摘要
為克服傳統光動力療法於腫瘤內缺氧環境療效不彰及光敏感藥物對腫瘤傳遞不佳的困境，本研究利用腫瘤趨向性骨髓分化單核球作為裝載光敏感藥物Chlorin e6 (Ce6)/超順磁奈米氧化鐵微粒(superparamagnetic iron oxide nanoparticles, SPIONs)之高分子含氧氣胞的傳遞媒介，對惡性腫瘤進行藥物/氧氣傳遞。透過氣胞內裝載的氧氣，促進腫瘤內活性氧自由基(reactive oxygen species, ROS)的轉化，提高光動力療效，並搭配磁熱(hyperthermia)治療，提升腫瘤缺氧區域的治療效率。本研究所開發的微米氣胞以含脂質共聚合高分子poly(acrylic acid-co-distearin acrylate) (poly(AAc-co-DSA))為主要材料，透過高分子於水相中自組裝的特性，形成具備緻密殼層的高分子膠囊，可以有效的裝載氧氣、光敏藥物及SPIONs。體外(in vitro)的細胞實驗結果顯示，裝載高分子含氧氣胞的單核球仍能維持良好的細胞活性(cell viability > 90%)及遷移能力(為未裝載氣胞之單核球的75%)，當與癌細胞共培養時，則能透過光動力及磁熱效應的複合療法，大幅抑制癌細胞生長。透過動物腫瘤模型評估，靜脈注射Ce6分子無法有效的累積在腫瘤區域，載藥單核球展現出優異的腫瘤靶向性與累積能力。腫瘤抑制的結果則顯示注射裝載微米氣胞之單核球的組別經光動力及磁熱複合療法後，能大幅抑制腫瘤生長(Tumor Growth Inhibition (TGI%) is ca 64.7%)。腫瘤切片的免疫螢光染色影像則進一步證實，單核球能有效將微米氣胞傳遞至腫瘤內甚至是腫瘤缺氧區域，經複合治療後，則能對該區域進行有效治療。綜合上述，本研究不僅成功的開發出以骨髓分化單核球為氧氣、光敏感藥物和SPIONs傳輸媒介的傳遞系統，更透過光動力/磁熱複合療法，對腫瘤生長抑制展現出絕佳的療效，並克服了傳統光動力療法對腫瘤缺氧環境療效不彰的缺憾。

Abstract
Tumor-homing bone marrow-derived monocytes were utilized as a cell-based vehicle to deliver chlorin e6 (Ce6)/superparamagnetic iron oxide nanoparticles (SPIONs)-loaded oxygen microbubbles to the hypoxia regions of malignant tumors for improving therapeutic efficacy of the combined hyperthermia and photodynamic therapy (PDT). The polymeric membranes of the oxygen microbubbles were mainly composed of poly(acrylic acid-co-distearin acrylate) (poly(AAc-co-DSA)) and able to efficiently carry Ce6 species and SPIONs. In the absence of pertinent external triggers
the SPION/Ce6-loaded oxygen bubbles after being internalized by monocytes are found rather benign to the host, thereby allowing to retain high cell viability and migration ability with the treatment under simulated tumor microenvironments. While being co-incubated with TRAMP-C1 cells (murine prostate cancer cells) and then exposed to both high frequency magnetic field (HFMF) and NIR illumination (660 nm), the payload-containing monocytes displayed prominent performance to inhibit tumor cell proliferation. Notably, compared to only slight deposition of both free Ce6 and cargo-loaded oxygen bubbles in the tumor region of TRAMP-C1 tumor-bearing mice after i.v. injection, the tumor accumulation of SPION/Ce6-encapsulated oxygen bubbles transported via monocytes was significantly enhanced. The tumor growth of TRAMP-C1 tumor-bearing mice intravenously injected with payload-containing monocytes and then subjected to both HFMF and NIR illumination treatment was greatly inhibited. In addition, the histological examinations of tumor sections confirmed the successful cellular transport of Ce6 molecules to the tumor hypoxic regions and the pronounced in vivo cytotoxicity elicited by the NIR-triggered generation of reactive oxygen species. This work demonstrates that the cellular delivery system using tumor-tropic monocytes to carry functionalized oxygen bubbles have great potential to enhance the antitumor efficacy, particularly in hypoxia regions, by combining the hyperthermia and PDT treatment.

