近年來，以奈米粒子作為藥物載體是一個十分熱門的研究課題。 由於在腫瘤位置的高滲透長滯留(EPR)效應，奈米粒子藉由自身的特性而能夠累積在腫瘤處。除此之外，奈米粒子能夠提高疏水性藥物的溶解度並能夠藉由不同的設計改變藥物釋放的模式，這些特性使得奈米粒子特別適合作為癌症治療的藥物載體。但是外來的奈米粒子容易被單核吞噬細胞系統(RES)所辨識並清除。在奈米粒子表面修飾上聚乙二醇(PEG)能透提高奈米粒子在生物體內的循環時間並在細胞與奈米粒子間產生一個排斥力量，使奈米粒子較不易被RES所清除，但同時也使奈米粒子較不易被腫瘤細胞攝取。不少奈米粒子載體修飾上腫瘤標靶配體像是葉酸，抗體，肽鏈，配體等等以提高奈米粒子在腫瘤處的累積量。近年來，由天然細胞膜所包覆的奈米粒子載體被發展出來，在生物體內產生極低的免疫反應，其在體內循環時間能夠比修飾上PEG的奈米粒子還長。在本論文中，我們建立了一個由具有腫瘤趨向性的單核球細胞膜包覆生物可降解的聚乳酸-甘醇酸(PLGA)高分子核心所製成的奈米藥物載體。我們的結果顯示出單核球所包覆的奈米粒子較不易被巨噬細胞所吞噬，並同時具有腫瘤趨向性。綜合以上成果，由單核球細胞膜所包覆的奈米粒子在腫瘤治療上具有潛力，並值得更深入的研究。

Nanoparticle-based drug delivery system has been intensively studied in recent years. Due to the enhanced permeability and retention (EPR) effect at the tumor region, nanoparticles can accumulate at tumor intrinsically. Additionally, nanoparticles are able to increase the solubility of hydrophobic drug and change the drug release profile depending on the design of the nanoparticle. These characteristics make nanoparticles attractive drug carriers for cancer therapy. However, the extrinsic nanoparticles can be recognized and eliminated by the reticuloendothelial system (RES). In order to prolong the circulation time of nanoparticles, surface modification of polyethylene glycol (PEG) on the nanoparticles can provide a repulsive force against cells resulting in reduced level of the RES recognition. The modification of PEG (PEGylation) also reduces the nanoparticle uptaken by tumor cells. Several nanoparticles with the conjugation of targeting ligands, such as folate, antibodies, peptides, and aptamers, have been developed to enhance the accumulation at tumor site. Recently, cell membrane-coated nanoparticles were developed by coating natural cell membrane on the nanoparticle. The cell membrane-coated nanoparticles exhibit minimum immunogenicity and show a longer circulation time than PEGylated nanoparticles. In this study, we established a monocyte membrane-coated nanoparticle delivery system, coating the cell membrane extracted from tumor-tropic bone marrow-derived monocyte (BMDM) on a biodegradable poly lactic-co-glycolic acid (PLGA) polymeric core. We demonstrate that a reduced engulfment of macrophage in monocyte membrane-coated nanoparticle compared to the bare nanoparticle. At the meantime, the monocyte membrane-coated nanoparticle shows the capability of tumor-tropism. These results indicate that the monocyte membrane-coated nanoparticle has the therapeutic potential in cancer therapy, and it is worthwhile to further investigate on it.

