現今，由於大多數的系統性用藥（systemic drug）對肝細胞癌（hepatocellular carcinoma, HCC）的治療沒有好的功效，因此科學家針對與肝癌細胞生長相關的訊號傳遞路徑進行研究並已開發出了一種標靶治療用藥（targeted therapy drug），稱為索拉非尼（Sorafenib）。索拉非尼是一種多激酶抑制劑（multikinase inhibitor），除了可以抑制腫瘤生長外，還能夠降低腫瘤微環境中的血管新生（angiogenesis）。然而，索拉非尼的療效有限，平均僅能延長肝癌病人約 3 個月的壽命。 其抗藥性的產生促使我們思索可能的原因和可以改善的方法。有研究曾指出，索拉非尼的抗血管新生特性會使腫瘤區域的缺氧（hypoxia）情形惡化。其中，缺氧誘導因子一（hypoxia induced factor-1, HIF1），此一轉錄因子扮演了重要的角色。其在缺氧條件下會被激活，進而促進癌細胞表現特定基因，包含促血管新生、負責糖分運輸代謝、調控細胞存活和參與腫瘤侵入轉移等基因 。在此，我們致力於開發一個能標靶肝癌細胞且能有效調解腫瘤區域缺氧情形的二氧化錳奈米藥物載體。此載體能催化腫瘤微環境中的雙氧水產生氧氣，藉此改善腫瘤缺氧情形，克服腫瘤細胞的抗藥性。我們發現搭載索拉非尼的二氧化錳奈米粒子能有效優化藥物在缺氧下抑制腫瘤細胞生長的效果。我們也展示了二氧化錳奈米粒子可以減低缺氧癌細胞的上皮與間質轉換（epithelial-mesenchymal transition, EMT），藉由改善缺氧反轉具轉移性和侵入性的間質細胞成為有較佳細胞間黏附的上皮細胞，也因而減低癌細胞的侵入性和轉移能力。進一步地，我們透過腫瘤小鼠模型證實了二氧化錳奈米藥物載體能成功抑制腫瘤生長和癌症轉移。

Chemotherapy drugs have been used to fight against cancers for decades. However, most systemic drugs have moderate therapeutic effect on hepatocellular carcinoma (HCC). Hence, a targeted therapy drug, sorafenib which can block the important pathways related to cancer proliferation has been developed. As a multikinase inhibitor, sorafenib not only can inhibit tumor growth but also can reduce tumor angiogenesis. However, sorafenib has limited therapeutic effect and the average lifespan of sorafenib-treated patients only prolongs for three months. Drug resistance of sorafenib prompts us to understand the mechanism and find out the solutions. Studies show that the anti-angiogenic effect of sorafenib would lead to serious hypoxia in tumor microenvironment (TME). While tumor becomes more hypoxic, a relevant transcription factor called hypoxia induced factor-1 (HIF1) will be activated, and promote the expression of proangiogenic genes. Thus, tumor hypoxia can unfortunately lead to the escape of HCC cells from antiangiogenic therapy. Besides, hypoxia also induces other genes associated with glycolysis, apoptosis, metastasis, cell proliferation, and genetic instability. These hypoxia-inducible genes give assistance to tumor progression and sorafenib resistance in liver cancer. Herein, we designed a PLGA-based manganese dioxide (PMD) nanoparticles (NPs) modified with SP94 peptides to carry sorafenib into tumor sites and utilized the reactivity and catalytic activity of MnO2 toward H2O2 for ameliorating hypoxia in liver cancer with oxygen production. Sorafenib-loaded PMD (PMDsor) nanoparticles successfully sensitized sorafenib and reduced cancer cell proliferation and cell viability in hypoxia. Furthermore, we also demonstrated PMD can attenuate epithelial-mesenchymal transition (EMT) in HCC cells under hypoxic condition by reversing migratory, invasive mesenchymal cells to epithelial cells with better cell-cell adhesion. Hence, the invasiveness of cancer cells and the metastasis can be reduced. Finally, our NPs showed potent efficacy on tumor growth and metastasis inhibition in vivo.

