TW201332588A - 具有超音波觸發釋藥功能之磁振影像引導藥物載體 - Google Patents
具有超音波觸發釋藥功能之磁振影像引導藥物載體 Download PDFInfo
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Abstract
本發明係關於具有超音波觸發釋藥功能之磁振影像引導藥物載體與系統,其可透過磁振造影追蹤藥物載體的位置,待藥物載體到達特定標靶位置並累積至足夠濃度時,再藉由醫用超音波於體外觸發藥物釋出,如此可使釋藥位置與時機的準確度大幅提高,並藉此降低藥物之副作用,同時可透過超音波的特性來加強化療藥物之效力。
Description
本發明係關於具有超音波觸發釋藥功能之磁振影像引導藥物載體與系統,以及藉由該藥物載體將藥物遞送至標靶位置的方法,其特徵在於磁振造影追蹤藥物載體的位置,待該藥物載體到達特定標靶位置並累積至足夠濃度時,再藉由醫用超音波於體外觸發藥物釋出。
目前的超音波導引藥物傳輸系統(ultrasound image-guided drug delivery system)主要是利用微氣泡(microbubble)型的商業化的超音波對比劑(ultrasound contrast agent)來攜載藥物,希望對比劑同時發揮載體追蹤造影(trafficking),與感音觸發藥物釋放(ultrasonically-triggered drug release)的功能。但習知的超音波導引藥物傳輸系統可能面臨的問題有:(1)於超音波造影過程中,一系列的影像探求(probing)中可能會使超音波在非患處「看」到對比劑,藥物即可能同時被觸發釋放出來,因此該法較難精準控制釋放的時機與位置;(2)對於微氣泡(microbubble)而言,其製程方式不易攜載足量之藥物,尤其不容易達成攜載足量疏水性藥物的目的;(3)超音波影像的解析度對於分子影像而言尚不夠高。基於上述考量,我們有必要在醫學診斷超音波外,另尋醫學影像技術來進行載體的追蹤。
一般習知的「超音影像導引藥物傳輸系統」常採用以白蛋白構成(albumin-based)(Duvshani-Eshet,M.等人Journal of Controlled Release 112,156-166(2006))或是以脂質構成(lipid-based)(Vlaskou D等人Advanced Functional Materials 20,3881-94(2010))之微氣泡作為超音波造影成像劑與藥物載體,但超音波成像常需先經一系列的影像探求,此過程很可能會將未到達標靶位置的微氣泡擊破;或是載體濃度尚未到達理想值,在超音波探查的同時即已使藥物釋出。一般習知的「超音影像導引藥物傳輸系統」常採用的是albumin-based或是lipid-based之微氣泡,這類氣泡雖有研究指出也可以有磁振造影的效果,但因其未含磁性物質,磁振造影效果十分有限,濃度不高時,很難有清晰的磁振影像。一般習知的「超音影像導引藥物傳輸系統」如果採用的是albumin-based或是lipid-based之微氣泡,則是將水難溶藥物攜載於微氣泡與內部氣體的介面層內(Tinkov,S.等人Journal of Controlled Release 148,368-372(2010)),或是直接將藥物直接嫁接於微氣泡殼層上(Liu,Y. Y.等人Journal of Controlled Release 114,89-99(2006)),然而此二方式之藥物攜載量有限,且皆需要特殊的製程技術與設備。