中文摘要 I
ABSTRACT II
致謝 III
CHAPTER I. INTRODUCTION 1
1.1 Cancer 1
1.2 Nanoparticle-based drug delivery system 1
1.2 Tumor-associated macrophages (TAM) 2
1.4 Cell membrane coated nanoparticles 3
CHAPTER II. MATERIALS AND METHODS 4
2.1 Chemicals 4
2.2 Synthesis of PLGA nanoparticles 6
2.3 Cells and animals 7
2.3.1 Cell lines 7
2.3.2 Animals 8
2.3.3 Preparation of bone marrow-derived monocytes (BMDM) 8
2.3.4 Training of BMDM by conditioned medium 9
2.4 BMDM phenotyping by flow cytometry 9
2.5 BMDM cell membrane (BMDMm) extraction 10
2.6 Preparation of BMDMm-coated PLGA NP (BMDMm-PLGA NP) 11
2.7 Characterization of nanoparticles 11
2.7.1 Size and zeta potential 11
2.7.2 Drug content in nanoparticles 12
2.8 Validation of membrane coating process 13
2.8.1 Evaluation of lipids on BMDMm-PLGA NP by DiI retention assay 13
2.8.2 Evaluation of proteins on BMDMm-PLGA NP by SDS-PAGE 13
2.9 Evaluation of photo-thermal effect of nanoparticles 16
2.10 Cellular uptake 16
2.10.1 Cellular uptake evaluated by fluorescence of IR780 using flow cytometry 16
2.10.2 Cellular uptake evaluated by DiI fluorescence using microscopy 16
2.11 Statistic analysis 17
CHAPTER III. RESULTS 18
3.1 Preparation and characterization of BMDMm-PLGA NP 18
3.1.1 Preparation of PLGA NP 18
3.1.2 BMDM differentiation 18
3.1.3 Preparation of BMDMm-PLGA NP 19
3.2 Validation of membrane coating process 20
3.2.1 Lipids on BMDMm-PLGA NP 20
3.2.2 Proteins on BMDMm-PLGA NP 20
3.3 The photo-thermal effect of BMDMm-PLGA NP 21
3.4 Cellular uptake of BMDMm-PLGA NP 21
3.5 The role of SDF-1 on BMDMm-PLGA NP cellular uptake 22
CHAPTER IV. DISCUSSION 23
4.1 Drug loading efficiency on PLGA NP 23
4.2 Coating BMDMm on PLGA NP 24
4.3 Cell source of cell membrane 24
4.4 Active targeting of BMDMm-PLGA NP 25
4.5 Exosomes 26
4.6 Conclusions 27
CHAPTER V. FIGURES 28
CHAPTER VI. REFERENCES 40

1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin D, Forman D, Bray F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer 2015;136(5).
2. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):646-674.
3. Remvikos Y, Beuzeboc P, Zajdela A, Voillemot N, Magdelenat H, Pouillart P. Correlation of pretreatment proliferative activity of breast cancer with the response to cytotoxic chemotherapy. Journal of the National Cancer Institute 1989;81(18):1383-1387.
4. Valeriote F, van Putten L. Proliferation-dependent Cytotoxicity of Anticancer Agents: A Review. Cancer Research 1975;35(10):2619-2630.
5. Fisher DE. Apoptosis in cancer therapy: crossing the threshold. Cell 1994;78(4):539-542.
6. Vaupel P, Thews O, Hoeckel M. Treatment Resistance of Solid Tumors. Medical Oncology 2001;18(4):243-260.
7. Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. The British journal of radiology 1953;26(312):638-648.
8. Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nature Reviews Cancer 2004.
9. Erler JT, Cawthorne CJ, Williams KJ, Koritzinsky M, Wouters BG, Wilson C, Miller C, Demonacos C, Stratford IJ, Dive C. Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and -independent mechanisms and contributes to drug resistance. Molecular and cellular biology 2004;24(7):2875-2889.
10. Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 1996;379(6560):88-91.
11. Sullivan R, Paré GCC, Frederiksen LJ, Semenza GL, Graham CH. Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity. Molecular cancer therapeutics 2008;7(7):1961-1973.
12. Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer research 2002;62(12):3387-3394.
13. Saggar JK, Tannock IF. Chemotherapy Rescues Hypoxic Tumor Cells and Induces Their Reoxygenation and Repopulation-An Effect That Is Inhibited by the Hypoxia-Activated Prodrug TH-302. Clinical cancer research : an official journal of the American Association for Cancer Research 2015;21(9):2107-2114.
14. Kim JJ, Tannock IF. Repopulation of cancer cells during therapy: an important cause of treatment failure. Nature reviews. Cancer 2005;5(7):516-525.
15. Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nature reviews. Cancer 2011;11(6):393-410.
16. Fuertges F, Abuchowski A. The clinical efficacy of poly(ethylene glycol)-modified proteins. Journal of Controlled Release 1990;11(1-3):139-148.