中文摘要 (i)
Abstract (ii)
致謝 (iii)
Table of Contents (iv)
Table of Charts (vi)
Table of Tables (vii)
Abbreviation (viii)
Chapter 1 Motivation and Aims (1)
1.1 Motivation (2)
1.2 Aims (3)
Chapter 2 Literature Review (6)
2.1 Hepatocellular Carcinoma, HCC (7)
2.2 Sorafenib for Advanced HCC Treatment (9)
2.3 Tumor Hypoxia (11)
2.3.1 Tumor Hypoxia and Sorafenib Resistance (12)
2.3.2 Tumor Hypoxia and EMT (13)
2.3.3 Tumor Hypoxia and Immunosuppression (14)
2.4 Modulation of Tumor Hypoxia by MnO2 NPs and MR Imaging using Mn-based Contrast Agents (15)
2.5 Advantages of Utilizing NPs for Drug Delivery (17)
Chapter 3 Materials and Methods (19)
3.1 Materials (20)
3.2 Cell Culture (20)
3.3 Preparation of Nanoparticles (20)
3.4 Characterization of Nanoparticles (22)
3.5 Quenching of H2O2 and Measurement of Oxygen (22)
3.6 Drug Release Profile (23)
3.7 In vitro Cellular Uptake (23)
3.8 Immunocytochemistry (24)
3.9 Cell Proliferation and Cell Viability (24)
3.10 Quantitative Real-time Polymerase Chain Reaction (25)
3.11 Invasion assay (26)
3.12 Experimental Animals (27)
3.13 MR Imaging (27)
3.14 Treatment Study (28)
3.15 Immunohistochemistry (28)
3.16 Hematoxylin and Eosin Staining (29)
3.17 Flow Cytometry (29)
3.18 Whole Cell Vaccine Therapy (29)
3.19 Statistics (30)
Chapter 4 Results (31)
4.1 Preparation and Characterization of PLGA-based MnO2 Nanoparticles (32)
4.2 pH-dependent Reactivity and Drug Release Profiles of PMD Nanoparticles (37)
4.3 In vitro Efficacy of Targeted SP94 PMDsor Nanoparticles (39)
4.4 Reversing EMT and Reducing invasion of HCA-1 under hypoxia (42)
4.5 In vitro and In vivo MR imaging of SP94 PMD nanoparticles (44)
4.6 In vivo efficacy of targeted SP94 PMDsor nanoparticles (46)
Chapter 5 Conclusion (50)
5.1 Conclusion (51)
Chapter 6 Discussion and Prospect (52)
6.1 Discussion and Prospect (53)
Chapter 7 References (55)

1 Liu, L. et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 66, 11851-11858, doi:10.1158/0008-5472.CAN-06-1377 (2006).
2 Blanchet, B. et al. Toxicity of sorafenib: clinical and molecular aspects. Expert Opin Drug Saf 9, 275-287, doi:10.1517/14740330903510608 (2010).
3 Gao, D. Y. et al. CXCR4-targeted lipid-coated PLGA nanoparticles deliver sorafenib and overcome acquired drug resistance in liver cancer. Biomaterials 67, 194-203, doi:10.1016/j.biomaterials.2015.07.035 (2015).
4 Hockel, M. & Vaupel, P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93, 266-276 (2001).
5 Torre, L. A. et al. Global cancer statistics, 2012. CA Cancer J Clin 65, 87-108, doi:10.3322/caac.21262 (2015).
6 Cancer Stat facts: Liver and Intrahepatic Bile Duct Cancer, (2017).
7 Perz, J. F., Armstrong, G. L., Farrington, L. A., Hutin, Y. J. & Bell, B. P. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 45, 529-538, doi:10.1016/j.jhep.2006.05.013 (2006).
8 Cancer Registry Annual Report, 2014, Taiwan. (Taiwan, 2016).
9 Pellicoro, A., Ramachandran, P., Iredale, J. P. & Fallowfield, J. A. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol 14, 181-194, doi:10.1038/nri3623 (2014).
10 El-Serag, H. B. Hepatocellular carcinoma. N Engl J Med 365, 1118-1127, doi:10.1056/NEJMra1001683 (2011).
11 El-Serag, H. B., Marrero, J. A., Rudolph, L. & Reddy, K. R. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 134, 1752-1763, doi:10.1053/j.gastro.2008.02.090 (2008).