目錄
摘要 I
ABSTRACT II
致謝 IV
目錄 V
表目錄 X
圖目錄 XI
中英文對照表 XIV
第一章緒論 1
1.1腫瘤微環境 2
1.1.1腫瘤微環境介紹 2
1.1.2腫瘤缺氧區域 3
1.1.3腫瘤相關巨噬細胞與缺氧區 5
1.2高分子載體 7
1.3細胞載具 8
1.4光動力治療 9
1.4.1光動力治療的歷史 9
1.4.2光動力應用於癌症治療 11
1.4.2.1光動力治療的作用機制 11
1.4.2.2光動力治療對細胞的影響 12
1.4.2.3光動力治療的瓶頸 14
1.5超順磁奈米氧化鐵應用於癌症治療 15
1.6研究動機與目的 17
第二章研究材料與方法 19
2.1研究架構 19
2.2POLY(AAC-CO-DSA)的製備與特性分析 20
2.2.1單體 N-acryloxysuccinimide (NAS)之製備[51] 20
2.2.2Poly(NAS)的製備 21
2.2.3Poly(AAc-co-DSA)的製備 22
2.2.4高分子組成分析 23
2.3親水性超順磁氧化鐵奈米粒子(SUPERPARAMAGNETIC IRON OXIDE NANOPARTICLES, SPIONS)之製備 24
2.4載藥微米含氧氣胞的製備及其特性分析 25
2.4.1SPION/Ce6微米含氧氣胞的製備 25
2.4.2載藥微米氣胞結構分析 25
2.4.2.1微米液胞與氣胞粒徑分析 25
2.4.2.2微米液胞型態分析 27
2.4.3載藥微米液胞之藥物包覆效率與包覆含量測定 27
2.4.4載藥微米液胞與氣胞經高頻磁場升溫測試 27
2.4.5載藥微米氣胞氧氣釋放 28
2.4.6載藥微米氣胞單態氧生成之光化學分析 28
2.5細胞實驗 30
2.5.1細胞種類 30
2.5.2配置細胞培養液與磷酸鹽緩衝溶液 30
2.5.3細胞繼代 31
2.5.4細胞計數 31
2.5.5骨髓分化單核球 32
2.5.5.1小鼠骨髓細胞萃取 32
2.5.5.2單核球分化 32
2.5.6單核球吞噬能力分析 33
2.5.7單核球吞噬微米氣胞之雷射共軛焦顯微鏡觀察 33
2.5.8單核球吞噬微米氣胞之超音波影像分析 33
2.5.9單核球對光敏感劑(Ce6)及超順磁奈米氧化鐵 (SPIONs)的裝載 34
2.5.9.1細胞胞內SPIONs含量分析 34
2.5.9.2細胞胞內Ce6含量分析 34
2.5.10載藥微米氣胞之細胞相容性 34
2.5.10.1高分子載體毒性分析 34
2.5.10.2載藥微米氣胞與光敏感劑毒性分析 35
2.5.10.3高頻交流磁場與光照對單核球體外治療評估 35
2.5.10.4高頻交流磁場與光照對癌細胞(GFP-tagged Tramp-C1) 體外治療評估 35
2.5.11單核球遷移能力測試 36
2.6動物實驗 37
2.6.1動物體內藥物累積分佈 37
2.6.2腫瘤抑制生長評估 37
2.6.3動物活體熱影像偵測 39
2.6.4動物犧牲與腫瘤組織包埋 39
2.6.5組織切片 39
2.6.5.1腫瘤組織切片Hematoxylin and eosin (H&E)染色 39
2.6.5.2組織切片免疫螢光染色 40
第三章結果與討論 41
3.1高分子組成鑑定 41
3.2載藥微米氣胞之特性分析 43
3.2.1微米氣胞的結構分析 44
3.2.2微米氣胞內的Ce6含量分析 46
3.2.3微米氣胞的磁熱效應 46
3.2.4微米氣胞的氧氣裝載及釋放 47
3.2.4.1氣胞氧氣釋放 48
3.2.5載藥微米氣胞的單態氧生成 49
3.2.5.1單態氧之光化學分析 49
3.3細胞實驗 51
3.3.1微米氣胞對單核球之相容性 51
3.3.1.1單核球對OMBs的裝載 51
3.3.1.2 裝載SPION/Ce6-loaded OMBs之單核球的雷射共軛焦顯微鏡觀察 52
3.3.1.3 SPION/Ce6-loaded OMBs對單核球的細胞毒性分析 53
3.3.1.4裝載OMBs之單核球的超音波影像分析 54
3.3.1.5單核球內Ce6及SPIONs含量分析 55
3.3.1.6裝載SPION/Ce6-loaded OMBs之單核球體外治療評估 56
3.3.1.7裝載SPION/Ce6-loaded OMBs之單核球對癌細胞體外治療評估 57
3.3.1.8單核球遷移能力測試 59
3.4動物實驗 61
3.4.1腫瘤以原位注射給藥 61
3.4.1.1腫瘤抑制生長評估 61
3.4.1.2腫瘤組織切片觀察 62
3.4.2腫瘤以靜脈注射給藥 65
3.4.2.1動物體內藥物累積分佈 65
3.4.2.2腫瘤生長抑制評估 66
3.4.2.3動物活體熱影像偵測 69
3.4.2.4腫瘤組織切片觀察 70
3.4.2.4.1腫瘤組織切片H&E染色 70
3.4.2.4.2腫瘤壞死區域免疫螢光染色觀察 71
3.4.2.4.3腫瘤缺氧區域的治療 73
第四章結論 76
第五章參考文獻 77

[1] Dougherty TJ, Gomer CJ, Henderson BW, Jori G, Kessel D, Korbelik M, et al. Photodynamic therapy. Journal of the National Cancer Institute. 1998;90:889-905.
[2] Castano AP, Mroz P, Hamblin MR. Photodynamic therapy and anti-tumour immunity. Nature reviews Cancer. 2006;6:535-45.