17. Barenholz YC. Doxil®—the first FDA-approved nano-drug: lessons learned. Journal of controlled release 2012.
18. Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R. Nanocarriers as an emerging platform for cancer therapy. Nature nanotechnology 2007;2(12):751-760.
19. 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 research 1986;46(12 Pt 1):6387-6392.
20. Alexis F, Pridgen E, Molnar LK, Farokhzad OC. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Molecular pharmaceutics 2008;5(4):505-515.
21. Yamamoto Y, Nagasaki Y, Kato Y, Sugiyama Y, Kataoka K. Long-circulating poly(ethylene glycol)-poly(D,L-lactide) block copolymer micelles with modulated surface charge. Journal of controlled release : official journal of the Controlled Release Society 2001;77(1-2):27-38.
22. Moghimi SM, Hunter AC, Murray JC. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacological reviews 2001;53(2):283-318.
23. Li H, Guo L, Huang A, Xu H, Liu X, Ding H, Dong J, Li J, Wang C, Su X and others. Nanoparticle-conjugated aptamer targeting hnRNP A2/B1 can recognize multiple tumor cells and inhibit their proliferation. Biomaterials 2015;63:168-176.
24. Allen TM. Ligand-targeted therapeutics in anticancer therapy. Nature reviews. Cancer 2002;2(10):750-763.
25. Abakumov MA, Nukolova NV, Sokolsky-Papkov M, Shein SA, Sandalova TO, Vishwasrao HM, Grinenko NF, Gubsky IL, Abakumov AM, Kabanov AV and others. VEGF-targeted magnetic nanoparticles for MRI visualization of brain tumor. Nanomedicine: Nanotechnology, Biology and Medicine 2015;11(4):825-833.
26. Liang C, Guo B, Wu H, Shao N, Li D, Liu J, Dang L, Wang C, Li H, Li S and others. Aptamer-functionalized lipid nanoparticles targeting osteoblasts as a novel RNA interference-based bone anabolic strategy. Nature medicine 2015;21(3):288-294.
27. Hung L-Y, Wang C-H, Che Y-J, Fu C-Y, Chang H-Y, Wang K, Lee G-B. Screening of aptamers specific to colorectal cancer cells and stem cells by utilizing On-chip Cell-SELEX. Scientific reports 2015;5:10326.
28. Barman J. Targeting cancer cells using aptamers: cell-SELEX approach and recent advancements. RSC Advances 2015;5(16):11724-11732.
29. Mantovani A, Bottazzi B, Colotta F, Sozzani S, Ruco L. The origin and function of tumor-associated macrophages. Immunology Today 1992;13(7):265-270.
30. Qian B-Z, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell 2010;141(1):39-51.
31. Shand FHW, Ueha S, Otsuji M. Tracking of intertissue migration reveals the origins of tumor-infiltrating monocytes. Proceedings of the National Academy of Sciences of the United States of America 2014.
32. Kitamura T, Qian B-Z, Pollard JW. Immune cell promotion of metastasis. Nature Reviews Immunology 2015;15(2):73-86.
33. Sica A, Schioppa T, Mantovani A, Allavena P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: Potential targets of anti-cancer therapy. European Journal of Cancer 2006;42(6):717-727.
34. Shiao SL, Ruffell B, DeNardo DG, Faddegon BA, Park CC, Coussens LM. TH2-Polarized CD4(+) T Cells and Macrophages Limit Efficacy of Radiotherapy. Cancer immunology research 2015;3(5):518-525.
35. Chen F-H, Fu S-Y, Yang Y-C, Wang C-C, Chiang C-S, Hong J-H. Combination of vessel-targeting agents and fractionated radiation therapy: the role of the SDF-1/CXCR4 pathway. International journal of radiation oncology, biology, physics 2013;86(4):777-784.
36. Ostuni R, Kratochvill F, Murray PJ, Natoli G. Macrophages and cancer: from mechanisms to therapeutic implications. Trends in immunology 2015;36(4):229-239.
37. Chiang C-S, Fu S-Y, Wang S-C, Yu C-F, Chen F-H, Lin C-M, Hong J-H. Irradiation promotes an m2 macrophage phenotype in tumor hypoxia. Frontiers in oncology 2012;2:89.
