TWI540319B - 以細胞質譜分析定量細胞所攝入之奈米/微米粒子 - Google Patents
以細胞質譜分析定量細胞所攝入之奈米/微米粒子 Download PDFInfo
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Description
本發明係關於細胞質譜分析法。特別是關於,藉由細胞質譜分析法偵測一細胞內是否有奈米微粒存在。更特別地,係關於以細胞質譜分析法測定一細胞內的奈米微粒數量。
奈米微粒已被廣泛研究做為一種有效的藥物遞送方式。因此,定量細胞所攝入的奈米微粒數量,對於瞭解細胞之胞飲及胞釋作用的機制而言非常重要(B. D. Chithrani,A等人,Nano Lett. 2006,6,662;B. D. Chithrani,W. C. W. Chan,Nano Lett. 2007,6,1542;F. Osaki等人,J. Am. Chem. Soc. 2004,126,6520;J. A. Champion,S. Mitragotri,Proc. Natl. Acad. Sci. U.S.A. 2006,103,4930;H. Jin等人,ACS nano 2009,3,149)。
習知用於定量哺乳動物細胞所攝入之奈米微粒的方法包含,感應耦合電漿原子發射光譜分析法(inductively coupled plasma atomic emission spectroscopy,ICP-AES;B. D. Chithrani等人,Nano Lett. 2006,6,662;B. D. Chithrani,W. C. W. Chan,Nano Lett. 2007,6,1542;F. Osaki等人,J. Am. Chem. Soc. 2004,126,6520;J. A. Champion,S. Mitragotri,Proc. Natl. Acad. Sci. U.S.A. 2006,103,4930;H. Jin等人,ACS nano 2009,3,149;J. A. Ryan等人,Anal. Chem. 2007,79,9150)及感應耦合電漿質譜分析法(inductively coupled plasma mass spectrometry,ICP-MS;P. Yang等人,Bioconjugate Chem. 2005,16,494)。此等分析法雖稱精確,但其應用受到元素種類限制,例如僅限用於奈米金粒子(NPs)。最近,雷射脫附游離質譜分析(laser desorption/ionization mass spectrometry)已被用來定量測量細胞所攝入之奈米金粒子,其中該等奈米金粒子係由做為質譜條碼之不同官能基所編碼(Z.-J. Zhu等人,J. Am. Chem. Soc. 2008,130,14139)。然而,其編碼方法既繁複且耗時。
因此,有需要提供一種快速定量攝入哺乳動物細胞中之奈米微粒的方法。亦需要一種用於定量所有類型奈米粒子,包括諸如聚合型奈米粒子(NPs)、微脂粒、病毒為主之NPs、奈米碳管、奈米鑽石粒子、聚合型微胞、奈米載體及病毒性奈米粒子等非金屬奈米微粒攝入哺乳動物細胞中的方法。進而,有需要一種用於定量所有類型,包括(但不限定於)病毒、細菌、病原性蛋白顆粒、酵母菌、真菌及寄生蟲等病原菌奈米粒子攝入哺乳動物細胞中的方法。
本發明提供一種用於研究及測定被攝入哺乳動物細胞中之病原性與非病原性奈米粒子的新穎方法。
細胞質譜分析法(CMS)是一種用於測定哺乳動物細胞所攝入之奈米金粒子量的快速、精確方法。該方法能夠用於測定個別單一細胞之奈米粒子數量,而ICP只能從全體細胞得到平均值。此外,CMS不僅可用於測量細胞對於金屬奈米粒子之攝入量,亦能夠用於測量非金屬奈米微粒。在本發明之某些具體實施例中,細胞質譜分析法係指電荷監測細胞質譜分析法(CMCMS)。
本發明關於一種用於測定細胞之奈米粒子或微粒子攝入的方法,該方法包含下列步驟:(a)將一細胞於適合使該細胞攝入奈米粒子或微粒子之條件下,與具有已知尺寸的奈米粒子或微粒子接觸;(b)經由細胞質譜分析法記錄於有及無暴露至該奈米粒子或微粒子之下所產生的質譜;及(c)測定於質量/電荷(m/z)比產生的位移,其中該m/z比位移相當於該奈米粒子或微粒子被該細胞攝入。該方法進一步包含:將在各別細胞所獲得之m/z值及相對應的電荷(z),轉換成受測量細胞之絕對質量。
本發明關於一種用於定量細胞所攝入之奈米粒子或微粒子數量的方法,該方法包含下列步驟:(a)將一細胞於適合使該細胞攝入奈米粒子或微粒子之條件下,與具有已知尺寸的奈米粒子或微粒子接觸;(b)經由細胞質譜分析法記錄該細胞之質譜;(c)將在每一各別細胞取得之m/z值與對應電荷(z)轉換成該細胞之質譜;(d)測定平均質量差;及(e)將該平均質量差與對應於已知數量,具有已知尺寸的奈米粒子或微粒子的預定差值進行比較。本發明之方法可進一步包含定時測量;並測得該奈米粒子或微粒子被細胞攝入的時間-數量圖。
本發明之一方面係提供一種用於測量標靶細胞之藥物攝入的方法,該方法包含:將標靶細胞與一藥物之奈米微粒接觸;及藉由根據本發明之方法,測定該藥物奈米微粒被標靶細胞攝入的數量。該藥物係選自抗生素、非類固醇(NSAIDs)與類固醇消炎藥、抗組織胺、肥大細胞安定劑、抗過敏藥及抗癌藥劑。
於一方面,本發明係提供一種用於測量受感染細胞內之病原菌力價的方法,該方法包含:提供一受到病原菌之奈米粒子或微粒子感染的細胞;及藉由根據本發明之方法,測定該受感染細胞內的病原菌奈米微粒數量,其中係將該受感染細胞之質譜數據與得自同一種類未受感染細胞的質譜數據進行比較。於某些具體實施例,病原菌係選自病毒、細菌、病原性蛋白顆粒、酵母菌、真菌及寄生蟲。於某些具體實施例,受感染細胞為人類細胞。
於一方面,病原菌為一種病毒顆粒。因此,本發明係提供一種測量病毒顆粒被受感染的哺乳動物細胞攝入入細胞內的方法,其中病毒係選自流感病毒、麻疹病毒、冠狀病毒、流行性腮腺炎病毒、馬堡(Marburg)病毒、伊波拉病毒、狂犬病毒、鼻病毒、脊髓灰白質病毒、A型肝炎病毒、天花病毒、雞痘病毒、嚴重急性呼吸道症候群病毒或SARS病毒。
奈米粒子或微粒子之尺寸係小於或為約10μm,小於或為約5 μm,小於或為約3μm,小於或為約1μm,小於或為約500 nm,小於或為250 nm,小於或為約100 nm,小於或為約50 nm,小於或為約30 nm,小於或為約20 nm,小於或為約10 nm,或是小於或為約5 nm。
奈米粒子或微粒子可為金屬,例如金、銀、鈀或任一種適合的金屬。
於某些具體實施例,奈米粒子或微粒子為非金屬,包含聚苯乙烯、奈米聚合物粒子(NPs)、微脂粒、病毒為主之NPs、奈米碳管、奈米鑽石粒子,及聚合型微胞、奈米載體、微脂粒、藥物奈米粒子或病毒性奈米粒子。
