TW202000687A - 合成多肽及其用途 - Google Patents
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- TW202000687A TW202000687A TW108122757A TW108122757A TW202000687A TW 202000687 A TW202000687 A TW 202000687A TW 108122757 A TW108122757 A TW 108122757A TW 108122757 A TW108122757 A TW 108122757A TW 202000687 A TW202000687 A TW 202000687A
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Abstract
本揭示內容是關於新穎之合成多肽,以及其於製備微脂體之用途。依據本揭示內容之實施方式,該合成多肽包含一破膜模體、一遮蔽模體,以及一用以連接該破膜模體及該遮蔽模體的連接子。連接子可經光照、蛋白酶或去磷酸酶等引信訊號而裂解。一旦連接至微脂體,接觸引信訊號會促使連接子產生裂解反應,使遮蔽模體與破膜模體分離,進而活化微脂體上破膜模體的破膜活性,破壞微脂體的完整結構,並將包覆於微脂體中的藥劑釋放至標的位置。本揭示內容亦提用利用本發明微脂體來診斷或治療一個體之疾病的方法。
Description
本揭示內容是關於治療疾病。更具體來說,本揭示內容是關於合成多肽及其於製備用以治療疾病之微脂體(liposome)的用途。
微脂體為包含至少一脂質雙層的球形囊泡,據以包覆一水性中心核;微脂體被視為化療藥物傳遞系統中,最重要的載體之一。相較於未包覆之藥物,由微脂體包覆的藥物可藉由增強滲透滯留效應(enhanced permeability retention (EPR) effect),於特定組織或器官產生較佳的生物分布。目前的微脂體主要是由飽和性脂質所組成,其會形成一穩定膜體以包覆治療藥物。該些微脂體遵守著非費克釋放模式(non-Fick’s release behaviour),即,無早期擴散釋放,因此當微脂體之水性中心核裝載高毒性藥物(例如,化療藥物)時,可保護健康組織不受到藥物傷害。然而,非費克釋放特性是一把雙面刃。雖然可用以保護健康組織,惟其亦使微脂體包覆之藥物具有較低的生物利用率。為了長時間存在於血液循環而設計的高穩定性,實際上阻礙了微脂體的釋放,該設計使微脂體包覆之藥物更安全之餘,亦降低了其作用功效。一般來說,傳統的微脂體雖然穩定,但卻是以被動生物降解方式釋出藥物,且通常緩慢、不完全且不易控制。為克服此困境,相關領域需要一種反應快速且穩定的引信訊號反應型的微脂體,藉以改善微脂體之藥物功效,並維持其既有之安全特性。智慧型微脂體可於特定位置接受引信訊號而快速放釋包覆藥物,避免緩慢且不完全的藥物被動式洩漏,且較不會使生物體長期曝露於低劑量藥物中,進而引發藥物抗性。
引信訊號釋放特性是微脂體的臨床應用研究重點之一。已有研究提出不同的引信訊號反應型微脂體,藉由接受引信訊號(舉例來說,溫度、pH、光照、酵素、近紅外光、超音波、氧化還原電位,以及磁場)來誘發微脂體釋放出包覆物質。絕大多數引信訊號反應型微脂體是由百分比很高的非天然性合成脂質所組成,作為利於釋放的調控開關。然而,使用非天然脂質來製備微脂體,往往引起轉譯醫學的毒性問題。另一方面,基於生物相容性及有效生物膜活性,胜肽提供另一種用以製備具有引信訊號釋放功效之微脂體的選擇。不幸的是,即使過去數十年引發熱烈的觀注並投入相當程度的努力,相關領域尚未利用肽基微脂體(peptidyl liposome)策略製備出令人滿意的引信訊號釋放型微脂體。到目前為止,相關領域仍無適用於固著在微脂體表面的引信訊號反應型破膜胜肽,其可接收光線或疾病相關酵素訊號而產生反應,且不會過早釋出包覆藥物。
有鑑於此,相關領域亟需一種經改良之引信訊號反應型微脂體,藉以更安全且準確的方式釋放包覆之藥物。
發明內容旨在提供本揭示內容的簡化摘要,以使閱讀者對本揭示內容具備基本的理解。此發明內容並非本揭示內容的完整概述,且其用意並非在指出本發明實施例的重要/關鍵元件或界定本發明的範圍。
本揭示內容的一態樣是關於一種合成多肽,其包含一破膜模體(membrane lytic motif)、一遮蔽模體(masking motif),以及一用以連接該破膜模體及該遮蔽模體的連接子(linker)。
依據本揭示內容之實施方式,該破膜模體包含14-30個胺基酸殘基,其中該破膜模體之疏水性胺基酸殘基的數量為5-10;該破膜模體之帶正電荷(positive-charged)之胺基酸殘基的數量為4-10;且該破膜模體之帶負電荷(negative-charged)之胺基酸殘基的數量等於或小於1。當將胺基酸殘基排列為具有複數個重複的α螺旋體時,每兩個轉折(turn)有7個胺基酸殘基。基本上,各重複中的胺基酸殘基是依據第1圖所標示的位置編號依序排列,其中將位於第一轉折之胺基酸殘基命為位置1-4,且將位於第二轉折之胺基酸殘基命為位置5-7。於α螺旋體之各重複中相同位置編號形成一對應位。於破膜模體中,包含一或多個帶正電荷之胺基酸殘基之對應位的數量為3或4,且至少二個包含一或多個帶正電荷之胺基酸殘基的對應位是彼此相鄰。
遮蔽模體是一包含至少10個帶負電荷之胺基酸殘基的胜肽,或是一磷酸基(phosphoryl group)。連接子是一光裂解型(photocleavable)或蛋白酶裂解型(protease-cleavable)結構部(moiety),或是一磷酸酯鍵(phosphoester bond)。
蛋白酶裂解型結構部可以是一胺基酸序列,其可為基質金屬蛋白酶(matrix metalloproteinase, MMP)或細胞自溶酶(cathepsin)所裂解。在某些實施例中,連接子是一包含序列編號:23或24之胺基酸序列的胜肽。在一特定實施例中,連接子是一纈胺酸-瓜胺酸(valine-citrulline, VC)雙胜肽殘基。
依據本揭示內容某些實施方式,遮蔽模體是磷酸基。在該些實施方式中,連接子是磷酸酯鍵,其係形成於該磷酸基,以及該破膜模體之絲胺酸(serine, S)、酪胺酸(tyrosine, Y)或蘇胺酸(threonine, T)任一殘基側鏈之間,其中具有磷酸基連接之絲胺酸、酪胺酸及/或蘇胺酸的數量至少為2,且包含一或多個該具有磷酸基連接之絲胺酸、酪胺酸及/或蘇胺酸殘基的對應位與包含一或多個該帶正電荷之胺基酸殘基的對應位不同。
一般來說,該疏水性胺基酸殘基是白胺酸(leucine, L)、異白胺酸(isoleucine, I)、纈胺酸(valine, V)、苯丙胺酸(phenylalanine, F)、色胺酸(tryptophan, W)或酪胺酸;該帶負電荷之胺基酸殘基是天門冬胺酸(aspartate, D)或麩胺酸(glutamate, E);且該帶正電荷之胺基酸殘基是離胺酸(lysine, K)、精胺酸(arginine, R)或組胺酸(histidine, H)。
依據本揭示內容某些實施方式,破膜模體包含(X1
)1-4
(X2
)1-13
(X1
)1-4
的胺基酸序列,其中各X1
個別是選自由離胺酸、精胺酸及組胺酸殘基所組成的群組;且各X2
個別是選自由絲胺酸、蘇胺酸、天冬醯胺酸(asparagine, N)、麩醯胺酸(glutamine, Q)、半胱胺酸(cysteine, C)、甘胺酸(glycine, G)、脯胺酸(proline, P)、丙胺酸(alanine, A)、纈胺酸、異白胺酸、白胺酸、甲硫胺酸(methionine, M)、苯丙胺酸、酪胺酸、色胺酸、天門冬胺酸,以及麩胺酸殘基所組成的群組。較佳地,各X2
個別是選自由絲胺酸、蘇胺酸、天冬醯胺酸、麩醯胺酸、半胱胺酸、甘胺酸、脯胺酸、丙胺酸、纈胺酸、異白胺酸、白胺酸、甲硫胺酸、苯丙胺酸、酪胺酸及色胺酸殘基所組成的群組。
在本揭示內容某些實施例中,破膜模體包含序列編號:1-12的任一條胺基酸序列。
依據本揭示內容某些實施方式,本發明合成多肽之遮蔽模體包含至少10個帶負電荷之胺基酸殘基 (即,天門冬胺酸及/或麩胺酸殘基)。依據本揭示內容某些實施例,遮蔽模體包含至少10個麩胺酸殘基。在一特定實施例中,遮蔽模體係由12個麩胺酸殘基所組成。
本揭示內容的另一態樣是關於本發明合成多肽於製備一微脂體的用途。結構上,該微脂體包含一中心核、一包覆該中心核之脂質層,以及一本揭示內容之合成多肽,其係與該脂質層連接。
中心核可以包含治療藥劑或顯影分子。依據特定目的,該治療藥劑可以是一抗腫瘤藥劑、一抗發炎藥劑、一抗微生物藥劑、一抗氧化藥劑、一生長因子、一神經傳遞分子,或是一蛋白抑制劑。該顯影分子可以是一顯影劑或一螢光分子。
本揭示內容亦提供用以診斷或治療一個體之疾病的方法。用以診斷一疾病的方法包含對該個體投予一有效量之本發明微脂體,其中該微脂體之中心核包含顯影分子。為達到治療個體之疾病的目的,係對該個體投予一有效量之本發明微脂體,其中該微脂體之中心核包含一治療藥劑,藉以減緩或改善與該疾病相關之病症。
本發明方法適用對象個體是一哺乳動物;較佳地,是一人類。
在參閱下文實施方式後,本發明所屬技術領域中具有通常知識者當可輕易瞭解本發明之基本精神及其他發明目的,以及本發明所採用之技術手段與實施態樣。
為了使本揭示內容的敘述更加詳盡與完備,下文針對了本發明的實施態樣與具體實施例提出了說明性的描述;但這並非實施或運用本發明具體實施例的唯一形式。實施方式中涵蓋了多個具體實施例的特徵以及用以建構與操作這些具體實施例的方法步驟與其順序。然而,亦可利用其他具體實施例來達成相同或均等的功能與步驟順序。
I. 定義
雖然用以界定本發明較廣範圍的數值範圍與參數皆是約略的數值,此處已盡可能精確地呈現具體實施例中的相關數值。然而,任何數值本質上不可避免地含有因個別測試方法所致的標準偏差。在此處,「約」通常係指實際數值在一特定數值或範圍的正負10%、5%、1%或0.5%之內。或者是,「約」一詞代表實際數值落在平均值的可接受標準誤差之內,視本發明所屬技術領域中具有通常知識者的考量而定。除了實驗例之外,或除非另有明確的說明,當可理解此處所用的所有範圍、數量、數值與百分比(例如,用以描述材料用量、時間長短、溫度、操作條件、數量比例及其他相似者)均經過「約」的修飾。因此,除非另有相反的說明,本說明書與附隨申請專利範圍所揭示的數值參數皆為約略的數值,且可視需求而更動。至少應將這些數值參數理解為所指出的有效位數與套用一般進位法所得到的數值。在此處,將數值範圍表示成由一端點至另一段點或介於二端點之間;除非另有說明,此處所述的數值範圍皆包含端點。
除非本說明書另有定義,此處所用的科學與技術詞彙之含義與本發明所屬技術領域中具有通常知識者所理解與慣用的意義相同。此外,在不和上下文衝突的情形下,本說明書所用的單數名詞涵蓋該名詞的複數型;而所用的複數名詞時亦涵蓋該名詞的單數型。
「胜肽」(peptide)、「多肽」(polypeptide)及「蛋白」(protein)在本揭示內容為可互換的詞彙,係指胺基酸聚合物,而不論該聚合物的長度。即使某些實施方式可包含或排除多肽的化學或表現後修飾,然而,該些詞彙未闡述或排除本發明多肽之化學或表現後修飾。在本揭示內容中,一多肽的任一特定位置皆是由該多肽的N端開始編號。除非特別指出異構體,否則當未明確指示胺基酸為D-或L-胺基酸時,則該胺基酸可以是L-胺基酸,或可以是D-或L-胺基酸。 此外,本揭示內容對於多肽胺基酸殘基的符號為本發明所屬技術領域具有通常知識者所熟知的縮寫。
在本揭示內容中,「合成多肽」(synthetic polypeptide)係指一多肽,其不包含完整的自然分子。可藉由諸如化學合成、重組基因技術或完整抗原片段等人為技術來製備「合成多肽」(synthetic polypeptide)。
「模體」(motif)一詞在本揭示內容係指本揭示內容之合成多肽的一部分。具體來說,「模體」(motif)一詞在本揭示內容可指一胺基酸序列或一化學基團(例如,一磷酸基)。較佳地,所述胺基酸序列具有至少10個胺基酸殘基。
本發明所屬技術領域具有通常知識者當可理解,本揭示內容之「結構部」(moiety)一詞係指一分子、一分子片段或一聚合物的一部分,舉例來說,一胺基酸殘基、胜肽或化合物的一部分。
