TWI686210B - 用以誘導病變組織血管正常化的套組及其用途 - Google Patents
用以誘導病變組織血管正常化的套組及其用途 Download PDFInfo
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Abstract
本發明有關於一種帶氧微氣泡用於製備誘導病變組織血管正常化套組之用途,其中,該帶氧微氣泡包含一氧氣以及一難溶於水的氣體,且該帶氧微氣泡的粒徑為0.5~20μm;其中,該套組包括一帶氧微氣泡混合液、以及一超音波發射裝置;一有效劑量之該帶氧微氣泡係以靜脈注射進入生物體內,再使用超音波發射裝置照射該病變組織,使得該帶氧微氣泡於該病變組織處破裂而釋放氧氣。
Description
本發明係有關於一種帶氧微氣泡用於製備誘導病變組織血管正常化套組之用途,尤指一種以靜脈注射該帶氧微氣泡並於病變組織處照射超音波以刺激帶氧微氣泡於病變組織局部釋放氧氣而誘導病變組織血管正常化之套組。
腫瘤組織成長到一定程度後,必須依靠新生血管以供應其養分,故腫瘤細胞本身或周圍的結締組織會分泌許多促進血管新生的生長因子,以誘導腫瘤處形成新的血管以供應腫瘤細胞養分。然而,腫瘤內部的新生血管不正常增生,導致血管彎曲且粗細不一,血管管壁的孔隙多,血管運輸血液的功能降低。因此,即使針對腫瘤組織投藥,投予的藥物無法順利到達腫瘤組織內部,故治療效果有限。
為了增加腫瘤治療的效率,在投藥治療前,通常會投以使得腫瘤血管正常化的藥物,然而,習知的藥物通常有效期限短暫,故治療藥物真正到達腫瘤組織內部的時間有限,導致腫瘤的治療效果常因此而受限。
腫瘤的血管正常化有助於治療藥物的傳遞,故目前亟需一種可誘發血管正常化的套組,除了可誘導腫瘤組織的血管正常化,改善腫瘤組織的血管型態以及功能外,更可延長血管正常化的時間窗。
為了達到上述之目的,本發明提供了一種帶氧微氣泡用於至被誘導病變組織血管正常化套組之用途,其中,該帶氧微氣泡包含一難溶於水的氣體以及一氧氣,且該帶氧微氣泡的粒徑為0.5~20μm,而該套組包括一帶氧微氣泡混合液、以及一超音波發射裝置,一有效劑量之該帶氧微氣泡係以靜脈注射進入生物體內,再使用超音波發射裝置照射該病變組織,使得該帶氧微氣泡於該病變組織處破裂而釋放氧氣。
於一較佳實施態樣中,該帶氧微氣泡的粒徑較佳為0.7~3.0μm,其中,大於3.0μm的帶氧微氣泡占總顆數之0.5%。
於一較佳實施態樣中,該帶氧微氣泡所包含的該難溶於水的氣體與該氧氣的體積比為1:1~3:1,其中,又以1:1~1.4:1為較佳。
於一較佳實施態樣中,該帶氧微氣泡中所包含的該難溶於水的氣體係選自由一全氟丙烷(C3F8)、全氟丁烷(C4F10)、氮氣(N2)、二氧化碳(CO2)、及其混合物所組成之群組。而其中係以全氟丙烷為較佳。
於一較佳實施態樣中,該帶氧微氣泡更包含一磷脂殼層,包覆該難溶於水的氣體以及該氧氣。而其中,該磷脂殼層較佳係由
1,2-二硬脂醯-sn-甘油-3-磷酸膽鹼(1,2-Distearoyl-sn-glycero-3-phosphorylcholine;DSPC)、以及1,2-二硬脂酰-sn-甘油基-3-磷酸乙醇胺-N-[10-(三甲氧基甲矽烷基)十一酰胺(聚乙二醇-2000)(1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[10-(trimethoxysilyl)undecanamide(polyethyleneglycol)-2000];DSPE-PEG-2000)所組成。
