研製包覆靛氰綠與喜樹鹼之 HER2 標靶全氟碳雙層奈米乳劑 用於乳癌光/化學治療之研究

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陳俊儒(Chun-Ju Chen) 查詢紙本館藏

畢業系所

生醫科學與工程學系

論文名稱

研製包覆靛氰綠與喜樹鹼之 HER2 標靶全氟碳雙層奈米乳劑用於乳癌光/化學治療之研究
(Development of HER2 Target Indocyanine Green- Camptothecin-Encapsulated Perfluorocarbon Double- Nanoagentsfor Photochemotherapy of Breast Cancer)

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至系統瀏覽論文 (2026-9-13以後開放)

摘要(中)

乳腺癌是女性中發生率最高的癌症。一般而言，由於乳腺癌具有侵襲性強、預後差、復發率高…等特性，早期發現並結合標靶治療以及化療，是可以有效地降低復發的風險，然而抗癌藥物引起的副作用嚴重干擾了患者的生理狀況，甚至可能因此對治療效果產生不利影響。因此我們的目標是通過標靶治療實現對乳腺癌的有效治療，並且可以減少化療藥物的使用。在本次研究中，我們開發了一種包覆靛氰綠(ICG)與喜樹鹼(CPT)之HER2標靶全氟碳雙層奈米乳劑(HER2 target ICG-CPT-encapsulated perfluorocarbon double-nanoagents; HICPDNAs)，可以在光照下同時提供化療以及光療。根據奈米粒徑及介面電位量測儀的分析結果，HICPDNAs 的粒徑和表面電位分別為 268.6 ± 20 nm 和 -25.7 ± 5 mV。ICG和CPT的包覆率分別為 97.842 ± 1.540% 和 46.400 ± 5.780%。與游離的ICG水溶液相比，在近紅外光(NIR)照射下（808 nm, 6 W/cm2），HICPDNAs表現出與游離的ICG水溶液相似的熱療效果，但是卻能夠顯著性地增加單態氧的生成量，顯示出HICPDNAs在光熱和光動力治療應用中具有十足的潛力。在體外細胞實驗中，HICPDNAs表現出了與兩種HER2陽性乳癌細胞的專一性(MDA-MB-453以及BT-474)，並且在細胞毒性的試驗中，也表現出比游離的CPT溶液更好的毒殺效果。在動物試驗中，包覆ICG與CPT之全氟碳雙層奈米乳劑(ICG- CPT-encapsulated perfluorocarbon double-nanoagents; ICPDNAs)表現出比游離的CPT溶液以及僅包埋ICG之奈米粒子(ICG-encapsulated perfluorocarbon double-nanoagents; IPDNAs)組別更好的腫瘤抑制效果，並且對於其他重要的臟器並沒有造成嚴重之傷害。在本次的研究中，我們證明了ICPDNAs對於乳癌之治療是有效的，並且在動物體中也擁有足夠之安全性，顯示出ICPDNAs有望在未來有更進一步的發展。

摘要(英)

Breast cancer is the most diagnosed cancer in women. In general, patients with breast cancer have high aggression, poor prognosis, and high recurrence rate. Based on the previous research efforts, treatment by early detection with target chemotherapy may effectively reduce the risk of recurrence. However, anticancer drug-induced side effects seriously interfere the physiological conditions of the patients and may adversely affect the therapeutic efficacy consequently. Therefore, we aim to achieve effective treatment for breast cancer through a target therapy with reduced the use of chemo-drugs. In this study, we have developed a type of HER2 target indocyanine green (ICG)-camptothecin (CPT)-encapsulated perfluorocarbon double-nanoagents (HICPDNAs) that may provide both chemotherapy and phototherapy upon light illumination. Through DLS analysis, the size and zeta potential of the HICPDNAs is about 2268.6 ± 20 nm and -25.7 ± 5 mV, respectively. The encapsulation efficiency for ICG and CPT is 97.842 ± 1.540% and 46.400 ± 5.780%, respectively. In comparison to freely dissolved ICG, the HICPDNAs with equal dose of ICG under near infrared (NIR) irradiation (808 nm, 6 W/cm2) can generate similar hyperthermia effect but significantly enhanced amount of singlet oxygen, showing a high potential for use in photothermal and photodynamic therapeutic applications. In the in vitro cell experiment, HICPDNAs showed specificity with two HER2-positive breast cancer cells (MDA-MB-453 and BT-474)，and in the cytotoxicity test, it also showed a better toxic effect than the free CPT solution. In the animal experiments, ICG-CPT-encapsulated perfluorocarbon double-nanoagents (ICPDNAs) showed better tumor suppression effects than the free CPT solution and ICG particles groups (ICG-encapsulated perfluorocarbon double-nanoagents; IPDNAs). ICPDNAs also didn’t cause serious damage to other important organs in the animal experiments. In this study, we have proved that ICPDNAs are effective in the treatment of breast cancer and have sufficient safety in animals, showing that ICPDNAs is expected to have further development in the future.

