4.3 高分子奈米微胞之生物體外試驗-----76
4.3.1 不同高分子奈米微胞細胞毒性測試-----76
4.3.2 高分子奈米微胞細胞吞噬情形-----79
4.3.3 高分子奈米微胞對細胞週期影響-----80
4.3.4 高分子奈米微胞逃脫核內體(Endosome)情形-----81
4.3.5 應答後C2H2之溶血測試-----83
4.3.6 高分子奈米微胞之ROS影響-----84
第五章 結論-----86
第六章 參考文獻-----87

圖目錄
圖 2 1、用於靶向癌症的奈米載體實例。-----4
圖 2 2、生物大分子載體的性質和應用以及代表性蛋白質和多醣的結構。-----6
圖 2 3、內源刺激：通過氧化還原電位、活性氧、酶和pH值等使藥物釋放。-----7
圖 2 4、外源觸發：通過熱、超聲波、磁能和光的刺激使藥物釋放。-----7
圖 2 5、奈米載體以不同形式將藥物遞送至腫瘤示意圖。-----9
圖 2 6、細胞氧化還原平衡示意圖。-----11
圖 2 7、哺乳動物細胞中葡萄糖代謝示意圖。-----12
圖 2 8、二硫鍵的合成方法示意圖。-----14
圖 2 9、氧化還原應答載體示意圖。-----14
圖 2 10、Histidine imidazolium質子化與pH值依賴關係及自組裝HA-PHIS微胞在細胞內pH值應答釋放藥物示意圖。-----15
圖 2 11、奈米載體利用質子海綿效應逃脫胞內體示意圖。-----16
圖 2 12、CD44蛋白和基因結構示意圖。-----17
圖 2 13、HA 的結構和功能。-----20
圖 2 14、HA修飾的奈米粒子或微胞標靶過表達CD44的癌細胞示意圖。-----22
圖 2 15、鉑類藥物結構圖。-----24
圖 2 16、奧沙利鉑的作用機制於DNA中Pt-GG錯合物的形成。-----26
圖 2 17、GSH對於順鉑抗藥性示意圖。-----27
圖 2 18、奧沙利鉑相關抗藥機制概述。-----27
圖 2 19、順鉑、DACHPt和奧沙利鉑的化學結構。-----28
圖 2 20、通過PAM-PGlu-b-PEG和DACHPt中的羧基之間的錯合形成搭載DACHPt單分子微胞(UM/DACHPt)示意圖。-----29
圖 2 21、奧沙利鉑的結構和搭載DACHPt微胞(DACHPt/m)示意圖。-----29
圖 3 1、Hyaluronic acid30k-L-Cys (HA30k-C) 之合成機制。-----36
圖 3 2、Hyaluronic acid30k-L-His ( HA30k-H ) 之合成機制。 -----37
圖 3 3、Hyaluronic acid30k-L-Cys, L-His ( HA30k-CH )合成之機制。-----38
圖 3 4、Hyaluronic acid30k-L-Cys-L-His ( HA30k-C-H ) 之合成機制。-----39
圖 3 5、DACHPt 改質示意圖。-----40
圖 4 1、高分子Hyaluronic acid30k-L-Cys之1H-NMR光譜圖。-----54
圖 4 2、高分子Hyaluronic acid30k-L-Cys之ATR圖譜。-----54
圖 4 3、高分子Hyaluronic acid30k-L-His之1H-NMR光譜圖。-----56
圖 4 4、高分子Hyaluronic acid30k-L-His之ATR圖譜。-----56
圖 4 5、高分子Hyaluronic acid30k-L-Cys-L-His之1H-NMR光譜圖。-----57
圖 4 6、高分子Hyaluronic acid30k-L-Cys-L-His之ATR圖譜。-----58
圖 4 7、高分子Hyaluronic acid30k-L-Cys 1, L-His 1之1H-NMR光譜圖。-----59
圖 4 8、高分子Hyaluronic acid30k-L-Cys 1, L-His 1之ATR圖譜。-----60
圖 4 9、高分子Hyaluronic acid30k-L-Cys 2, L-His 2之1H-NMR光譜圖。-----61
圖 4 10、高分子Hyaluronic acid30k-L-Cys 2, L-His 2之ATR圖譜。-----62
圖 4 11、高分子Hyaluronic acid30k-L-Cys 3, L-His 3之1H-NMR光譜圖。-----63
圖 4 12、高分子Hyaluronic acid30k-L-Cys 3, L-His 3之ATR圖譜。-----64
圖 4 13、Hyaluronic acid30k-L-Cys 2, L-His 2 (C2H2)不同pH 值之界面電位。-----65