於某些具體實施例,奈米微粒為一種選自微脂粒、脂質-核酸複合體、脂質-藥物複合體、固態脂質顆粒及微乳膠液滴之油脂性顆粒。
於某些具體實施例,奈米微粒包含一種適合接附於奈米載體粒子上之生物分子,其中該生物分子係選自:蛋白質、核酸、核苷、核苷酸、DNA、激素、胺基酸、肽類、擬肽類、RNA、脂質、白蛋白、抗體、磷脂類、醣脂類、固醇類、維生素、神經傳導物質、碳水化合物、糖類、雙糖、單糖、寡肽、多肽、寡糖、多糖及其混合物。
於某些具體實施例、奈米微粒進一步包含一種被納入的生物活性部分,其選自:診斷劑、對比劑、放射性核種、螢光劑、發光劑,及磁性部分、預防藥劑、疫苗與營養劑。
於某些具體實施例,奈米微粒進一步包含一種被納入的治療劑,其選自:小分子、核酸、siRNA、RNAi、微RNA、蛋白質、抗體、肽類、脂質、碳水化合物、激素、金屬、放射活性化合物、藥物、疫苗、免疫試劑及其組合物。
於下述實施方式中進一步詳述本發明之一或多項具體實施實施例。本發明之此等及其他特徵或優點,將藉由下列結合圖式的較佳實施例之詳述彰顯出來,然而習於該項技藝人士應瞭解,在未偏離本發明所揭示之新穎概念的精神及範圍下,可進行各種改變與修飾。
在本發明說明書所使用的術語,具有其於該技藝、於本發明內文及使用各術語之特別文章中一般使用的意義。如下所用的某些特殊術語是提供熟悉該技藝者能更進一步瞭解本發明內容。為了方便起見,一些特殊術語將會使用斜體字或引號標示出來。但這些被標示出來的部分並不會影響到特殊術語本身的範圍或意義;不論是否被標示出來,在同一內文中相同術語的範圍或意義一樣。應瞭解,同樣的事情會有一個以上的說法。因此,本文中所論述之一或多個術語可使用替代性的語言及同義詞,其是否在本文中被詳細描述或討論並不特別重要。會使用到一些特殊術語的同義詞。一或多個同義詞之引用並不排除可使用其他同義詞。在本發明所使用之,包括了任一本文中所論述之術語的實施例,係僅作為輔助說明,並非用於限制本發明或任何所例舉術語之範圍與定義。同樣,本發明不受限於各種在本說明書中所載之實施態樣。
除非另有規定,本文中所使用的技術和科學術語,具有和習於本發明所屬技藝者一般所瞭解的為相同的定義。若是有所衝突的情況下,本發明將會給予名詞新的定義。
細胞藉以從外界經由其細胞膜將粒子(例如蛋白質)攝入細胞之過程,已知被稱做細胞吞噬作用。細胞吞噬作用可調節許多過程,包括營養物攝取、病原菌進入、抗原展示及藥物遞送。在各種細胞吞噬途徑中,籠形蛋白(Clathrin)介導之胞飲作用涉及到直徑大約100 nm之小囊胞,其具有由主要與籠形蛋白締合之蛋白質複合體所組成的具形態特徵之結晶型表層。實際上,在所有細胞中皆有籠形蛋白包覆之小囊胞(CCVs),且會形成胞質膜的功能域,稱做覆有籠形蛋白的小窩(clathrin-coated pits)。
亦相信,胞外分子之攝入係專一地經由小窩內的受體藉導,其係由膽固醇-結合蛋白窖蛋白(caveolin,Vip21)與富含膽固醇與醣脂類之雙層膜所組成。小窩(Caveolae)為存在細胞內之小的(直徑大約50 nm)酒瓶狀小窩。巨胞飲作用(Macropinocytosis)為細胞膜內陷形成一口袋,然後向內縮入細胞內而形成一非專一性充滿大量胞外液體與分子之小囊胞(直徑0.5-5 μm)。吞噬作用(Phagocytosis)為細胞藉以與直徑大於0.75 μm左右之特定物質,例如細小塵埃顆粒、細胞碎片、微生物及自我凋亡之細胞結合,並將其內化的過程。
配體-受體對、病毒與其他病原菌以及非病毒性基因遞送載體,已知係藉由受體結合,隨後經由受體介導之胞飲作用,進入覆有籠形蛋白的小窩及小囊胞中,而進到細胞內。某些毒素及病原菌,例如炭疽毒素會管制籠形蛋白介導之內化作用進入細胞。籠形蛋白介導之途徑似乎不僅只被病毒利用,亦會被較病毒大許多的細菌病原菌,例如單核細胞增生李斯特菌所利用。病原性蛋白顆粒及一些細菌係藉由其他與籠形蛋白無關之路徑進入細胞(參見Miaczynska M.等人,J Cell Biol. 2008年一月14日;180(1): 7.11)。
奈米微粒在生物醫藥上的應用相當重要,範圍從利用基因療法治療人類疾病,擴及到以標定探針來瞭解基本的細胞功能。目前有可能合成具有幾乎任何特性或大小之奈米微粒,將彼等導向特定細胞,及將彼等功能化使其靶定到細胞內的位置。
然而,仍欠缺用於測量奈米微粒攝入之有效、精確的方法。
已研發出細胞質譜分析法(CMS),用於在氣相直接測量細胞質量。已經藉由同時測量質量-對-電荷比(m/z)及電荷(z),證明可快速測定細胞與聚苯乙烯微粒的質量分佈。(W.-P. Peng等人Angew. Chem. Int. Ed. 2007,46:3865;W-P. Peng等人Anal. Chem. 2008,80,2524)。得到m/z值範圍從109至1012之質譜,具有良好的信號雜訊比。可清楚辨別出不同種類的單核細胞、癌細胞及紅血球。(W.-P. Peng等人,Angew. Chem. Int. Ed. 2007,46,3865;Z. Nie等人,Anal. Chem. 2007,79,7401;Z. Nie等人,Int. J. Mass Spectrom. 2008,270,8)。藉由此等方法,能達到的~100質量解析度以及~1%的質量精確度。(Z. Nie等人,Int. J. Mass Spectrom. 2008,270:8)。由CMS測得之結果大概和以ICPMS測得的相同。可用於光散射或電荷測量法(CMCMS),來測量所選擇細胞的質量。
使用細胞質譜儀偵測奈米微粒的方法,已揭示於PCT申請案公開號WO/2009/076535,其完整內容以引用方式納入本文做為參考。WO/2009/076535揭示一種裝置包括:用於裝設及使受分析物脫附/蒸發之組成元件;用於增強受分析物之靜電電荷的組成元件;用於依據受分析物與電場及/或磁場之相互作用來測定其質荷比(m/z)的質量分析儀;及用於測量受分析物之電荷的電荷偵測器。WO/2009/076535所揭示之方法可用於直接偵測生物粒子,例如病毒、巨分子複合體、核醣體、胞器、粒線體、葉綠體、突觸體、染色體、完整細胞、癌細胞、細菌細胞、花粉粒及孢子。WO/2009/076535所揭示之方法亦適用於直接測量小分子、奈米微粒及聚合物。
已意外發現,質譜分析方法可用於偵測及測量細胞之粒子攝入。粒子之種類可為奈米粒子、微粒子、病毒、蛋白質及小分子藥物。本發明係測量細胞的質量差異,以測定出被細胞攝入的粒子數。於一項具體實施例,係測量被細胞攝入的奈米粒子數量。
已研發出電荷監測細胞質譜分析法(CMCMS)用於快速測量細胞及微粒子之質量與質量分佈。受控放電會增加微粒子上之電荷數,以增加CMCMS之質量測量的精確度。(W.-P. Peng等人Anal. Chem. 2008,80,2524)。
