TWI461203B - 腫瘤血管栓塞劑以及金奈米粒子之用途 - Google Patents
腫瘤血管栓塞劑以及金奈米粒子之用途 Download PDFInfo
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Description
本發明係有關於一種腫瘤血管栓塞劑，且特別是有關於一種奈米粒子腫瘤血管栓塞劑。
頭、頸及中樞神經系統血管腫瘤栓塞術已經成為在手術治療外附加的一種重要腫瘤治療方法。這種栓塞術可以減少病發及死亡率，同時能協助移除部份腫瘤。在不能進行手術治療的腫瘤中，栓塞術可能會被用以作為主要的治療方式。阻塞通常透過血管運輸的方式進行，但亦可能會直接把栓塞物穿刺注射至腫瘤內。血管運輸的方式通常係透過微導管侵入性地穿刺進動脈(例如，鼠蹊部的股動脈、頸動脈等)後引至腫瘤位置注射栓塞物以阻塞腫瘤的血液供應。這種栓塞物可為永久或暫時性，例如，液體(乙醇、丙烯酸、Onyx)或粒子(聚乙烯醇、Gelfoam)。
金奈米粒子目前已應用於多種奈米科技如生物感測、生物影像、以及奈米級治療。在健康、診斷、以及對抗惡性疾病如癌症等生醫領域中，金奈米粒子扮演重要的角色。金奈米粒子具有小尺寸以及在腫瘤部位滲透及停留作用增強等性質，可選擇性地凝聚於癌組織中，因此適合作為藥物傳輸載體或放射治療增強劑。
目前仍需一種新的血管栓塞劑，其對腫瘤具有專一性並阻斷腫瘤血管以達到抑制腫瘤生長，且可達到即時監測的效果。
本發明提供一種腫瘤血管栓塞劑，其包括：未經修飾之金奈米粒子；以及一藥學上可接受之介質。
本發明另提供一種金奈米粒子之用途，其係用於製備腫瘤血管栓塞劑，其中前述腫瘤血管栓塞劑用於投予至一生物體內，以累積於前述生物體中之一腫瘤處並栓塞前述腫瘤之血管。
第1圖為將金奈米粒子以動脈注射進小鼠體內後，金奈米粒子累積並栓塞於腫瘤血管之X光圖(曝光時間為100毫秒)，圓圈處為腫瘤之範圍。
以下說明本發明實施例之製作與使用。然而，可輕易了解本發明實施例提供許多合適的發明概念而可實施於廣泛的各種特定背景。所揭示的特定實施例僅僅用於說明以特定方法製作及使用本發明，並非用以侷限本發明的範圍。
本發明主要係將未經修飾之金奈米粒子作為腫瘤血管栓塞劑注射至生物體內之腫瘤之血管中，並且以一X光源照射上述生物體，使高吸收對比的金奈米粒子累積並栓塞於腫瘤血管，再利用此金奈米粒子的X光顯影來觀察腫瘤的情形。
上述的X光源可包括一同步輻射X光源、醫用X光源、或實驗用X光源。在一些實施例中，X光源可包括一同步輻射X光源。在一實施例中，同步輻射X光源之波長約介於700-850 nm，其能量約介於4 keV-20 MeV之間，可克服光子在生物體內穿透性不足的問題，得以有效激發投予至生物體內之奈米粒子。此外，由於X光源劑量足夠，其照射上述生物體的時間可小於約1秒，較佳小於約200毫秒，且上述X光源照射該生物體的可穿透之有效深度約為表面至組織深層30 cm。由於本發明所採用之X光源在活體組織中具有穿透性，因此可透過本發明之X光顯影技術即時監測活體組織內的腫瘤細胞，毋須根據傳統醫學影像的處理方式自活體採樣切片。
本發明適用於阻斷生物體內的腫瘤之血管。在一實施例中，生物體包括：哺乳類、鳥類、兩棲類、爬蟲類、魚類、昆蟲類、或其他合宜之多細胞動物。
在一些實施例中，上述腫瘤之種類可包括但不限於，上皮細胞腫瘤、腦部腫瘤、黑色素腫瘤、淋巴腫瘤、漿細胞瘤、肉瘤、神經膠質瘤、以及胸腺瘤；或位於口腔、食道、消化系統、呼吸系統、骨骼、關節、軟組織、皮膚、乳房、生殖系統、泌尿系統、眼與眼眶、腦部與其他神經系統、內分泌系統、淋巴、或骨髓等之腫瘤。
在一實施例中，將未經修飾之金奈米粒子投予生物體內腫瘤的方法可包括，但不限於：靜脈注射、動脈注射、動脈注射、淋巴注射、或局部器官注射。在一實施例中，上述奈米粒子係注射至腫瘤上游動脈中。