「α螺旋體」(alpha-helix或α-helix)或「α螺旋體結構」(alpha-helical structure)是指一多肽的二級排列結構,其中該多肽的胺基酸殘基係以特定氫鍵模式相互作用,並藉以定義螺旋體結構。舉例來說,在一標準α螺旋體中,氫鍵模式係位於「n」位置之殘基的羰基氧,以及「n+4」位置之另一殘基的醯胺氫之間。對310-螺旋體來說,氫鍵是個別形成於「n」及 「n+3」位置之殘基之間。對派-螺旋體(pi-helix或π-helix)來說,氫鍵是個別形成於「n」及 「n+5」位置之殘基之間。在標準α螺旋體、310-螺旋體及派-螺旋體中,α螺旋體各轉折的殘基數量分別約為3.6、3.0及4.4個。α螺旋體可以為右手或左手螺旋體結構。在本揭示內容中,「轉折」(turn)及「螺旋轉折」(helical turn)為可互換的詞彙,用以指螺旋體結構中的單一迴圈(circle)。
習知技藝人士當可理解「螺旋輪狀圖」(helical wheel diagram)一詞係指任何用以說明多肽之α螺旋體特性的圖或視覺表示。一般來說,可將多肽的胺基酸序列以旋轉方式繪製,其中連續胺基酸之間的旋轉角度約為100°,最後係以俯視角度來看螺旋體中心軸。
在此處,「連接」(link或couple)或「鍵結」(conjugate)為可互換的詞彙,係指透過直接或間接的連結關係,將兩個元件連結在一起。
當與個體連用時,「投予」(administered或administering) 在本揭示內容係指一傳遞送模式,其包含,但不限於,靜脈內、肌肉內、腹腔內、動脈內、顱內或皮下遞送本揭示內容之藥劑(例如,本發明微脂體)。
在本揭示內容中,「診斷」(diagnosis)一詞係指習知技藝人士用以評估及/或決定一個體罹患一特定疾病、病症或症徵之可能性的方法。「診斷」(diagnosis)一詞亦包含偵測罹患一疾病、病症或症徵的傾向,決定一藥物治療的治療功效,或是預測對藥物治療的反應。本揭示內容之診斷方法可單獨進行,或與其他用以分析疾病、病症或症徵之診斷及/或分期方法同時進行。診斷「確定」不必然表示該診斷是100%準確的。
「治療」(treatment或treat)一詞此處是包含對一哺乳動物(特別是人類)進行預防性(例如,預防性藥物(prophylactic))、治療性(curative)或舒減性(palliative)治療;且包含(1)預防、治療或減緩一個體罹患一疾病(例如癌症),其中該個體為罹患該疾病之高風險族群,或是已罹患該疾病而尚未確診斷定;(2) 抑制一疾病(例如抑制其發生);或是(3) 減輕一疾病(例如減輕與該疾病相關之徵狀)。
「有效量」(effective amount) 在此處係指一藥劑的用量足以產生欲求的療效反應。有效量亦指一種化合物或組合物,其治療利益效果超越其毒性或有害影響。藥劑的有效量不必然能夠治癒疾病或病症,但能夠延緩、阻礙或防止該疾病或病症的發生,或是可緩減與疾病或病症相關的病徵。可將治療有效量可分成一、二或更多劑,而以適當的劑型在指定期間內施用一次、二次或更多次。具體的治療有效量取決於多種因素,例如欲治療的特定狀況、個體的生理條件(如,個體重、年齡或性別)、接受治療的個體類型、治療持續時間、併行治療(如果有的話)的本質以及所用的具體配方和化合物或其衍生物的結構。舉例來說,可將治療有效量表示成活性成分的總重量,譬如以克、毫克或微克來表示;或表示成活性成分重量相對於體重的比例,譬如表示為每公斤體重多少毫克(mg/kg)。或者是,可將有效量表示成活性成分(例如,本揭示內容之微脂體) 的濃度,例如莫耳濃度、重量濃度、體積濃度、重量莫耳濃度、莫耳分率、重量分率及混合比值。習知技藝人士可依據動物模式的劑量來計算藥劑(如本揭示內容之微脂體) 的人體等效劑量(human equivalent dose, HED)。舉例來說,習知技藝人士可依據美國食品藥物管理局(US Food and Drug Administration, FDA)所公告之「估算成人健康志願者在初始臨床治療測式之最大安全起始劑量」(Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers)來估算人體使用之最高安全劑量。
「個體」(subject)一詞是指包含人類的動物,其可接受本發明微脂體及/或方法的治療。除非特定指出,否則「個體」(subject)一詞同時意指男性及女性。
II. 發明敍述
本揭示內容旨在提供一種引信訊號反應型(stimuli-responsive) 微脂體,進而以更安全且準確的方式來診斷或治療疾病。該引信訊號反應型微脂體的特徵在於具有與脂質層連接之特定多肽。在投予一引信訊號後,該多肽會產生裂解反應,破壞微脂體的結構,以達到對診斷或治療藥劑產生標的傳輸(targeted delivery)及/或控制釋放(controlled release, CR)的功效。
據此,本揭示內容的第一態樣是關於一種合成多肽,其係重新設計且以化學修飾天然抗微生物多肽而得到的多肽。本發明合成多肽包含一破膜模體、一遮蔽模體,以及一連接子,其中該連接子係用以連接該破膜模體及該遮蔽模體。
破膜模體包含14-30個胺基酸殘基,其中破膜模體之疏水性胺基酸殘基(即,白胺酸、異白胺酸、纈胺酸、苯丙胺酸、色胺酸,及/或酪胺酸殘基)的數量為5-10;破膜模體之帶正電荷之胺基酸殘基(即,離胺酸、精胺酸,及/或組胺酸殘基)的數量為4-10;且破膜模體之帶負電荷之胺基酸殘基(即,天門冬胺酸及/或麩胺酸殘基)的數量等於或小於1。
本發明合成多肽之破膜模體的特徵在於,當排列為α-螺旋體結構時,具有獨特的特性。具體來說,當將破膜模體的胺基酸序列排列為α-螺旋體結構時,該螺旋體每二轉折具有一七肽重複(heptad repeat),其中第一螺旋轉折具有4個胺基酸殘基,而第二螺旋轉折則具有3個胺基酸殘基。將第一螺旋轉折的4個胺基酸殘基分別命為位置1-4,而將第二螺旋轉折的3個胺基酸殘基命為位置5-7。為清楚闡述及理解,可將各重複之位置1-7表示為第1圖之螺旋輪狀圖,其中各重複之胺基酸序列係依序以位置編號(即,由位置1至位置7)進行排列。於α螺旋體之各重複中相同位置編號形成一對應位。依據本揭示內容之實施方式,在破膜模體中,包含一或多個帶正電荷之胺基酸殘基(即,離胺酸、精胺酸,及/或組胺酸殘基)之對應位的數量為3或4,且至少二個包含帶正電荷之胺基酸殘基的對應位係彼此相鄰。
以下提供數種本發明破膜模體的實例。首先參見第2A圖,其中係將蛙皮素2 (序列編號:1)的α-螺旋體結構投射為螺旋輪狀圖。依據第2A圖,蛙皮素2的α-螺旋體結構具有4重複,其中在第一重複中,位置1到7分別包含胺基酸殘基G、I、G、K、F、L及H;在第二重複中,位置1到7分別包含胺基酸殘基S、A、K、K、F、G及K;在第三重複中,位置1到7分別包含胺基酸殘基A、F、V、G、E、I及M;而在第四重複中,位置1及2則分別包含胺基酸殘基N及S。在第2A圖中,以「*」標記帶正電荷之胺基酸殘基(即,離胺酸、精胺酸,及/或組胺酸殘基)。位於位置1之胺基酸殘基G、S、A及N共同形成對應位 1。相似地,位於位置2之胺基酸殘基I、A、F及S共同形成對應位 2;而位於位置3之胺基酸殘基G、K及V則共同形成對應位 3;以下類推。如第2A圖所示,包含帶正電荷之胺基酸殘基之對應位的數量為3,即對應位3、4及7。具體來說,對應位3具有1個帶正電荷之胺基酸殘基,而對應位4及7則分別具有2個帶正電荷之胺基酸殘基。此外,所述對應位3、4及7於螺旋輪狀圖中係彼此相鄰。當破膜模體為第2A圖所示之蛙皮素2時,遮蔽模體(例如,包含至少10個麩胺酸殘基的胜肽)係藉由連接子連接至位於破膜模體對應位2之絲胺酸(S)殘基的C端。
第2B圖及第2C圖提供了本發明破膜模體的其他實例,其分別闡述截斷型蛙皮素2 (序列編號:2)及突變型蛙皮素2 (序列編號:3)的螺旋輪狀圖。第2B圖及第2C圖之胺基酸序列的排列方式與第2A圖所述之排列方式相似,因此,為求簡潔,在此不再贅述。依據第2B圖及第2C圖,截斷型蛙皮素2及突變型蛙皮素2皆具有3個相鄰對應位(即,對應位3、4及7),其分別包含1、2及2個帶正電荷之胺基酸殘基。當破膜模體為第2B圖所示之截斷型蛙皮素2,或是第2C圖所示之突變型蛙皮素2時,遮蔽模體係藉由連接子連接至位於破膜模體對應位3之纈胺酸(V)殘基的C端。
本發明例示性之破膜模體亦包含蜂毒肽(序列編號:4)及其突變型(序列編號:5)。如第2D圖所示,蜂毒肽之螺旋輪狀圖具有4個對應位,即,對應位1、2、3及7,其分別包含1、1、1及2個帶正電荷之胺基酸殘基,且對應位3及7彼此相鄰。相似地,突變型蜂毒肽之螺旋體輪具有3個對應位,即,對應位3、4及7,其彼此相鄰,且分別包含1、2及2個帶正電荷之胺基酸殘基(第2E圖)。當破膜模體為第2D圖所示之蜂毒肽時,則遮蔽模體是藉由連接子連接至位於破膜模體對應位5之麩醯胺酸(Q)殘基的C端。亦或是,當破膜模體是第2E圖所示之突變型蜂毒肽時,則遮蔽模體是藉由連接子連接至位於破膜模體對應位3之精胺酸(R)殘基的C端。
破膜模體的另一實例為培西加南(序列編號:6),第2F圖闡述其螺旋輪狀圖。在此種實施方式中,培西加南具有4個對應位,即,對應位1、3、4及7,其分別包含1、1、3及3個帶正電荷之胺基酸殘基,且對應位3、4及7彼此相鄰。當破膜模體為第2F圖所示之培西加南時,則遮蔽模體是藉由連接子連接至位於破膜模體對應位7之離胺酸(K)殘基的C端。
破膜模體的另一實例為EP1 (序列編號:7),第2G圖闡述其螺旋輪狀圖。EP1具有對應位1、4及5共3個彼此相鄰之對應位,其分別包含2、1及2個帶正電荷之胺基酸殘基。當本揭示內容之合成多肽為第2G圖所示之破膜模體時,遮蔽模體是藉由連接子連接至位於破膜模體對應位7之纈胺酸(V)殘基的C端。
依據本揭示內容某些實施方式,本發明合成多肽之遮蔽模體為一胜肽,其包含至少10個(例如,10、11、12、13、14、15、16、17、18、19、20或更多個)帶負電荷之胺基酸殘基,藉以破壞破膜模體的二級結構。較佳地,遮蔽模體包含至少10個麩胺酸殘基。在本揭示內容一特定實施例中,遮蔽模體係由12個麩胺酸殘基所組成。
用以連接本發明合成多肽之破膜模體及遮蔽模體的連接子是一引信訊號反應型連接子;舉例來說,一光裂解型或蛋白酶裂解型結構部。依據某些實施方式,本揭示內容之連接子是一光裂解型結構部,其係源自非天然胺基酸3-胺基-3-(2-硝苯基)丙酸 (3-amino-3-(2-nitrophenyl)propionic acid, ANP)或4-(4-(1-胺乙基)-2-甲氧基-5-硝苯氧基)丁酸(4-(4-(1-aminoethyl)-2-methoxy-5-nitrophenoxy)butanoic acid)。在一特定實施方式中,光裂解型結構部具有式(I)或式(II)之結構:(I)、(II)。
依據替代性之實施方式,本揭示內容之連接子是一蛋白酶裂解型結構部;舉例來說,一可為基質金屬蛋白酶或細胞自溶酶所裂解的結構部。在某些特定的實施例中,連接子包含序列編號:23或24的胺基酸序列。在一特定實施例中,連接子是纈胺酸-瓜胺酸雙胜肽殘基。
亦或是,本發明合成多肽之遮蔽模體為一磷酸基(PO3 2-
),其係藉由一磷酸酶裂解型連接子(例如,磷酸酯鍵)連接至破膜模體中可磷酸化之胺基酸殘基的側鏈(例如,絲胺酸(S)、酪胺酸(Y),及/或蘇胺酸(T)殘基的側鏈),藉以形成一磷酸化胺基酸殘基。在某些實施方式中,本發明合成多肽之磷酸化S、Y及/或T殘基的數量至少為2 (例如,2、3、4、5、6、7或更多)。當將破膜模體排列為α-螺旋體結構時,包含與遮蔽模體(即,磷酸基)連接之S、Y及/或T殘基的對應位,係與包含一或多個帶正電荷之胺基酸殘基的對應位不同。換言之,磷酸化之S、Y及/或T殘基與K, R及/或H殘基不會出現於同一對應位中。
首先參見第3A圖,其係將蛙皮素2-3pY (序列編號:8)的α螺旋體結構投射為螺旋輪狀圖。在第3A圖中,將帶正電荷之胺基酸殘基(即,K、R及/或H殘基)以「*」標記,而將具有磷酸基連接的胺基酸殘基(即, 磷酸化的胺基酸殘基)以「p」標記。依據第3A圖,磷酸化之胺基酸殘基的數量為3,即3個分別位於對應位2及5的Y殘基,其中對應位2及5與包含帶正電荷之胺基酸殘基( 即,對應位3、4及7)之對應位不同。
第3B圖提供了本發明合成多肽的另一實施例,其係關於蛙皮素2-2pY (序列編號:9)的螺旋輪狀圖。如第3B圖所示,蛙皮素2-2pY包含2個磷酸化的Y殘基,其係分別位於對應位2及5;以及5個帶正電荷之胺基酸殘基,其係分別位於對應位3、4及7。
本發明合成多肽的另一實例為蛙皮素2-2pS (序列編號:10)。蛙皮素2-2pS的胺基酸序列包含2個磷酸化的S殘基。如第3C圖所示,2個磷酸化S殘基係位於對應位1,而5個帶正電荷之胺基酸殘基 (即,如第3C圖所示之1個H 殘基,以4個K殘基)則分別位於對應位3、4及7。
本發明合成多肽的另一實例為突變型蜂毒肽-2pY (序列編號:11)。如第3D圖所示,對應位2包含2個磷酸化之Y殘基,而彼此相鄰的對應位3、4及7則分別包含1、2及2個帶正電荷之胺基酸殘基.