於一較佳實施態樣中,該帶氧微氣泡的劑量為每日2.5~3.5μL/每公斤。
於一較佳實施態樣中,該超音波裝置為一高強度聚焦式超音波裝置。而於一較佳實施態樣中,該超音波發射裝置的參數為:聲壓為1.5~2.5MPa;週期為500~1500;脈衝重複頻率(pulse repetition frequency,PRF)為1~5Hz。
於一較佳實施態樣中,該病變組織為腫瘤組織、血管栓塞導致缺氧之正常組織或受損血管。
圖1係具有不同全氟丙烷:氧氣的體積比的帶氧微氣泡的粒徑分布圖。
圖2係具有不同全氟丙烷:氧氣的體積比的帶氧微氣泡的體積分布圖。
圖3係不同組別微氣泡之溶氧量變化圖。
圖4係全氟丙烷微氣泡以及帶氧微氣泡之超音波影像系統照影的影像亮度圖變化示意圖。
圖5係全氟丙烷微氣泡以及帶氧微氣泡經超音波刺激釋放氣體於腫瘤局部之灌注比例示意圖。
圖6係全氟丙烷微氣泡以及帶氧微氣泡經超音波刺激釋放氣體於腫瘤局部之腫瘤血管的密度示意圖。
圖7係不同劑量的帶氧微氣泡的對於腫瘤的血流灌注比的變化示意圖。
圖8係投以全氟丙烷微氣泡及帶氧微氣泡後第4天的PHD2、HIF-1 α、VEGF、TGF-β的表現量示意圖。
[帶氧微氣泡的製備方法]-薄膜水合法
本實施例係採用薄膜水合法製作帶氧微氣泡,以下為薄膜水合法的步驟:(1)製備磷脂薄膜:將2.5mg的1,2-二硬脂醯-sn-甘油-3-磷酸膽鹼(1,2-Distearoyl-sn-glycero-3-phosphorylcholine;DSPC)、以及1mg的1,2-二硬脂酰-sn-甘油基-3-磷酸乙醇胺-N-[10-(三甲氧基甲矽烷基)十一酰胺(聚乙二醇-2000)(1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[10-(trimethoxysilyl)undecanamide(polyethyleneglycol)-2000];DSPE-PEG-2000)加入2mL的樣品瓶中,以0.25mL的氯仿(Chloroform)作為溶劑將DSPC及DSPE-PEG-2000均勻溶解混合,並藉
由水浴法以60℃加熱1小時候抽乾氯仿,接著將樣品瓶置於減壓濃縮機中,以真空狀態下持續抽乾24小時,待有機溶劑完全除去後,會在樣品瓶的底部形成一層脂質薄膜,該樣品瓶可保存於-20℃中。(2)製備帶氧微氣泡:將磷酸鹽緩衝溶液(Phosphate buffered saline,PBS)與甘油(Glycerol)以20:0.1的體積比混合,於樣品瓶中加入0.8mL的PBS甘油溶液,藉由水浴法以60℃加熱10分鐘,並使用水浴式超音波均質機(Model 2510,Branson,NY,USA)將磷脂膜溶解並混合均勻後,以抽氣幫浦將樣品瓶內抽成真空狀態,並填充全氟丙烷(C3F8)氣體進入該樣品瓶中,接著將全氟丙烷氣體抽出後,在填充氧氣回該樣品瓶中,再使用高速震盪機(VIALMIX,Bristol-Myers Squibb Medical Imaging,NY,USA)於常溫下震盪45秒,在震盪的過程中,磷脂質分子會自組裝並包覆全氟丙烷以及氧氣以形成帶氧微氣泡。本實施例中調整樣品瓶中全氟丙烷:氧氣的氣體體積比為1:1、1.4:1、2:1、3:1、1:0,並以帶氧微氣泡的粒徑分布以及濃度來決定樣品瓶中全氟丙烷:氧氣的最佳氣體體積比。