圖 4 14、利用Ellman's reagent測其L-Cystein檢量線。-----66
圖 4 15、不同奈米微胞於4 ℃時穩定度粒徑分析圖。-----69
圖 4 16、不同奈米微胞之GSH與酸鹼應答粒徑變化。-----71
圖 4 17、不同奈米微胞之GSH與酸鹼應答粒徑分布。-----72
圖 4 18、不同奈米微胞在不同GSH與pH值環境下反應48小時後TEM型態圖。-----74
圖 4-19、C2H2-D4奈米微胞在不同GSH與酸鹼環境中藥物釋放情形。-----75
圖 4 20、不同高分子奈米微胞之HCT116胞毒性測試。-----78
圖 4 21、不同高分子奈米微胞之L929胞毒性測試。-----79
圖 4 22、C2H2-D4細胞吞噬情況。-----80
圖 4 23、DACHPt水錯合物與搭載DACHPt之高分子奈米微胞對於細胞週期之影響。-----81
圖 4 24、標定FITC之C2H2-D4奈米微胞在高GSH與低pH環境的人類大腸癌細胞株(HCT116)之共軛焦顯微鏡影像。-----83
圖 4 25、C2H2在低pH 值下於不同時間點與紅血球共培養6和12小時之溶血情形。-----84
圖 4 26、標定FITC之C2H2-D4奈米微胞在高GSH與低pH環境的人類大腸癌細胞株(HCT116)之共軛焦顯微鏡影像。-----85

表目錄
表 2 1、利用HA作為靶向治療研究的實例。-----21
表 4 1、HA之高分子合成進料莫爾比與組成比例。-----53
表 4 2、不同比例DACHPt之奈米微胞基本性質。-----66
表 4 3、不同奈米微胞基本性質。-----67

[1] R. Duncan, "Polymer conjugates as anticancer nanomedicines," Nat. Rev. Cancer, vol. 6, no. 9, p. 688, 2006.
[2] S. Guo and L. Huang, "Nanoparticles containing insoluble drug for cancer therapy," Biotechnology advances, vol. 32, no. 4, pp. 778-788, 2014.
[3] D. Peer, J. M. Karp, S. Hong, O. C. FaroKhzad, R. Margalit, and R. Langer, "Nanocarriers as an emerging platform for cancer therapy," (in English), Nat. Nanotechnol., Review vol. 2, no. 12, pp. 751-760, Dec 2007, doi: 10.1038/nnano.2007.387.
[4] E. Rodríguez-Velázquez, M. Alatorre-Meda, and J. F Mano, "Polysaccharide-based nanobiomaterials as controlled release systems for tissue engineering applications," Current pharmaceutical design, vol. 21, no. 33, pp. 4837-4850, 2015.
[5] S. Nitta and K. Numata, "Biopolymer-based nanoparticles for drug/gene delivery and tissue engineering," International journal of molecular sciences, vol. 14, no. 1, pp. 1629-1654, 2013.
[6] S. Mizrahy and D. Peer, "Polysaccharides as building blocks for nanotherapeutics," Chemical Society Reviews, vol. 41, no. 7, pp. 2623-2640, 2012.
[7] A. O. Elzoghby, W. M. Samy, and N. A. Elgindy, "Protein-based nanocarriers as promising drug and gene delivery systems," J. Control. Release, vol. 161, no. 1, pp. 38-49, 2012.