第3E圖提供了另一種本發明合成多肽的實施例,其係關於EP1-2pY (序列編號:12)的螺旋輪狀圖。在EP1-2pY的螺旋排列中,於對應位3及6具有2個磷酸化的Y殘基,而於對應位1、4及5則具有5個帶正電荷之胺基酸殘基。
除了上述α-螺旋體結構及螺旋輪狀圖之外,亦可以式(X1
)1-4
(X2
)1-13
(X1
)1-4
來表示本發明合成多肽,其中各X1
個別是選自由離胺酸、精胺酸及組胺酸殘基所組成的群組;且各X2
個別是選自由絲胺酸、蘇胺酸、天冬醯胺酸、麩醯胺酸、半胱胺酸、甘胺酸、脯胺酸、丙胺酸、纈胺酸、異白胺酸、白胺酸、甲硫胺酸、苯丙胺酸、酪胺酸、色胺酸、天門冬胺酸及麩胺酸殘基所組成的群組。較佳地,各X2
個別是選自由絲胺酸、蘇胺酸、天冬醯胺酸、麩醯胺酸、半胱胺酸、甘胺酸、脯胺酸、丙胺酸、纈胺酸、異白胺酸、白胺酸、甲硫胺酸、苯丙胺酸、酪胺酸及色胺酸殘基所組成的群組。此外,當本發明合成多肽包含二或多個X1
胺基酸殘基及一或多個X2
胺基酸殘基時,在式(X1
)1-4
(X2
)1-13
(X1
)1-4
之第一及第二組(X1
)1-4
中,各X1
可以是相同或不同的胺基酸殘基;相似地,在式(X1
)1-4
(X2
)1-13
(X1
)1-4
之(X2
)1-13
中,各X2
可以是相同或不同的胺基酸殘基。
當破膜模體是蛙皮素2 (序列編號:1)時,在式(X1
)1-4
(X2
)1-13
(X1
)1-4
中,第一及第二組(X1
)1-4
之X1
分別是K及H;而式(X1
)1-4
(X2
)1-13
(X1
)1-4
之(X2
)1-13
則具有「FL」的胺基酸序列。至於蜂毒肽(序列編號:4),式(X1
)1-4
(X2
)1-13
(X1
)1-4
之第一組(X1
)1-4
的X1
是K,式(X1
)1-4
(X2
)1-13
(X1
)1-4
之(X2
)1-13
具有 「VLTTGLPALISWI」(序列編號:25)的胺基酸序列,而式(X1
)1-4
(X2
)1-13
(X1
)1-4
之第二組(X1
)1-4
則具有「KRKR」(序列編號:26)的胺基酸序列。
依據本揭示內容某些操作實施例,破膜模體包含序列編號:1-12之任一條胺基酸序列。
本揭示內容之任一實施方式所述之合成多肽皆可用以製備一引信訊號反應型微脂體,其可於接觸光照或投予酵素(例如,MMP或磷酸酶)處理等引信訊號後,釋放出包覆於其中的藥劑(例如,治療藥劑,或是顯影劑)。具體來說,一旦與微脂體之脂質層連接,本發明合成多肽係處於非活化狀態;直到接觸引信訊號後,該引信訊號會促使連接子產生裂解反應,使遮蔽模體與破膜模體分離,進而活化微脂體中破膜模體的破膜活性,破壞微脂體的完整結構,並將包覆於微脂體中的藥劑釋放至標的位置。
依據本揭示內容某些實施方式,微脂體包含一用以包覆治療藥劑或顯影分子的中心核;一用以包覆該中心核的脂質層;以及一與該脂質層連接的合成多肽;其中該合成多肽可以是本揭示內容所述之任一種多肽。
本發明所屬技術領域具有通常知識知皆知用以製備微脂體的方法。適用於製備本發明微脂體的方法包含,但不限於,擠壓法(extrusion)、逆相蒸發法(reverse phase evaporation)、超音波(ultrasonic)處理、溶劑(例如,乙醇)注射、微射流法(microfluidization)、清潔劑透析法(detergent dialysis)、乙醚注射法(ether injection)、脫水/再水合反應(dehydration/rehydration),以及其組合。
為了將多肽連接至微脂體,可於製備微脂體之前或之後,將胜肽生物性鍵結至微脂體的脂質層上,據以製備最終產物-肽基微脂體,其中微脂體之組成成分(例如,脂質)包含少於1%之肽基脂質。可於製備微脂體之前,藉由混合微量之肽基脂質(低於總脂質之1%)來得到與胜肽連接之脂質膜;亦或是,可藉由混合微量之反應性脂質(低於1%)來形成表面反應性微脂體,以進行後續之胜肽生物鍵結。為使胜肽及脂質相互連接,可於微脂體形成之前或之後,藉由形成醯胺鍵(amide bond)、硫醚鍵(thioether bond),或點擊化學反應(click chemistry)的方式來連接多肽及脂質。可以N-羥基琥珀醯亞胺酯(N-hydroxysuccinimide ester, NHS)、琥珀醯基(succinyl group)、氰基(cyano group)、戊二醯基(glutaryl group)或羧酸(carboxylic acid)等醯胺反應基團來修飾微脂體的組成成分(例如,脂質)。亦或是,可以順丁烯二醯亞胺(maleimide group)、溴化/碘化烷基(alkyl bromide/iodide)、碘乙醯胺(iodoacetamide)或吡啶基二硫代丙酸酯(pyridyldithiopropionate, PDP)等硫醇反應基團來修飾微脂體的組成成分(例如,脂質)。據此,多肽可藉由硫醇-順丁烯二醯亞胺反應(thiol-maleimide reaction,其係發生於多肽之硫醇基及微脂體之硫醇反應基之間)與微脂體連接。當可想見,亦可藉由羧酸反應基團、疊氮化物反應基團(azide reactive group)或二苯並環辛炔(dibenzocyclooctyne,DBCO)等其他基團來修飾微脂體,使具有對應基團之多肽經由適當反應與微脂體連接。依據本揭示內容一實施方式,本發明多肽是以硫醇-順丁烯二醯亞胺反應與微脂體連接,其中係於本發明多肽之N端加上一半胱胺酸殘基修飾,以使多肽連接至微脂體的順丁烯二醯亞胺化脂質。
可依據使用需求來選擇治療藥劑。舉例來說,治療藥劑可以是抗腫瘤藥劑、抗發炎藥劑、抗微生物藥劑、抗氧化藥劑、生長因子、神經傳遞分子或蛋白抑制劑。
例示性之抗腫瘤藥劑包含,但不限於,薑黃素(curcumin)、干擾素(interferon, IFN)、細胞激素、抗體(例如曲妥珠單抗(trastuzumab, HERCEPTIN®
)、T-DM1、貝伐單抗(bevacizumab, AVASTIN®
)、西妥昔單抗(cetuximab, ERBITUX®
)、帕尼單抗(panitumumab, VECTIBIX®
)、利妥昔(rituximab, RITUXAN®
)及百克沙(tositumomab, BEXXAR®
))、抗雌性素(anti-estrogen,例如他莫昔芬(tamoxifen)、雷洛昔芬(raloxifene)及甲地孕酮(megestrol))、黃體釋素促效劑(LHRH agonist,例如戈舍瑞林(goscrclin)及醋酸亮丙瑞林(leuprolide))、抗雄性素(anti-androgen,例如氟他胺(flutamide)及比卡魯胺(bicalutamide))、光動力治療(photodynamic therapies,例如維替泊芬(vertoporfin, BPD-MA)、酞菁(phthalocyanine)、光敏劑Pc4 (photosensitizer Pc4)及去甲氧基竹紅菌素(demethoxy-hypocrellin A, 2BA-2-DMHA))、氮芥(nitrogen mustard,例如環磷醯胺(cyclophosphamide)、異環磷醯胺(ifosfamide)、氯乙環磷醯胺(trofosfamide)、苯丁酸氮芥(chlorambucil)、雌莫司汀(estramustine)及美法崙(melphalan))、亞硝基尿素(nitrosoureas,例如卡莫司汀(carmustine, BCNU)及洛莫司汀(lomustine, CCNU))、烷基磺酸(alkylsulphonate,例如白消安(busulfan)及蘇消安(treosulfan))、三氮烯(triazene,例如達卡巴嗪(dacarbazine)及替莫唑胺(temozolomide))、含鉑化合物(platinum containing compound,例如順鉑(cisplatin)、卡鉑(carboplatin)及奧沙利鉑(oxaliplatin))、長春花生物鹼(vinca alkaloid,例如長春新鹼(vincristine)、長春花鹼(vinblastine)、長春地辛(vindesine)及長春瑞濱(vinorelbine))、類紫杉醇(taxoid,例如紫杉醇(paclitaxel)或與奈米粒子白蛋白結合之紫杉醇(Abraxane)、與十二碳六烯酸結合之紫杉醇(DHA-paclitaxel, Taxoprexin)、與聚谷氨酸結合之紫杉醇(PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX)、腫瘤活化前趨藥物ANG1005(Angiopep-2 bound to three molecules of paclitaxel)、紫杉醇-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1)及與葡萄糖結合之紫杉醇(例如依託泊苷(etoposide)、磷酸依託泊苷(etoposide phosphate)、替尼泊苷(teniposide)、托泊替康(topotecan)、9-氨基喜樹鹹(9-aminocamptothecin)、康托替康(camptoirinotecan)、伊立替康(irinotecan)、甲磺酸(crisnatol)及絲裂黴素C (mytomycin C))等紫杉醇等效物)、抗代謝藥物(anti-metabolite)、二氫葉酸還原酶抑制劑(DHFR inhibitor,例如氨甲喋呤(methotrexate)、二氯甲氨蝶呤(dichloromethotrexate)、三甲蝶呤(trimetrexate)及依達曲沙(edatrexate))、肌苷-5'-單磷酸去氫酶抑制劑(IMP dehydrogenase inhibitor,例如黴酚酸(mycophenolic acid)、噻唑呋林(tiazofurin)、利巴韋林(ribavirin)及EICAR))、核糖核苷酸還原酶抑制劑(ribonuclotide reductase inhibitor,例如羥基尿素(hydroxyurea)及去鐵胺(deferoxamine))、尿嘧啶相似物(uracil analog,例如5-氟尿嘧啶(5-fluorouracil, 5-FU)、氟尿苷(floxuridine)、去氧氟尿苷(doxifluridine)、雷替曲塞(ratitrexed)、替加氟尿嘧啶(tegafur-uracil)及卡培他濱(capecitabine))、胞嘧啶相似物(cytosine analog,例如阿糖胞苷(cytarabine, ara C或cytosine arabinoside)及氟達拉濱(fludarabine))、嘌呤相似物(purine analog,例如巰基嘌呤(mercaptopurine)及硫鳥嘌呤(Thioguanine))、維生素D3相似物(Vitamin D3 analog,例如EB 1089、CB 1093及KH 1060)、異戊二烯抑制劑(isoprenylation inhibitor,例如洛伐他汀(lovastatin))、多巴胺能神經毒素(dopaminergic neurotoxin,例如1-甲基-4-苯基吡啶離子(1-methyl-4-phenylpyridinium ion))、細胞週期抑制劑(例如星形孢菌素(staurosporine))、放線菌素(actinomycin,例如放線菌素D)、博萊黴素(bleomycin,例如博萊黴素A2、博萊黴素B2及培洛黴素(peplomycin))、蒽環類藥物(anthracycline,例如柔紅黴素(daunorubicin)、多柔比星(doxorubicin)、聚乙二醇化微脂體多柔比星(pegylated liposomal doxorubicin)、伊達比星(idarubicin)、表柔比星(epirubicin)、吡柔比星(pirarubicin)、佐柔比星(zorubicin)及米托蒽醌(mitoxantrone))、多重抗藥性抑制劑(MDR inhibitor,例如維拉帕米(verapamil))、鈣離子三磷酸腺苷酶抑制劑(Ca2+
ATPase inhibitor,例如毒胡蘿蔔素(thapsigargin))、伊馬替尼(imatinib)、沙利度胺(thalidomide)、來那度胺(lenalidomide)、酪胺酸激酶抑制劑(tyrosine kinase inhibitor,例如阿西替尼(axitinib, AG013736)、波舒(bosutinib, SKI-606)、尼布(cediranib, RECENTINTM, AZD2171)、達沙替尼(dasatinib, SPRYCEL®
, BMS-354825)、厄洛替尼(erlotinib, TARCEVA®
)、吉非替尼(gefitinib, IRESSA®
)、伊馬替尼(imatinib, Gleevec®