[3] Ortel B, Calzavara-Pinton P. Advances in photodynamic therapy. A review. Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia. 2010;145:461-75.
[4] Danquah MK, Zhang XA, Mahato RI. Extravasation of polymeric nanomedicines across tumor vasculature. Advanced drug delivery reviews. 2011;63:623-39.
[5] Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer and Metastasis Reviews. 2007;26:225-39.
[6] Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer metastasis reviews. 2007;26:225-39.
[7] Vaupel P, Thews O, Hoeckel M. Treatment resistance of solid tumors. Med Oncol. 2001;18:243-59.
[8] Vaupel P, Mayer A, Hockel M. Tumor hypoxia and malignant progression. Methods in enzymology. 2004;381:335-54.
[9] Vaupel P, Briest S, Hockel M. Hypoxia in breast cancer: pathogenesis, characterization and biological/therapeutic implications. Wiener medizinische Wochenschrift (1946). 2002;152:334-42.
[10] Kizaka-Kondoh S, Inoue M, Harada H, Hiraoka M. Tumor hypoxia: A target for selective cancer therapy. Cancer Sci. 2003;94:1021-8.
[11] Cosse JP, Michiels C. Tumour hypoxia affects the responsiveness of cancer cells to chemotherapy and promotes cancer progression. Anti-cancer agents in medicinal chemistry. 2008;8:790-7.
[12] Bertout JA, Patel SA, Simon MC. The impact of O2 availability on human cancer. Nature reviews Cancer. 2008;8:967-75.
[13] Rees AJ. Monocyte and macrophage biology: an overview. Seminars in nephrology. 2010;30:216-33.
[14] Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nature reviews Immunology. 2008;8:958-69.
[15] Biswas SK, Sica A, Lewis CE. Plasticity of macrophage function during tumor progression: regulation by distinct molecular mechanisms. Journal of immunology. 2008;180:2011-7.
[16] Allavena P, Sica A, Solinas G, Porta C, Mantovani A. The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Critical reviews in oncology/hematology. 2008;66:1-9.
[17] Murdoch C, Giannoudis A, Lewis CE. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood. 2004;104:2224-34.
[18] Bosco MC, Reffo G, Puppo M, Varesio L. Hypoxia inhibits the expression of the CCR5 chemokine receptor in macrophages. Cellular immunology. 2004;228:1-7.
[19] Bosco MC, Puppo M, Pastorino S, Mi Z, Melillo G, Massazza S, et al. Hypoxia selectively inhibits monocyte chemoattractant protein-1 production by macrophages. Journal of immunology. 2004;172:1681-90.