在一些實施例中，金奈米粒子係未經修飾的。在一實施例中．本發明所使用之金奈米粒子係以同步輻射方法生長的，其包括提供含有金離子之前驅物溶液，例如金氯酸(HAuCl4
．3H2
O)溶液，並將此前驅物溶液的pH值調整至鹼性以避免凝聚以及尺寸不均的現象，約pH8-11左右，再利用同步輻射X射線照射此前驅物溶液(例如：BL01A儲存環中4-30 keV之X射線)，以將前驅物轉化為金奈米粒子，其中金奈米粒子的尺寸可根據照射時間調整，照射時間越長可得尺寸較小的金奈米粒子。在一些實施例中，金奈米粒子係介於1 nm-100 μm之間，較佳為1-50nm之間，相對較為惰性且大致上無毒，對生物體係無害的。
在一些實施例中．金奈米粒子可與一藥學上可接受之介質結合，例如可包括溶劑、分散液、或等滲劑(isotonic agent)等。在一些實施例中，藥學上可接受之介質可包括，水、生理食鹽水、糖、膠體、多孔基質、防腐劑等，或前述之組合。在一些實施例中，藥學上可接受之介質為水。在一實施例中，金奈米粒子之濃度可介於1-1000 mg/ml，較佳為1-300 mg/ml之間，例如約190 mg/ml，以及其注射劑量係介於0.0001-100 g/kg，較佳為0.0001-2 g/kg，例如約0.19 g/kg。
本實驗所使用的小鼠皆由Academia Sinica Institutional Animal Care and Utilization Committee(AS IACUC)所代為飼養之BALB/c小鼠(購自國家實驗動物中心，台灣)，其飼養條件為：每5隻小鼠飼養於一籠子中，維持環境於溫度24±2℃，溼度
40%-70%下，每12小時日夜交替一次。
4-5周之小鼠以10 μl的Zoletil 50(50 mg/kg；Virbac Laboratories,Carros,France)於肌肉注射麻醉，將PE-08導管穿刺於小鼠(體重約~20-25g)頸動脈。接著以上述PE-08導管(PE-08 catheters，BB31695,Scientific Commodities,Inc.,I.D.：0.2 mm,O.D.：0.36 mm)將上述含有奈米金的顯影劑取1000 μl,50 mM從頸動脈(femoral artery)注入小鼠體內晚期腫瘤(late-stage tumor，16天)，其中各組顯影劑注入的速度為1 μl/s。在顯影過程中，小鼠皆維持在被含有1% isoflurene(麻醉氣體)之氧氣(1% isoflurene in oxygen)麻醉的情況下。影像為自頸動脈注射進入小鼠體內5分鐘後之X光影像、其曝光時間為100毫秒，同步輻射X光源之波長約介於700-850 nm，其能量約介於4 keV-20 MeV之間，劑量小於約100 Gy。結果如第1圖，其顯示小鼠體內腫瘤血管之X光影像，金奈米粒子累積並栓塞腫瘤血管。
雖然本發明已以較佳實施例揭露如上，然其並非用以限定本發明，任何所屬技術領域中具有通常知識者，在不脫離本發明之精神和範圍內，當可作更動、替代與潤飾。舉例來說，任何所屬技術領域中具有通常知識者可輕易理解此處所述的許多特徵、功能、製程及材料可在本發明的範圍內作更動。
Claims (13)
- 一種腫瘤血管栓塞劑，包括：未經修飾之金奈米粒子；以及一藥學上可接受之介質。
- 如申請專利範圍第1項所述之腫瘤血管栓塞劑，其中該腫瘤血管栓塞劑係注射進一生物體之腫瘤動脈中。
- 如申請專利範圍第2項所述之腫瘤血管栓塞劑，其中該生物體包括：哺乳類、鳥類、兩棲類、爬蟲類、魚類、昆蟲類、或其他合宜之多細胞動物。
- 如申請專利範圍第1項所述之腫瘤血管栓塞劑，其中該腫瘤包括上皮細胞腫瘤、腦部腫瘤、黑色素腫瘤、淋巴腫瘤、漿細胞瘤、肉瘤、神經膠質瘤、胸腺瘤，或位於口腔、食道、消化系統、呼吸系統、骨骼、關節、軟組織、皮膚、乳房、生殖系統、泌尿系統、眼與眼眶、腦部與其他神經系統、內分泌系統、淋巴、以及骨髓之腫瘤。