, CGP57148B, STI-571)、拉帕替尼(lapatinib, TYKERB®
, TYVERB®
)、來他替尼(lestaurtinib, CEP-701)、那替尼(neratinib, HKI-272)、尼洛(nilotinib, TASIGNA®
)、馬沙尼(semaxanib, semaxinib, SU5416)、舒尼替尼(sunitinib, SUTENT®
, SU11248)、托西尼布(toceranib, PALLADIA®
)、凡德他尼(vandetanib, ZACTIMA®
, ZD6474)、瓦他拉尼(vatalanib, PTK787, PTK/ZK)、曲妥珠單抗(trastuzumab, HERCEPTIN®
)、貝伐單抗(bevacizumab, AVASTIN®
)、利妥昔單抗(rituximab, RITUXAN®
)、西妥昔單抗(cetuximab, ERBITUX®
)、帕尼單抗(panitumumab, VECTIBIX®
)、蘭尼單抗(ranibizumab, Lucentis®
)、尼洛(nilotinib, TASIGNA®
)、索拉非尼(sorafenib, NEXAVAR®
)、依維莫司(everolimus, AFINITOR®
)、阿崙單抗(alemtuzumab, CAMPATH®
)、吉妥單抗(gemtuzumab ozogamicin, MYLOTARG®
)、西羅莫司(temsirolimus, TORISEL®
)、ENMD-2076、PCI-32765、AC220、多韋替尼乳酸鹽(dovitinib lactate, TKI258, CHIR-258)、BIBW 2992 (TOVOKTM)、SGX523、PF-04217903、PF-02341066、PF-299804、BMS-777607、ABT-869、MP470、BIBF 1120 (VARGATEF®
)、AP24534、JNJ-26483327、MGCD265、DCC-2036、BMS-690154、CEP-11981、替洛尼(tivozanib, AV-951)、OSI-930、MM-121、XL-184、XL-647、及/或XL228)、蛋白酶抑制劑(proteasome inhibitor,例如硼替佐米(bortezomib, Velcade))、哺乳類斥消靈標的蛋白抑制劑(mTOR inhibitor,例如雷帕黴素(rapamycin)、西羅莫司(temsirolimus, CCI-779)、依維莫司(everolimus, RAD-001)、雷帕黴素衍生物(ridaforolimus, AP23573, Ariad)、AZD8055 (AstraZeneca)、BEZ235 (Novartis)、BGT226 (Norvartis)、XL765 (Sanofi Aventis)、PF-4691502 (Pfizer)、GDC0980 (Genetech)、SF1126 (Semafoe)及OSI-027 (OSI))、奧利默森(oblimersen)、吉西他濱(gemcitabine)、洋紅黴素(carminomycin)、亞葉酸鈣(leucovorin)、培美曲塞(pemetrexed)、環磷醯胺(cyclophosphamide)、達卡巴嗪(dacarbazine)、甲基芐肼(procarbizine或procarbazine)、潑尼松龍(prednisolone)、地塞米松(dexamethasone)、喜樹鹼(campathecin)、普卡黴素(plicamycin)、天門冬醯胺酶(asparaginase)、氨基蝶呤(aminopterin)、甲氨蝶呤(methopterin)、紫菜黴素(porfiromycin)、美法崙(melphalan)、異長春鹼(leurosidine)、環氧長春鹼(leurosine)、苯丁酸氮芥(chlorambucil)、曲貝替定(trabectedin)、海綿內酯(discodermolide)、洋紅黴素(carminomycin)及六甲基三聚氰胺(hexamethyl melamine)。依據本揭示內容某些操作實施例,治療藥劑是多柔比星(doxorubicin, DOX)。
例示性的抗發炎藥劑包含,但不限於,薑黃素、非類固醇類的抗發炎藥物(non-steroidal anti-inflammatory drug, NASID),包含阿氯芬酸(alclofenac)、阿氯米松雙丙酸酯(alclometasone dipropionate)、阿孕奈德(algestone acetonide)、α澱粉酶(alpha amylase)、安西法爾(amcinafal)、安西非特(amcinafide)、氨芬酸鈉(amfenac sodium)、鹽酸氨普立糖(amiprilose hydrochloride)、阿那白滯素(anakinra)、阿尼祿酸(anirolac)、阿尼紮芬(anitrazafen)、阿紮丙宗(apazone)、巴柳氮二鈉 (balsalazide disodium)、節達酸(bendazac)、苯噁洛芬(benoxaprofen)、鹽酸節達明(benzydamine hydrochloride)、鳳梨蛋白酶(bromelains)、溴呱莫(broperamole)、布地奈德(budesonide)、卡布洛芬 (carprofen)、環洛芬(cicloprofen)、辛噴他宗(cintazone)、克利洛芬(cliprofen)、丙酸氯倍他索(clobetasol propionate)、丁氯倍他松(clobetasone butyrate)、 氯比酸(clopirac)、氯硫卡松丙酸鹽(cloticasone propionate)、醋酸三氟米松(cormethasone acetate)、可托多松(cortodoxone)、癸酸鹽(decanoate)、地夫可特(deflazacort)、 庚酸睾酮(delatestryl)、能普-睾酮(depo-testosterone)、地奈德(desonide)、去輕米松(desoximetasone)、二丙酸地塞米松(dexamethasone dipropionate)、雙氯芬酸鉀(diclofenac potassium)、雙氯芬酸鈉 (diclofenac sodium)、雙醋二氟拉松(diflorasonediacetate)、二氟米酮鈉 (diflumidone sodium)、二氟尼柳 (diflunisal)、二氟潑尼醋(difluprednate)、雙酞嘆酮(diftalone)、二甲基亞碸(dimethyl sulfoxide)、輕西奈德(drocinonide)、甲地松(endrysone)、恩莫單抗(enlimomab)、依諾利康鈉 (enolicam sodium)、依匹挫(epirizole)、依託度酸(etodolac)、依託芬那醋(etofenamate)、聯苯乙酸(felbinac)、非那莫(fenamole)、芬布芬(fenbufen)、芬氯酸(fenclofenac)、苯克洛酸(fenclorac)、芬度柳(fendosal)、苯吡噁二酮(fenpipalone)、芬替酸(fentiazac)、夫拉紮酮(flazalone)、氟紮可特(fluazacort)、氟芬那酸(flufenamic acid)、氟咪挫 (flumizole)、醋酸氟尼縮松(flunisolide acetate)、氟尼辛(flunixin)、氟尼辛葡甲胺(flunixin meglumine)、氟考丁醋(fluocortin butyl)、氟米龍醋酸醋(fluorometholone acetate)、苯氟喹酮(fluquazone)、氟比洛芬(flurbiprofen)、氟瑞托芬(fluretofen)、丙酸氟替卡松(fluticasone propionate)、咲喃洛芬(furaprofen)、咲羅布芬(furobufen)、 哈西奈德(halcinonide)、丙酸齒倍他索(halobetasol propionate)、醋酸齒潑尼 松(halopredone acetate)、異丁芬酸(ibufenac)、布洛芬(ibuprofen)、布洛芬錯 (ibuprofen aluminum)、皮考布洛芬(ibuprofen piconol)、伊洛達普(ilonidap)、吲噪美辛(indomethacin)、吲噪美辛鈉 (indomethacin sodium)、吲噪布洛芬(indoprofen)、吲四挫(intrazole)、醋異氟龍(isoflupredone acetate)、氧卓乙酸(isoxepac)、伊索昔康(isoxicam)、酮基布洛芬(ketoprofen)、鹽酸洛非咪挫(lofemizole hydrochloride)、氯諾昔康(lomoxicam)、氯替潑諾碳酸乙醋(loteprednol etabonate)、 甲氯滅酸鈉 (meclofenamate sodium)、甲氯芬那酸(meclofenamic acid)、甲氯松二丁醋(meclorisone dibutyrate)、甲芬那酸(mefenamic acid)、美沙拉嗪(mesalamine)、美西拉宗(meseclazone)、甲二氛睾酬(mesterolone)、美雄酬(methandrostenolone)、 美替諾龍(methenolone)、美替諾龍醋酸醋(methenolone acetate)、磺庚甲潑尼龍 (methylprednisolone suleptanate)、嗎尼氟醋(momiflumate)、萘丁美酮(nabumetone)、諾龍(nandrolone)、萘普生(naproxen)、萘普生鈉 (naproxen sodium)、甲氧萘丙醇 (naproxol)、尼馬宗(nimazone)、奧沙拉嗪鈉(olsalazinesodium)、肝蛋白(orgotein)、奧帕諾辛(orpanoxin)、氧甲氫龍(oxandrolane)、奧沙普秦(oxaprozin)、羥基保 泰松(oxyphenbutazone)、輕甲稀龍(oxymetholone)、鹽酸瑞尼托林(paranyline hydrochloride)、戊聚糖多硫酸鈉 (pentosan polysulfate sodium)、甘油保泰松鈉 (phenbutazone sodium glycerate)、吡非尼酮(pirfenidone)、吡羅昔康(piroxicam)、 肉桂酸吡羅昔康(piroxicam cinnamate)、吡羅昔康乙醇胺(piroxicam olamine)、比諾布洛芬(pirprofen)、潑那紮特(prednazate)、普立非酮(prifelone)、普羅度酸 (prodolic acid)、普羅喹宗(proquazone)、普羅沙挫(proxazole)、枸橡酸普羅沙挫 (proxazolecitrate)、利美索龍(rimexolone)、氯馬紮利(romazarit)、水楊酸膽鹼硫酸儀(salcolex)、沙那西定(salnacedin)、雙水楊醋(salsalate)、血根氯鞍(sanguinarium chloride)、司克拉宗(seclazone)、絲美辛(sermetacin)、康力龍(stanozolol)、舒多昔 康(sudoxicam)、舒林酸(sulindac)、舒洛芬(suprofen)、他美辛(talmetacin)、氟煙酞醋(talniflumate)、他洛柳醋(talosalate)、特丁非隆(tebufelone)、替尼達普(tenidap)、替尼達普鈉(tenidap sodium)、替諾昔康(tenoxicam)、氧喹苯胺(tesicam)、辛叉異喹酮(tesimide)、睾酮、睾酮混合物(testosterone blends)、四氫甲吲胺(tetrydamine)、硫平酸(tiopinac)、替可的松匹伐醋(tixocortol pivalate)、托美丁(tolmetin)、托美丁鈉 (tolmetin sodium)、三氯氟松(triclonide)、三氟氨醋(triflumidate)、齊多美辛(zidometacin)及苯醯吡酸鈉 (zomepirac sodium)。
抗微生物藥劑可以是抗細菌藥劑、抗病毒藥劑、抗真菌藥劑,或是抗寄生蟲藥劑。
例示性之抗老化劑包含,但不限於,胺類(例如,N,N-二乙基羥基胺(N,N-diethylhydroxylamine)及胺基胍(amino-guanidine))、精胺酸吡酮(arginine pilolate)、抗壞血酸(ascorbic acid)及其鹽類、脂肪酸之抗壞血酸酯(ascorbyl ester of fatty acid)、生物類黃酮(bioflavonoid)、丁基化羥基苯甲酸(butylated hydroxy benzoic acid)及其鹽類、二羥基反丁烯二酸(dihydroxy fumaric acid)及其鹽類、沒食子酸(gallic acid)及其烷基酯(例如,沒食子酸丙酯(propyl gallate)及尿酸)、