12 Wilhelm, S. M. et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64, 7099-7109, doi:10.1158/0008-5472.CAN-04-1443 (2004).
13 Chang, Y. S. et al. Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol 59, 561-574, doi:10.1007/s00280-006-0393-4 (2007).
14 Calvisi, D. F. et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 130, 1117-1128, doi:10.1053/j.gastro.2006.01.006 (2006).
15 Semela, D. & Dufour, J. F. Angiogenesis and hepatocellular carcinoma. J Hepatol 41, 864-880, doi:10.1016/j.jhep.2004.09.006 (2004).
16 Villanueva, A., Newell, P., Chiang, D. Y., Friedman, S. L. & Llovet, J. M. Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis 27, 55-76, doi:10.1055/s-2006-960171 (2007).
17 Palmer, D. H. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359, 2498; author reply 2498-2499 (2008).
18 Cheng, A. L. et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10, 25-34, doi:10.1016/S1470-2045(08)70285-7 (2009).
19 Ezzoukhry, Z. et al. EGFR activation is a potential determinant of primary resistance of hepatocellular carcinoma cells to sorafenib. Int J Cancer 131, 2961-2969, doi:10.1002/ijc.27604 (2012).
20 Zhu, Y. J., Zheng, B., Wang, H. Y. & Chen, L. New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharmacol Sin 38, 614-622, doi:10.1038/aps.2017.5 (2017).
21 Wilhelm, S. et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5, 835-844, doi:10.1038/nrd2130 (2006).
22 Harris, A. L. Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer 2, 38-47, doi:10.1038/nrc704 (2002).
23 Yang, Z. F. & Poon, R. T. Vascular changes in hepatocellular carcinoma. Anat Rec (Hoboken) 291, 721-734, doi:10.1002/ar.20668 (2008).
24 Steeg, P. S. Angiogenesis inhibitors: motivators of metastasis? Nat Med 9, 822-823, doi:10.1038/nm0703-822 (2003).
25 von Marschall, Z. et al. Dual mechanism of vascular endothelial growth factor upregulation by hypoxia in human hepatocellular carcinoma. Gut 48, 87-96 (2001).
26 Yang, Z. F., Poon, R. T., To, J., Ho, D. W. & Fan, S. T. The potential role of hypoxia inducible factor 1alpha in tumor progression after hypoxia and chemotherapy in hepatocellular carcinoma. Cancer Res 64, 5496-5503, doi:10.1158/0008-5472.CAN-03-3311 (2004).
27 Chen, Y. et al. Differential effects of sorafenib on liver versus tumor fibrosis mediated by stromal-derived factor 1 alpha/C-X-C receptor type 4 axis and myeloid differentiation antigen-positive myeloid cell infiltration in mice. Hepatology 59, 1435-1447, doi:10.1002/hep.26790 (2014).
28 Duda, D. G. et al. CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies? Clin Cancer Res 17, 2074-2080, doi:10.1158/1078-0432.CCR-10-2636 (2011).
29 Chatterjee, S., Behnam Azad, B. & Nimmagadda, S. The intricate role of CXCR4 in cancer. Adv Cancer Res 124, 31-82, doi:10.1016/B978-0-12-411638-2.00002-1 (2014).
30 Ahmadi, M. et al. Hypoxia modulates the activity of a series of clinically approved tyrosine kinase inhibitors. Br J Pharmacol 171, 224-236, doi:10.1111/bph.12438 (2014).
31 Strese, S., Fryknas, M., Larsson, R. & Gullbo, J. Effects of hypoxia on human cancer cell line chemosensitivity. BMC Cancer 13, 331, doi:10.1186/1471-2407-13-331 (2013).
32 Xu, H. et al. MiR-338-3p inhibits hepatocarcinoma cells and sensitizes these cells to sorafenib by targeting hypoxia-induced factor 1alpha. PLoS One 9, e115565, doi:10.1371/journal.pone.0115565 (2014).
33 Ma, L. et al. 2-Methoxyestradiol synergizes with sorafenib to suppress hepatocellular carcinoma by simultaneously dysregulating hypoxia-inducible factor-1 and -2. Cancer Lett 355, 96-105, doi:10.1016/j.canlet.2014.09.011 (2014).
