臺灣博碩士論文加值系統

轉移為癌症嚴重性重要指標，因 90 ％癌症死亡與癌症轉移有相關性。於口腔癌病例中，約50 ％的轉移行口腔癌病患，在5年內預後生存率下降約30 ％。因此本次研究，計畫模擬口腔癌轉移，因此將6.3×105個SAS-G418細胞接種到裸鼠的舌頭上，建立模擬原位轉移性口腔癌模型。並在SAS-G418細胞接種後第7天，觀察到宮頸區域包括淺表型頸淋巴結（SCL），深部頸淋巴結（DCL）和頜下腺（SG），是否有近端轉移發生。建立的轉移模型目的為評估脂質 - 氯化鉑納米顆粒（LPC NP），是否對原位轉移性口腔癌模型有達到治療效果。於本次實驗所採用的LPC NPs粒徑為23.8±1.2 nm，LPC NPs外圍接上標靶物質氨基乙基茴香酰胺(aminoethyl anisamide)，目的靶向的SAS細胞模表面所過度表達的sigma 受體。 在本次研究中，預合成 LPC NP的CDDP前趨物產率為91.6±6.7 wt％，LPC NPs的CDDP包封率和藥物載量％分別為2.4±0.1wt％和89.14±8.91wt％。體外細胞存活率顯示，LPC NPs與CDDP相比顯著誘導細胞死亡（p <0.05），IC50數據顯示對於口腔癌細胞珠LPC NP 比CDDP 有效治療2.4~2.8倍(SAS: IC50 7±1.7μM LPC，17±1.7μM CDDP；SCC4 IC50: 5±4.6μM LPC，14±1.7μM CDDP)。
使用Kaplan-Meier生存分析，LPC_AEAA(-) 和LPC_AEAA（+）與CDDP或PBS組相比，顯示與動物存活率有顯著性差異（P <0.001）。然而LPC_AEAA(-) 組與LPC_AEAA（+）組相比，動物存活率無顯著性差異（P> 0.05），PBS組與CDDP組相比無統計學意義（P> 0.05）。此外與PBS（19天），CDDP（22天）相比，LPC_AEAA（-）和LPC_AEAA（+）的動物存活平均值顯著延長 (P<0.001），其中LPC_AEAA（-）和LPC_AEAA（-）分別為80天和89天。 LPC治療組在細胞增殖（Ki-67），腫瘤微血管（CD31），DNA損傷（TP53）和凋亡（切割的半胱天冬酶-3和TUNEL測定）標記物的IHC分析中顯示出顯著差異（P <0.001）。在LPC處理組中，總P53的蛋白質水平和P53對絲氨酸15的磷酸化在單個小鼠上變化。此外與CDDP或PBS組相比，LPC_AEAA（-） （P <0.05）和LPC_AEAA（+）（P <0.001），觀察到cleaved caspase-3蛋白水平的顯著誘導。
LPC NPs治療組肝、腎、肌肉功能各項指標差異無統計學意義（P>0.05），但CDDP組在肝臟（天冬氨酸氨基轉移酶，AST）表達差異有統計學意義（P <0.05），腎臟（血尿素氮，BUN）和肌肉（乳酸脫氫酶，LDH）功能。結果表明，LPC NPs與CDDP相比具有最小的副作用。通過酶聯免疫吸附測定（ELISA）檢測細胞因子炎症因子（IL-6，IL-12和INF-γ）的活化無差異（P> 0.05）。總體而言，我們證明LPC NPs可以大大提高順鉑的抗癌作用，延長動物存活率，可能是治療晚期HOSCC的潛在抗轉移藥物。

Metastasis is one hallmark of cancers responsible for 90% of cancer-related deaths. In oral cancer, ~50% of metastases have found at the prognosis declining ~30% of the 5-year survival rate. In this study, orthotopic metastatic oral cancer model was established by inoculation 6.3 x 105 SAS-G418 cells onto tongue of nude mice. The metastasis was observed to cervical area including superficial cervical lymph node (SCL), deep cervical lymph node (DCL) and submandibular gland (SG) on day 7 post SAS-G418 cells inoculation. The established metastasis model allowed to further therapeutic evaluation of lipid-platinum-chloride nanoparticles (LPC NPs). The measured LPC NPs size was 23.8±1.2nm and enhanced with outer leaflet of aminoethyl anisamide, a ligand of overexpressed sigma receptor on the surface of SAS cells for targeted therapy. The %yield of CDDP precursor was 91.6±6.7wt%, but the %encapsulation efficiency and %drug loading of LPC NPs were 2.4±0.1wt% and 89.14±8.91wt%, respectively. In vitro cell viability showed that LPC NPs significantly induced cell death (p<0.05) and promoted 2.4 or 2.8 folds stronger to reach IC50 on SAS (7±1.7µM LPC, 17±1.7µM CDDP) and SCC4 (5±4.6µM LPC, 14±1.7µM CDDP) cells, respectively.