甘胺酸吡酮酸鹽(glycine pidolate)、6-羥基-2,5,7,8-四甲基二氫苯並呱喃-2-羧酸(6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid)、硫辛酸(lipoic acid)、離胺酸(lysine)、黑色素(melanin)、甲硫胺酸(methionine)、降二氫癒創木酸 (nordihydroguaiaretic acid)、脯胺酸(proline)、水飛薊素(silymarin)、山梨酸(sorbic acid)及其鹽類、巰基化合物(例如麩胺基硫(glutathione))、超氧化物歧化酶(superoxide dismutase)、過氧化氫酶(catalase)、茶萃取物、葡萄皮/種子萃取物、迷迭香萃取物、生育酚醋酸鹽(tocopherol acetate)、生育酚、生育酚山梨酸鹽(tocopherol sorbate)及其組合。
例示性之生長因子包含,但不限於,血管生長素(angiopoietin)、巨噬細胞群落刺激因子(macrophage colony-stimulating factor, M-CSF)、顆粒性白血球群落刺激因子(granulocyte colony-stimulating factor, G-CSF)、顆粒性白血球巨噬細胞群落刺激因子(granulocyte macrophage colony-stimulating factor, GM-CSF)、胎盤生長因子(placental growth factor, PLGF)、血管內皮生長因子(vascular endothelial growth factor, VEGF)、纖維母細胞生長因子(fibroblast growth factor, FGF)、表皮生長因子(epidermal growth factor, EGF)、骨形成蛋白(bone morphogenetic protein, BMP)、內皮因子(endoglin)、內皮素(endothelin)、瘦素(leptin)、濾泡抑素(follistatin)、肝細胞生長因子(hepatocyte growth factor, HGF)、類胰島素生長因子(insulin-like growth factor, IGF)、角質細胞生長因子(keratinocyte growth factor, KGF)、神經生長因子(nerve growth factor, NGF)、轉形生長因子-α (transforming growth factor-α, TGF-α)、轉形生長因子-β (TGF-β)、軟骨生長因子(cartilage growth factor, CGF)、幹細胞因子(stem cell factor, SCF)、腦神經滋養因子(brain-derived neurotrophic factor, BDNF)、血小板衍生生長因子(platelet-derived growth factor, PDGF)、介白素(interleukin, IL)及肝配(ephrin)。
例示性之神經傳遞分子包含,但不限於,麩胺酸、天門冬胺酸、D-絲胺酸、γ-丁胺酸(γ-aminobutyric acid, GABA)、甘胺酸、一氧化氮(nitric oxide, NO)、一氧化碳(carbon monoxide, CO)、硫化氫(hydrogen sulfide, H2
S)、多巴胺(dopamine, DA)、正腎上腺素(norepinephrine或noradrenaline)、腎上腺素(epinephrine或adrenaline)、組織胺(histamine)、血清素(serotonin, SER, 5-HT)、苯乙胺(phenethylamine)、N-甲基苯乙胺(N-methylphenethylamine)、酪胺(tyramine)、3-碘類甲腺質(3-iodothyronamine)、章魚胺(octopamine)、色胺(tryptamine)、催產素(oxytocin)、體抑素(somatostatin)、物質P (substance P)、乙醯膽鹼(acetylcholine, ACh)、大麻素(anandamide),及其組合物。
此外或亦或是,中心核可包含一顯影分子,例如一顯影劑或一螢光分子。顯影劑可以是任何用以改善醫學影像中結構或流體之對比度的物質。例示性之顯影劑包含,但不限於,順磁性顯影劑、超順磁性顯影劑,以及質子密度顯影劑。
更具體來說,顯影劑可以是含釓顯影劑(gadolinium-based contrast agent, GBCA)、聚合型枝狀釓複合體(polymeric (dendrameric) gadolinium complex)、含錳核磁共振顯影劑(manganese-based MRI contrast agent),或是超順磁性氧化鐵(superparamagnetic iron oxide, SPIO)。例示性之GBCA包含,但不限於,釓特酸(gadoteric acid)及其鹽類(例如,甲基葡胺鹽(meglumine salt);舉例來說,Gd-DOTA)、釓噴酸(gadopentetic acid)及其鹽類(例如,二甲葡胺鹽(dimeglumine salt);舉例來說,Gd-DTPA)、釓雙胺(gadodiamide;舉例來說,GdGd-DTPA-BMA)、釓貝酸(gadobenic acid)及其鹽類(例如,二甲葡胺鹽;舉例來說,Gd-BOPTA)、釓塞酸(gadoxetic acid)及其鹽類(例如,二鈉鹽;舉例來說,Gd-EOB-DTPA)、釓特醇(gadoteridol;舉例來說,Gd-HP-DO3A)、釓氟塞胺(gadoversetamide;舉例來說,Gd-DTPA-BMEA)、釓布醇(gadobutrol;舉例來說,Gd-DO3A-butrol)、釓磷維塞(gadofosveset)及其鹽類(例如,三鈉鹽;舉例來說,MS-325),以及釓考酸(gadocoletic acid)及其鹽類(例如,三鈉鹽;舉例來說,B22956/1)。例示性之聚合型枝狀釓複合體包含,但不限於,釓美利醇(gadomelitol;舉例來說, P792)、釓登酯(gadodenterate;舉例來說, SH L 643 A),以及釓化合物17 (gadomer 17)。含錳核磁共振顯影劑可以是錳福地吡(mangafodipir)及其鹽類(例如,三鈉鹽;舉例來說,Mn-DPDP)、Mn-DTPA-SA、Mn-EDTA,或是Mn-卟啉衍生物(包含,TPP、TPPS2、TPPS3、TPPS4、中紫質(mesoporphyrin)、血紫質(hematoporphyrin)、尿紫質(uroporphyrin)、ATN-10、HOP-8P等)。至於SPIO,其可以是類鐵劑(ferumoxytol)、瑞瑟維斯(ferucarbotran),或是菲力磁(ferumoxide)。依據本揭示內容一特定實施例,顯影分子是二乙烯三胺五乙酸釓(III) (diethylenetriaminepentaacetic acid gadolinium (III), Gd3+-DTPA)。
至於螢光分子,其可以是任何在光激發下重新發光的分子;舉例來說,花青染劑(cyanine,包含Cy2、Cy3、Cy3B、Cy3.5、Cy5、Cy5.5及Cy7)、綠色螢光蛋白(green fluorescent protein, GFP)、增強型綠色螢光蛋白(enhanced green fluorescent protein, eGFP)、紅色螢光蛋白(red fluorescent protein, RFP)、黃色螢光蛋白(yellow fluorescent protein, YFP)、螢光異硫氰酸鹽(fluorescein isothiocyanate, FITC)、藻紅素(phycoerythrin, PE),或是異藻藍蛋白(allophycocyanine, APC)。依據一操作實施例,螢光分子是Cy5.5。
本揭示內容亦提供利用本發明微脂體來診斷或治療一個體之疾病的方法。用以診斷疾病之方法包含對該個體投予一有效量之本發明微脂體,其中心核包含一顯影分子(例如,Gd3+-DTPA)。為治療一個體之疾病,係對該個體投予一有效量之本發明微脂體,其中心核包含一治療藥劑(例如,DOX),藉以改善或減緩與該疾病相關之病症。
可以本發明微脂體及/或方法治療之疾病包含腫瘤、發炎性疾病、感染性疾病、與氧化壓力或生長因子表現異常相關之疾病或病狀,以及神經性疾病。
該個體為一哺乳動物;例如,一人類、小鼠、大鼠、天竺鼠、猴子、黑猩猩、兔子、豬、貓、狗、馬、年、綿羊或山羊。較佳地,該個體為人類。
下文提出多個實驗例來說明本發明的某些態樣,以利本發明所屬技術領域中具有通常知識者實作本發明,且不應將這些實驗例視為對本發明範圍的限制。據信習知技藝者在閱讀了此處提出的說明後,可在不需過度解讀的情形下,完整利用並實踐本發明。此處所引用的所有公開文獻,其全文皆視為本說明書的一部分。
實施例
材料及方法
試劑
由Avanti Polar Lipids, Inc購買磷質、1,2-二硬脂醯基-sn-甘油-3-磷酸乙醇胺-N-[甲氧基(聚乙二醇)-2000](1,2-distearoyl-sn-glycero- 3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000)、1,2-二棕櫚醯基-sn-甘油-3-磷酸乙醇胺-N-[4-(p-馬來醯亞胺基)環己烷-羧醯胺](1,2-dipalmitoyl-sn- glycero-3-phosphoethanolamine-N-[4-(p-maleimidomethyl)cyclohexane-carboxamide](16:0 PE MCC)、1,2-二油醯基-sn-甘油-3-磷酸乙醇胺-N- [4-(p-馬來醯亞胺基) 環己烷-羧醯胺](1,2-dioleoyl- sn-glycero-3-phosphoethanolamine-N-[4-(p-maleimidomethyl)cyclohexane- carboxamide]) (18:1 PE MCC)、氫化大豆L-α-卵磷脂(L-α- phosphatidylcholine, hydrogenated (Soy), HSPC),以及1,2-二硬脂醯基-sn-甘油-3-磷膽鹼(1,2-distearoyl- sn-glycero-3-phosphocholine, DSPC)。由Sigma購買膽固醇、三(羥甲基)甲基甘氨酸(tricine)及碳酸氫鈉。由Toronto Research Chemicals 購買多柔比星-HCl。由Anaspec 購買芴甲氧羰基-胺基酸(Fmoc-amino acid),以及2-(6-氯-1H-苯並三唑-1-基)-1,1,3,3-四甲基六氟磷酸鹽(2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3- tetramethylaminium hexafluorophosphate, HCTU)。由Advanced chemtech 購買4-{4-[1-(9-芴甲氧羰基)乙基]-2-甲氧基-5-硝基苯氧基}丁酸(4-{4-[1-(9-fluorenylmethyloxycarbonyl)ethyl]-2-methoxy-5-nitrophenoxy}butanoic acid (芴甲氧羰基-光連接子),以及1-[雙(二甲氧基)亞甲基]-1H-1,2,3-三唑[4,5-b]吡啶陽離子3-氧化物六氟磷酸鹽(1-[bis(dimethylamino)methylene]-1H- 1,2,3-triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate, HATU)。由Alfa aesar 購買N,N-二異丙基乙基胺(N,N-diisopropylethylamine, DIPEA)、三氟乙酸(trifluoroacetic acid, TFA),以及三異丙基矽烷(triisopropylsilane, TIPS)。由Uniregion biotech 購買DTT。由Biological Industries 購買胎牛血清(Fetal bovine serum, FBS),並將其置於56°C 30分鐘,以進行去活性反應。由Acros Organics 購買三(2-羧乙基)磷鹽酸鹽(Tris(2-carboxyethyl)phosphine hydro- chloride, TCEP)。分別由Gibco及Merck購買DMEM、MEM,及3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四氮唑溴鹽(3-[4,5-dimethylthiazol- 2-yl]-2,5-diphenyltetrazolium bromide, MTT)。由BioVision購買聯膜蛋白V-Cy5 (Annexin V-Cy5)凋亡套組。所有本實驗使用的化學藥品皆為分析試劑等級。在本實驗中,是利用人類癌化KB細胞來評估微脂體的建構。