事實上已經可藉由利用輕脫附技術,例如雷射導致超音波脫附法(LIAD)之質譜儀來測量完整生物粒子,包括病毒、細菌及整個哺乳動物細胞。質譜分析法一般需要將受分析物蒸發成氣相以進行後續的分析,特別是藉由質量分析儀進行分析。脫附法是一種將受分析物蒸發成氣相的常用方法。根據本發明,可使用多種脫附法。可使用雷射導致超音波脫附法(LIAD),只需在該裝置架構一種可將受分析物架設於其上的基材,而無需底層基質。以雷射照射該基材可用以使受分析物從該基材脫離出來,而使受分析物能進入氣相,並接受由該裝置之其他組成元件產生的電場及/或磁場。
其他類型脫附法包括(但不限定於)介質輔助雷射脫附遊離法(MALDI)、表面增強雷射脫附遊離法(SELDI)、矽層上脫附遊離法(DIOS)、脫附電噴灑遊離法(DESI)、電漿脫附法及場脫附法(FD)。本發明亦包括其他脫附型式,例如電子遊離(El)、化學遊離(Cl)、場遊離(Fl)、快速原子轟擊(FAB)、離子附著遊離(IA)、電噴灑(ES)、熱噴灑(TS)、大氣壓遊離(API)、大氣壓光致遊離(APP)、大氣壓化學遊離(APCI)與即時直接分析(DART)。
可使用一種包含阱之質量分析儀進行光散射測量,來測定這些被攝入的生物粒子之質荷比(m/z)。該質量分析儀可使用電磁場,將受分析物根據其質荷比而以空間或時間進行分類。本發明可關於利用許多類型質量分析儀之質譜儀。受分析物可於離子阱中進行分析。離子阱可為一種立體四極離子阱,已知亦稱做Paul離子阱,其可具有末端蓋電極與環電極。末端蓋電極可呈雙曲線型。末端蓋電極可為橢圓體。於末端蓋電極可鑽孔洞以使能觀察光散射,並使受分析物能通過其排出。可根據受分析物之質荷比掃描振動頻率而使其從離子阱排出。離子阱可為一種線形離子阱(LIT),已知亦稱做平面式離子阱。可與一種以上偵測器結合,以偵測到從軸向及徑向排出的受分析物。
質量分析儀可為一種飛行時間分析器(time-of-flight analyzer)。飛行時間分析器可包括用於在一個使受分析物加速的區域內產生電場的電極,隨後接一個無電場區域,再接著一偵測器。飛行時間分析器可為反射式飛行時間分析器,其中反射器或靜電反射器可增加受分析物的總飛行長度與時間。飛行時間分析器可藉由延遲脈衝萃取進行操作,其中係以校正離子能量散佈的方式控制加速場,且/或加速場只在接續於吸附後的延遲之後才出現。其他適用於本發明之質量分析儀包括(但不限定於四極質譜儀、扇形磁場質譜儀、軌道離子阱及離子迴旋共振分析器。
電荷監測細胞質譜分析法(CMCMS)可用於測量高速細胞/微粒子的質量。關於此裝置,係將細胞或微粒子樣本放置於矽晶片上。雷射導致超音波脫附法(LIAD)用於將細胞/微粒子震離而進入離子阱中。藉由掃描捕集頻率將帶電荷之細胞排出,而測得細胞的m/z比。使用法拉第圓盤測量該粒子上之電荷數目,以使能測得帶電粒子的質量。CMCMS有一些特性與市面上大多數習知的質譜儀相當。包括(1)LIAD使帶電粒子脫附進入四極離子阱(QIT)中,(2)使用以質量選擇不安定法操作之頻率掃描獲得非常高的m/z比,(3)直接測量粒子上的電荷(z)數量而不需要將次級電子放大,及(4)於微粒子上進行電暈放電以增加電荷數量(Id.)。
為證明CMS儀器能夠定量奈米/微米粒子之細胞攝入,首先將NTERA2細胞與30nm及250nm奈米金粒子進行培育,並記錄其質譜。質譜的m/z範圍係從109至1010。以法拉第平盤電荷偵測器來檢測各細胞上所攜帶之電荷(代表性地大於一萬)。圖1顯示,所觀察到有攝入奈米金粒子之NTERA2細胞的質譜高峰位,被位移到較高的範圍。
如圖2所示,當細胞攝入60nm、100nm及1μm NIST聚苯乙烯(非金屬)粒子時,得到類似的實驗結果。所有於本發明使用之聚苯乙烯球尺寸標準粒子,係購自國家標準與技術研究院(NIST)。標準參考樣品(SRM)包括SRM 1964(60nm)、SRM 1963(0.1μm)、SRM 1691(0.3μm)與SRM 1690(1μm)。觀察到的質譜高峰係介於109至1010。
於圖3b及圖3a分別列示,有和無攝入奈米金粒子之NTERA2細胞的代表性質量分佈分析。對於每一質量柱狀圖分佈分析,係以CMS測量六百個細胞。將於各細胞取得之m/z
值與相對應的電荷(z)轉換成受測量細胞之絕對質量。應注意在執行高斯擬合程式時,必須截斷高的質量叢。所收集到3μm NIST聚苯乙烯球之質譜的質量分佈顯示,平均質量在重覆八次測量後,偏離了大約1.8%。而當以海拉細胞(HeLa cells)進行奈米金攝入測量,得到質量精確度為~2.1%。本發明CMS儀器之質量精確度,能夠區別有和無攝入奈米金粒子之細胞。
圖4列示大小為30nm及250nm之奈米金的細胞攝入隨培養時間之變化圖。對於NTERA2細胞所攝入之30nm奈米金,在培養24小時後測量到平均質量差為約60%。如圖4a所示,此平均質量差相當於~260,000個30nm奈米金。圖4b顯示經過24小時培養後平均質量偏離200%,相當於~800個250nm奈米金被NTERA2細胞攝入。
圖5a列示使用CMS及ICP-MS測量50nm奈米金攝入進入NTERA2細胞之動力圖。以該二種測量方法測得之攝入趨向及攝入量十分相近。對於CMS測量法,係於將細胞以4%溶於PBS之三聚甲醛固定後測定細胞重量。
於是,CMS係測量每一各別細胞,並因而反映出細胞所攝入的奈米金數量。由此等結果得知,細胞質譜分析是一種能滿足時間-解析測量細胞所攝入之奈米金的方法。圖5b列示使用Raw264.7細胞株測量得之奈米聚苯乙烯球的攝入動力圖。
CMS不僅是一種測定細胞所攝入入之奈米金數量的快速、精確方法,亦可測定每一各別細胞所攝入之奈米粒子數量,而ICP只能得到所有細胞的平均值。
總觀奈米金之定量測量法,CMS為一種可應用於定量所有類型奈米粒子的有用方法(K.Cho等人,Clin Cancer Res.,2008,14,1310),包括奈米聚合物粒子(B.L.Zhang等人,Small,2009,5,2716)、微脂粒、病毒為主之NPs、奈米碳管、奈米鑽石粒子(H.J.Johnston等人,Toxicol.Appl.Pharmacol.2010,242,66)及聚合型微胞。