[帶氧微氣泡的的粒徑分布與濃度]
使用粒徑分析儀(Model Multisizer 3,Beckman Coulter Inc.,CA,USA)量測上述全氟丙烷:氧氣的體積比為1:1、1.4:1、2:1、3:1、1:0所製備的帶氧微氣泡以及以全氟丙烷微氣泡作為對照組的粒徑分布及濃度、平均粒徑、以及體積分布。其平均粒徑與濃度係如以下表1所示,而粒徑與體積分布係分別如圖1及圖2所示:表1、不同氣體比例之帶氧微氣泡的平均粒徑與濃度。
由圖1及圖2可看出全氟丙烷:氧氣體積比為1:1以及3:1的帶氧微氣泡有較多大於2μm的微氣泡,且整體濃度較低,而使用1.4:1比例製作出的帶氧微氣泡,其粒徑與體積分布皆與1:0的全氟丙烷微氣泡相似(請參考表1),故以下測定以及活體實驗係使用全氟丙烷:氧氣體積比為1.4:1所製備的帶氧微氣泡來進行。
[帶氧微氣泡的溶氧量]
使用溶氧計量測帶氧微氣泡的溶氧量,分別量測去氣後的PBS、PBS+全氟丙烷+氧氣、全氟丙烷微氣泡、帶氧微氣泡(C3F8:O2=1.4:1)、經清洗的帶氧微氣泡(C3F8:O2=1.4:1)共五組。其中,PBS+全氟丙烷+氧氣係指沒有微氣泡包覆氣體的充氣水溶液,經清洗的帶氧微氣泡係指將製備好的帶氧微氣泡經過2000rcf、離心一分鐘後,將下清液置換成去氣的PBS,此組別是為了剔除PBS溶液中的溶氧量,進而推算出在帶氧微氣泡上的氧濃度。溶氧量的量測方式係將全濃的800μL的帶氧微氣泡置於20mL的樣品瓶中,將溶氧計探棒插入其中,使探棒頂端的監測器被帶氧微氣泡淹沒,量測過程中溶氧計探棒需以三軸平台固定之,待溶氧量數值穩定後亮數值穩定,紀錄各組溶氧量的變化。上述各組的溶氧量變化係如圖3所示,其中,以全氟丙烷:氧氣體積比為
1.4:1所製備的帶氧微氣泡的含氧量為8.9±0.02mg/L,相較於全氟丙烷微氣泡增加了2.07±0.14mg/L的含氧量,而比較帶氧微氣泡以及經清洗的帶氧微氣泡兩個組別的含氧量可發現,溶氧量並不會因為置換PBS而有顯著的改變(p>0.05),由此量測結果可知,氧氣大多被包覆在微氣泡中,而非溶於PBS中。
[帶氧微氣泡的穩定度]
本實施例係利用商用超音波影像系統(Model 3000,Terason,Burlington,MA)搭配自製的仿體架構,模擬活體37℃下帶氧微氣泡以及全氟丙烷微氣泡的聲學穩定度。
本實施例係以瓊脂粉末(UltraPureTM Agarose,Invitrogen,CA,USA)製作仿體,將重量分比2%的瓊脂粉末與去氣的蒸餾去離子水(Distilled deionized water,DDW)均勻混合,於加熱攪拌的過程中使得瓊脂粉末完全溶解,當混合溶液呈現清澈透明無色時,倒入自製的仿體容器中定型,在未固化前插入0.5mm的實心圓柱狀的玻璃管模型,作為仿體的腔室,待仿體完全固化後,移除該玻璃管模型,即可完成該仿體的製備。
接著,先將該仿體埋沒於去氣水中,並使用夾具夾住超音波影像系統的影像探頭,在仿體腔室中分別注入以生理食鹽水稀釋4000倍後的帶氧微氣泡(C3F8:O2=1.4:1)以及全氟丙烷微氣泡以進行造影,為了模擬活體的體內環境,使用加熱棒控制水箱溫度在37℃,每10分鐘收取一張超音波影像,連續收取至60分鐘,重複三次實驗後,再利用MATLAB(2010a;MathWorks,Natick,MA,USA)進行影像分析,