[20] Colson YL, Grinstaff MW. Biologically responsive polymeric nanoparticles for drug delivery. Advanced materials (Deerfield Beach, Fla). 2012;24:3878-86.
[21] Chiu H-C, Lin Y-W, Huang Y-F, Chuang C-K, Chern C-S. Polymer Vesicles Containing Small Vesicles within Interior Aqueous Compartments and pH-Responsive Transmembrane Channels. Angewandte Chemie International Edition. 2008;47:1875-8.
[22] Huang W-C, Chiang W-H, Lin S-J, Lan Y-J, Chen H-L, Chern C-S, et al. Lipid-Containing Polymer Vesicles with pH/Ca2+-Ion-Manipulated, Size-Selective Permeability. Advanced Functional Materials. 2012;22:2267-75.
[23] Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. Journal of controlled release : official journal of the Controlled Release Society. 2000;65:271-84.
[24] Loo C, Lowery A, Halas N, West J, Drezek R. Immunotargeted nanoshells for integrated cancer imaging and therapy. Nano letters. 2005;5:709-11.
[25] Batrakova EV, Gendelman HE, Kabanov AV. Cell-mediated drug delivery. Expert opinion on drug delivery. 2011;8:415-33.
[26] Chokri M, Lopez M, Oleron C, Girard A, Martinache C, Canepa S, et al. Production of human macrophages with potent antitumor properties (MAK) by culture of monocytes in the presence of GM-CSF and 1,25-dihydroxy vitamin D3. Anticancer Res. 1992;12:2257-60.
[27] Stephan MT, Moon JJ, Um SH, Bershteyn A, Irvine DJ. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nature medicine. 2010;16:1035-41.
[28] Menon LG, Kelly K, Yang HW, Kim SK, Black PM, Carroll RS. Human bone marrow-derived mesenchymal stromal cells expressing S-TRAIL as a cellular delivery vehicle for human glioma therapy. Stem cells (Dayton, Ohio). 2009;27:2320-30.
[29] Choi MR, Stanton-Maxey KJ, Stanley JK, Levin CS, Bardhan R, Akin D, et al. A cellular Trojan Horse for delivery of therapeutic nanoparticles into tumors. Nano Lett. 2007;7:3759-65.
[30] Dolmans DEJGJ, Fukumura D, Jain RK. Photodynamic therapy for cancer. Nat Rev Cancer. 2003;3:380-7.
[31] Castano AP, Mroz P, Hamblin MR. Photodynamic therapy and anti-tumour immunity. Nat Rev Cancer. 2006;6:535-45.
[32] Mroz P, Yaroslavsky A, Kharkwal GB, Hamblin MR. Cell Death Pathways in Photodynamic Therapy of Cancer. Cancers. 2011;3:2516-39.
[33] Kessel D, Luo Y. Photodynamic therapy: a mitochondrial inducer of apoptosis. Cell death and differentiation. 1999;6:28-35.
[34] Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993;74:609-19.
[35] Cory S, Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nature reviews Cancer. 2002;2:647-56.
[36] Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science (New York, NY). 1996;274:782-4.
[37] Criollo A, Maiuri MC, Tasdemir E, Vitale I, Fiebig AA, Andrews D, et al. Regulation of autophagy by the inositol trisphosphate receptor. Cell death and differentiation. 2007;14:1029-39.
[38] Weyergang A, Berg K, Kaalhus O, Peng Q, Selbo PK. Photodynamic therapy targets the mTOR signaling network in vitro and in vivo. Molecular pharmaceutics. 2009;6:255-64.
[39] Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116:205-19.
[40] Kitsis RN, Molkentin JD. Apoptotic cell death "Nixed" by an ER-mitochondrial necrotic pathway. Proceedings of the National Academy of Sciences of the United States of America. 2010;107:9031-2.
[41] Gollnick SO, Vaughan L, Henderson BW. Generation of effective antitumor vaccines using photodynamic therapy. Cancer Res. 2002;62:1604-8.
[42] Nowis D, Makowski M, Stoklosa T, Legat M, Issat T, Golab J. Direct tumor damage mechanisms of photodynamic therapy. Acta biochimica Polonica. 2005;52:339-52.
[43] Sitnik TM, Hampton JA, Henderson BW. Reduction of tumour oxygenation during and after photodynamic therapy in vivo: effects of fluence rate. British journal of cancer. 1998;77:1386-94.