於某些具體實施例,微粒子或奈米粒子是指油脂性顆粒。油脂性顆粒為包括至少一種形成濃縮液相之油脂組成分的微粒子或奈米粒子。代表性地,油脂性奈米粒子在其組成物中具有大量脂質。例舉來說,濃縮液相係指固態非晶型或真正結晶型相;同晶型液相(液滴);及各種水合介晶型定向液相例如液態結晶與偽晶型雙層相(逆六方晶體H-I、H-II、立方Pn3m)(參見生物膜之結構,P. Yeagle編著,CRC出版,Boca Raton,Fla.,1991,特別是第1-5章,以引用方式納入本文參考)。脂肪性微粒包括(但不限定於)微脂粒、脂質-核酸複合體、脂質-藥物複合體、固態脂質顆粒及微乳膠液滴。製造及使用這類油脂性微粒子與奈米粒子,以及在其上接附親和性部分(例如抗體)的方法,為該技術領域已知的(參見,美國專利U.S. Pat. Nos. 5,077,057;5,100,591;5,616,334;6,406,713(脂質-藥物複合體);U.S. Pat. Nos. 5,576,016;6,248,363;Bondi等人(2003) Drug Delivery 10: 245-250;Pedersen等人(2006) Eur. J. Pharm. Biopharm. 62: 155-162(固態油脂性顆粒);U.S. Pat. Nos. 5,534,502;6,720,001;Shiokawa等人(2005) Clin. Cancer Res. 11: 2018-2025(微乳膠液滴);U.S. Pat. No. 6,071,533(脂質-核酸複合體))
微脂粒一般定義為包含一或多層脂質雙層,包圍著內部結構(代表性地是含水性內部)的粒子。因此,微脂粒通常是指一種由雙層脂質膜形成的囊泡。已有許多製備微脂粒之方法。其中有些是用來製備小囊泡(d<0.05微米),有些用於製備較大囊泡(d>0.05微米)。有些是用於製備多層囊泡,有些則係製備單層的。於本發明之某些具體實施例係以單層囊泡為較佳,因為發生在膜上的溶解事件,即意味該完整囊泡被溶解。然而,也可使用多層囊泡,或許效率會比較低。微脂粒之製備方法已充分描述於一些回顧文獻中,例如Szoka與Papahadjopoulos(1980) Ann. Rev. Biophys. Bioengg.,9: 467;Deamer與Uster(1983) Pp. 27-51於:微脂粒,M. J. Ostro編著,Marcel Dekker出版,紐約等。
以根據本發明之方法偵測其細胞攝入的奈米結構化材料,所具有之結構可選自:六面體、立方體、菱面體、斜方晶體、單斜晶體、三斜晶體及其組合型式。尤其,該奈米結構化材料具有六方晶格結構。
以根據本發明之方法偵測其細胞攝入的奈米結構化材料,其至少一維的大小是<1000 nm。例如<100 nm,特別是小於50 nm。特別地,該奈米結構化材料之至少一維的大小是<25 nm。甚至更特別地,其至少一維的大小係<10 nm。
根據本發明之一方面,係提供一種偵測奈米結構化材料攝入之方法,其中該奈米結構化材料接附上一種生物分子。生物分子可為任一種適合的生物分子。例如,該生物分子係選自蛋白質、核酸、核苷、核苷酸、DNA、激素、胺基酸、肽類、擬肽類、RNA、脂質、白蛋白、抗體、磷脂類、醣脂類、固醇類、維生素、神經傳導物質、碳水化合物、糖類、雙糖、單糖、寡肽、多肽、寡糖、多糖及其混合物。
本發明之CMS方法不僅可用於測量奈米金屬粒子之細胞攝入,亦可用於偵測非金屬奈米/微米粒子。(J.A. Champion,S. Mitragotri,Proc. Natl. Acad. Sci. U.S.A. 2006,103,4930)。
已發展出用於將藥物遞送到及並部位之奈米-規格非金屬藥物載體,例如微脂粒及聚合物囊泡,且逐漸被普遍用於臨床。已逐漸瞭解奈米載體的設計原理,及其在生物學上之相互作用,使能設計出具有特殊藥物遞送、靶定及釋出特徵的奈米載體。
亟需要將細胞毒性或化學治療藥劑遞送至固體腫瘤部位,因為這些藥劑不僅會殺死腫瘤細胞,也能殺死身體內的正常細胞。此對於正常細胞之毒性,會限制細胞毒性藥劑的使用劑量,而因此減低其治療效能。
本發明之CMS法可用於測量奈米載體的量,例如被攝入入癌細胞(T. Minko等人,Anti-Canc. Agents Med. Chem. 2006,6,537)之藥物遞送用微脂粒(Y. Aoyama等人,J. Am. Chem. Soc. 2003,125,3455;J. M. De la Fuente等人,Langmuir,2006,22,3286;A. Elbakry,等人,Nano Lett. 2009,9,2059)。
微粒子及奈米粒子(包括微脂粒)之厭水性奈米微粒核心內,可納入存在水性介質或有機溶劑中的治療劑(生物活性部分)。
生物活性劑(治療劑)包括(而不限定於)治療藥劑(例如抗癌劑)、診斷試劑(例如對比劑;放射性核種;及螢光劑、發光劑與磁性部分)、預防劑(例如疫苗)及/或營養製劑(例如維生素、礦物質等)。生物活性劑可能已經投藥給如本文所揭示的個體。欲根據本發明進行遞送之例舉性治療劑包括(而不限定於)小分子(例如細胞毒性劑)、核酸(例如siRNA、RNAi與微RNA)、蛋白質(例如抗體)、肽類、脂質、碳水化合物、激素、金屬、放射活性元素與化合物、藥物、疫苗、免疫試劑等及/或其組合物。於有些具體實施例,欲進行遞送之藥劑為一種可用於治療癌症(例如前列腺癌)的藥劑。
一些可置於根據本發明所製得之奈米粒子內,進行遞送的治療劑實例包括(但不限定於)諸如青黴素、胺基青黴素、與青黴素酶抑制劑及/或抗真菌劑聯結之青黴素、頭孢菌素、頭黴素與碳青黴素烯類、氟化喹啉酮、四環菌素、大環內酯及胺基糖苷類等藥劑。特殊實例包括(但不限定於)紅黴素、枯草菌素鋅、多黏桿菌素、硫酸多黏桿菌素、新黴素、慶大黴素、妥布黴素、滅革蘭菌素、塞普沙辛、曲美普林、氧氟沙星、左氟沙星、加替沙星、莫西沙星、諾氟沙星、磺胺醋醯鈉、氯黴素、四環黴素、阿奇黴素、克拉黴素、硫酸曲美普林及枯草菌素。
其他適合包封於所揭示之奈米粒子中的治療劑實例為非類固醇(NSAIDs)與類固醇消炎藥,一般稱做消炎藥劑(包括COX-I及COX-2抑制劑)。實例包括(但不限定於)皮質類固醇、甲羥松、潑尼松龍、潑尼松龍醋酸鹽、潑尼松龍磷酸鈉鹽、氟米龍、地塞米松、地塞米松磷酸鈉鹽、貝皮質醇、氟米松龍、安他唑啉、氟米龍醋酸鹽、利美索龍、洛替潑諾、雙氯酚酸(雙氯酚酸鈉)、酮咯酸、酮咯酸氨丁三酸醇鹽、氫化皮質酮、溴芬酸、氟白普洛芬、安他唑啉及賽洛唑啉。
其他可納入本文所揭示之奈米粒子中的治療劑包括抗組織胺、肥大細胞安定劑、抗過敏藥及其他抗過敏藥劑。實例包括(但不限定於)色甘酸鈉、洛草胺酸氨丁三醇、奧洛他定HCl、奈多羅米鈉、酮替芬延胡索酸鹽、左卡巴司汀HCL、氮卓司丁HCL、派米拉特(派米拉特鉀)、依匹那丁HCL、萘甲唑啉HCL、依美司丁、安他唑啉、苯吡丙胺、色甘酸二鈉、N-乙醯基-天冬胺醯基麩胺酸及氨米占諾。