關鍵字(中)

★ 乳腺癌
★ HER2
★ 靛氰綠
★ 喜樹鹼
★ 全氟化合物
★ 奈米試劑
★ 光化學療法

關鍵字(英)

論文目次

第一章緒論...........1
1-1研究背景...........1
1-2研究目的...........3
第二章文獻探討...........4
2-1乳癌介紹...........4
2-1-1乳癌之分期...........4
2-1-2乳癌之亞型...........6
2-1-3乳癌之治療方式...........8
2-2光療介紹...........11
2-3藥品介紹...........16
2-3-1靛氰綠...........16
2-3-2喜樹鹼...........18
2-3-3全氟化合物...........20
第三章實驗材料及步驟...........22
3-1實驗藥品及儀器設備...........22
3-1-1實驗藥品...........22
3-1-2儀器設備...........24
3-2實驗流程...........25
3-3全氟碳雙層奈米乳劑之製備...........26
3-3-1 Pluronic F-68 之尾端羧基修飾...........26
3-3-2製備包覆靛青綠(ICG)以及喜樹鹼(CPT)之全氟炭雙層奈米乳劑...........26
3-3-3表面修飾第二型人類表皮生長因子接受體(HER2)單株抗體...........28
3-4 HICPDNAs之基礎物理性質試驗...........30
3-4-1包覆率分析...........30
3-4-2載藥率分析...........30
3-4-3粒徑分析...........31
3-4-4表面電位分析...........31
3-4-5 HICPDNAs表面修飾抗體試驗...........31
3-5 HICPDNAs之光治療效果試驗...........32
3-5-1升溫效果試驗...........32
3-5-2單態氧生成效果試驗...........32
3-6 HICPDNAs之體外細胞試驗...........33
3-6-1細胞培養...........33
3-6-2 HICPDNAs表面修飾抗體之專一性試驗...........33
3-6-3 HICPDNAs之體外細胞毒性試驗...........34
3-7 動物實驗...........35
3-7-1動物實驗流程...........35
3-7-2 ICPDNAs之體內細胞毒性試驗...........36
3-7-3 生化及血球數分析...........37
3-7-4 ICPDNAs之CPT殘藥量試驗...........37
3-7-5 器官之組織學分析...........37
第四章實驗結果與討論...........39
4-1 HICPDNAs之基礎物理性質試驗...........39
4-1-1 HICPDNAs之外觀觀察...........39
4-1-2 HICPDNAs之包覆率以及載藥率...........40
4-1-3 HICPDNAs之粒徑以及表面電位...........40
4-1-4 HICPDNAs之表面修飾抗體分析...........41
4-2 HICPDNAs之光治療效果試驗...........43
4-2-1 HICPDNAs之升溫效果試驗...........43
4-2-1 HICPDNAs之單態氧生成效果試驗...........45
4-3 HICPDNAs之體外細胞試驗...........46
4-3-1 HICPDNAs表面修飾抗體之專一性試驗...........46
4-3-2 HICPDNAs之體外細胞毒性試驗...........47
4-4 動物實驗...........50
4-4-1 ICPDNAs之體內細胞毒性試驗...........50
4-4-2 生化及血球數分析...........52
4-4-3 ICPDNAs之CPT殘藥量試驗...........55
4-4-4 器官之組織學分析...........56
第五章結論與未來展望...........57
參考文獻...........59

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指導教授

李宇翔(Yu-Hsiang Lee)

審核日期

2021-9-14

推文