LPC_AEAA(-) and LPC_AEAA(+) showed a significant difference (P<0.001) in animal survival rate analyzed using Kaplan-Meier survival analysis compared to CDDP or PBS group. However, LPC_AEAA(-) group showed no significant difference (P>0.05) in animal survival rate compared to LPC_AEAA(+) group and so did PBS group compared to CDDP group. In addition, the average of animal survival in LPC_AEAA(-) and LPC_AEAA(+) were significantly prolonged (P<0.001) compared to PBS (19 days), CDDP (22 days), where animal survival days for LPC_AEAA(-) and LPC_AEAA(-) were 80 and 89 days, respectively. LPC-treated groups showed significantly different (P<0.001) on IHC analysis against cell proliferation (Ki-67), tumor microvessel (CD31), DNA damage (TP53), and apoptosis (cleaved caspase-3 and TUNEL assay) markers. The protein levels of total P53 and phosphorylation of P53 on serine 15 enhanced on LPC-treated groups but varied on individual mouse. In addition, a significant induction of cleaved caspas-3 protein level was observed on LPC_AEAA(-) (P<0.05) and LPC_AEAA(+) (P<0.001) compared to CDDP or PBS group.
LPC NPs-treated groups showed no difference (P>0.05) in all parameters of liver, kidney, and muscle functions compared to PBS group, but CDDP group showed significant difference (P<0.05) on some markers including liver (aspartate aminotransferase, AST), kidney (blood urea nitrogen, BUN) and muscle (lactate dehydrogenase, LDH) functions. Results suggest that LPC NPs served minimum side effects compared to CDDP. No difference (P>0.05) activation of cytokines inflammatory factors (IL-6, IL-12 and INF-γ) were detected by enzyme-linked immunosorbent assay (ELISA). Overall, we demonstrated that LPC NPs highly improved the anticancer effect of cisplatin, prolonged animal survival rate, and could be a potential antimetastatic drug for treatment against advanced HOSCC

Table of Contents
摘要 I
Abstract III
Acknowledgments V
Table of Contents VII
List of Figures X
List of Tables XII
List of abbreviations XIII
Chapter I Introduction 1
1.1 Objectives 3
Chapter II Research Outline 4
2.1 Experimental Design 4
Chapter III Literature Reviews 5
3.1 Introduction of Oral and Oropharyngeal Cancer 5
3.1.2 Carcinogenesis of Oral and Oropharyngeal Cancer 7
3.2 Mechanism of Metastases 9
3.2.1 Metastasis of Oral Cancer 16
3.2.2 Animal Model in Head and Neck Cancer 17
3.2.2.1 Carcinogen Induced Model 17
3.2.2.2 Transgenic Model 17
3.2.2.3 Orthotopic Metastasis Animal Model 18
3.2.3 Monitoring Tumor Growth In Vivo using Imaging Technologies 21
3.2.3.1 Bioluminescence Imaging (BLI) 21
3.3 Cancer Therapy 22
3.3.1 Chemotherapy 22
3.3.1.1 Cisplatin (cis-diamminedichloroplatinum(II), CDDP) 23
3.3.1.2 Liposome Technology Development 26
3.3.2.1 Lipid Platinum Chloride Nanoparticles (LPC NPs) 34
3.3.2.2 Sigma Receptor and Aminoethyl Anisamide for Targeted Therapy 36
Chapter IV Methodology 43
4.1 Cell cultures 43
4.1.1 SAS or SCC4 Stable Clones Establishment 43
4.1.2 SAS or SCC4 cell viability assay 44
4.2 Syntheses of Lipid Platinum Chloride Nanoparticles (LPC NPs) 44
4.2.1 Synthesis of CDDP Precursor 44
4.2.2 Synthesis of CDDP NPs or LPC NPs 44
4.2.3 Optimization the Encapsulation Efficiency (EE) of CDDP in LPC NPs 45
4.2.4 Characterization of CDDP NPs or LPC NPs 45