合成及分析胜肽
利用自動化胜肽合成器,以芴甲氧羰基固相胜肽合成法,於經偶合劑處理之樹脂來合成本發明多肽,其中是利用偶合劑HATU來偶合脯胺酸,並以偶合劑HCTU來偶合其餘胺基酸。利用DIPEA作為基底。在切割胜肽時,是以TFA/TIPS/H2
O (95:2.5:2.5,體積比)溶液處理樹脂90分鐘,以得到粗製胜肽,接著以冰乙醚沉澱後,利用高效液層析法(high performance liquid chromatography, HPLC)進行純化。藉由分析式逆相HPLC (analytical reversed phase HPLC, RP-HPLC)及電噴灑游離質譜儀(electrospray ionization-mass spectrometry, ESI-MS)來確認光裂解之前及之後的胜肽。
表1總結了本發明合成胜肽及其胺基酸序列。
製備
微脂體及肽基微脂體
以已知技術來製備微脂體DOX (即,包覆多柔比星的微脂體)。簡單來說,係利用HSPC或DSPC的脂質組合物、膽固醇、DSPE-PEG2000及順丁烯二醯亞胺化脂質,以莫耳比分別為38-60%、40-55%、0-5%及0.1-2%的條件進行製備。將脂質成分(12毫克)溶解於裝有氯仿之圓底燒瓶中,並以旋轉蒸發器進行蒸發以形成脂質膜,以捕獲劑緩衝液(硫酸銨)進行水合反應後,冷凍-解凍處理數次。輕輕攪拌脂質懸浮液,並利用小型擠壓器以聚碳酸酯膜(孔徑為0.1微米)擠出,據以得到粒徑均一的微脂體。利用150 mM NaCl溶液作為沖提掖,以微脂體的粒徑排除色層分析法來產生微脂體的交叉膜硫酸胺梯度。將DOX (5 mM,50微升)加入收集之包含微脂體(5 mM,500微升)的硫酸胺溶液中,並於60°C反應45分鐘,以主動將DOX裝載至微脂體中。接著以經三(羥甲基)甲基甘氨酸緩衝液(50 mM三(羥甲基)甲基甘氨酸、100 mM NaCl,pH 7.4)處理之凝膠進行過濾,以由未包覆DOX之微脂體中,純化包覆DOX的微脂體。將包覆DOX的微脂體保存於4°C。DOX的裝載率約為95%。
在連接胜肽-順丁烯二醯亞胺化微脂體時,是以三(羥甲基)甲基甘氨酸緩衝液(50 mM三(羥甲基)甲基甘氨酸、100 mM NaCl,pH 7.4)還原半胱胺醯基-胜肽,之後以適當莫耳比(胜肽/脂質比介於1/1200到1/300之間)加至包覆DOX的微脂體溶液。輕輕搖晃反應液,接著加入DTT (1 mM),於37°C反應30分鐘,以由微脂體表面移除未反應之順丁烯二醯亞胺基。利用粒徑排除色層分析法來純化本揭示內容所有的微脂體。表2總結了可作為治療藥劑之包覆DOX的肽基微脂體。
分析藥物釋放
為評估本發明肽基微脂體的藥物釋放(以DOX作為包覆模式藥物)特性,對光反應微脂體投予或不投予UV照射(每平方公分5毫瓦,10分鐘),並於37°C培養1小時。將微脂體培養於包含或不包含ALP (每毫升50 U)之37°C環境3小時,以測量磷酸酶反應微脂體的螢光表現量。將微脂體培養於包含或不包含MMP2 (每毫升300奈克) 之37°C環境1小時,以測量MMP2反應微脂體的螢光表現量。以公式(1)來計算藥物釋放百分比,表3總結分析結果。
分析微脂體
利用已知方法來定量分析磷脂質濃度。簡單來說,將8.9 N之H2
SO4
(0.45毫升)分別加至微脂體(15及30微升)及標準溶液(NaH2
PO4
,32.5到227.5奈莫耳)中,之後加熱至200°C反應25分鐘。冷卻後,將10% H2
O2
(0.15毫升)加入檢體及標準溶液,重新加熱至200°C反應30分鐘。冷卻後,依序加入H2
O (3.9毫升)、四水合鉬酸銨(ammonium molybdate tetrahydrate,2.5%重量/體積,0.5毫升)及抗壞血酸(10%重量/體積,0.5毫升)之混合物,之後重新加熱至100°C反應7分鐘。於OD820
,利用標準溶液的校正曲線計算微脂體之磷脂質濃度。在測量微脂體之粒徑大小及表面界達電位時,係將100微升之微脂體溶液稀釋於1毫升之三(羥甲基)甲基甘氨酸緩衝液(50 mM三(羥甲基)甲基甘氨酸、100 mM NaCl,pH 7.4)中,之後置於微量比色管或表面界達電位比色管,以三重複檢測各檢體。
以螢光量評估
微脂體釋放
DOX
投予或不投予UV 照射(每平方公分5毫瓦,0-60分鐘),並於37°C培養1小時後,測量由引信訊號釋放型微脂體所釋放之DOX的螢光強度(I
)。藉由加入1% Triton™ X-100,並於70°C培養2分鐘,得到由微脂體完全釋放之DOX的螢光強度(I 最大
)。以公式(1)來計算胜肽光活化所產生的釋放百分比:
引信訊號誘發釋放(%) = [(I
-Io
)/(I 最大 -Io
)] x 100% (1)
其中Io
為微脂體於引信訊號活化前的初始螢光強度。
以低溫電子顯微鏡
(cryo-electron microscopy, cryo-EM)
評估由
微脂體釋放之
DOX
將經照射(每平方公分5毫瓦,10分鐘)或黑暗處理之微脂體溶液於37°C培養1小時,以完全釋放DOX。利用低溫-TEM來得到微脂體的低溫-EM影像。簡單來說,在(Ar, O2
)環境中,使400篩目之銅網格於碳側輝光放電10秒。將4微升之微脂體溶液(每毫升0.2-0.4毫克之總脂質)加入網格表面。於4°C ,將網格置於100%溼度的環境印漬3-4秒,之後投入以液態氮冷卻之液態乙烷浴中。以公式(2)來計算光引信訊號型微脂體的DOX釋放百分比 :
引信訊號誘發型釋放= (EL微脂體
-ELDDL- 黑暗
) / (100% -ELDDL- 黑暗
) (2)
其中,EL是低溫-EM影像中,未包覆之微脂體的百分比。
未包覆之
DOX
及肽基
微脂體的細胞
DOX
攝取量
在以螢光顯微鏡分析細胞對DOX的攝取量時,是將KB細胞(每孔洞5 x 105
細胞)種植於35毫米的培養盤中,以10% FBS於37°C培養24小時。之後,以含有未包覆之DOX的MEM培養液(不含FBS),或是含有 DDL、1-MDL或2-MDL 之MEM培養液(不含FBS)替換培養,並投予或不投予光照射(每平方公分5毫瓦,4分鐘),於37°C另培養20小時。洗滌細胞後,將其置於含有10% FBS之MEM中,以螢光顯微鏡進行觀察。以赫斯特33342 (Hoechst 33342)染色細胞,於37°C反應20分鐘,以觀察細胞核。利用預設過濾管來觀察赫斯特及DOX的螢光量。
在進行時間相關性之細胞攝取DOX實驗時,是將KB細胞(每孔洞3 x 104
細胞)種植於8孔洞之培養盤中,於包含10% FBS之DMEM於37°C培養24小時。之後,以含有未包覆之DOX的MEM培養液(不含FBS),或是含有DDL或1-MDL 之MEM培養液(不含FBS)替換培養液,並投予或不投予光照射(每平方公分5毫瓦,4分鐘)。利用共軛焦顯微鏡每15分鐘以40倍率觀測一次螢光影像。
為以流式細胞儀來分析光誘發型微脂體之DOX釋放量及細胞凋亡的關聯性,將KB細胞(每孔洞2 x 105
細胞)種植於12孔洞盤,於包含10% FBS之DMEM於37°C培養24小時。之後,以含有未包覆之DOX的MEM培養液(不含FBS),或是含有DDL或1-MDL 之MEM培養液(不含FBS)替換培養液,並投予或不投予光照射(每平方公分5毫瓦,4分鐘);接著置於37°C培養20小時。利用1毫升PBS洗滌細胞後,以1毫升胰蛋白酶-EDTA處理3分鐘,之後藉由1000 rpm轉速離心收集產物。以500微升之包含1% FBS 的PBS懸浮細胞沉澱物。加入7微升之聯膜蛋白V-Cy5,並避光培養5分鐘。利用流式細胞儀分析各檢體之細胞(共計10,000個細胞)。
為以多參數細胞影像分析光誘發型微脂體之DOX釋放量細胞凋亡的關聯性,將KB細胞 (每孔洞1 x 104
細胞)種植於96孔洞盤,於包含10% FBS之DMEM於37°C培養24小時。之後,以含有未包覆之DOX的MEM培養液(不含FBS),或是含有DDL或1-MDL 之MEM培養液(不含FBS)替換培養液,並投予或不投予光照射(每平方公分5毫瓦,4分鐘);接著置於37°C培養20小時。洗滌細胞後,將其置於包含10% FBS之MEM中。以赫斯特33342及聯膜蛋白V-Cy5染色細胞,分別於37°C反應20及5分鐘,藉以觀察細胞核及凋亡細胞。利用共軛焦定量影像細胞儀來分析各孔洞之細胞(共計>2,000個細胞)。
MTT
試驗
在評估以微脂體包覆之DOX的半抑制濃度(IC50
)時,是將KB細胞(每孔洞1.1 x 104
細胞) 種植於96孔洞盤,於包含10% FBS之DMEM於37°C培養24小時。之後,以含有未包覆之DOX的MEM培養液(不含FBS),或是含有DDL或MDL 之MEM培養液(不含FBS)替換培養液,並投予或不投予光照射(每平方公分5毫瓦,4分鐘);接著置於37°C培養20小時。另以包含10% FBS之MEM替換培養液後,於37°C培養20小時。將20微升之MTT原液(每毫升5毫克,溶於PBS)加至各孔洞,之後於37°C培養2小時;接著,移除170微升之培養液,並加入200微升之DMSO溶解紫色甲䐶產物,於37°C在120 rpm轉速之往復振動器上反應10分鐘。利用盤讀取器測量光波為540奈米時,DMSO溶液中甲䐶產物的吸光量,據以評估細胞存活率。
將
Cy5.5
遠端裝載至
微脂體
將脂質成分溶解於裝有氯仿之圓底燒瓶中,並以旋轉蒸發器進行蒸發以形成脂質膜。以捕獲劑緩衝液(100 mM之蔗糖八硫酸酯銨(sucrose octasulfate ammonium))進行水合反應後,冷凍-解凍處理十次。輕輕攪拌脂質懸浮液,並利用小型擠壓器以聚碳酸酯膜(孔徑為0.1微米)擠出,據以得到粒徑均一的微脂體。利用150 mM NaCl溶液作為沖提掖,以微脂體的粒徑排除色層分析法,移除未包覆之蔗糖八硫酸酯銨,據以產生微脂體的穿膜捕獲劑梯度。將Cy5.5 (總脂質之0.02莫耳當量)加至收集的微脂體。接著利用粒徑排除色層分析法進行過濾,以純化Cy5.5微脂體。利用公式(3)來計算Cy5.5微脂體的包覆效率百分比:
包覆效率(%) = (ML
/MT
) * 100% (3);
其中,ML
為Cy5.5於微脂體分餾中的含量,而MT
則為Cy5.5於純化前的總量。經計算,Cy5.5的裝載效率約為80%。
製備包覆
Gd3+
-DTPA
之光誘發型
微脂體及其釋放分析
將脂質成分(24毫克)溶解於裝有氯仿之圓底燒瓶中,並以旋轉蒸發器進行蒸發以形成脂質膜。以1毫升之200 mM Gd3+
-DTPA (pH 7.4)對脂質膜進行水合反應,之後冷凍-解凍處理十次。輕輕攪拌脂質懸浮液,並利用小型擠壓器以聚碳酸酯膜(孔徑為0.1微米)擠出,或以超音波振盪法,得到粒徑均一(約100奈米)的微脂體。利用經三(羥甲基)甲基甘氨酸緩衝液(50 mM三(羥甲基)甲基甘氨酸、100 mM NaCl,pH 7.4)處理之粒徑排除色層分析進行過濾,以純化包覆Gd3+
-DTPA的微脂體。為進行光引信訊號釋放,以三(羥甲基)甲基甘氨酸緩衝液(50三(羥甲基)甲基甘氨酸、100 mM NaCl,pH 7.4)於室溫還原胜肽1 (0.2 mM) 15分鐘,藉以減少胜肽之間的雙硫鍵結;之後,以適當莫耳比(胜肽/脂質比介於1/900到1/300之間)加入包覆Gd3+
-DTPA的微脂體溶液。置於轉速設定為120 rpm轉速之往復振動器上,於37°C反應1小時;接著加入DTT (1 mM),於37°C反應30分鐘,以由微脂體表面移除未反應之順丁烯二醯亞胺基。將胜肽1加至Gd3+
-DTPA 微脂體(GL)以製備與胜肽1鍵結之Gd3+
-DTPA微脂體(稱為「1-MGL」),或是與DTT鍵結之Gd3+
-DTPA微脂體(稱為「DGL」)。利用粒徑排除法純化肽基微脂體。投予或不投予UV 照射(每平方公分5毫瓦,10分鐘),並於37°C培養1小時,以測量微脂體包覆之Gd3+
-DTPA的引信訊號釋放率。以T1
-加權自旋回波序列得到的影像來計算微脂體溶液的T1
遲豫時間,其中TR=90、120、150、180、230、290、330、380、450、550、680、850、1000、1500、2000、3000、5000、8000 ms,TE=8 ms,激發次數=1,視野=6.5×6.5平方公分,且影像矩陣尺寸=256×256。
實施例
1
分析本發明
微脂體
依照材料及方法所述步驟來分析本發明合成微脂體的藥物釋放特性。表3總結分析結果。