[44] Dai T, Huang YY, Hamblin MR. Photodynamic therapy for localized infections-State of the art. Photodiagnosis and photodynamic therapy. 2009;6:170-88.
[45] Jeong H, Huh M, Lee SJ, Koo H, Kwon IC, Jeong SY, et al. Photosensitizer-Conjugated Human Serum Albumin Nanoparticles for Effective Photodynamic Therapy. Theranostics. 2011;1:230-9.
[46] Lee SJ, Koo H, Lee DE, Min S, Lee S, Chen X, et al. Tumor-homing photosensitizer-conjugated glycol chitosan nanoparticles for synchronous photodynamic imaging and therapy based on cellular on/off system. Biomaterials. 2011;32:4021-9.
[47] Yin M, Li Z, Liu Z, Ren J, Yang X, Qu X. Photosensitizer-incorporated G-quadruplex DNA-functionalized magnetofluorescent nanoparticles for targeted magnetic resonance/fluorescence multimodal imaging and subsequent photodynamic therapy of cancer. Chem Commun (Camb). 2012;48:6556-8.
[48] Yoo D, Lee JH, Shin TH, Cheon J. Theranostic magnetic nanoparticles. Accounts of chemical research. 2011;44:863-74.
[49] Jordan A, Scholz R, Maier-Hauff K, van Landeghem FK, Waldoefner N, Teichgraeber U, et al. The effect of thermotherapy using magnetic nanoparticles on rat malignant glioma. Journal of neuro-oncology. 2006;78:7-14.
[50] Thomas CR, Ferris DP, Lee JH, Choi E, Cho MH, Kim ES, et al. Noninvasive remote-controlled release of drug molecules in vitro using magnetic actuation of mechanized nanoparticles. Journal of the American Chemical Society. 2010;132:10623-5.
[51] Adalsteinsson O, Lamotte A, Baddour RF, Colton CK, Pollak A, Whitesides GM. Preparation and Magnetic Filtration of Polyacrylamide Gels Containing Covalently Immobilized Proteins and a Ferrofluid. J Mol Catal. 1979;6:199-225.
[52] Sahoo Y, Goodarzi A, Swihart MT, Ohulchanskyy TY, Kaur N, Furlani EP, et al. Aqueous ferrofluid of magnetite nanoparticles: Fluorescence labeling and magnetophoretic control. The journal of physical chemistry B. 2005;109:3879-85.
[53] Cui W, Bei J, Wang S, Zhi G, Zhao Y, Zhou X, et al. Preparation and evaluation of poly(L-lactide-co-glycolide) (PLGA) microbubbles as a contrast agent for myocardial contrast echocardiography. Journal of biomedical materials research Part B, Applied biomaterials. 2005;73:171-8.
[54] Cavalli R, Bisazza A, Giustetto P, Civra A, Lembo D, Trotta G, et al. Preparation and characterization of dextran nanobubbles for oxygen delivery. International journal of pharmaceutics. 2009;381:160-5.
[55] Tegos GP, Anbe M, Yang CM, Demidova TN, Satti M, Mroz P, et al. Protease-stable polycationic photosensitizer conjugates between polyethyleneimine and chlorin(e6) for broad-spectrum antimicrobial photoinactivation. Antimicrobial agents and chemotherapy. 2006;50:1402-10.
[56] Stout RD, Jiang CC, Matta B, Tietzel I, Watkins SK, Suttles J. Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J Immunol. 2005;175:342-9.
[57] Liang CC, Park AY, Guan JL. In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nature protocols. 2007;2:329-33.
[58] Moreno-Bueno G, Peinado H, Molina P, Olmeda D, Cubillo E, Santos V, et al. The morphological and molecular features of the epithelial-to-mesenchymal transition. Nature protocols. 2009;4:1591-613.
[59] Chiu HC, Lin YW, Huang YF, Chuang CK, Chern CS. Polymer vesicles containing small vesicles within interior aqueous compartments and pH-responsive transmembrane channels. Angewandte Chemie. 2008;47:1875-8.
[60] Chiang WH, Ho VT, Chen HH, Huang WC, Huang YF, Lin SC, et al. Superparamagnetic hollow hybrid nanogels as a potential guidable vehicle system of stimuli-mediated MR imaging and multiple cancer therapeutics. Langmuir : the ACS journal of surfaces and colloids. 2013;29:6434-43.