38. Chen F-HH, Chiang C-SS, Wang C-CC, Tsai C-SS, Jung S-MM, Lee C-CC, McBride WH, Hong J-HH. Radiotherapy decreases vascular density and causes hypoxia with macrophage aggregation in TRAMP-C1 prostate tumors. Clinical cancer research : an official journal of the American Association for Cancer Research 2009;15(5):1721-1729.
39. Jiang P-S, Yu C-F, Yen C-Y, Woo C, Lo S-H, Huang Y-K, Hong J-H, Chiang C-S. Irradiation Enhances the Ability of Monocytes as Nanoparticle Carrier for Cancer Therapy. PloS one 2015;10(9).
40. Huang W-C, Chiang W-H, Cheng Y-H, Lin W-C, Yu C-F, Yen C-Y, Yeh C-K, Chern C-S, Chiang C-S, Chiu H-C. Tumortropic monocyte-mediated delivery of echogenic polymer bubbles and therapeutic vesicles for chemotherapy of tumor hypoxia. Biomaterials 2015;71:71-83.
41. Griffiths L, Binley K, Iqball S, Kan O, Maxwell P, Ratcliffe P, Lewis C, Harris A, Kingsman S, Naylor S. The macrophage - a novel system to deliver gene therapy to pathological hypoxia. Gene therapy 2000;7(3):255-262.
42. Choi J, Kim H-Y, Ju EJ, Jung J, Park J, Chung H-K, Lee JS, Lee JS, Park HJ, Song SY and others. Use of macrophages to deliver therapeutic and imaging contrast agents to tumors. Biomaterials 2012;33(16):4195-4203.
43. Hu C-MJM, Zhang L, Aryal S, Cheung C, Fang RH, Zhang L. Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform. Proceedings of the National Academy of Sciences of the United States of America 2011;108(27):10980-10985.
44. Kaneti L, Bronshtein T, Malkah Dayan N, Kovregina I, Letko Khait N, Lupu-Haber Y, Fliman M, Schoen BW, Kaneti G, Machluf M. Nanoghosts as a Novel Natural Nonviral Gene Delivery Platform Safely Targeting Multiple Cancers. Nano letters 2016;16(3):1574-1582.
45. Lai PY, Huang RY, Lin SY, Lin YH, Chang CW. Biomimetic stem cell membrane-camouflaged iron oxide nanoparticles for theranostic applications. RSC Advances 2015.
46. Toledano Furman NE, Lupu-Haber Y, Bronshtein T, Kaneti L, Letko N, Weinstein E, Baruch L, Machluf M. Reconstructed stem cell nanoghosts: a natural tumor targeting platform. Nano letters 2013;13(7):3248-3255.
47. Gao C, Wu Z, Lin Z, Lin X, He Q. Polymeric capsule-cushioned leukocyte cell membrane vesicles as a biomimetic delivery platform. Nanoscale 2016;8(6):3548-3554.
48. Evangelopoulos M, Parodi A, Martinez JO, Yazdi IK, Cevenini A, van de Ven AL, Quattrocchi N, Boada C, Taghipour N, Corbo C and others. Cell source determines the immunological impact of biomimetic nanoparticles. Biomaterials 2016;82:168-177.
49. Xuan M, Shao J, Dai L, Li J, He Q. Macrophage Cell Membrane Camouflaged Au Nanoshells for in Vivo Prolonged Circulation Life and Enhanced Cancer Photothermal Therapy. ACS applied materials & interfaces 2016;8(15):9610-9618.
50. Zhou J, Patel TR, Sirianni RW, Strohbehn G, Zheng M-QQ, Duong N, Schafbauer T, Huttner AJ, Huang Y, Carson RE and others. Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma. Proceedings of the National Academy of Sciences of the United States of America 2013;110(29):11751-11756.
51. Park J, An K, Hwang Y, Park J-G, Noh H-J, Kim J-Y, Park J-H, Hwang N-M, Hyeon T. Ultra-large-scale syntheses of monodisperse nanocrystals. Nature materials 2004;3(12):891-895.
52. Huang R-Y, Chiang P-H, Hsiao W-C, Chuang C-C, Chang C-W. Redox-Sensitive Polymer/SPIO Nanocomplexes for Efficient Magnetofection and MR Imaging of Human Cancer Cells. Langmuir : the ACS journal of surfaces and colloids 2015;31(23):6523-6531.