34 Liang, Y. et al. Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1alpha inhibition in hepatocellular carcinoma. Hepatology 57, 1847-1857, doi:10.1002/hep.26224 (2013).
35 van Zijl, F. et al. Epithelial-mesenchymal transition in hepatocellular carcinoma. Future Oncol 5, 1169-1179, doi:10.2217/fon.09.91 (2009).
36 van Malenstein, H. et al. Long-term exposure to sorafenib of liver cancer cells induces resistance with epithelial-to-mesenchymal transition, increased invasion and risk of rebound growth. Cancer Lett 329, 74-83, doi:10.1016/j.canlet.2012.10.021 (2013).
37 Nagai, T. et al. Sorafenib inhibits the hepatocyte growth factor-mediated epithelial mesenchymal transition in hepatocellular carcinoma. Mol Cancer Ther 10, 169-177, doi:10.1158/1535-7163.MCT-10-0544 (2011).
38 Zhang, L. et al. Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor -1alpha in hepatocellular carcinoma. BMC Cancer 13, 108, doi:10.1186/1471-2407-13-108 (2013).
39 Zhang, X. D., Dong, X. Q., Xu, J. L., Chen, S. C. & Sun, Z. Hypoxia promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells via inducing Twist1 expression. Eur Rev Med Pharmacol Sci 21, 3061-3068 (2017).
40 Huang, S. G. et al. Hypoxia promotes epithelial--mesenchymal transition of hepatocellular carcinoma cells via inducing GLIPR-2 expression. PLoS One 8, e77497, doi:10.1371/journal.pone.0077497 (2013).
41 Zhang, P. F. et al. Galectin-1 induces hepatocellular carcinoma EMT and sorafenib resistance by activating FAK/PI3K/AKT signaling. Cell Death Dis 7, e2201, doi:10.1038/cddis.2015.324 (2016).
42 Cancer Facts and Figures 2017, (2017).
43 Du, R. et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13, 206-220, doi:10.1016/j.ccr.2008.01.034 (2008).
44 Chiu, D. K. et al. Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma. Nat Commun 8, 517, doi:10.1038/s41467-017-00530-7 (2017).
45 Henze, A. T. & Mazzone, M. The impact of hypoxia on tumor-associated macrophages. J Clin Invest 126, 3672-3679, doi:10.1172/JCI84427 (2016).
46 Laoui, D. et al. Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. Cancer Res 74, 24-30, doi:10.1158/0008-5472.CAN-13-1196 (2014).
47 Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559-563, doi:10.1038/nature13490 (2014).
48 Facciabene, A. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 475, 226-230, doi:10.1038/nature10169 (2011).
49 Barsoum, I. B., Smallwood, C. A., Siemens, D. R. & Graham, C. H. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res 74, 665-674, doi:10.1158/0008-5472.CAN-13-0992 (2014).
50 Doedens, A. L. et al. Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nat Immunol 14, 1173-1182, doi:10.1038/ni.2714 (2013).
51 Hatfield, S. M. et al. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci Transl Med 7, 277ra230, doi:10.1126/scitranslmed.aaa1260 (2015).
52 Zhang, M. et al. MnO2-Based Nanoplatform Serves as Drug Vehicle and MRI Contrast Agent for Cancer Theranostics. ACS Appl Mater Interfaces 9, 11337-11344, doi:10.1021/acsami.6b15247 (2017).
53 Abbasi, A. Z. et al. Hybrid Manganese Dioxide Nanoparticles Potentiate Radiation Therapy by Modulating Tumor Hypoxia. Cancer Res 76, 6643-6656, doi:10.1158/0008-5472.CAN-15-3475 (2016).
54 Chen, Q. et al. Intelligent Albumin-MnO2 Nanoparticles as pH-/H2 O2 -Responsive Dissociable Nanocarriers to Modulate Tumor Hypoxia for Effective Combination Therapy. Adv Mater 28, 7129-7136, doi:10.1002/adma.201601902 (2016).