[8] J. T. Andersen et al., "Extending serum half-life of albumin by engineering neonatal Fc receptor (FcRn) binding," Journal of Biological Chemistry, vol. 289, no. 19, pp. 13492-13502, 2014.
[9] Y. Zhang, T. Sun, and C. Jiang, "Biomacromolecules as carriers in drug delivery and tissue engineering," Acta Pharm Sin B, vol. 8, no. 1, pp. 34-50, Jan 2018, doi: 10.1016/j.apsb.2017.11.005.
[10] N. Kamaly, B. Yameen, J. Wu, and O. C. Farokhzad, "Degradable Controlled-Release Polymers and Polymeric Nanoparticles: Mechanisms of Controlling Drug Release," (in English), Chem. Rev., Review vol. 116, no. 4, pp. 2602-2663, Feb 2016, doi: 10.1021/acs.chemrev.5b00346.
[11] Y. Matsumura and H. Maeda, "A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs," Cancer research, vol. 46, no. 12 Part 1, pp. 6387-6392, 1986.
[12] P. Couvreur and C. Vauthier, "Nanotechnology: intelligent design to treat complex disease," Pharmaceutical research, vol. 23, no. 7, pp. 1417-1450, 2006.
[13] V. P. Torchilin, "Recent advances with liposomes as pharmaceutical carriers," Nature reviews Drug discovery, vol. 4, no. 2, p. 145, 2005.
[14] F. Yuan et al., "Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size," Cancer research, vol. 55, no. 17, pp. 3752-3756, 1995.
[15] M. Ferrari, "Cancer nanotechnology: opportunities and challenges," Nat. Rev. Cancer, vol. 5, no. 3, p. 161, 2005.
[16] D. Peer and R. Margalit, "Fluoxetine and reversal of multidrug resistance," Cancer letters, vol. 237, no. 2, pp. 180-187, 2006.
[17] R. K. Jain and T. Stylianopoulos, "Delivering nanomedicine to solid tumors," Nature reviews Clinical oncology, vol. 7, no. 11, p. 653, 2010.
[18] S. Kawanishi, Y. Hiraku, S. Pinlaor, and N. Ma, "Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammation-related carcinogenesis," Biological chemistry, vol. 387, no. 4, pp. 365-372, 2006.
[19] J. Boonstra and J. A. Post, "Molecular events associated with reactive oxygen species and cell cycle progression in mammalian cells," Gene, vol. 337, pp. 1-13, 2004.
[20] W.-S. Wu, "The signaling mechanism of ROS in tumor progression," Cancer and Metastasis Reviews, vol. 25, no. 4, pp. 695-705, 2006.
[21] P. T. Schumacker, "Reactive oxygen species in cancer cells: live by the sword, die by the sword," Cancer cell, vol. 10, no. 3, pp. 175-176, 2006.
[22] D. Trachootham, J. Alexandre, and P. Huang, "Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?," Nature reviews Drug discovery, vol. 8, no. 7, p. 579, 2009.
[23] X. M. Zhang, Y. X. Lin, and R. J. Gillies, "Tumor pH and Its Measurement," (in English), J. Nucl. Med., Article vol. 51, no. 8, pp. 1167-1170, Aug 2010, doi: 10.2967/jnumed.109.068981.
[24] W. Yuan, H. Zou, W. Guo, T. Shen, and J. Ren, "Supramolecular micelles with dual temperature and redox responses for multi-controlled drug release," Polym. Chem., vol. 4, no. 9, pp. 2658-2661, 2013.
[25] F. Q. Schafer and G. R. Buettner, "Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple," Free radical biology and medicine, vol. 30, no. 11, pp. 1191-1212, 2001.
[26] M. Huo, J. Yuan, L. Tao, and Y. Wei, "Redox-responsive polymers for drug delivery: from molecular design to applications," Polym. Chem., vol. 5, no. 5, pp. 1519-1528, 2014.
[27] G. Wu, Y.-Z. Fang, S. Yang, J. R. Lupton, and N. D. Turner, "Glutathione metabolism and its implications for health," The Journal of nutrition, vol. 134, no. 3, pp. 489-492, 2004.