一般習知技術中要製作具有磁振造影功能的藥物載體,主要是透過高分子實心球體或是高分子微胞,來包覆藥物與磁性奈米顆粒(Talelli,M.等人Langmuir 25,2060-2067(2009)),然而,此法所形成之造影載體並不具有超音波觸發釋藥的功能。
一般習知之「多功能造影及藥物傳輸系統」包括具超音波與磁振雙造影功能的造影劑,可由「高分子空心多層球體」來構成,其是在高分子空心球核心部分填充SF6(或等效)之氣體,可發揮超音波造影的功能:於高分子殼層中分別埋置磁性顆粒與藥物,來發揮磁振造影與藥物載體的功能(Fang,Y.等人Biomaterials,30,3882-3890(2009)),然而,此類載體因殼層過於堅固,無法被超音波擊破,因此不具有超音波敏感釋藥的功能。另外,一般具超音波與磁振雙造影功能的造影劑,亦可由微氣泡透過不同方式批覆磁性奈米顆粒來構成,但此類先前技術所形成之雙功能造影劑較難攜載疏水性藥物(Vlaskou,D.等人Advanced Functional Materials 20,3881-3894(2010);Lee,M. H.等人Langmuir 26,2227-2230(2010))。而本案中微氣泡攜載藥物之方式與此二先前技術有相當之差異。
本案為一種「具有超音波敏感觸發釋藥功能的磁振影像導引藥物傳輸系統」。本發明雖仍採用由白蛋白(albumin-based)或是脂質(lipid-based)所構成之微氣泡,但本案特徵是透過微氣泡表面含有磁性奈米顆粒的微胞來產生磁振訊號,因此可藉由磁振造影探查載體位置與到達標靶位置之載體濃度,確認釋藥位置與時機皆正確後,再透過超音波將微氣泡擊破,然後釋出藥物。此外,本案是預先將水難溶性藥物包覆在自組裝微胞內,再將自組裝奈米微胞吸附於微氣泡表面,與習知技術攜載藥物之方式有明顯不同。
一種相關的習知技術為台北科技大學呂志誠教授實驗室所揭示,其主要利用化學修飾磁性奈米顆粒,使磁性奈米顆粒得以與微氣泡嫁接(中華民國專利,呂志誠,申請號096105671“磁導性微氣泡及其製備方法”)。亦有一些國際學術研究已揭示,透過流體製程來形成帶有磁性奈米顆粒的微氣泡(Lee,M. H.等人Langmuir 26,2227-2230(2010))。但因微氣泡結構非常脆弱,很難透過原位合成的方式,直接將磁性奈米顆粒成長於氣泡表面或氣泡殼層結構當中,如果透過化學製程來修飾磁性顆粒後再以化學鍵嫁接,常會發生三個問題:(1)化學嫁接製程會破壞脆弱的微氣泡結構,使微氣泡破裂或消失;(2)磁性奈米顆粒不會選擇性吸附在微氣泡表面,也同時會存在於氣泡周遭的溶液環境中,因此不易將微氣泡與未吸附的磁性顆粒分離,會影響到磁振造影效果;(3)先前技術很難將微氣泡同時加載磁性奈米顆粒與藥物。本案則開發出一種新穎的方式,可在不破壞微氣泡結構的前提下,將磁性顆粒與藥物同時加載於微氣泡表面,其結構與製程均與先前技術有相當大差異,也不需透過複雜或特別的設備即可達成。