其他可能適合納入奈米粒子中之治療劑的非限制性實例包括抗癌劑,例如5-氟尿嘧啶(5-FU)、CPT-I1、10-羥基-7-乙基喜樹鹼(SN38)、S-I卡培他濱、喃氟定、5’-去氧氟尿苷、UFT、恩尿嘧啶、去氧胞苷、5-氮胞嘧啶、5-氮去氧胞嘧啶、異嘌呤醇、2-氯腺苷、氨基蝶呤、亞甲基-10-脫氮氨蝶呤(MDAM)、草酸鉑、匹考鉑、四鉑、磺咪鉑、奧馬鉑、CI-973、JM 216及其類似物、9-胺基喜樹鹼、1 Ojl 1-亞甲二氧基喜樹鹼、卡雷提辛(karenitecin)、9-硝基喜樹鹼、TAS 103、L-苯丙胺酸氮芥、異環磷醯胺、三芥環磷醯胺、卡莫司汀、埃博黴素A-E、雷替曲塞、6-巰嘌呤、6-硫鳥嘌呤、阿昔洛韋、伐昔洛韋、更昔洛韋、金剛烷胺、金剛乙胺、拉美夫定、奇弗定、癌思停(bevacizumab)、曲妥珠單抗(trastuzumab)、利妥昔單抗(rituximab)、20-epi-l、25二羥基維生素D3、4-甘薯黑疤黴二醇、5-乙炔尿嘧啶、9-二氫紫杉醇、阿比特龍、阿西維辛、阿克拉黴素、阿考達唑鹽酸鹽、阿克羅寧、乙醯非林(acylfiilvene)、阿得西酚(adecypenol)、阿多來新、阿地白介素、全-tk拮抗劑、六甲密胺、安巴氮芥、丙胺肽黴素、阿美蒽醌醋酸鹽、艾米多索(amidox)、阿米斯丁、氨魯米特、胺基乙醯丙酸、氨柔比星、安吖啶、氯喹咪唑酮、阿那曲唑、穿心蓮內酯、血管生成抑制劑、拮抗劑D、拮抗劑G、安雷利克斯、安拉黴素、抗背化形態發生蛋白-1、抗動情激素、抗瘤酮、反義寡核苷酸、艾菲地可寧甘胺酸鹽、凋亡基因調制劑、凋亡作用調節劑、無嘌呤核酸、ARA-CDP-DL-PTBA、精胺酸脫胺酶、天冬醯胺酶、曲林菌素、阿舒吖啶、阿他美坦、阿莫司汀、阿新司丁(axinastatin) 1、阿新司丁(axinastatin) 2、阿新司丁(axinastatin) 3、阿紮胞苷、阿紮司瓊、阿紮毒素(azatoxin)、阿薩太羅欣、阿紮替派、阿左黴素、巴卡亭III衍生物、巴拉醇(balanol)、巴馬司他、苯甲醯氯、苯甲替呱、苯甲醯司他孢素(benzoylstaurosporine)、貝他內醯胺衍生物、貝他-alethine、貝他克拉黴素B、白樺脂酸、BFGF抑制劑、比卡魯胺、比生群、比生群鹽酸鹽、雙舒啶基精胺、雙奈法德、雙奈法德二甲磺酸鹽、比史他汀(bistratene) A、比折來新、博來黴素、博來黴素硫酸鹽、BRC/ABL拮抗劑、佈雷酸鹽、布喹那鈉、溴匹利胺、布朵替坦、白消安、丁硫堇、放線菌素C、鈣泊三醇、鈣磷司丁C、卡普睪酮、喜樹鹼衍生物、金絲雀痘病毒IL-2、卡培他濱、卡拉醯胺、卡貝替姆、卡鉑、胺甲醯胺-胺基三唑、羰氧醯胺基三唑、卡雷斯(carest) M3、卡莫司汀、earn 700、軟骨衍生之抑制劑、卡柔比星鹽酸鹽、卡折來新、酪蛋白激酶抑制劑、栗樹精胺、抗菌肽B、cedefmgol、西曲瑞克、苯丁酸氮芥、氯劑、氯喹噁啉磺醯胺、西卡前列腺素、西羅黴素、順鉑、順-卟啉、克拉屈濱、氯米芬類似物、克黴唑、覆蓋黴素A、覆蓋黴素B、坎培司汀(combretastatin) A4、坎培司汀類似物、conagenin、甘藍海綿素(crambescidin)816、克雷斯托、克雷斯托甲磺酸鹽、念珠藻環肽(cryptophycin) 8、念珠藻環肽A衍生物、珊瑚菌素(curacin) A、環戊蒽醌、環磷醯胺、環普拉坦(cycloplatam)、塞普黴素(cypemycin)、阿糖胞苷、阿糖胞苷酯、細胞溶解因數、細胞靜止素、達卡巴嗪、達昔單抗、放線菌素D、鹽酸柔紅黴素、地西他濱、脫氫膜海鞘素B、地洛瑞林、右磷醯胺、右奧馬鉑、右雷佐生、右維拉帕米、地紮胍寧、地紮胍寧甲磺酸鹽、地吖醌、膜海鞘素、didox、二乙精胺、二氫-5-氮胞苷、地奧黴素(dioxamycin)、二苯基螺莫司汀、多西他賽、二十二烷醇、朵拉司瓊、多西氟尿啶、阿黴素、阿黴素鹽酸鹽、著洛西芬、著洛西芬檸檬酸鹽、羥甲雄酮丙酸酯、四氫大麻酚、偶氮黴素、杜康黴素(duocannycin) SA、依布硒、依考莫司汀、依達曲沙、依地福新、依決洛單抗、依氟鳥氨酸、依氟鳥氨酸鹽酸鹽、欖烯、依沙蘆星、乙嘧替氟、恩洛鉑、恩普氨酯、依匹呱啶、表柔比星、表柔比星鹽酸鹽、依立雄胺、厄布洛唑、紅血球基因療法載體系統、依索比星鹽酸鹽、雌莫司汀、雌莫司汀類似物、磷酸鈉雌莫司汀、雌激素促動劑、雌激素拮抗劑、依他硝唑、依託泊苷、依託泊苷磷酸鹽、氯苯乙嘧胺、依西美坦、法倔唑、法倔唑鹽酸鹽、法紮拉濱、芬維A胺、非格司亭、非那雄胺、flavopiridol、氟噻司汀、氮尿苷、氟阿斯酮(fluasterone)、氟達拉濱、氟達拉濱磷酸鹽、氟達尼新(fluorodaunorunicin)鹽酸鹽、氟尿嘧啶、氟西他濱、福酚美克、福美坦、磷喹酮、福司曲星、福司曲星鈉、福莫司汀、釓德卟啉、硝酸鎵、加洛他濱、加尼瑞克、明膠酶抑制劑、吉西他濱、吉西他濱鹽酸鹽、谷胱甘肽抑制劑、庚舒法姆(hepsulfam)、生長因子heregulin(HRG)、六亞甲雙乙醯胺、羥基脲、金絲桃素、伊班膦酸、伊達比星、伊達比星鹽酸鹽、艾多昔芬、伊決孟酮、異環磷醯胺、伊諾福星(ihnofosine)、伊洛馬司他、咪唑吖啶酮、咪喹莫特、免疫刺激肽、類胰島素生長因數-1受體抑制劑、幹擾素促動劑、幹擾素阿伐-2A、幹擾素阿伐-2B、幹擾素阿伐-N1、幹擾素阿伐-N3、幹擾素貝他-IA、幹擾素加瑪-IB、幹擾素、介白素、碘苄胍、碘多柔比星、異丙鉑、伊立替康鹽酸鹽、伊羅普拉、伊索拉定、異苄加唑、異同海利康(isohomohalicondrin) B、伊他司瓊、杰拉諾肽(jasplakinolide)、海蛞蝓肽kahalalide F、片螺素-N三醋酸鹽、蘭瑞肽、蘭瑞肽醋酸鹽、來那黴素、來格司亭、硫酸香菇多醣、leptolstatin、來曲唑、介白素抑制因數、白血病阿伐幹擾素、利普安、利普安/雌激素/黃體酮、亮丙瑞林、左旋咪唑、利阿唑、利阿唑鹽酸鹽、線形聚胺類似物、親脂性雙糖肽、親脂性鉑化合物、利索林胺(lissoclinamide)、洛鉑、蚯蚓氨酸、洛美曲索、洛美曲索鈉、洛莫司汀、氯尼達明、洛索蒽醌、洛索蒽醌鹽酸鹽、洛伐他汀、洛索立賓、勒托替康、鑥德卟啉、來費林(lysofylline)、溶解肽、美坦新、甘露司汀A、馬立馬司他、馬索羅酚、馬司平、基質分解素抑制劑、基質金屬蛋白酶抑制劑、美登素、鹽酸氮芥、甲地孕酮醋酸鹽、美侖孕酮醋酸鹽、美法侖、美諾立爾、美巴龍、巰基嘌呤、美替瑞林(meterelin)、甲硫胺酸酶、甲胺蝶呤、甲胺蝶呤鈉、甲氧氯普胺、氯苯氯啶、四甲尿烷亞胺、微藻蛋白激酶C抑制劑、MIF抑制劑、米非司酮、米替福星、米英司定、錯配雙股RNA、米汀多醯胺、絲裂卡菌素、絲裂紅素、絲裂吉菌素、丙米腙、二溴衛矛醇、絲裂馬菌素、絲裂黴素、絲裂黴素類似物、胺硝萘酞胺、絲裂帕菌素、米托坦、絲裂毒素成纖維細胞生長因數-皂草素、米托蒽醌、米托蒽醌鹽酸鹽、莫法羅汀、莫格拉司替姆、單株抗體、蒙匹胺醇、多重藥物抗性基因抑制劑、芥子抗癌劑、過氧麥卡(mycaperoxide)B、分枝桿菌胞壁抽出物、麥考酚酸、麥立普隆(myriaporone)、n-乙醯基地那林、那法瑞林、nagrestip、納洛酮/噴他佐辛、napavin、萘特平、那托司亭、奈達鉑、奈莫柔比星、奈立膦酸、中性內肽酶、尼魯米特、尼沙黴素、一氧化氮調制劑、氮氧抗氧化劑、尼魯來恩(nitrullyn)、諾考達唑、諾加拉黴素、n-取代苄醯胺、06-苄基胍、奧曲肽