量化帶氧微氣泡以及全氟丙烷微氣泡產生的影像對比效果,在每個時間點下圈選相同大小的感興趣區域(region of interest,ROI),且於等高度位置之水的背景強度做相除,進而得到不同時間點的聲學強度訊號的改變情形(signal-to-noise ratio,SNR)。其量測結果係如圖4所示,由量測結果可得知,無論是帶氧微氣泡或全氟丙烷微氣泡,於超音波影像系統照影60分鐘內皆無顯著的影像亮度下降,可證實微氣泡中添加氧氣不會使得微氣泡變得不穩定。
[活體實驗驗證帶氧微氣泡促進血管正常化]
本實施例係使用C57BL/6JNarl品系小黑鼠,性別為雄性,年齡介於6-8周,體重約30g,由國家動物實驗中心提供。皮下腫瘤模型係使用小鼠攝護腺癌細胞(Transgenic Adenocarcinoma Mouse Prostate cell line,TRAMP),取1x106顆TRAMP細胞植入小鼠右腿皮下,等待7天後,腫瘤生長至直徑約7mm再進行實驗。實驗過程中,小鼠以腹腔注射的方式進行麻醉,麻醉藥物為50μL體積比1:1的舒泰(Zoletil 50,Virbac,TW)和若朋(Rompun 20,Bayer,TW)的混合液。待小鼠麻醉後,先以剃毛刀將腫瘤位置之毛髮剃除,並均勻塗抹除毛膏,使腫瘤表皮區域完全乾淨。實驗過程中,為了避免小鼠失溫,以加熱墊維持小鼠體溫在37℃。
接著架設超音波影像導引治療系統進行活體驗證,將種有腫瘤的小鼠右後腿放置在自製含有保鮮膜窗孔水箱下方,將2MHz高強度聚焦式超音波探頭(High intensity focused ultrasound,HIFU)與商用超音波影像系統的影像探頭置入水箱中,共同聚焦在皮下腫瘤的
同一個切面上,以2MHz的高強度聚焦式超音波探頭刺激帶氧微氣泡釋放氧氣,同時利用商用超音波影像系統的影像探頭提供的超音波影像以監測治療的過程,並定位腫瘤位置進而調整治療區域。
詳細的實驗過程如下:
(1)給氧前全腫瘤的血流灌注影像:首先,先注射全氟丙烷微氣泡至腫瘤內部以獲得血流灌注的資訊,為了在收取整顆腫瘤之超音波影像時,腫瘤內含有固定濃度之全氟丙烷微氣泡,本實施例用注射幫浦自小鼠眼窩持續注入濃度為2×109/mL的全氟丙烷微氣泡,注射流速為0.3mL/h,待全氟丙烷微氣泡循環1分鐘後,以商用超音波影像系統搭配三軸平台移動小鼠,每間隔0.5mm收取一張切面影像,以獲得整顆腫瘤之給氧前血流灌注影像。
(2)帶氧微氣泡釋放氧氣:等待30分鐘使得全氟丙烷微氣泡代謝完畢後,自眼窩注射第一劑1×107的帶氧微氣泡(C3F8:O2=1.4:1;N=9),循環1分鐘後,以高強度聚焦式超音波探頭擊破帶氧微氣泡以釋放氧氣,其超音波的參數包括聲壓為2MPa、週期為1000、脈衝重複頻率(Pulse repetition frequency,PRF)為2Hz。為了避免血管內的帶氧微氣泡因被擊破後,尚來不及補充帶氧微氣泡而導致高強度聚焦式超音波照射無效,故以照射6秒後停止照射6秒的方式,搭配三軸平台移動小鼠,治療完一半腫瘤時(約注射後10分鐘),再注射第二劑1×107的帶氧微氣泡,並再以高強度聚焦式超音波掃描半顆腫瘤,總掃描時間約為20分鐘,兩劑的1×107的帶氧微氣泡可確保高強度聚焦式超音波掃描腫瘤前後段的帶氧微氣泡的均勻性,總治療劑量為每隻小鼠2×107個帶氧微