本案之微氣泡內含SF6(或等效)之氣體,可發揮超音波造影功能;氣泡薄殼層係由白蛋白或脂質構成,表層吸附的自組裝微胞內含有藥物與磁性顆粒,可發揮磁振造影功能,且可透過高頻(1-3 MHz或以上)與低功率密度(0.5 W/cm2以下)的醫學診斷超音波將藥物載體擊破,發揮超音波觸發釋藥功能。
基於上述考量,本發明開發出一種具攜載疏水性藥物能力,且可進行磁振造影功能的超音波觸發釋藥載體,其可透過磁振造影追蹤載體之位置,待載體在特定標靶位置累積足夠濃度時,再藉由醫用超音波於體外將載體震破,使藥物釋放出來,透過這樣的方式,可使釋藥的位置與時機精準度大幅提高,可降低藥物的使用量與副作用,同時也可透過超音波原有的加速藥物穿透與吸收(sonophoresis)以及提升組織溫度的特性來使化療藥物效力加強。
本發明之一特徵為,將帶有藥物與超順磁性顆粒的奈米微胞(micelle)以靜電吸引力或化學鍵,稼接於一般超音波微氣泡(microbubble)對比劑表面,形成一個具有攜載疏水性藥物能力,以及磁振造影能力的超音波觸發釋放藥物載體(示意圖如圖1)。本案之微氣泡內含SF6(或等效)之氣體,可發揮超音波造影功能,該微氣泡薄殼層可由白蛋白或脂質所構成;微氣泡表層吸附的自組裝微胞內含有藥物與磁性顆粒,可發揮磁振造影功能,且可透過高頻(1-3 MHz或以上)與低功率密度(0.5 W/cm2以下)的醫學診斷超音波將藥物載體擊破,發揮超音波觸發釋藥功能。
因此,於一方面,本案係提出一種攜載疏水性藥物之釋藥載體,其包含一可攜載水難溶氣體的微氣泡;以及多數吸附於該微氣泡表面的微胞,其包含雙親性高分子、水難溶性藥物及超順磁性奈米顆粒。
於本發明之一項具體態樣,前述之微氣泡可由白蛋白、磷脂質或其他具有起泡作用的介面活性劑及高分子材料所構成,且該微氣泡內含SF6或其他等效之氣體,如全氟化丙烷C3F8。可依需求,透過製程技術將微氣泡之尺度調控成0.3 μm到10 μm。微氣泡本身可產生超音波造影效果,亦可被具適當MI(mechanical index)值的超音波擊破。
於本發明之一具體實例載體的微氣泡內係填充SF6氣體,當其被高頻(1-10 MHz)之超音波觸發擊破,會進而使存在微氣泡表面的奈米微胞散開,使前述之微胞得以進入標靶位置被細胞吞噬。又,微氣泡被高頻超音波擊破破裂後之震波,不僅可使奈米微胞破裂,而釋出其中所包覆的藥物,也可使標靶細胞之細胞膜產生暫時開口,使所釋出之藥物進入細胞。
前述之微胞包含雙親性高分子、藥物以及磁性奈米顆粒,其尺度可依需求透過製程技術,被調控成粒徑從50 nm到200 nm。該等微胞可透過靜電吸引力或化學鍵結,來吸附於微氣泡表面。雙親性高分子具有親水性基團與疏水性基團,親水性基團可使所成之微胞均勻分散於水中,而疏水性基團則可將油溶性超順磁性奈米顆粒及水難溶性藥物,經由自組裝方式包覆在前述之微胞中。
於本發明之一項具體實例,前述之自組裝奈米微胞是由雙親性幾丁聚醣與磁性奈米顆粒,透過自組裝製程所形成的奈米球體,前述之微胞結構(外部親水、內部疏水)可提供疏水性藥物的包覆能力;而磁性顆粒則可發揮磁振造影的成像功能。本發明載體具親水性的表面,可維持其整體結構在水溶液中的分散性,再者,微胞可具有帶電的表面,易與微氣泡之表面透過靜電吸引力稼接;或是具有帶有NH2與COOH基的表面,而易藉由化學鍵與微氣泡表面稼接。因此,由奈米無機磁性顆粒自組裝形成的奈米微胞,本身也具有超音波觸發釋藥性質,接合在微氣泡後可使微氣泡帶有磁性,易於進行分離製程。