53. Wang S-C, Hong J-H, Hsueh C, Chiang C-S. Tumor-secreted SDF-1 promotes glioma invasiveness and TAM tropism toward hypoxia in a murine astrocytoma model. Laboratory investigation; a journal of technical methods and pathology 2012;92(1):151-162.
54. Hsieh C-C, Kang S-T, Lin Y-H, Ho Y-J, Wang C-H, Yeh C-K, Chang C-W. Biomimetic Acoustically-Responsive Vesicles for Theranostic Applications. Theranostics 2015;5(11):1264-1274.
55. Makadia HK, Siegel SJ. Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier. Polymers 2011;3(3):1377-1397.
56. Peng C-LL, Shih Y-HH, Lee P-CC, Hsieh TM, Luo T-YY, Shieh M-JJ. Multimodal image-guided photothermal therapy mediated by 188Re-labeled micelles containing a cyanine-type photosensitizer. ACS nano 2011;5(7):5594-5607.
57. Li Q, Rycaj K, Chen X, Tang DG. Cancer stem cells and cell size: A causal link? Seminars in cancer biology 2015;35:191-199.
58. Goethem E, Poincloux R, Gauffre F, Maridonneau-Parini I, Cabec V. Matrix Architecture Dictates Three-Dimensional Migration Modes of Human Macrophages: Differential Involvement of Proteases and Podosome-Like Structures. The Journal of Immunology 2010;184(2):1049-1061.
59. Hoffman RA. Current Protocols in Cytometry. Current protocols in cytometry / editorial board, J. Paul Robinson, managing editor ... [et al.] 2009;Chapter 1.
60. Godement P, Vanselow J, Thanos S, Bonhoeffer F. A study in developing visual systems with a new method of staining neurones and their processes in fixed tissue. Development (Cambridge, England) 1987;101(4):697-713.
61. Yuan A, Qiu X, Tang X, Liu W, Wu J, Hu Y. Self-assembled PEG-IR-780-C13 micelle as a targeting, safe and highly-effective photothermal agent for in vivo imaging and cancer therapy. Biomaterials 2015;51:184-193.
62. Chen Y, Li Z, Wang H, Wang Y, Han H, Jin Q, Ji J. IR-780 Loaded Phospholipid Mimicking Homopolymeric Micelles for Near-IR Imaging and Photothermal Therapy of Pancreatic Cancer. ACS Applied Materials & Interfaces 2016;8(11):6852-6858.
63. Fang RH, Hu C-MJM, Chen KN, Luk BT, Carpenter CW, Gao W, Li S, Zhang D-EE, Lu W, Zhang L. Lipid-insertion enables targeting functionalization of erythrocyte membrane-cloaked nanoparticles. Nanoscale 2013;5(19):8884-8888.
64. Ling Y, Huang Y. Preparation and Release Efficiency of Poly (lactic-co-glycolic) Acid Nanoparticles for Drug Loaded Paclitaxel. Preparation and Release Efficiency of Poly (lactic-co-glycolic) Acid Nanoparticles for Drug Loaded Paclitaxel 2008;19:514-517.
65. Aryal S, Hu C-MJM, Fang RH, Dehaini D, Carpenter C, Zhang D-EE, Zhang L. Erythrocyte membrane-cloaked polymeric nanoparticles for controlled drug loading and release. Nanomedicine (London, England) 2013;8(8):1271-1280.
66. Zolnik BS, Leary PE, Burgess DJ. Elevated temperature accelerated release testing of PLGA microspheres. Journal of controlled Release 2006;112(3):293-300.
67. Zheng M, Yue C, Ma Y, Gong P, Zhao P, Zheng C, Sheng Z, Zhang P, Wang Z, Cai L. Single-Step Assembly of DOX/ICG Loaded Lipid–Polymer Nanoparticles for Highly Effective Chemo-photothermal Combination Therapy. ACS Nano 2013;7(3):2056-2067.
68. Guo F, Yu M, Wang J, Tan F, Li N. Smart IR780 Theranostic Nanocarrier for Tumor-Specific Therapy: Hyperthermia-Mediated Bubble-Generating and Folate-Targeted Liposomes. ACS applied materials & interfaces 2015;7(37):20556-20567.