55 Song, M., Liu, T., Shi, C., Zhang, X. & Chen, X. Bioconjugated Manganese Dioxide Nanoparticles Enhance Chemotherapy Response by Priming Tumor-Associated Macrophages toward M1-like Phenotype and Attenuating Tumor Hypoxia. ACS Nano 10, 633-647, doi:10.1021/acsnano.5b06779 (2016).
56 Fan, W. et al. Intelligent MnO2 Nanosheets Anchored with Upconversion Nanoprobes for Concurrent pH-/H2O2-Responsive UCL Imaging and Oxygen-Elevated Synergetic Therapy. Adv Mater 27, 4155-4161, doi:10.1002/adma.201405141 (2015).
57 Lopez-Lazaro, M. Dual role of hydrogen peroxide in cancer: possible relevance to cancer chemoprevention and therapy. Cancer Lett 252, 1-8, doi:10.1016/j.canlet.2006.10.029 (2007).
58 Chiche, J., Brahimi-Horn, M. C. & Pouyssegur, J. Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer. J Cell Mol Med 14, 771-794, doi:10.1111/j.1582-4934.2009.00994.x (2010).
59 Rockwell, S., Dobrucki, I. T., Kim, E. Y., Marrison, S. T. & Vu, V. T. Hypoxia and radiation therapy: past history, ongoing research, and future promise. Curr Mol Med 9, 442-458 (2009).
60 Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat Med 19, 1423-1437, doi:10.1038/nm.3394 (2013).
61 Yang, G. et al. Hollow MnO2 as a tumor-microenvironment-responsive biodegradable nano-platform for combination therapy favoring antitumor immune responses. Nat Commun 8, 902, doi:10.1038/s41467-017-01050-0 (2017).
62 Gale, E. M. et al. A Manganese-based Alternative to Gadolinium: Contrast-enhanced MR Angiography, Excretion, Pharmacokinetics, and Metabolism. Radiology 286, 865-872, doi:10.1148/radiol.2017170977 (2018).
63 Semelka, R. C., Commander, C. W., Jay, M., Burke, L. M. & Ramalho, M. Presumed Gadolinium Toxicity in Subjects With Normal Renal Function: A Report of 4 Cases. Invest Radiol 51, 661-665, doi:10.1097/RLI.0000000000000318 (2016).
64 Kanda, T. et al. Gadolinium-based Contrast Agent Accumulates in the Brain Even in Subjects without Severe Renal Dysfunction: Evaluation of Autopsy Brain Specimens with Inductively Coupled Plasma Mass Spectroscopy. Radiology 276, 228-232, doi:10.1148/radiol.2015142690 (2015).
65 Roberts, D. R. et al. High Levels of Gadolinium Deposition in the Skin of a Patient With Normal Renal Function. Invest Radiol 51, 280-289, doi:10.1097/RLI.0000000000000266 (2016).
66 Chen, Y. et al. Structure-property relationships in manganese oxide--mesoporous silica nanoparticles used for T1-weighted MRI and simultaneous anti-cancer drug delivery. Biomaterials 33, 2388-2398, doi:10.1016/j.biomaterials.2011.11.086 (2012).
67 Kim, T. et al. Urchin-shaped manganese oxide nanoparticles as pH-responsive activatable T1 contrast agents for magnetic resonance imaging. Angew Chem Int Ed Engl 50, 10589-10593, doi:10.1002/anie.201103108 (2011).
68 Prasad, P. et al. Multifunctional albumin-MnO(2) nanoparticles modulate solid tumor microenvironment by attenuating hypoxia, acidosis, vascular endothelial growth factor and enhance radiation response. ACS Nano 8, 3202-3212, doi:10.1021/nn405773r (2014).
69 De Jong, W. H. & Borm, P. J. Drug delivery and nanoparticles:applications and hazards. Int J Nanomedicine 3, 133-149 (2008).
70 Chen, Y. et al. Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors. Sci Rep 7, 44123, doi:10.1038/srep44123 (2017).
71 Li, J., Yang, Y. & Huang, L. Calcium phosphate nanoparticles with an asymmetric lipid bilayer coating for siRNA delivery to the tumor. J Control Release 158, 108-114, doi:10.1016/j.jconrel.2011.10.020 (2012).