氣泡,尚再安全劑量的範圍3.9~6.9×107個微氣泡/小鼠的範圍內。另外,本實施例更包括一未做任何注射及照射超音波的控制組(N=6),以及注射全氟丙烷微氣泡並照射超音波的比較組(N=8),此比較組的實驗方式即注射全氟丙烷微氣泡取代上述實驗組的帶氧微氣泡。
(3)給氧後的全腫瘤血流灌注影像:收取全腫瘤血流灌注影像的時間點為注射帶氧微氣泡(實驗組)或注射全氟丙烷微氣泡(比較組)後的第0(1分鐘後)、2、4、6、8天,取像的方法同上述的步驟(1),以注射幫浦自小鼠眼窩持續注入濃度為2×109/mL全氟丙烷微氣泡,注射流速為0.3mL/h,待全氟丙烷微氣泡循環1分鐘後,以商用超音波影像系統搭配三軸平台移動小鼠,每間隔0.5mm收取一張切面影像,藉此收取整顆腫瘤的給氧後的血流灌注影像。接著將超音波影像進一步分析,以計算如圖5所示之血液灌注比例,以及如圖6所示腫瘤血管的密度,並藉此評估腫瘤血流灌注的變化是因為血管正常化伴隨的功能修復、抑或是因為單純的血管增生所導致。
由圖5所示的實驗結果可得知,僅有注射帶氧微氣泡並照射超音波的實驗組中,血流灌注比有顯著的上升,一直到給氧後第8天還能維持1.95±0.78的血流灌注比,而控制組以即注射全氟丙烷微氣泡並照射超音波的比較組於第2至4天時血流灌注比皆低於1。因此,認為本實施例使用帶氧微氣泡並使用超音波照射腫瘤局部以釋放氧氣可誘發腫瘤血管正常化,進而導致腫瘤血流灌注上升。再者,由圖6所示的實驗結果可得知,實驗組(N=5)、比較組(N=4)、以及控制組(N=6)的腫瘤
血管的密度皆無顯著的上升或下降,因此可推論,腫瘤血流灌注比的提升是因為血管功能的正常化,而不是因為血管增生而導致的。
[活體實驗驗證帶氧微氣泡促進血管正常化的時間窗長度]
接著,本實施例以不同劑量的帶氧微氣泡進行測試,其實驗方法大致上係與上述的實驗組相同,唯不同組別中,帶氧微氣泡的劑量為每隻小鼠0.5x107(N=2)、1x107(N=4)、2x107(N=8)、4x107(N=3)個帶氧微氣泡,另外,本實施例亦包括未注射為氣泡且未照射超音波的控制組(N=6)。圖7所示為腫瘤血流灌注比於不同劑量下的變化,由圖7所示的的結果可得知,調整不同帶氧微氣泡的劑量可影響血管正常化的時間窗長短,且其中劑量為每隻小鼠2x107個帶氧微氣泡的組別從第2天開始與控制組相比,其血流灌注比例即有顯著的上升,若以灌注比例=1為基準,其血管正常化的時間窗為給氧後的第2-10天。
[血管正常化相關因子分析]
本實施例以給氧後第4天作為血管正常化的時間點,再給氧治療後的第4天犧牲小鼠,取下整顆腫瘤進行組織萃取,以西方墨點分析法(Western blot)量測血管內皮細胞上之氧氣偵測酵素(Prolyl hydroxylase domain-containing protein 2,PHD2)、缺氧誘導因子-1 α(Hypoxia-inducible factor-1 α,HIF-1 α)、血管內皮增生因子(Vascular endothelial growth factor,VEGF)、以及轉化生長因子-β(Transforming growth factor-β,TGF-β)的表現量。其量測結果如圖8所示。
經文獻資料表明,腫瘤血管正常化會提升氧氣的遞送效率,再高氧氣濃度的環境下,血管內皮細胞上的氧氣偵測酵素(PHD2)會分解缺氧誘導因子(HIF-1 α),進而減少HIF-1 α的表現,並導致下游基因之血管內皮增生因子(VEGF)的表現量降低,使腫瘤血管的生長速度變慢,而有時間修復腫瘤中不正常的血管,使得腫瘤血管正常化。另外,轉化生長因子(TGF-β)的表現量可評估腫瘤血管正常化之後,是否會影響腫瘤細胞增生的速度。