- 如申請專利範圍第1項所述之腫瘤血管栓塞劑，其中該奈米粒子之直徑係介於1 nm-100 μm。
- 如申請專利範圍第1項所述之腫瘤血管栓塞劑，其中該藥學上可接受之介質包括溶劑、分散液、或等滲劑。
- 一種金奈米粒子之用途，其係用於製備腫瘤血管栓塞劑，其中該腫瘤血管栓塞劑用於投予至一生物體內，以累積於該生物體中之一腫瘤處並栓塞該腫瘤之血管。
- 如申請專利範圍第7項所述金奈米粒子之用途，其中更包括以一X光源照射該生物體之該腫瘤處，以即時監測該腫瘤栓塞劑於該生物體之該腫瘤處的情形。
- 如申請專利範圍第8項所述之金奈米粒子之用途，其中該X光源包括一同步輻射X光源、醫用X光源、或實驗用X光源。
- 如申請專利範圍第8項所述之金奈米粒子之用途，其中該X光源的劑量小於約100 Gy。
- 如申請專利範圍第8項所述之金奈米粒子之用途，其中該X光源的劑量介於約1-30 Gy之間。
- 如申請專利範圍第8項所述之金奈米粒子之用途，其中該X光源照射該生物體的時間約小於1分鐘。
- 如申請專利範圍第8項所述之金奈米粒子之用途，其中該X光源照射該生物體的時間約小於200毫秒。
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| TW102123932A TWI461203B (zh) | 2013-07-04 | 2013-07-04 | 腫瘤血管栓塞劑以及金奈米粒子之用途 |
| CN201410317077.1A CN104274841A (zh) | 2013-07-04 | 2014-07-04 | 肿瘤血管栓塞剂以及金纳米粒子的用途 |
| US14/324,183 US20150011818A1 (en) | 2013-07-04 | 2014-07-05 | Tumor vessel embolizing agent and method of embolizing tumor vessel |
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| TW102123932A TWI461203B (zh) | 2013-07-04 | 2013-07-04 | 腫瘤血管栓塞劑以及金奈米粒子之用途 |
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| WO2000006244A2 (en) * | 1998-07-30 | 2000-02-10 | Hainfeld James F | Loading metal particles into cell membrane vesicles and metal particle use for imaging and therapy |
| EP2242539B1 (en) * | 2008-01-16 | 2015-04-01 | Nanospectra Biosciences, Inc. | Nanoparticles for focused hyperthermia to increase efficacy of radiation therapy |
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| Neurology,Vol.2(64),17 Oct. 2001 * |
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| CN104274841A (zh) | 2015-01-14 |
| TW201501715A (zh) | 2015-01-16 |
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