[28] T. Kurz, J. W. Eaton, and U. T. Brunk, "Redox activity within the lysosomal compartment: implications for aging and apoptosis," Antioxidants & redox signaling, vol. 13, no. 4, pp. 511-523, 2010.
[29] H. Xu, W. Cao, and X. Zhang, "Selenium-containing polymers: promising biomaterials for controlled release and enzyme mimics," Accounts of chemical research, vol. 46, no. 7, pp. 1647-1658, 2013.
[30] M. Huo, J. Yuan, L. Tao, and Y. Wei, "Redox-responsive polymers for drug delivery: from molecular design to applications," Polym. Chem., vol. 5, no. 5, pp. 1519-1528, 2014, doi: 10.1039/c3py01192e.
[31] B. A. Webb, M. Chimenti, M. P. Jacobson, and D. L. Barber, "Dysregulated pH: a perfect storm for cancer progression," Nat. Rev. Cancer, vol. 11, no. 9, p. 671, 2011.
[32] B. Yameen, W. I. Choi, C. Vilos, A. Swami, J. Shi, and O. C. Farokhzad, "Insight into nanoparticle cellular uptake and intracellular targeting," J. Control. Release, vol. 190, pp. 485-499, 2014.
[33] L. P. Qiu et al., "Self-assembled pH-responsive hyaluronic acid-g-poly(L-histidine) copolymer micelles for targeted intracellular delivery of doxorubicin," (in English), Acta Biomater., Article vol. 10, no. 5, pp. 2024-2035, May 2014, doi: 10.1016/j.actbio.2013.12.025.
[34] J. Hu, J. He, M. Zhang, and P. Ni, "Precise modular synthesis and a structure–property study of acid-cleavable star-block copolymers for pH-triggered drug delivery," Polym. Chem., vol. 6, no. 9, pp. 1553-1566, 2015.
[35] O. Boussif et al., "A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine," Proceedings of the National Academy of Sciences, vol. 92, no. 16, pp. 7297-7301, 1995.
[36] Q. Mou, Y. Ma, X. Jin, and X. Zhu, "Designing hyperbranched polymers for gene delivery," Molecular Systems Design & Engineering, vol. 1, no. 1, pp. 25-39, 2016.
[37] D. Naor, S. Nedvetzki, I. Golan, L. Melnik, and Y. Faitelson, "CD44 in cancer," Critical reviews in clinical laboratory sciences, vol. 39, no. 6, pp. 527-579, 2002.
[38] C. Chen, S. Zhao, A. Karnad, and J. W. Freeman, "The biology and role of CD44 in cancer progression: therapeutic implications," J Hematol Oncol, vol. 11, no. 1, p. 64, May 10 2018, doi: 10.1186/s13045-018-0605-5.
[39] M. Kaufmann, G. von Minckwitz, K. Heider, H. Ponta, P. Herrlich, and H. Sinn, "CD44 variant exon epitopes in primary breast cancer and length of survival," The Lancet, vol. 345, no. 8950, pp. 615-619, 1995.
[40] M. Todaro et al., "CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis," Cell stem cell, vol. 14, no. 3, pp. 342-356, 2014.
[41] L. Lv et al., "Upregulation of CD44v6 contributes to acquired chemoresistance via the modulation of autophagy in colon cancer SW480 cells," Tumor Biology, vol. 37, no. 7, pp. 8811-8824, 2016.
[42] S. Courtois et al., "Metformin targets gastric cancer stem cells," European journal of cancer, vol. 84, pp. 193-201, 2017.
[43] G. Kogan, L. Šoltés, R. Stern, and P. Gemeiner, "Hyaluronic acid: a natural biopolymer with a broad range of biomedical and industrial applications," Biotechnology letters, vol. 29, no. 1, pp. 17-25, 2007.