69. Almutairi A, Lessard-Viger M, Sheng W. Polymeric nanocarriers with light-triggered release mechanism. Google Patents; 2013.
70. Luk BT, Hu C-MJM, Fang RH, Dehaini D, Carpenter C, Gao W, Zhang L. Interfacial interactions between natural RBC membranes and synthetic polymeric nanoparticles. Nanoscale 2014;6(5):2730-2737.
71. Xuan M, Shao J, Dai L, He Q, Li J. Macrophage Cell Membrane Camouflaged Mesoporous Silica Nanocapsules for In Vivo Cancer Therapy. Advanced healthcare materials 2015;4(11):1645-1652.
72. Gelmini S, Mangoni M, Serio M, Romagnani P, Lazzeri E. The critical role of SDF-1/CXCR4 axis in cancer and cancer stem cells metastasis. Journal of Endocrinological Investigation 2008;31(9):809-819.
73. Ben-Baruch A. Organ selectivity in metastasis: regulation by chemokines and their receptors. Clinical & experimental metastasis 2008;25(4):345-356.
74. Li Y, Rogoff HA, Keates S, Gao Y, Murikipudi S, Mikule K, Leggett D, Li W, Pardee AB, Li CJ. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proceedings of the National Academy of Sciences 2015;112(6):1839-1844.
75. Lu H, Clauser KR, Tam WL, Fröse J, Ye X, Eaton EN, Reinhardt F, Donnenberg VS, Bhargava R, Carr SA and others. A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nature cell biology 2014;16(11):1105-1117.
76. Gwak J, Jang M, Kim D, Seo A, Park S. Prognostic Value of Tumor-Associated Macrophages According to Histologic Locations and Hormone Receptor Status in Breast Cancer. PLOS ONE 2015;10(4).
77. Shimura S, Yang G, Ebara S, Wheeler TM, Frolov A, Thompson TC. Reduced Infiltration of Tumor-associated Macrophages in Human Prostate Cancer: Association with Cancer Progression. Cancer Research 2000;60(20):5857-5861.
78. Zhang BC, Gao J, Wang J, Rao ZG, Wang BC, Gao JF. Tumor-associated macrophages infiltration is associated with peritumoral lymphangiogenesis and poor prognosis in lung adenocarcinoma. Medical Oncology 2011;28(4):1447-1452.
79. Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, Brown MJ. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. The Journal of clinical investigation 2010;120(3):694-705.
80. Riihijärvi S, Fiskvik I, Taskinen M, Vajavaara H, Tikkala M, Yri O, Karjalainen-Lindsberg M-L, Delabie J, Smeland E, Holte H and others. Prognostic influence of macrophages in patients with diffuse large B-cell lymphoma: a correlative study from a Nordic phase II trial. Haematologica 2015;100(2):238-245.
81. Zhang Q-w, Liu L, Gong C-y, Shi H-s, Zeng Y-h, Wang X-z, Zhao Y-w, Wei Y-q. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PloS one 2012;7(12).
82. Azmi AS, Bao B, Sarkar FH. Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review. Cancer metastasis reviews 2013;32(3-4):623-642.
83. Sun D, Zhuang X, Xiang X, Liu Y, Zhang S, Liu C, Barnes S, Grizzle W, Miller D, Zhang H-GG. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Molecular therapy : the journal of the American Society of Gene Therapy 2010;18(9):1606-1614.
84. Tang K, Zhang Y, Zhang H, Xu P, Liu J, Ma J, Lv M, Li D, Katirai F, Shen G-XX and others. Delivery of chemotherapeutic drugs in tumour cell-derived microparticles. Nature communications 2012;3:1282.
85. Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, Yu Y, Chow A, O'Connor ST, Chin AR and others. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer cell 2014;25(4):501-515.
86. Hoshino A, Costa-Silva B, Shen T-LL, Rodrigues G, Hashimoto A, Tesic Mark M, Molina H, Kohsaka S, Di Giannatale A, Ceder S and others. Tumour exosome integrins determine organotropic metastasis. Nature 2015;527(7578):329-335.