4.2.5 Drug Loading Measurement 46
4.3 Animal Study 46
4.3.1 Animal Strain 46
4.3.1.1 Establishment of Orthotopic Metastatic Oral Cancer 46
4.3.1.2 Pilot Study of Starting Time Point of Metastasis Condition 47
4.3.1.3 In vivo Study Design and Treatment Protocol 47
4.3.1.2 Bioluminescence Imaging (BLI) 48
4.3.2 Histoathologycal Assay for Metastases Confirmation 48
4.3.2.1 Hematoxylin and Eosin Staining 48
4.3.2.2 Cytokeratin-5 Immunohistochemistry Staining 48
4.4. In vivo Therapeutic Effect 49
4.4.1 Preliminary Study of LPC NPs Therapeutic Effect 49
4.5 Western blot assay 51
4.5 Histology Staining Pre and Post Therapy 51
4.5.1 Hematoxylin and Eosin Staining 51
4.5.2 Ki-67 Immunohistochemistry Staining 52
4.5.3 CD31 Immunohistochemistry Staining 52
4.5.4 Cleaved caspase-3 Immunohistochemistry Staining 52
4.5.6 TUNEL Assay 53
4.6 In vivo Toxicity Assay 53
4.7 Statistical Analysis 53
Chapter V Results 55
5.1 CDDP Precursor Synthesis Results 55
5.2 LPC NPs Synthesis Results 55
5.3 Optimization the Encapsulation Efficiency (EE) of CDDP in LPC NPs 56
5.4 LPC NPs Drug loading (DL) Measurement 56
5.5 Characterization of LPC NPs 57
5.6 SAS or SCC4 Stable Clones 59
5.7 In Vitro Cell Viability 59
5.7.1 MTT Assay 59
5.8 In Vivo Study 63
5.8.1 Establishment of Orthotopic Metastasis Animal Model 63
5.8.2 Validation of Metastases Condition 64
5.8.2.1 Validation of Metastasis Animal Model using IVIS 64
5.8.2.2 Validation of Metastasis Animal Model Histopathological Staining 65
5.9 In Vivo Study of LPC NPs Treatment 74
5.10 Histopathological Analysis Post Treatment 81
5.11 Immunohistochemistry (IHC) Analysis 84
5.12 Western Blot Assays 93
5.13 In Vivo Toxicity Analysis 94
Chapter VI Discussions 96
Chapter VII Conclusion 103
References 104
Appendix 1 Meeting Minutes 113


 
List of Figures
Figure 2.1 Flowchart of experimental design 4
Figure 3.1 The structure of oral cavity and oropharyngeal area 5
Figure 3.2 Models of genetic instability and progression in head and neck cancer 8
Figure 3.3 Clinical, pathological, and molecular progression of oral cancer 9
Figure 3.4 Schematic representation of metastasis model purposed by Wen et al. 10
Figure 3.5 Schematic representation of the multiple stages of metastatic 11
Figure 3.6 Hypoxia is one supportive condition for metastases 12
Figure 3.7 A collective network supporting metastatic dissemination and colonization at secondary sites 13
Figure 3.8 Metastasis arise from residual disseminated tumor cells (DTCs) 14
Figure 3.9 Angiogenesis visualized of SAS-GFP cells on othotopic mouse model 20
Figure 3.10 Orthotopic mouse model of SAS-GFP cell 20
Figure 3.11 Reaction mechanism of bioluminescence signals (BLS) 21
Figure 3.12 Chemical structure of clinically used platinum-based anticancer drugs 23
Figure 3.13 Four possible behaviour of bifunctional adducts by 24
Figure 3.14 Mechanism of cisplatin-mediated cellular effects 25
Figure 3.15 Illustration of liposome structure and the carried-able drugs moieties 27
Figure 3.16 Cellular uptake routes of nanoparticles 28
Figure 3.17 Scheme to synthesis cisplatin 34
Figure 3.18 Scheme to synthesis LPC NPs 35
Figure 3.19 In vitro and in vivo illustration of LPC NPs neighboring effect 36