因此,由圖8所示的量測結果顯示,注射帶氧微氣泡並利用超音波於腫瘤部位釋放氧氣進行血管正常化之後,PHD2、HIF-1 α、以及VEGF的表現量皆下降,而TGF-β則沒有顯著差異。其中,PHD2、HIF-1 α、以及VEGF的表現量下降係與上述的理論相符,故進一步地證實了帶氧微氣泡於腫瘤部位釋放氧氣可誘發腫瘤的血管正常化。
[統計分析]
本實施態樣的數據係使用Student’s t-test雙尾檢定法進行統計分析。
綜合以上的測試結果,證實了注射帶氧微氣泡利用超音波於腫瘤部位釋放氧氣可誘導腫瘤部位的血管正常化,藉以增加腫瘤部位的血流灌注,且血管正常化的時間窗可長達給氧後2-10天。
Claims (10)
- 一種用以誘導病變組織血管正常化的套組,該套組包括:具有一帶氧微氣泡的一混合液、以及一超音波發射裝置;其中,該帶氧微氣泡包含一氧氣以及一難溶於水的氣體,該帶氧微氣泡所包含的該難溶於水的氣體與該氧氣的體積比為1:1~1.4:1,且該帶氧微氣泡的粒徑為0.5~20μm;其中,一有效劑量之該帶氧微氣泡係以靜脈注射進入生物體內,再使用超音波發射裝置照射該病變組織,使得該帶氧微氣泡於該病變組織處破裂而釋放氧氣以誘導病變組織血管正常化。
- 如申請專利範圍第1項所述之套組,其中,該帶氧微氣泡的粒徑為0.7~3.0μm。
- 如申請專利範圍第1項所述之套組,其中,該帶氧微氣泡中所包含的該難溶於水的氣體係至少一選自由全氟丙烷(C3F8)、全氟丁烷(C4F10)、氮氣(N2)、二氧化碳(CO2)、及其混合物所組成之群組。
- 如申請專利範圍第1項所述之套組,其中,該帶氧微氣泡更包含一磷脂殼層,包覆該氧氣以及該難溶於水的氣體。
- 如申請專利範圍第4項所述之套組,其中,該磷脂殼層係由1,2-二硬脂醯-sn-甘油-3-磷酸膽鹼(1,2-Distearoyl-sn-glycero-3-phosphorylcholine;DSPC)、以及1,2-二硬脂酰-sn-甘油基-3-磷酸乙醇胺-N-[10-(三甲氧基甲矽烷基)十一酰胺(聚乙二醇-2000])(1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[10-(t rimethoxysilyl)undecanamide(polyethyleneglycol)-2000];DSPE-PEG-2000)所組成。
- 如申請專利範圍第1項所述之套組,其中,該帶氧微氣泡的劑量為每日2.5~3.5μL/每公斤。
- 如申請專利範圍第1項所述之套組,其中,該超音波裝置為一高強度聚焦式超音波裝置。
- 如申請專利範圍第7項所述之套組,其中,該超音波發射裝置的參數為:聲壓為1.5~2.5MPa;週期為500~1500;脈衝重複頻率為1~5Hz。
- 如申請專利範圍第1項所述之套組,其中,該病變組織為腫瘤組織、血管栓塞導致缺氧之組織、或受損血管。
- 一種帶氧微氣泡用於製備誘導病變組織血管正常化套組之用途,其中,該套組係如申請專利範圍第1項至第9項中任一項所述之套組,該帶氧微氣泡包含一氧氣以及一難溶於水的氣體,該難溶於水的氣體與該氧氣的體積比為1:1~1.4:1,且該帶氧微氣泡的粒徑為0.5~20μm。
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