、歐奇辛酮(okicenone)、寡核苷酸、奧那司酮、昂丹司瓊、奧拉辛、口服細胞因子誘導劑、奧馬鉑、奧沙特隆、奧沙利铂、氧諾黴素(oxaunomycin)、奧昔舒侖、紫杉醇、紫杉醇類似物、紫杉醇衍生物、普勞胺、棕櫚醯基根黴素、帕米磷酸、人蔘三醇、帕諾米芬、三羥水楊胺、帕折普汀、培天冬胺酸酶、peldesine、培利黴素、奈莫司汀、木聚硫鈉、噴司他丁、戊四唑、培洛黴素硫酸鹽、全氟溴烷、培磷醯胺、芥子醇、吩嗪黴素、醋酸苯酚酯、磷酸酶抑制劑、沙培林、毛果芸香鹼鹽酸鹽、哌泊溴烷、哌泊舒凡、吡柔比星、吡曲克辛、吡羅蒽醌鹽酸鹽、普拉昔丁(placetin) A、普拉昔丁B、纖溶酶原活化劑抑制劑、鉑錯合物、鉑化合物、鉑-三胺錯合物、普卡黴素、普洛美坦、卟吩姆鈉、泊非黴素、潑尼莫司汀、丙卡巴肼鹽酸鹽、雙吖啶丙酯、前列腺素J2、前列腺癌抗雄激素、蛋白解體抑制劑、蛋白降低免疫調制劑、蛋白激酶C抑制劑、蛋白酪胺酸、磷酸酶抑制劑、嘌呤核苷酸磷酸化酶抑制劑、嘌羅黴素、嘌羅黴素鹽酸鹽、羥基茜草素、唑吡黴素、唑吡并吖啶、吡哆酸化血紅素聚氧乙烯共軛物、RAF拮抗劑、雷替曲塞、雷莫司瓊、RAS法尼基蛋白質轉移酶抑制劑、RAS抑制劑、RAS-GAP抑制劑、二甲基化雷替尼卜定、錸RE 186伊替膦酸鈉、根黴素、核酶、RH瑞替那肽、RNAi、吡魯米特、羅土凱(rohitukine)、胞壁醯基二肽、羅喹美克、柔比隆B1、ruboxyl、沙芬戈、沙芬戈鹽酸鹽、賽恩托平(saintopin)、肌氨酸亞硝脲、肌肉葉綠醇A、沙格司亭、SDIl模擬肽、司莫司汀、老化衍生抑制劑1、有義寡核苷酸、訊號傳導抑制劑、訊號傳導調節劑、辛曲秦、單鏈抗原結合蛋白、西佐喃、索布佐生、硼卡鈉、苯乙酸鈉、所維羅(solverol)、生長調節素結合蛋白、索纳明、斯帕磷酸鈉、斯帕磷酸、司帕索黴素、斯比卡黴素D、鍺螺胺鹽酸鹽、螺莫司汀、螺鉑、斯耐潘定、海綿素1、角鯊胺、幹細胞抑制劑、幹細胞分裂抑制劑、提比醯胺(stipiamide)、鏈黑黴素、鏈唑黴素、溶基質素抑制劑、磺苄辛(sulfinosine)、磺氯苯脲、超活性血管活性腸肽拮抗劑、舒迪司他(suradista)、舒拉明、苦馬豆素、合成型糖胺聚醣、他利黴素、他莫司汀、他莫昔芬甲碘化物、牛磺莫司汀、他扎罗汀、螺旋藻多糖鈉、替加氟、替魯吡喃鎓(tellurapyrylium)、端粒酶抑制劑、替洛蒽醌鹽酸鹽、替莫泊芬、替莫唑胺、替尼泊苷、替罗昔隆、睾内酪、四氯癸烷氧化物、四唑胺、厚果唐松草鹼、沙利度胺、硫唑鳥嘌呤、硫可拉林(thiocoraline)、硫鳥嘌呤、塞替派、血小板生長因子、血小板生長因子模擬肽、胸腺法新、胸腺生成素受體促動劑、胸腺曲南、甲狀腺刺激激素、噻唑呋林、乙基初卟啉锡、替拉扎明、二氯二茂鈦、拓撲替康鹽酸鹽、topsentin、托瑞米芬、托瑞米芬檸檬酸鹽、全能性幹細胞因子、轉譯抑制劑、曲托龍醋酸鹽、維A酸、三乙脲、曲西立濱、曲西立濱磷酸鹽、三甲曲沙、三甲曲沙葡萄醛酸鹽、曲普瑞林、托烷司瓊、妥布氯唑鹽酸鹽、妥羅雄脲、酪胺酸激酶抑制劑、酪磷司汀(tyrphostins)、UBC抑制劑、烏苯美司、烏拉莫司汀、烏瑞替派、尿生殖竇-衍生之生長抑制因數、尿激酶受體拮抗劑、伐普肽、海綿素variolin B、維拉雷瑣、維拉明、維定(verdins)、維替泊芬、長春堿硫酸鹽、長春新堿硫酸鹽、長春地辛、長春地辛硫酸鹽、長春匹定硫酸鹽、長春甘酯硫酸鹽、長春羅新硫酸鹽、長春瑞濱、長春瑞濱酒石酸鹽、長春羅定硫酸鹽、長春塞丁、長春利定硫酸鹽、vitaxin、伏氯唑、紮諾特隆、折尼鉑、亞苄維C(2H)、淨司他丁、淨司他丁苯馬聚合物或佐柔比星鹽酸鹽,及其組合物。
於一項具體實施例,本發明之奈米粒子可含有siRNA做為治療劑。較佳地,siRNA分子之長度具有約10-50或以上個核苷酸。更佳地,siRNA分子之長度具有約15-45個核苷酸。甚至更佳地,siRNA分子之長度具有約19-40個核苷酸。甚至更佳地,siRNA分子之長度具有約21-23個核苷酸。本發明之siRNA較佳係介導RNAi對抗一標靶mRNA。市售之設計工具與套組,例如可購自Ambion,Inc.(奧斯汀,TX)及T之懷特海德生物醫學研究所(劍橋,MA)者,可用於設計和製造siRNA。
本發明之CMS方法可用於評估病毒奈米粒子之細胞攝入(J. Mercer,A. Helenius,Science 2008,320,531;A. Cooper,Y. Shaul, J. Biol. Chem. 2006,281,16563;G. Bao,X. R. Bao,Proc. Natl. Acad. Sci. U.S.A.2005,102(29):9997-8)。
真核細胞利用胞飲作用來執行許多功能,包括攝入細胞外的營養物及調節細胞表面受體,而且毒素、病毒與微生物亦藉此作用進入細胞。胞飲作用包含許多不同過程,例如較大(>250 nm)顆粒的吞噬作用。關於受體介導胞飲作用之機制的了解與定量分析,不僅對巨分子及病毒之吞噬作用很重要,對於使用在胞內顯影與標靶治療的巨分子及奈米粒子也具有重要意義(Gao,H.,Shi,W. & Freund,L. B.(2005) Proc. Natl. Acad. Sci. USA 102:9469-9474)。
雖然以每毫升複製數表示之病毒負載量(其係測量存在血流中的病毒顆粒數),已用於治療判定及監測治療功效,然而測定病毒粒子之胞內攝入,可提供更精確的免疫反應分析,以及決定治療療程。例如,最近在以卡波西肉瘤相關之加瑪皰疹病毒的研究觀察到,皰疹病毒通常係藉由胞內局部化,來避開在感染期間發生的有效免疫反應(Adang LA等人J. Virol. 81(10):5079-5090(2007))。
小於100 nm之顆粒係指,涵蓋一定尺寸範圍的奈米物質,包括諸如禽流感病毒及HIV等人類病毒。HIV病毒粒子之平均大小為約100 nm,C型肝炎病毒粒子則為約35-40 nm。經空氣傳染之病毒感染,一般係藉由攝入含有病毒粒子的水滴所引起。含有病毒粒子之較大液滴陳積在鼻內,而較小的液滴或奈米粒子,則到達其進入人類呼吸道或肺泡的管道。SARS病毒係經由咳嗽及噴嚏所產生,具有大小約100-500 nm左右的液滴而四處散布(Donnelly等人Lancet,361,1761-1777,(2003))。本發明提供一種方法用以偵測及定量,在受病毒感染之哺乳動物細胞內的病毒數,該病毒較佳係選自流感病毒、麻疹病毒、冠狀病毒、流行性腮腺炎病毒、馬堡病毒、伊波拉病毒、狂犬病毒、鼻病毒、脊髓灰白質病毒、A型肝炎病毒、天花病毒、雞痘病毒、嚴重急性呼吸道症候群病毒或SARS病毒(亦稱做SARS冠狀病毒)、人類免疫缺陷病毒(HIV)與相關的非人類動物免疫缺陷反轉錄病毒,例如猴免疫缺陷病毒(SIV)、輪狀病毒、諾瓦克病毒及腺病毒。流感病毒包括該病毒的人類與禽類形式。於本發明之另一項具體實施例,病毒係選自螺旋對稱型病毒、二十面體病毒、具外膜之病毒及複雜病毒。