表3之分析數據指出,經引信訊號後,微脂體編號:1-5、9-13、16-18分別具有80%、50%、80%、50%、45%、70%、70%、45%、70%、35%、50%、40%及25%的釋放率。該些肽基微脂體為本發明引信訊號釋放型微脂體之成功實例,且可利用本揭示內容所述設計來製備該些與微脂體鍵結之胜肽的遮蔽模體。同時,經引信訊號後,微脂體編號:6-8、14-15及19分別僅具15%、10%、15%、10%、10%及10%的釋放率。該些肽基微脂體為引信訊號釋放的失敗實例。對於該些不符合本揭示內容所述之破膜模體準則的胜肽來說,不是對膜的活性過大而無法遮蔽,就是對膜的惰性而無法產生微脂體釋放效果;據此,與該些胜肽連接之微脂體無法達到引信訊號釋放的功效。相較於其他胜肽,蛙皮素2 (W12)衍生物為最佳之用以製備引信訊號釋放型微脂體(例如,微脂體編號:1、9、10、11、16及17)的破膜模體。因此,本研究進一步選擇微脂體編號:1、6 (作為實驗負對照組)、10、11、16及17進行後續分析,結果分別闡述於實施例2、3及4中。
表1-3之結果指出,即使序列編號:15-22之胜肽可與12 E殘基鍵結,然而,12 E殘基並無法遮蔽或抑制該些抗微生物胜肽的破膜活性。該結果總結,唯有符合本揭示內容所述之破膜模體準則的胜肽可經由遮蔽模體(例如12 E殘基)所遮蔽。除了12 E殘基,本實驗也分析4 E殘基、8 E殘基及10 E殘基的遮蔽功效。結果顯示,唯有 12 E殘基具有完全遮蔽破膜活性之功效,而至少10 E殘基對遮蔽破膜活性功效可產生令人滿意的結果(結果未顯示)。因此,由該些分析數據可知,本發明用以製備引信訊號釋放型微脂體之合成多肽的遮蔽模體至少包含10個E殘基。表1-3之結果亦指示,僅與單一個磷酸基鍵結之胜肽(例如,序列編號:13及14之胜肽)的藥物釋放功效明顯低於至少與二個磷酸基鍵結之胜肽(例如,序列編號:8、9及10之胜肽)。基於該結果可知,本發明合成多肽至少需要二個磷酸基方可對破膜模體之破膜活性產生遮蔽功效。
總結上述,唯有符合本揭示內容所述之準則的胜肽可作為破膜模體,進而經由多麩胺酸或雙(或更多)磷酸化修飾,得到可用以製備引信訊號釋放型微脂體之本發明合成多肽。
實施例
2
分析
微脂體
DDL
、
1-MDL
及
2-MDL
如表3所總結,經光引信訊號後,微脂體1-MDL可有效釋放包覆的藥劑(即,DOX)。為更進一步評估1-MDL於治療疾病的應用,本實施例將確認1-MDL 的物化特性及生物活性。表4及第4-9圖分別闡述分析結果。
2.1
物化特性
實施例2.1將分析合成微脂體之粒徑大小、多分散性指數(polydispersity index, PDI)及表面界達電位。表4總結分析數據。
依據表4的結果可知,動態光散射(dynamic light scattering, DLS)及低溫-EM分析皆顯示包含擠壓完成、DOX裝載、胜肽鍵結及光照射等不同時期之微脂體的粒徑大小約為130奈米。然而,由於微脂體表面的胜肽鍵結及化學轉態,不同時期之微脂體具有顯著不同的表面界達電位。於擠壓後,微脂體表面界達電位為-2.2毫伏,而DOX裝載後之表面界達電位則為-2.3毫伏(表4)。未經光照射之與胜肽1或胜肽2鍵結的微脂體表面界達電位會負向移至-6.7及-6.2毫伏,而於光照射後則會正向移至-2.9及-1.7毫伏(表4)。與胜肽鍵結後,微脂體的表面界達電位會由-2.3降低至-6.7毫伏,推測原因為微脂體表面與包含12麩胺酸之胜肽連接所造成(表4)。
表4 確認特定微脂體
對照組:未裝載DOX之微脂體。
DL:DOX 微脂體;未與任何胜肽或DTT連接,且包覆DOX的微脂體。
DDL:DTT-DOX 微脂體;與DTT連接,且包覆DOX之微脂體。
1-MDL:與胜肽1連接,且包覆DOX之微脂體。
2-MDL:與胜肽2連接,且包覆DOX之微脂體。
2.2
以螢光表現分析藥物釋放效率
利用螢光去淬滅試驗(fluorescence dequenching assay)來研究微脂體的DOX釋放效率。第4A圖繪示肽基微脂體之DOX 釋放百分比與不同照射時間的關聯性,藉以確認光活化之最佳照射時間;結果指出,3分鐘的照射即足以使1-MDL光活化,並釋放出包覆藥物。另一方面,2-MDL 光活化僅會釋放15%的DOX。該結果顯示,可藉由引信訊號誘發蛙皮素2的去遮蔽反應,進而釋放出微脂體的包覆藥劑;且蛙皮素2的破膜活性具有高度序列相關性,而非僅基於胜肽整體的疏水性。經照射後,無任何胜肽或DDL連接的DOX微脂體幾乎觀測不到任何釋放(<5%),結果確認了無胜肽連接之微脂體不具光反應性。
亦可由具時間相關性之表面界達電位改變來確認照射後,光裂解移除遮蔽模體(即,聚麩胺酸),其中1-MDL及2-MDL的表面界達電位會顯著增加,而DDL則無改變(第4B圖)。此外,本研究亦分析照射後,微脂體完全釋放DOX所需時間;結果繪示於第4C圖。不論培養時間多長,1-MDL、2-MDL及DDL於黑暗中皆無釋放反應。然而,光照射後之1-MDL具有類一級螢光增加(釋放)曲線,其需要約30分鐘完成,2-MDL具有部分基本釋放量,而DDL於光照射後之120分鐘的培養時間內則幾乎無釋放反應(第4C圖)。基於該分析結果,所有微脂體誘發實驗皆於37°C 額外培養1小時,其為使微脂體釋放DOX的必要條件。
亦分析不同的胜肽/指質鍵結比例(介於1/300到1/1200之間)與誘發微脂體釋放包覆物質的關聯性,結果繪示於第4D圖。於光照射後,1-MDL具有較大的動態釋放範圍(由80%降低至15%),而2-MDL的釋放範圍則較小(由15%降低至3%)。
接著,本實驗將進一步了解光誘發肽基微脂體釋放包覆藥劑與溫度(介於25°C到46°C之間)的關聯性;結果繪示於第5圖。即使溫度升高至46°C,所有未進行光照射的微脂體皆無顯著釋放;該結果指出,在未給予引信訊號前,所有肽基及對照微脂體皆具溫度穩定性。另檢測該些微脂體於黑暗環境中的長期穩定性。於諸如25°C等低溫環境中,1-MDL的光活化會造成較低的釋放量(第5圖)。當溫度升高後,與溫度相關之引信訊號釋放反應會逐漸增加,且於37°C時達到飽和狀態(第5圖)。2-MDL呈現相似的溫度相關反應,惟具有較低的釋放動態範圍,且其於光活化後的飽和溫度為43°C,而非37°C (第5圖)。如第6圖所示,所有的微脂體皆保存於37°C培養箱,而於放置的7天內,皆未觀察到明顯的釋放反應。
為證實溫度可控制光引信訊號型1-MDL的釋放反應,利用螢光影像紀錄來觀測由微脂體釋放之DOX。第7圖分別闡述投予光照射之前(小圖(a))及之後(小圖(b)),微脂體釋放的影像篩選照片。測試管#1包含DDL,其中無DOX釋放,因此其於光照射之前及之後皆無觀測到螢光量。測試管#2包含1-MDL,於光照射後,具有強烈的光誘發DOX螢光量。測試管#3及#4分別顯示1-MDL於光活化前及經清潔劑處理後,完全釋放DOX螢光的結果。
2.3
以低溫
-EM
分析藥物釋放效率
進一步以低溫-EM來檢測所有微脂體的形態。在引信訊號前,如商業販售之DOX微脂體或對照組微脂體(二者均無與胜肽連接),包覆DOX之微脂體皆分散良好,並呈現粒徑均一的狀態,且略呈橢圓形,直徑約130奈米(第8圖,小圖(a)及(b))。1-MDL及2-MDL於光活化前,形態皆無改變(第8圖,小圖(c)及(e))。然而,1-MDL於光活化後,會釋放出包覆的DOX,並形成如第8之小圖(d)所示之中空微脂體。相較之下,2-MDL於光照射後,仍會包覆DOX,而無釋放反應(第8圖,小圖(f))。基於顯著數量之微脂體低溫-EM影像(>103
微脂體),直接以低溫-EM影像定量分析光誘發之微脂體釋放百分比,其中1-MDL-黑暗的釋放百分比為3%,而1-MDL-UV的釋放百分比則為73% (結果未顯示)。2-MDL-黑暗及2-MDL-UV皆具有非常低的釋放百分比,分別為3%及12% (結果未顯示)。
該些結果證實由螢光去淬滅試驗所得到的DOX釋放百分比,與由低溫-EM影像得到之個別微脂體計算結果相符合;基於該觀察結果,微脂體之釋放反應是屬於全有或全無釋放形式。
2.4
細胞攝取肽基
微脂體之
DOX
及
引信訊號
釋放之
DOX
DOX於細胞內的分布位置顯示引信訊號釋放型微脂體的重要性。記錄在有或無光照射的情況下,經未包覆之DOX、DDL及1-MDL處理之KB細胞的螢光影像。DOX為蒽環抗生素藥物,具有膜穿透性,且對DNA具高親和性,可阻斷拓樸異構酶II (topoisomerase II)的活性。因此,未包覆之DOX可保留且集中於細胞核中,而微脂體包覆之DOX則會位於細胞質或胞內體/溶酶體中。經DDL-黑暗、2-MDL-黑暗及1-MDL-黑暗處理的細胞於細胞質具有點狀DOX 螢光分布,而細胞核則無;結果指出,DOX仍穩定地包覆於微脂體中(微脂體則位於胞內體中),而DOX攝取量不足有可能是因有限的胞吞再生週期所導致(結果未顯示)。因此,如同未包覆之DOX,不具引信訊號釋放功能的微脂體需要更高劑量及更長的微脂體降解時間,以產生相同程度的DOX攝取量(結果未顯示)。相較之下,即使經1-MDL-黑暗處理的KB細胞具有與經DDL-黑暗處理之KB細胞相似的螢光表現,經1-MDL-UV處理的KB細胞具有顯著的DOX攝取量,且於細胞質及細胞核皆呈現強烈的DOX螢光量(結果未顯示)。1-MDL-UV定量釋放包覆之DOX,擴散至KB細胞中,並使DOX的攝取量達到最大化(結果未顯示)。經未包覆之DOX處理的KB細胞對DOX具有12.5 μM的最大攝取量(結果未顯示)。相較於未包覆之DOX,1-MDL-UV釋放出相似量的DOX供細胞攝取,且具有額外的引信訊號設計開啟釋放。
與該些分析數據一致,定量評估細胞之DOX劑量及後續的凋亡反應。在本實驗中,是於投予或未投予光照射的情況下,以DDL、1-MDL或未包覆之DOX處理KB細胞後,利用流式細胞儀及共軛焦定量影像細胞儀進行分析,以了解細胞之DOX螢光強度(DOX攝取量)及聯膜蛋白-V螢光強度(細胞凋亡程度)的關聯性(結果未顯示)。經DDL及1-MDL-黑暗處理的KB細胞具有較少的DOX攝取量,其凋亡程度亦較低。另一方面,1-MDL-UV定量釋放大量的DOX,使細胞對DOX的攝取量達到最大化,進而造成高百分比的細胞凋亡率(結果未顯示)。相同的情況亦可見於經未包覆之DOX處理的KB細胞(結果未顯示)。
2.5
與劑量相關之光活化
微脂體的細胞毒性
利用MTT試驗來分析在投予或未投予UV照射的情況下,經未包覆之DOX、DDL或1-MDL處理之KB細胞的劑量相關毒性,其中DOX的外顯濃度(apparent concentration)係介於0.1到160 µM。依據第9圖之數據,若以IC50
來表示1-MDL-UV 的細胞毒性,約為2 µM,其係與DOX-黑暗(0.7 µM)及DOX-UV (3 µM)的毒性相似,而無引信訊號釋放的微脂體(DDL-黑暗、DDL-UV及1-MDL-黑暗)則需極高之DOX外顯濃度來產生相等功效(IC50
>160 µM)。在光照射之前,與傳統DOX微脂體相似,1-MDL具有低毒性(高IC50
值);而經引信訊號後,誘發的細胞毒性會提升80倍(第9圖)。毒性的動態範圍具有於特定作用位置開啟作用的潛力。該些結果指出,一旦配予引信訊號釋放機制,將可擴大傳統微脂體劑量的治療窗口。
實施例
3
分析
微脂體
3-MDL
及
4-MDL
依據包含0%、1.66%、3.33%或5% PEF2000脂質之3-MDL的DOX釋放動力學,於5% 聚乙二醇化之3-MDL可觀察到3小時之ALP處理即足以使3-MDL的釋放量達到最大化(第10A圖)。記錄投予未包覆之DOX、DDL或3-MDL之具高及低ALP表現量之HS-5及KB細胞的螢光影像,其中所有微脂體及未包覆之DOX具有 12.5 µM的DOX外顯濃度;相較於HS-5細胞(具有低ALP表現量),3-MDL於KB細胞 (具有高ALP表現量)呈現顯著的釋放量(結果未顯示)。
亦分析可經ALP酵素引信訊號而釋放之4-MDL微脂體(胜肽/脂質比 = 1/300)的最佳PEG2000脂質百分比(結果未顯示)。結果指出,2%聚乙二醇化之4-MDL具有最佳的DOX 釋放百分比(第10B圖)。2%聚乙二醇化之4-MDL雖具有略高的釋放量;然而,其基礎釋放量亦較高。由於PEG2000脂質會阻礙ALP,因此5%聚乙二醇化之4-MDL無法產生令人滿意的引信訊號釋放量。4-MDL 的釋放量較少有可能是因去磷酸化不完全所造成。
實施例
4
分析
微脂體
5-MDL
及
6-MDL
將REF52細胞(低MMP2表現量)培養於含有未包覆之DOX或微脂體的培養液中,且該培養液(1)無包含MMP2,(2)包含商業販售之活性MMP2 (每毫升300奈克),或是(3)包含HT1080條件培養液,於37°C培養20個小時。包含DDL及5-MDL等所有微脂體,以及未包覆之DOX具有12.5 µM 的DOX外顯濃度(結果未顯示)。培養含有5-MDL (有或無PEG2000脂質)之活性MMP2或HT1080條件培養液中的所有細胞皆會釋放DOX,而培養於含有DDL (有或無PEG2000脂質)之活性MMP2或HT1080條件培養液中的 REF52細胞則不會釋放DOX (結果未顯示)。
推測6-MDL 無法產生令人滿意之釋放反應是由於胜肽6之不良釋放動力學所造成(結果未顯示).