本案提出之藥物載體結構,可經由高頻(1-10 MHz)低功率密度(0.5 W/cm2以下)超音波觸發破裂後,使帶有藥物的微胞分散開來,微胞本身也會受低頻(20-500 KHz)超音波與氣泡破裂震波的雙重影響而破裂,進一步將水難溶性藥物釋放出來(示意圖如圖1)。
本發明載體之微胞所含的無機顆粒在無超音波作用時,其作用可穩定微胞結構並阻止藥物外洩;而於超音波轟擊後,可因自組裝無機顆粒的微弱鍵結本質,使微胞產生快速破裂,並阻止高分子的再組裝行為,因此可快速將藥物釋出。此外,前述之無機磁性奈米顆粒在載體未被觸發前,可發揮MRI T2造影對比功能,而在施予超音波能量觸發之後,因微氣泡破裂或微胞破裂均會造成,超順磁性奈米顆粒的分散程度改變,故而使磁場不均勻性產生變化。因此,在超音波作用前後會有T2與T2*對比訊號的差異,可做為載體是否被觸發的判別參考。
本發明之其他特色及優點將於下列較佳實施範例中被進一步舉例與說明,而該實施範例僅作為輔助說明,並非用於限制本發明之範圍。
參照下述的描述及圖示雖已揭示本發明之較佳實施例,但必須瞭解到各種增添、修改和取代均可能用於本發明的較佳實施例,而不會脫離如所附申請專利範圍所界定的本創作原理之精神及範圍。因此,熟悉該項領域具有通常知識者技藝者將可體會,本發明可能使用於很多形式、結構和材料的修改。
於本案之一項較佳具體實施例,本發明之藥物載體結構表面的微胞內含有具超順磁性之Fe3O4奈米顆粒,故可得到MRI T2-加權影像(weighted image)(如圖7)。本案提出之藥物載體結構在經超音波觸發後產生破裂,造成超順磁性奈米顆粒之間距與分散程度會產生變化,使MR訊號在R2*斜率與R2斜率兩斜率差值上產生明顯變化(如圖8),因此可做為載體狀態之判別參考。
參照圖2所示,本發明之藥物載體結構包含一個可攜載水難溶氣體(例如SF6或其他等效氣體,如全氟化丙烷C3F8)的微氣泡(材料可為白蛋白albumin或脂質lipid),以及多個吸附於微氣泡表面的微胞(內含雙親性高分子、藥物以及磁性奈米顆粒)。製備方法如下所述。
首先製備胎牛血清白蛋白(BSA)微氣泡。於20 mL玻璃樣品瓶中置入5 mL葡萄糖溶液,將樣品瓶置於油浴鍋中加熱,再加入胎牛血清白蛋白粉末攪拌至完全溶解,接著將0.3 mL甘胺酸加入並將瓶口密封。將氣體針頭插入瓶中,持續通入六氟化硫(SF6)氣體1分鐘。隨後伸入超音波均質機之探頭,並開啟超音波振盪3分鐘,溶液的顏色立刻從黃色透明轉變成乳白色。於振盪3分鐘後關閉超音波,並從油浴鍋中取出樣品瓶,接著將所成之胎牛血清白蛋白微氣泡分散於戊二醛溶液中攪拌2小時,之後以1000 rpm離心10分鐘,此時為氣泡會浮在上層,用針筒吸除下層溶液後,即得到交聯胎牛血清白蛋白微氣泡。圖3顯示所得BSA微氣泡共軛焦顯微鏡影像(圖3a)及可見光顯微影像(圖3b)。由圖3清楚可見,微氣泡的型態完整且只有微氣泡之外圈殼層呈現綠色螢光,而內部呈現黑色表示內部不含有螢光染劑,證明白蛋白只存在於微氣泡殼層。