除了可更準確測量感染之嚴重性,精確測量存在受感染細胞中的胞內病毒顆粒(ICV),亦能夠更專一測量抗病毒治療的有效性。雖然傳統上已藉由偵測與特定病毒連結粒子之量,來測量濃度(例如,以南方轉漬法測量mRNA,或以免疫分析法測量病毒顆粒),但此等方法並未測得該受感染細胞中完整病毒粒子的濃度,且結果往往高估ICV之量。
偵測及定量存在細胞中之病毒粒子的CMS方法,能夠準確測量胞內病毒顆粒(ICV)。吞噬作用為身體天生免疫作用的首要組件,其中巨噬細胞與其他抗原展示細胞,會吞噬大的(>0.5 μm)粒化標靶物,包括該等包含病毒及其他病原菌者。測量惰性(例如聚苯乙烯)粒子之胞內攝入為一種已接受模式用於,測量粒子(例如病原菌,包括病毒)胞內攝入之測定方法的效能(Champion JA與Mitragotri S Proc Natl Acad Sci U S A. 2006 March 28,103(13): 4930-4934)。
於本發明之另一項具體實施例,生物樣本係選自感染性主體、引起疾病之主體、及微生物。於本發明之又另一項具體實施例,感染性試劑係選自細菌、病毒、真菌、原生動物及寄生蟲。
於各種具體實施態樣中,本發明方法係測量選自下列之粒子的攝入:奈米粒子、微粒子、微膠囊、細胞毒素、藥物、微脂粒及抗體。於某些實施例,該粒子包含一選自:微脂粒及聚合物奈米粒子之部分。於某些實施例,該粒子包含一含有選自:抗癌藥、可偵測標記及放射敏化劑之部分的微脂粒。於某些實施例,該粒子包含一脂肪性微粒或奈米粒子(例如,微脂粒、脂質-核酸複合體、脂質-藥物複合體、固態脂質顆粒、微乳膠液滴等)。於某些實施例,該微粒或奈米粒子包含一種藥劑。於某些實施例,該微粒或奈米粒子係微脂粒(例如,多層微脂粒或單層微脂粒)。微脂粒可(視需要地)為經硬脂酸安定的微脂粒。於某些實施例,該微脂粒或其他脂肪性顆粒含有一種抗癌藥劑或抗癌siRNA,或另一種活性劑。
無意於限制本發明之範圍,以下將呈現根據本發明各種實施例之例舉性儀器、裝置、方法和其相關結果。應注意,實施例中為了方便讀者閱讀所使用的標題或副標題,並不以任何方式限制本發明的範圍。此外,在本文中所提出和披露的某些理論,但無論他們是對還是錯,只要該創作是根據本發明所實施的,而不需考慮任何特定的理論或行動的計畫,都應被限制在本發明的範圍之內。
CMS之實驗裝備包含無基質微粒子之雷射導致超音波脫附法,用於超大m/z測量之低頻四極離子阱,用以增加細胞或微粒子上之電荷數的壓力受控電暈放電,以及用於測量總電荷之緊密及低雜訊電荷偵測器。將具有脈衝時間大約為的二倍頻石榴石雷射光束(λ=532 nm,Laser Technik,柏林,德國),直接打在樣品盤的背面上,而藉由具有功率密度約108 W/cm2之雷射導致超音波脫附(LIAD)使細胞震出。使用設定於30 mJ/脈衝之雷射能量,從晶片背面照射樣本。RF電壓設定於~3000 Vp-p。將從雷射脫附法震出的微粒子,以存在氦氣緩衝溶液(ca.65 mTorr)中之交流電場(約350 Hz-20 Hz,5 sec)束縛住。為製備用於LIAD之樣本,將定量(10 μL)之已純化粒子懸浮液(含有~1x107個粒子/mL)滴在厚度~400 μm的矽晶片上,並置於乾燥箱中乾燥。
小鼠白血病單核球巨噬Raw 264.7細胞株、人類畸胎瘤NTERA2細胞株、與人類子宮頸癌HeLa細胞株係得自美國國家幹細胞資源中心(ATCC),並根據其說明書加以較低程度修改進行培養。簡述之,將細胞置於37℃及5% CO2大氣下,於含有10%胎牛血清(FCS)、2 mM左旋麩醯胺酸與1%標準青黴素/鏈黴素(10,000 IU/ml)(皆購自Life Technologies,Carlsbad,CA)之杜貝可修改英格培養基(Dulbecco's Modified Eagle's Medium,DMEM)或RPMI 1640培養基中培養。於本實驗,係將HeLa、Raw264.7及NTERA2細胞與不同尺寸之奈米金或聚苯乙烯球,共同置於完整培養基中培養一段所指定的時間。於指定的時間後,使用胰蛋白酶使細胞從培養皿表面脫離,以均質器將細胞打破,然後以杜貝可磷酸鹽緩衝食鹽水(PBS,Gibco BRL)清洗,並使用4%三聚甲醛之PBS溶液於室溫下固定15分鐘。之後,將細胞於去離子蒸餾水中清洗三次,接著經由Vi-CELL系列細胞存活分析儀(Beckman Coulter,USA)進行計數,測定出細胞總數,並在其置入質譜儀或ICP-MS中進行分析之前將其再懸浮。
使用X系列II ICP-MS(Thermo-Electron,Winsford,Cheshire,UK)測定金濃度。使用裝備有溫度與壓力感應器之微波消化器(MARSXpress,CEM Corporation,U.S.A.)進行細胞樣本消化。
將所有聚丙烯容器浸泡於7% v/v硝酸HNO3(Ultrex II,J.T.Baker Inc.,Phillipsburg,NJ)中24小時,再以去離子水清洗。將精確稱重之200mL細胞樣本轉移到已預先清潔的高壓消化瓶內,其中加入2mL王水。將這些消化瓶關閉,並於微波消化器中使用最佳化微波程式,於200W功率下將其加熱15分鐘,直到溫度達190℃,而步驟2係於190℃、功率下下保持加熱10分鐘。將這些消化瓶冷卻到室溫。這些溶液是使用去離子水稀釋到50mL,未使用任何乾燥步驟。各種奈米金粒子(AuNPs)之細胞攝入實驗皆進行3重複,且各重複均以ICP-MS測量7次。校正標準溶液(1000mg/L,ICP標準金溶液,Merck,Darmstadt,德國)以去離子水稀釋(標準濃度:50ppb、25ppb、10ppb、5ppb、1ppb)。
將各標準溶液以進行測量,並製作線性回歸直到c=0.9999。所得到的檢量線用於測定每一各別樣本中,被細胞攝入的奈米金數量。在每次分析之間,使用硝酸溶液清洗儀器以助去除金粒子。
將人類白血病CEM細胞株與慢病毒(MOI=3),於含有8μg/ml聚凝胺之完整培養基中培養一段所指定的時間。經過指定的時間後,將細胞以冰的杜貝可PBS(Gibco BRL)清洗去除未結合的病毒,並以4%三聚甲醛之PBS溶液於室溫下固定15分鐘。然後將細胞於去離子蒸餾水中清洗三次,並使用Vi-CELL系列細胞存活分析儀(Beckman Coulter,USA)進行計數,而測定出細胞總數。細胞在置入細胞質譜儀進行分析之前,先將其再懸浮。
如圖6所示,在感染後5小時,受感染細胞的質量增加約3.0×1013Da(質量差)。每一慢病毒之分子量為3.55108Da,因此平均大約有84,500個病毒被單一CEM細胞攝入。
所有於本說明書中所引用之公開案及專利申請案,皆以引用之方式納入本文,就如同各別的公開案或專利申請案經過特別且個別地表明係以引用之方式納入。