[61] Kizaka-Kondoh S, Inoue M, Harada H, Hiraoka M. Tumor hypoxia: a target for selective cancer therapy. Cancer science. 2003;94:1021-8.
[62] Riess JG. Oxygen carriers ("blood substitutes")--raison d'etre, chemistry, and some physiology. Chemical reviews. 2001;101:2797-920.
[63] Liu K, Liu X, Zeng Q, Zhang Y, Tu L, Liu T, et al. Covalently assembled 紅色 nanoplatform for simultaneous fluorescence imaging and photodynamic therapy of cancer cells. ACS nano. 2012;6:4054-62.
[64] Kraljić I, Mohsni SE. A NEW METHOD FOR THE DETECTION OF SINGLET OXYGEN IN AQUEOUS SOLUTIONS. Photochemistry and photobiology. 1978;28:577-81.
[65] Kuznetsova NA, Gretsova NS, Yuzhakova OA, Negrimovskii VM, Kaliya OL, Luk'yanets EA. New Reagents for Determination of the Quantum Efficiency of Singlet Oxygen Generation in Aqueous Media. Russian Journal of General Chemistry. 2001;71:36-41.
[66] Aderem A, Underhill DM. Mechanisms of phagocytosis in macrophages. Annual review of immunology. 1999;17:593-623.
[67] Kawaguchi H, Koiwai N, Ohtsuka Y, Miyamoto M, Sasakawa S. Phagocytosis of latex particles by leucocytes. I. Dependence of phagocytosis on the size and surface potential of particles. Biomaterials. 1986;7:61-6.
[68] Champion JA, Walker A, Mitragotri S. Role of particle size in phagocytosis of polymeric microspheres. Pharmaceutical research. 2008;25:1815-21.
[69] Pegaz B, Debefve E, Borle F, Ballini JP, Wagnieres G, Spaniol S, et al. Preclinical evaluation of a novel water-soluble chlorin E6 derivative (BLC 1010) as photosensitizer for the closure of the neovessels. Photochemistry and photobiology. 2005;81:1505-10.
[70] Sengee GI, Badraa N, Shim YK. Synthesis and biological evaluation of new imidazolium and piperazinium salts of pyropheophorbide-a for photodynamic cancer therapy. International journal of molecular sciences. 2008;9:1407-15.
[71] Yoon I, Li JZ, Shim YK. Advance in photosensitizers and light delivery for photodynamic therapy. Clinical endoscopy. 2013;46:7-23.
[72] Halter M, Tona A, Bhadriraju K, Plant AL, Elliott JT. Automated live cell imaging of green fluorescent protein degradation in individual fibroblasts. Cytometry Part A : the journal of the International Society for Analytical Cytology. 2007;71:827-34.
[73] Onodera S, Suzuki K, Matsuno T, Kaneda K, Takagi M, Nishihira J. Macrophage migration inhibitory factor induces phagocytosis of foreign particles by macrophages in autocrine and paracrine fashion. Immunology. 1997;92:131-7.
[74] Henderson BW, Fingar VH. Oxygen limitation of direct tumor cell kill during photodynamic treatment of a murine tumor model. Photochemistry and photobiology. 1989;49:299-304.
[75] Tromberg BJ, Orenstein A, Kimel S, Barker SJ, Hyatt J, Nelson JS, et al. In vivo tumor oxygen tension measurements for the evaluation of the efficiency of photodynamic therapy. Photochemistry and photobiology. 1990;52:375-85.
[76] Park SY, Baik HJ, Oh YT, Oh KT, Youn YS, Lee ES. A Smart Polysaccharide/Drug Conjugate for Photodynamic Therapy. Angewandte Chemie International Edition. 2011;50:1644-7.
[77] Kostenich GA, Zhuravkin IN, Zhavrid EA. Experimental grounds for using chlorin e6 in the photodynamic therapy of malignant tumors. Journal of photochemistry and photobiology B, Biology. 1994;22:211-7.
[78] Gurinovich GP, Zorina TE, Melnov SB, Melnova NI, Gurinovich IF, Grubina LA, et al. Photodynamic activity of chlorin e6 and chlorin e6 ethylenediamide in vitro and in vivo. Journal of photochemistry and photobiology B, Biology. 1992;13:51-7.