[44] G. Mattheolabakis, L. Milane, A. Singh, and M. M. Amiji, "Hyaluronic acid targeting of CD44 for cancer therapy: from receptor biology to nanomedicine," Journal of drug targeting, vol. 23, no. 7-8, pp. 605-618, 2015.
[45] B. Chen, R. J. Miller, and P. K. Dhal, "Hyaluronic acid-based drug conjugates: state-of-the-art and perspectives," Journal of biomedical nanotechnology, vol. 10, no. 1, pp. 4-16, 2014.
[46] K. Y. Choi, G. Saravanakumar, J. H. Park, and K. Park, "Hyaluronic acid-based nanocarriers for intracellular targeting: interfacial interactions with proteins in cancer," Colloids and Surfaces B: Biointerfaces, vol. 99, pp. 82-94, 2012.
[47] S. Banerji et al., "Structures of the Cd44–hyaluronan complex provide insight into a fundamental carbohydrate-protein interaction," Nature structural & molecular biology, vol. 14, no. 3, p. 234, 2007.
[48] J. M. Wickens et al., "Recent advances in hyaluronic acid-decorated nanocarriers for targeted cancer therapy," Drug Discov Today, vol. 22, no. 4, pp. 665-680, Apr 2017, doi: 10.1016/j.drudis.2016.12.009.
[49] S. Misra et al., "Hyaluronan–CD44 interactions as potential targets for cancer therapy," The FEBS journal, vol. 278, no. 9, pp. 1429-1443, 2011.
[50] X. Liang, L. Fang, X. Li, X. Zhang, and F. Wang, "Activatable near infrared dye conjugated hyaluronic acid based nanoparticles as a targeted theranostic agent for enhanced fluorescence/CT/photoacoustic imaging guided photothermal therapy," Biomaterials, vol. 132, pp. 72-84, 2017.
[51] H. S. Han et al., "Bioreducible core-crosslinked hyaluronic acid micelle for targeted cancer therapy," J. Control. Release, vol. 200, pp. 158-166, 2015.
[52] R. Siegel, C. DeSantis, and A. Jemal, "Colorectal cancer statistics, 2014," CA: a cancer journal for clinicians, vol. 64, no. 2, pp. 104-117, 2014.
[53] V. J. Wielenga et al., "Expression of CD44 variant proteins in human colorectal cancer is related to tumor progression," Cancer Research, vol. 53, no. 20, pp. 4754-4756, 1993.
[54] H. Lee, C. H. Ahn, and T. G. Park, "Poly [lactic‐co‐(glycolic acid)]‐grafted hyaluronic acid copolymer micelle nanoparticles for target‐specific delivery of doxorubicin," Macromolecular Bioscience, vol. 9, no. 4, pp. 336-342, 2009.
[55] G. Pitarresi, F. S. Palumbo, A. Albanese, C. Fiorica, P. Picone, and G. Giammona, "Self-assembled amphiphilic hyaluronic acid graft copolymers for targeted release of antitumoral drug," Journal of drug targeting, vol. 18, no. 4, pp. 264-276, 2010.
[56] L. Kelland, "The resurgence of platinum-based cancer chemotherapy," Nat. Rev. Cancer, vol. 7, no. 8, p. 573, 2007.
[57] P. Heffeter et al., "Resistance against novel anticancer metal compounds: differences and similarities," Drug resistance updates, vol. 11, no. 1-2, pp. 1-16, 2008.
[58] V. Benedetti et al., "Modulation of survival pathways in ovarian carcinoma cell lines resistant to platinum compounds," Mol. Cancer Ther., vol. 7, no. 3, pp. 679-687, 2008.
[59] N. J. Wheate, S. Walker, G. E. Craig, and R. Oun, "The status of platinum anticancer drugs in the clinic and in clinical trials," Dalton transactions, vol. 39, no. 35, pp. 8113-8127, 2010.
[60] X. Wang and Z. Guo, "Targeting and delivery of platinum-based anticancer drugs," Chemical Society Reviews, vol. 42, no. 1, pp. 202-224, 2013.
[61] A. d. de Gramont et al., "Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer," J. Clin. Oncol., vol. 18, no. 16, pp. 2938-2947, 2000.