雖然前述發明已為了清楚了解本發明目的,而藉由例舉說明及實施例的方式加以詳細說明,但熟悉該技藝者應顯而易知,經由本發明之教示,可在不脫離如所附申請專利範圍所界定的精神及範圍下,對本發明進行某種程度的修改和變更。
圖1a-1b顯示NTERA2細胞在攝入250nm奈米金粒子(FIG.1a)及30nm奈米金粒子(FIG.1b)後的質譜。圖1c顯示NTERA2細胞之質譜。
圖2a-2c顯示Raw264.7細胞在攝入NIST 1μm聚苯乙烯球(2a)、NIST 100nm苯乙烯球(2b)及NIST 60nm聚苯乙烯球(2c)後的質譜。圖2d顯示Raw264.7細胞之質譜。
圖3a-3b分別顯示NTERA2細胞(3a)及NTERA2細胞在攝入30 nm奈米金粒子後(3b)的質量分布圖。
圖4a-4b分別顯示30 nm奈米金粒子(4a)及250 nm奈米金粒子(4b)的細胞攝入動力學圖。
圖5a-5b顯示分別以CMS(紅色圓點)及ICP-MS(黑色方塊)技術定量(5a) 50 nm奈米金粒子被NTERA2細胞攝入之隨培養時間變化的動力學圖,及(5b) 100 nm聚苯乙烯球被Raw264.7細胞攝入之隨培養時間變化的動力學圖。(其中插圖為TEM顯像照片)。
圖6顯示使用細胞質譜分析(CMS)測定奈米/微米粒子被攝入細胞之量。以細胞質譜分析測得之奈米金粒子攝入量,大約與藉由感應耦合電漿質譜分析(ICP-MS)測得的相同。
圖7顯示以細胞質譜分析測定之人類CEM細胞株於受慢病毒(MOI=3)感染後,歷經5小時培養期的質量變化。
Claims (28)
- 一種用於定量各別細胞所攝入之奈米粒子或微粒子數目的方法,該方法包含:(a)將一細胞於適合使該細胞攝入奈米粒子或微粒子之條件下,與具有已知尺寸的奈米粒子或微粒子接觸;(b)經由細胞質譜分析法記錄該細胞之質譜;(c)測定該細胞的質量/電荷(m/z)比值;(d)將在每一各別細胞所獲得之m/z值及相對應的電荷(z)轉換成受測量細胞之絕對質量;(e)測定平均質量差;及(f)將該平均質量差與對應於已知數量之具有已知尺寸的奈米粒子或微粒子的預定差值進行比較;其中該步驟(c)係包含下列步驟以測定該細胞中是否存在奈米粒子或微粒子:(c1)測定該細胞在有接觸及無接觸該奈米粒子或微粒子之下的m/z比值;及(c2)測定於有接觸與無接觸該奈米粒子或微粒子之細胞間產生的質量/電荷(m/z)位移,其中該m/z比位移相當於該奈米粒子或微粒子被該細胞攝入。
- 根據申請專利範圍第1項之方法,其進一步包含:以法拉第平盤電荷偵測器來檢測各細胞上所攜帶之電荷。
- 根據申請專利範圍第1項之方法,其中該質譜的m/z範圍係從109至1010。
- 根據申請專利範圍第1項之方法,其進一步包含:採取歷時測量;及測定該細胞攝入奈米粒子或微粒子的時間-解析圖譜。
- 根據申請專利範圍第1項之方法,其中該奈米粒子或微粒子之尺寸係介於10μm~5nm之間。
- 根據申請專利範圍第1項之方法,其中該奈米粒子或微粒子為 金屬。
- 根據申請專利範圍第6項之方法,其中該奈米粒子或微粒子係選自金、銀或鈀。
- 根據申請專利範圍第1項之方法,其中該奈米粒子或微粒子為非金屬。
- 根據申請專利範圍第8項之方法,其中該奈米粒子或微粒子為奈米聚苯乙烯球。
- 根據申請專利範圍第8項之方法,其中該奈米粒子包含聚合物奈米粒子(NPs)、微脂粒、病毒為主之NPs、奈米碳管、奈米鑽石粒子,及聚合型微胞、奈米載體、微脂粒、藥物奈米粒子或奈米病毒粒子。
- 根據申請專利範圍第10項之方法,其中該奈米粒子包含油脂性顆粒。
- 根據申請專利範圍第11項之方法,其中該油脂性顆粒係選自微脂粒、脂質-核酸複合體、脂質-藥物複合體、固態脂質顆粒及微乳膠液滴。
- 根據申請專利範圍第8項之方法,其中該奈米粒子包含選自:六面體、立方體、菱面體、斜方晶體、單斜晶體、三斜晶體及其組合型式之結構。
- 根據申請專利範圍第8項之方法,其中該奈米粒子包含一適合接附於奈米載體粒子上之生物分子。
- 根據申請專利範圍第14項之方法,其中該生物分子係選自:蛋白質、核酸、核苷、核苷酸、DNA、激素、胺基酸、肽類、擬肽類、RNA、脂質、白蛋白、抗體、磷脂類、醣脂類、固醇類、維生素、神經傳導物質、碳水化合物、糖類、雙糖、單糖、寡肽、多肽、寡糖、多糖及其混合物。
- 根據申請專利範圍第1項之方法,其中該奈米粒子及微粒子具有一被納入其厭水核心的治療劑或生物活性部分。
- 根據申請專利範圍第16項之方法,其中該生物活性部分係選自:診斷劑、對比劑、放射性核種、螢光劑、發光劑,及磁性 部分、預防藥劑、疫苗與營養劑。
- 根據申請專利範圍第17項之方法,其中該治療劑係選自:小分子、核酸、siRNA、RNAi、微RNA、蛋白質、抗體、肽類、脂質、碳水化合物、激素、金屬、放射活性化合物、藥物、疫苗、免疫試劑及其組合物。
- 一種測量標靶細胞之藥物攝入量的方法,該方法包含:將一標靶細胞與一藥物之奈米微粒接觸;及藉由根據申請專利範圍第1項之方法,測定該藥物奈米微粒被該標靶細胞攝入的數量。
- 根據申請專利範圍第19項之方法,其中該藥物係選自抗生素、非類固醇(NSAIDs)與類固醇消炎藥、抗組織胺、肥大細胞安定劑、抗過敏藥及抗癌藥劑。
- 一種用於測量受感染細胞內之病原菌奈米粒子及微粒子力價的方法,該方法包含:提供一受到病原菌奈米粒子或微粒子感染的細胞;及藉由根據申請專利範圍第1項之方法,測定該受感染細胞內的病原菌奈米粒子或微粒子數量,其中係將該受感染細胞之質譜數據與同一種類未受感染細胞的質譜數據進行比較。
- 根據申請專利範圍第21項之方法,其中該病原菌係選自病毒、細菌、病原性蛋白顆粒、酵母菌、真菌及寄生蟲。
- 根據申請專利範圍第22項之方法,其中該病原菌奈米粒子或微粒子為一種人類或非人類哺乳動物病毒。
- 根據申請專利範圍第23項之方法,其中該病毒係選自流感病毒、麻疹病毒、冠狀病毒、流行性腮腺炎病毒、馬堡病毒、伊波拉病毒、狂犬病毒、鼻病毒、脊髓灰白質病毒、A型肝炎病毒、天花病毒、雞痘病毒、嚴重急性呼吸道症候群病毒(SARS病毒)、人類免疫缺陷病毒(HIV)、猴免疫缺陷病毒(SIV)、輪狀病毒、諾瓦克病毒及腺病毒。
- 根據申請專利範圍第22項之方法,其中該受感染細胞為人類細胞。
- 根據申請專利範圍第23項之方法,其中該病毒係選自螺旋對稱型病毒、二十面體病毒、具外膜之病毒及複雜病毒。
- 根據申請專利範圍第1-26項中任一項之方法,其中該細胞質譜分析為電荷監測細胞質譜分析法(CMCMS),或具有以光掃描偵測進行捕捉的能力之質譜分析。
- 根據申請專利範圍第27項之方法,其中該具有捕捉的能力之質譜分析為離子阱質譜分析或傅立業轉換離子迴旋共振(FTICR)質譜分析。
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