N,O-羧甲基幾丁聚醣(NOCC)之製備。將50 mL異丙醇加入內含5克幾丁聚醣之250 mL單頸圓底燒瓶中,攪拌30分鐘使其呈懸浮溶液。待幾丁聚醣完全溶解於異丙醇後,再將12.5 mL 10N NaOH水溶液分五次加入。於最後一次NaOH加入後,在5分鐘內迅速加入25克氯乙酸,並攪拌30分鐘。之後,將反應移置60℃油浴鍋中攪拌4小時。反應完成後,將反應瓶置於室溫下冷卻,並以抽氣過濾方式收集產物,以甲醇沖洗後,將產物放入65℃烘箱中乾燥24小時,即得到呈水溶性淡白色粉末之N,O-羧甲基幾丁聚醣(NOCC)。取2克前述之NOCC於15 mL反應瓶中,並加入50 mL去離子水,將其攪拌一天至完全溶解,再加入50 mL甲醇攪拌一天使其混合均勻。之後,加入1.4 mL己酸酐反應8小時。反應完成後,即得到黃色透明黏稠產物羧甲基己醯基幾丁聚醣(CHC),將產物置於65℃烘箱中乾燥24小時。
先將疏水性藥物伊布洛芬(ibuprofen)與含有超順磁性氧化鐵(Fe3O4)奈米顆粒(superparamagnetic iron oxide,SPIO)之微胞溶液,於冰浴中以超音波均質機振盪2分鐘,使該藥物透過自組裝法裝載(load)於CHC-Fe3O4(carboxymethyl hexanoyl chitosan)微胞中,將多餘未裝載之藥物以管柱分離法分離掉,再將所得到之奈米微胞懸浮液(micelle suspension)加入前述製備得之交聯胎牛血清白蛋白微氣泡溶液中,使其透過靜電引力吸附在由BSA所形成的微氣泡表面(圖2)。
前述之CHC為幾丁聚醣改質而來的雙親性高分子,因具有親水性羧甲基基團而可均勻分散於水溶液中;且具有疏水性己醯基基團,而可將油溶性氧化鐵奈米顆粒與難溶性藥物,藉由超音波自組裝步驟包覆於CHC微胞中。
由圖4之電子顯微鏡TEM檢視結果,所成之微胞內含雙親性高分子、藥物以及磁性奈米顆粒,油相氧化鐵奈米顆粒被CHC包圍,而形成100-200 nm之微胞(圖4a)。而圖4b係透過HR-TEM觀察微胞之原子排列(lattice fringe),確認該奈米顆粒確實為Fe3O4。
圖5顯示本案之具體實施例MB@CHC-Fe3O4載體,經超音波觸發後之釋藥情形。將所製得之MB@CHC-Fe3O4載體以物理治療用超音波(1 MHz,0.4 W/cm2)持續刺激20分鐘,接著使用離心機將藥物載體分離出,並加入等量己烷將載體破壞,並使剩餘藥物被萃取到己烷層中,而從該載體中剩餘之藥物含量來反推載體之藥物釋放率。結果顯示,施予超音波10分鐘時,可得到約80%的藥物釋放量,而持續施予超音波20分鐘後,藥物釋放量已達到90%,表示微氣泡可被高頻超音波(頻率1 MHz,功率0.4 W/cm2)擊破,因此可以將微胞內之藥物釋放出來。
一般,磁振造影之T2造影劑為順磁性材料,常見的如氧化鐵奈米顆粒可以增加T2弛緩速度,減緩T2弛緩時間而使T2加權影像隨濃度增加而變暗。圖6為本實例所使用及製備得之MB@CHC-Fe3O4載體的磁滯曲線分析圖,從圖中觀察到本具體實施例之MB@CHC-Fe3O4載體與Fe3O4奈米顆粒兩者均未呈現磁滯圈,表示彼等均為超順磁性材料,因此適合做為磁振造影之T2造影劑。
對於超順磁材料作為T2造影劑而言,r2值(造影劑濃度對R2作圖所得之斜率)為T2造影劑的重要指標,r2值越大代表顯應對比與濃度的相關性越高。由圖7之結果顯示,本發明之藥物載體所包含的超順磁奈米顆粒,在本發明之釋藥載體未被超音波觸發前,可發揮MRI T2造影對比功能,因此可透過磁振造影來進行載體影像追蹤,能夠較精準控制藥物釋放的位置與時機,而此功能可藉由調整SPIO奈米點的數量而得到調控。