Figure 3.20 Confidence of sigma receptor compartments in subcellular localization, the figure is adapted from Genecard system 38
Figure 3.21 mRNA expression of SIGMAR1 in normal human tissues 38
Figure 3.22 Proteomics protein expression of SIGMAR1 in normal 39
Figure 3.23 Sigma receptor and aminoethyl anisamide targeting ligand 40
Figure 4.1 Cell inoculation site and tumor lesion appearance of established orthotopic metastasis model 47
Figure 4.2 Tongue and salivary glands harvested from the established mouse model 47
Figure 4.3 Preliminary study design and result 50
Figure 5.1 Characterization of LPC core nanoparticles 58
Figure 5.2 Characterization of LPC nanoparticles 58
Figure 5.3 Establishment of SAS or SCC4 stable clones 59
Figure 5.4 Cell viability of SAS and SCC4 cells treated with CDDP and LPC NPs. 62
Figure 5.5 Establishment of metastasis oral cancer mouse model 65
Figure 5.6 Negative and positive control of metastasis validation 67
Figure 5.7 Histopathological staining of mouse metastatic oral cancer. 69
Figure 5.8 Histopathological staining of local invasion of metastasis condition of the established animal model. 73
Figure 5.9 Therapeutic effect of four designed treatment groups 77
Figure 5.10 In vivo imaging of treated group. 78
Figure 5.11 SCC4-G418 cells were unable to form tumor lesion at different cell amounts. 79
Figure 5.12 Survival curve and body weight of 4 treatment groups 80
Figure 5.13 Tongue and salivary glands of 4 treatment groups. 81
Figure 5.14 Observable appearance of tongue LPC NPs treated groups and CDDP side effect. 82
Figure 5.15 Hematoxylin and eosin (H&E) staining. 83
Figure 5.16 Immunohistochemistry (IHC) staining. 89
Figure 5.17 Immunohistochemistry (IHC) staining of tongue tumor and the quantifications. 91
Figure 5.18 Immunohistochemistry (IHC) stains using sigma receptor. 92
Figure 5.19 Western blot analysis. 93

 
List of Tables
Table 3.1 Cancer grading system 6
Table 3.2 The TNM staging for oral cancer 6
Table 3.3 Definition of the TNM staging adapted from 7
Table 3.4 The most common metastasis sites of head and neck cancer 16
Table 3.5 Immuno-compromised mouse strains used for xenotransplantation adapted from 18
Table 3.6 Cisplatin nanoparticle and other nanomedicines formulations on market and undergoing clinical investigation 30
Table 3.7 Potential targeting ligands used for targeted therapy 41
Table 4.1 SAS orthotopic metastatic model treatment group 51
Table 5.1 The measured concentration of platinum (Pt) or CDDP from CDDP precursor 55
Table 5.2 The measured concentration of platinum (Pt) or CDDP from LPC NPs 56
Table 5.3 Encapsulation efficiency of LPC NPs proportionally increased to KCl concentration 56
Table 5.4 The calculated drug loading of LPC NPs 57
Table 5.5 SAS or SCC4 cell viability 63
Table 5.6 Establishment of SAS-G418 or SCC4-G418 orthotopic metastasis model 64
Table 5.7 Incidence of distant metastasis to cervical lymph node from each group post treatment 75
Table 5.7 Serum levels for liver function 94
Table 5.8 Serum levels for kidney function 94
Table 5.9 Serum levels for liver and kidney function 95
Table 5.10 Serum levels for muscle function 95
Table 5.11 Enzyme-linked immunosorbent assay (ELISA) 95

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