72 Hsu, F. F. et al. Signal peptide peptidase-mediated nuclear localization of heme oxygenase-1 promotes cancer cell proliferation and invasion independent of its enzymatic activity. Oncogene 34, 2360-2370, doi:10.1038/onc.2014.166 (2015).
73 Schmittgen, T. D. & Livak, K. J. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3, 1101-1108 (2008).
74 Justus, C. R., Leffler, N., Ruiz-Echevarria, M. & Yang, L. V. In vitro cell migration and invasion assays. J Vis Exp, doi:10.3791/51046 (2014).
75 Huang, Y. et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A 109, 17561-17566, doi:10.1073/pnas.1215397109 (2012).
76 Lo, A., Lin, C. T. & Wu, H. C. Hepatocellular carcinoma cell-specific peptide ligand for targeted drug delivery. Mol Cancer Ther 7, 579-589, doi:10.1158/1535-7163.MCT-07-2359 (2008).
77 Ashley, C. E. et al. The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers. Nat Mater 10, 389-397, doi:10.1038/nmat2992 (2011).
78 Ashley, C. E. et al. Cell-specific delivery of diverse cargos by bacteriophage MS2 virus-like particles. ACS Nano 5, 5729-5745, doi:10.1021/nn201397z (2011).
79 Guo, C. X., Chitre, A. A. & Lu, X. DNA-assisted assembly of carbon nanotubes and MnO2 nanospheres as electrodes for high-performance asymmetric supercapacitors. Phys Chem Chem Phys 16, 4672-4678, doi:10.1039/c3cp54911a (2014).
80 Huang, M. et al. Merging of Kirkendall growth and Ostwald ripening: CuO@MnO2 core-shell architectures for asymmetric supercapacitors. Sci Rep 4, 4518, doi:10.1038/srep04518 (2014).
81 Sharma, N. M., P.; Lin S. S. Effect of process and formulation variables on the preparation of parenteral paclitaxel-loaded biodegradable polymeric nanoparticles: A co-surfactant study. Asian Journal of Pharmacutical Sciences, 404-416, doi:10.1016/j.ajps.2015.09.004 (2015).
82 Mu, L. & Feng, S. S. A novel controlled release formulation for the anticancer drug paclitaxel (Taxol): PLGA nanoparticles containing vitamin E TPGS. J Control Release 86, 33-48 (2003).
83 Wang, G. et al. Controlled preparation and antitumor efficacy of vitamin E TPGS-functionalized PLGA nanoparticles for delivery of paclitaxel. Int J Pharm 446, 24-33, doi:10.1016/j.ijpharm.2013.02.004 (2013).
84 Sies, H. Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: Oxidative eustress. Redox Biol 11, 613-619, doi:10.1016/j.redox.2016.12.035 (2017).
85 Liu, C. H. et al. A multifunctional nanocarrier for efficient TRAIL-based gene therapy against hepatocellular carcinoma with desmoplasia in mice. Hepatology 67, 899-913, doi:10.1002/hep.29513 (2018).
86 McKeown, S. R. Defining normoxia, physoxia and hypoxia in tumours-implications for treatment response. Br J Radiol 87, 20130676, doi:10.1259/bjr.20130676 (2014).
87 Pan, D., Schmieder, A. H., Wickline, S. A. & Lanza, G. M. Manganese-based MRI contrast agents: past, present and future. Tetrahedron 67, 8431-8444, doi:10.1016/j.tet.2011.07.076 (2011).
88 Zhang, W. et al. Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects. Clin Cancer Res 16, 3420-3430, doi:10.1158/1078-0432.CCR-09-2904 (2010).
89 Vuillefroy de Silly, R., Dietrich, P. Y. & Walker, P. R. Hypoxia and antitumor CD8(+) T cells: An incompatible alliance? Oncoimmunology 5, e1232236, doi:10.1080/2162402X.2016.1232236 (2016).
90 Kieda, C. et al. Stable tumor vessel normalization with pO(2) increase and endothelial PTEN activation by inositol trispyrophosphate brings novel tumor treatment. J Mol Med (Berl) 91, 883-899, doi:10.1007/s00109-013-0992-6 (2013).
91 Muggia, F. M. Doxorubicin-polymer conjugates: further demonstration of the concept of enhanced permeability and retention. Clin Cancer Res 5, 7-8 (1999).