[62] J. C. Bendell et al., "Treatment patterns and clinical outcomes in patients with metastatic colorectal cancer initially treated with FOLFOX–bevacizumab or FOLFIRI–bevacizumab: results from ARIES, a bevacizumab observational cohort study," The oncologist, vol. 17, no. 12, pp. 1486-1495, 2012.
[63] S. Ahmad, "Platinum–DNA interactions and subsequent cellular processes controlling sensitivity to anticancer platinum complexes," Chemistry & biodiversity, vol. 7, no. 3, pp. 543-566, 2010.
[64] M. A. Graham, G. F. Lockwood, D. Greenslade, S. Brienza, M. Bayssas, and E. Gamelin, "Clinical pharmacokinetics of oxaliplatin: a critical review," Clinical Cancer Research, vol. 6, no. 4, pp. 1205-1218, 2000.
[65] J. M. Woynarowski et al., "Oxaliplatin-induced damage of cellular DNA," Molecular pharmacology, vol. 58, no. 5, pp. 920-927, 2000.
[66] O. M. Alian, A. S. Azmi, and R. M. Mohammad, "Network insights on oxaliplatin anti-cancer mechanisms," Clinical and translational medicine, vol. 1, no. 1, p. 26, 2012.
[67] N. Nishiyama and K. Kataoka, "Preparation and characterization of size-controlled polymeric micelle containing cis-dichlorodiammineplatinum (II) in the core," J. Control. Release, vol. 74, no. 1-3, pp. 83-94, 2001..
[68] R. Tummala, D. Wolle, S. P. Barwe, V. B. Sampson, A. K. Rajasekaran, and L. Pendyala, "Expression of Na, K-ATPase-β 1 subunit increases uptake and sensitizes carcinoma cells to oxaliplatin," Cancer chemotherapy and pharmacology, vol. 64, no. 6, pp. 1187-1194, 2009.
[69] W. Zhang et al., "Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia," Nature cell biology, vol. 14, no. 3, p. 276, 2012.
[70] H. Cabral, N. Nishiyama, S. Okazaki, H. Koyama, and K. Kataoka, "Preparation and biological properties of dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt)-loaded polymeric micelles," (in English), J. Control. Release, Article; Proceedings Paper vol. 101, no. 1-3, pp. 223-232, Jan 2005, doi: 10.1016/j.jconrel.2004.08.022.
[71] E. Martinez-Balibrea et al., "Tumor-Related Molecular Mechanisms of Oxaliplatin Resistance," (in English), Mol. Cancer Ther., Review vol. 14, no. 8, pp. 1767-1776, Aug 2015, doi: 10.1158/1535-7163.mct-14-0636.
[72] E. Raymond, S. Faivre, S. Chaney, J. Woynarowski, and E. Cvitkovic, "Cellular and molecular pharmacology of oxaliplatin1," Mol. Cancer Ther., vol. 1, no. 3, pp. 227-235, 2002.
[73] G. Liu et al., "DACHPt-Loaded Unimolecular Micelles Based on Hydrophilic Dendritic Block Copolymers for Enhanced Therapy of Lung Cancer," ACS Appl Mater Interfaces, vol. 9, no. 1, pp. 112-119, Jan 11 2017, doi: 10.1021/acsami.6b11917.
[74] T. Nirei et al., "Polymeric micelles loaded with (1,2-diaminocyclohexane)platinum(II) against colorectal cancer," J Surg Res, vol. 218, pp. 334-340, Oct 2017, doi: 10.1016/j.jss.2017.06.056.
[75] D. Arango et al., "Molecular mechanisms of action and prediction of response to oxaliplatin in colorectal cancer cells," British journal of cancer, vol. 91, no. 11, p. 1931, 2004.
[76] J. Gumulec et al., "Cisplatin-resistant prostate cancer model: Differences in antioxidant system, apoptosis and cell cycle," International Journal of Oncology, vol. 44, no. 3, pp. 923-933, 2014.