另外,由圖8顯示,本發明之釋藥載體所包含的超順磁性氧化鐵奈米顆粒,在超音波作用前後的間距與分散程度會產生很大的變化(奈米顆粒由聚集態變為分散態),亦會使磁場不均勻性產生變化,使MR訊號在R2*斜率與R2斜率兩斜率差值上產生明顯變化。所以會使MR訊號在R2*斜率與R2斜率兩斜率差值(r2*-r2)上產生明顯變化,亦即釋藥載體在經超音波轟擊作用後,R2*-R2斜率差值有顯著降低。
圖9為本發明具體實施例MB@CHC-Fe3O4載體經靜脈注射進入SD大鼠體內之活體內測試結果,如圖9a所示,在注射MB@CHC-Fe3O4載體之前,先確認靜脈及動脈血管皆呈現黑色影像,而當將MB@CHC-Fe3O4載體注射入大鼠之髂靜脈後,馬上可觀察到靜脈血管出現白色雲霧狀流體快速流動,且同樣在數秒後,即觀察到在動脈血管內也出現白色雲霧狀流體,以脈衝式流動流經動脈;又觀察大鼠之肝臟與腎臟血管,確實在肝臟與腎臟血管中可明顯觀察到有白色雲霧狀流體快速流動。由上述之結果證明,本發明之具多重造影與超音波觸發釋藥功能之為氣泡結構,在施用於生物體內仍保持超音波造影特性,也說明載體可順利進入身體循環。
綜合上述,本發明提出之釋藥載體可藉由磁振造影來可探知載體位置與濃度,再藉由商業化醫療診斷用超音波來觸發載體釋放藥物,可進一步提升標靶投藥的時機精準度,降低化療藥物對於其他正常部位的毒性傷害。又,本發明之釋藥載體係以超音波做為觸發能量,利用醫學診斷用超音波即可觸發載體破裂釋出藥物,而目前超音波已經高度商業化,且具備高度安全性的醫用超音波尚具有能量聚焦、精準定向傳播與軟組織穿透深度等優點。再者,超音波還具有加速藥物穿透與吸收的功能,已經被廣泛應用在經皮給藥、癌症治療與物理治療的臨床醫學治療用途中。另外,目前醫學領域已有將診斷超音波整合於磁振造影設備上的臨床經驗,所以本發明之技術可利用既有的設備來實現,故為兼具實用性與安全性之發明。
本說明書中所揭示之全部特徵可以任何組合方式組合。於是,本說明書中所揭示之各別特徵可由依相同、相等或類似目的之替代特徵取代。因此,除非另行清楚地指示,所揭示之各特徵僅為一系列同等物或類似特徵之實例。
從前述之說明,習於該項技藝人士可容易地確定本發明之基本特徵,且在未偏離其範圍下,可進行本發明之各種改變與修飾,以使其適於各種不同用途與狀況。因此,於申請專利範圍內亦包含其他具體態樣。
圖1為本案提出之「具磁振造影功能的超音波觸發藥物載體」之結構與運作原理示意圖。
圖2為本案之具體實施例,MB@CHC-Fe3O4載體之TEM影像(包含一個白蛋白微氣泡,及多個吸附於該微氣泡表面的奈米微胞)。
圖3為本案之一項具體實施例中,MB@CHC-Fe3O4載體所採用之BSA微氣泡的(a)共軛焦顯微鏡影像;(b)可見光顯微影像。
圖4為本案之具體實施例MB@CHC-Fe3O4載體,(a)為內含雙親性高分子材料(CHC)、藥物以及磁性奈米顆粒的(Fe3O4)奈米微胞之TEM影像;(b)為奈米微胞內的Fe3O4磁性奈米顆粒之HR-TEM影像。
圖5顯示本案之具體實施例MB@CHC-Fe3O4載體超音波觸發後之釋藥情形。
圖6為本案之具體實施例MB@CHC-Fe3O4載體與Fe3O4奈米顆粒之磁滯曲線。兩者均未呈現磁滯圈,顯示該二者均為超順磁性材料。
圖7為本案之具體實施例MB@CHC-Fe3O4載體與BSA微氣泡之(a) MRI T2影像以及(b) R2 mapping。可觀察到:MB@CHC-Fe3O4載體具有相當明顯之T2對比,BSA微氣泡則無,而且MB@CHC-Fe3O4載體之R2值與濃度的關聯性遠高於BSA微氣泡。
圖8為本案之具體實施例MB@CHC-Fe3O4載體經超音波觸發前後之R2-R2*mapping,可觀察到在超音波轟擊(a)前與(b)後,其R2與R2*之斜率差值(r2*-r2)產生明顯變化。
圖9為本案之具體實施例MB@CHC-Fe3O4載體,經靜脈注射進入SD大鼠體內之(a)前;(b)後之靜脈超音波影像圖。
Claims (14)
- 一種攜載疏水性藥物之超音波觸發釋藥載體,其包含:一其中充填水難溶氣體的微氣泡(microbubble);及多個接附於該微氣泡表面的奈米微胞(micelle),其包含雙親性高分子、親油性超順磁性奈米顆粒及水難溶藥物。
- 如申請專利範圍第1項所述之釋藥載體,其中該微氣泡係由白蛋白、磷脂質或其他具有起泡作用的介面活性劑及高分子材料所構成,且微氣泡之粒徑係介於0.3 μm到10 μm之間。
- 如申請專利範圍第2項所述之釋藥載體,其中該微氣泡係由白蛋白所構成。
- 如申請專利範圍第1項所述之釋藥載體,其中該微氣泡內充填之水難溶氣體為六氟化硫(SF6)或全氟化丙烷(C3F8)氣體。
- 如申請專利範圍第1項所述之釋藥載體,其中該奈米微胞是由雙親性高分子材料與超順磁性奈米顆粒,透過自組裝製程所形成的奈米球體,水難溶藥物包覆於疏水性內層中,且粒徑範圍係介於50 nm到200 nm。
- 如申請專利範圍第5項所述之釋藥載體,其中該雙親性高分子材料為具有親水性羧甲基基團與疏水性己醯基基團之雙親性幾丁聚醣。
- 如申請專利範圍第1或5項所述之釋藥載體,其中該超順磁性奈米顆粒為具超順磁性的氧化鐵(superparamagnetic ironoxide,SPIO)奈米顆粒。
- 如申請專利範圍第1項所述之釋藥載體,其具有磁振造影對比功能,在進行造影追蹤的同時藉由磁振造影確認該載體之分佈。
- 如申請專利範圍第1項所述之釋藥載體,其特徵在於該奈米微胞係於高頻低功率密度的超音波轟擊下產生破裂。
- 一種利用超音波觸發釋藥載體遞送藥物之方法,其包含下列步驟:(1) 將如申請專利範圍第1項所述之釋藥載體投藥予需要的個體;(2) 透過磁振造影(magnetic resonance imaging,MRI)進行載體影像追蹤;及(3) 於該載體到達標靶位置並累積到有效治療濃度時,以超音波做為觸發能量觸發藥物釋出。
- 如申請專利範圍第10項所述之方法,其中該載體係以高頻低功率密度的超音波轟擊,藉由使藥物載體結構產生破裂且無法再組裝(或再包覆),而將藥物釋放出。
- 如申請專利範圍第10項所述之方法,其進一步包含藉由該釋藥載體結構改變所引發的磁振(MR)訊號變化,探查該載體之釋藥狀態。
- 如申請專利範圍第12項所述之方法,其中該磁振訊號變化係指在R2*斜率與R2斜率兩斜率差值上所產生的明顯變化。
- 一種製備如申請專利範圍第1項所述之釋藥載體的方法,其係將帶有藥物與超順磁性顆粒的奈米微胞(micelle)以靜電吸引力或化學鍵,接附於一超音波微氣泡(microbubble)對比劑表面,而形成一個具有攜載疏水性藥物能力,以及磁振造影能力的超音波觸發釋放藥物載體。
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