實施例
5
分析包含
Cy5.5
或
Gd3+
-DTPA
的
微脂體
除了DOX,也分別將諸如Cy5.5及Gd3+
-DTPA等不同藥劑裝載於脂質與胜肽1鍵結的微脂體中。本實施例將闡述該些分析結果。
依據低溫-EM的數據,分別利用醋酸鈣及蔗糖八硫酸酯銨作為捕獲劑,可成功將Cy5.5包覆於微脂體中(第11圖)。
此外,可藉由200 mM Gd3+
-DTPA對脂質膜進行水合反應,將Gd3+
-DTPA被動裝載於微脂體中。表5列示Gd3+
-DTPA 微脂體的詳細尺寸及表面界達電位。
表5 在有或無光照的情況下,特定微脂體之流體動力學直徑及表面界達電位
GL:Gd3+
-DTPA 微脂體;DGL:與DTT鍵結之Gd3+
-DTPA 微脂體;1-MGL:與胜肽1鍵結之Gd3+
-DTPA 微脂體。
第12A及12B的結果指出,相較於DGL,1-MGL經光誘發釋放後,在T1
-加權遲豫率(第12A圖)及T1
-圖譜訊號(第12B圖)皆可強烈增加Gd3+
-DTPA對比度。
總結上述,本揭示內容提供數種類型之分別與特定多肽連接的微脂體。一旦經由適當引信訊號(舉例來說,光或酵素)活化後,本發明微脂體可將包覆藥劑或分子釋放於標的位置。因此,本發明微脂體可以更安全且準確的方法診斷或治療疾病。
雖然上文實施方式中揭露了本發明的具體實施例,然其並非用以限定本發明,本發明所屬技術領域中具有通常知識者,在不悖離本發明之原理與精神的情形下,當可對其進行各種更動與修飾,因此本發明之保護範圍當以附隨申請專利範圍所界定者為準。
為讓本發明的上述與其他目的、特徵、優點與實施例能更明顯易懂,所附圖式之說明如下:
第1圖是依據本揭示內容一實施方式所繪示之螺旋輪狀圖(helical wheel diagram),其闡述於破膜模體之各螺旋重複中,胺基酸序列的排列方式。
第2A到2G圖是依據本揭示內容另一實施方式所繪示之螺旋輪狀圖,其分別闡述本發明多肽之破膜模體的胺基酸排列,包含蛙皮素2 (Magainin 2;第2A圖)、截斷型蛙皮素2 (第2B圖)、突變型蛙皮素2 (第2C圖)、蜂毒肽(Melittin;第2D圖)、突變型蜂毒肽(第2E圖)、培西加南(Pexiganan;第2F圖),以及石斑魚抗菌胜肽-1 (Epinecidin-1, EP1;第2G圖)。
第3A到3E圖是依據本揭示內容另一實施方式所繪示之螺旋輪狀圖,其分別闡述具有磷酸基遮蔽之破膜模體的胺基酸排列,其中該破膜模體包含蛙皮素2-3pY (第3A圖)、蛙皮素2-2pY (第3B圖)、蛙皮素2-2pS (第3C圖)、突變型蜂毒肽-2pY (第3D圖),以及EP1-2pY (第3E圖)。
第4A到4D圖是依據本揭示內容實施例2.2所繪示之數據,其係關於特定微脂體的釋放特性。第4A圖:釋放百分比與照射時間的點狀圖,結果指出3分鐘之UV照射即可誘發有效的釋放。第4B圖:微脂體之表面界達電位(zeta-potential)與照射時間的點狀圖,結果亦顯示3分鐘之UV照射即可光裂解移除引信訊號反應型遮蔽模體,其中該引信訊號反應型遮蔽模體是由多麩胺酸所組成。第4C圖:照射後所需培養時間與釋放百分比的點狀圖,結果指出照射後僅需30分鐘的培養時間,據足以使微脂體完全釋放DOX。第4D圖:胜肽置換量與釋放百分比的柱狀圖,結果顯示1-MDL於胜肽/脂質比為1/300時,具有最大的照射後釋放量。DDL:包覆DOX且與二硫蘇糖醇(dithiothreitol, DTT)連結的微脂體;1-MDL:包覆DOX且與光反應蛙皮素2 (W12)(胜肽1)連結的微脂體;2-MDL:包覆DOX且與光反應打亂序列之(scrambled)蛙皮素2 (胜肽2)連結的微脂體。DDL及2-MDL為本實驗的對照組。
第5圖是依據本揭示內容實施例2.2所繪示的線性圖,其闡述光誘發之微脂體釋放百分比與培養溫度的關聯性,其中1-MDL及2-MDL的胜肽置換比為胜肽/脂質=1/300。數據指出培養溫度至少需為37°C,以達到最大釋放量。
第6圖是依據本揭示內容實施例2.2所繪示之點狀圖,其闡述於37°C未投予光照射時,具有不同胜肽置換量(胜肽/脂質比 = 1/500、1/400及1/300)之DDL與1-MDL的長期穩定度。
第7圖是依據本揭示內容實施例2.2所闡述的照片,其係關於(1) DDL,(2) 1-MDL,(3) 1-MDL + 前UV照射,以及(4) 1-MDL + 前Triton™-X100培養之微脂體DOX溶液。1-MDL的胜肽置換比為胜肽/脂質比 = 1/300。在投予UV照射之前(小圖(a))及之後(小圖(b)),DOX 微脂體釋放之DOX會劇烈增加(2) 1-MDL的螢光量。
第8圖是依據本揭示內容實施例2.3所闡述之低溫電子顯微鏡(cryo-electron microscopy, cryo-EM)照片。DOX是穩定圈限(trap)於DDL-黑暗(小圖(a))、DDL-UV (小圖(b))、1-MDL-黑暗(小圖(c))、2-MDL-黑暗(小圖(e))及2-MDL-UV (小圖(f))之中。1-MDL及2-MDL的胜肽置換比為胜肽/脂質比 = 1/300。DOX是顯著地於1-MDL-UV (小圖(d))所釋放。2-MDL-黑暗(小圖(e))及2-MDL-UV (小圖(f))會將DOX圈限於微脂體之中。比例尺:所有照片皆為100奈米。
第9圖是依據本揭示內容實施例2.5所繪示之線性圖,其係關於KB細胞的存活率。經以微脂體包覆之DOX或未包覆之DOX處理後,投予(4分鐘)或未投予照射,並培養40個小時後,細胞的存活率。1-MDL的胜肽置換比為胜肽/脂質比 = 1/300。DDL-黑暗、DDL-UV及1-MDL-黑暗的IC50
>160 μM,而1-MDL-UV的IC50
約為2 μM,與DOX-黑暗 (IC50
約為0.7 μM)及DOX-UV (IC50
約為3 μM)相似。光活化使1-MDL的DOX功效提升80倍。
第10A及10B圖是依據本揭示內容實施例3所繪示之數據,其係關於投予或未投予ALP處理之微脂體3-MDL (第10A圖)及4-MDL (第10B圖)的藥物釋放分析結果。ALP:鹼性磷酸酶(alkaline phosphatase)。
第11圖是依據本揭示內容實施例5所闡述之低溫-EM照片,其分別關於未包覆之微脂體(小圖(a))及包覆Cy5.5之微脂體(小圖(b))的影像分析結果。比例尺:所有照片皆為100奈米。
第12A及12B圖之照片是關於胜肽置換比為胜肽/脂質比 = 1/900、1/600及1/300時,光誘發1-MGL 微脂體的釋放結果。第12A圖:於TR = 550時,T1
-加權遲豫率(weighted relaxation rate)(S0
為引信訊號活化前,微脂體的初始訊號量;S 最大
為加入1% Triton™-X100後,完全釋放Gd3+
-DTPA之微脂體的最大訊號量)。第12B圖:投予或未投予光照射,並於37°C 培養1小時後,Gd3+
-DTPA微脂體的T1
-圖譜(T0
為引信訊號活化前,微脂體的初始遲豫時間;T 最大
為加入1% Triton™-X100後,完全釋放Gd3+
-DTPA之微脂體的最大遲豫率)。白光框線指出光照射後,1-MGL的訊號改變。
根據慣常的作業方式,圖中各種特徵與元件並未依比例繪製,其繪製方式是為了以最佳的方式呈現與本發明相關的具體特徵與元件。此外,在不同圖式間,以相同或相似的元件符號來指稱相似的元件/部件。
無
Claims (18)
- 一種合成多肽,包含一破膜模體、一遮蔽模體,以及一用以連接該破膜模體及該遮蔽模體的連接子,其中, 該破膜模體包含14-30個胺基酸殘基,其中 該破膜模體之疏水性胺基酸殘基的數量為5-10; 該破膜模體之帶正電荷之胺基酸殘基的數量為4-10; 該破膜模體之帶負電荷之胺基酸殘基的數量等於或小於1;以及 當該胺基酸殘基排列為各重複具有7個胺基酸殘基的α螺旋體時,各重複具有一第一轉折及一第二轉折,且各重複是以第1圖所標示的位置編號依序排列,其中位置1-4是位於第一轉折,位置5-7是位於第二轉折,且於該α螺旋體之各重複中相同位置編號形成一對應位,其中於該破膜模體中,包含一或多該帶正電荷之胺基酸殘基之對應位的數量為3或4,且至少二個該包含一或多該帶正電荷之胺基酸殘基的對應位是彼此相鄰; 第1圖 該遮蔽模體是一包含至少10個帶負電荷之胺基酸殘基的胜肽,或是一磷酸基;以及 該連接子是光裂解型或蛋白酶裂解型結構部,或是一磷酸酯鍵;其中 當該遮蔽模體是該胜肽時,則該連接子是該光裂解型或該蛋白酶裂解型結構部;或是 當該遮蔽模體是該磷酸基時,則該連接子是該磷酸酯鍵,其係形成於該磷酸基,以及該破膜模體之絲胺酸、酪胺酸或蘇胺酸任一殘基之間,其中具有該磷酸基連接之絲胺酸、酪胺酸及/或蘇胺酸的數量至少為2,且包含一或多該具有該磷酸基連接之絲胺酸、酪胺酸及/或蘇胺酸殘基的對應位與該包含一或多該帶正電荷之胺基酸殘基的對位置不同。
- 如請求項1所述之合成多肽,其中 該疏水性胺基酸殘基是白胺酸、異白胺酸、纈胺酸、苯丙胺酸、色胺酸或酪胺酸; 該帶負電荷之胺基酸殘基是天門冬胺酸或麩胺酸;以及 該帶正電荷之胺基酸殘基是離胺酸、精胺酸或組胺酸。
- 如請求項2所述之合成多肽,其中該破膜模體包含(X1 )1-4 (X2 )1-13 (X1 )1-4 之胺基酸序列,其中各X1 個別是選自由離胺酸、精胺酸及組胺酸殘基所組成的群組;且各X2 個別是選自由絲胺酸、蘇胺酸、天冬醯胺酸、麩醯胺酸、半胱胺酸、甘胺酸、脯胺酸、丙胺酸、纈胺酸、異白胺酸、白胺酸、甲硫胺酸、苯丙胺酸、酪胺酸、色胺酸、天門冬胺酸及麩胺酸殘基所組成的群組。
- 如請求項3所述之合成多肽,其中各X2 個別是選自由絲胺酸、蘇胺酸、天冬醯胺酸、麩醯胺酸、半胱胺酸、甘胺酸、脯胺酸、丙胺酸、纈胺酸、異白胺酸、白胺酸、甲硫胺酸、苯丙胺酸、酪胺酸及色胺酸殘基所組成的群組。
- 如請求項4所述之合成多肽,其中該破膜模體包含序列編號:1-12之任一條胺基酸序列。
- 如請求項1所述之合成多肽,其中該遮蔽模體包含至少10個麩胺酸殘基。
- 如請求項6所述之合成多肽,其中該遮蔽模體是由12個麩胺酸殘基所組成。
- 如請求項1所述之合成多肽,其中該連接子可為基質金屬蛋白酶或細胞自溶酶所裂解。
- 如請求項9所述之合成多肽,其中該連接子包含序列編號:23或24的胺基酸序列。
- 如請求項9所述之合成多肽,其中該連接子是一纈胺酸-瓜胺酸雙胜肽殘基。
- 一種微脂體,包含 一中心核, 一包覆該中心核的脂質層,以及 如請求項1所述之合成多肽,其係與該脂質層連接。
- 如請求項12所述之微脂體,其中該中心核包含一治療藥劑或一顯影分子。
- 如請求項13所述之微脂體,其中該治療藥劑是選自由抗腫瘤藥劑、抗發炎藥劑、抗微生物藥劑、抗氧化藥劑、生長因子、神經傳遞分子及蛋白抑制劑所組成的群組。
- 如請求項14所述之微脂體,其中該治療藥劑是該抗腫瘤藥劑或該蛋白抑制劑。
- 如請求項13所述之微脂體,其中該顯影分子是一顯影劑或一螢光分子。
- 一種如請求項12所述之微脂體於製備一藥物之用途,其中該藥物可用以診斷或治療一個體之疾病。
- 如請求項17所述之用途,其中該個體是一人類。
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US6872705B2 (en) * | 2001-07-13 | 2005-03-29 | Allergan, Inc. | Use of antimicrobial peptides as preservatives in ophthalmic preparations, including solutions, emulsions, and suspensions |
US7985401B2 (en) * | 2003-10-31 | 2011-07-26 | The Regents Of The University Of California | Peptides whose uptake by cells is controllable |
US20090016962A1 (en) * | 2005-10-03 | 2009-01-15 | The General Hospital Corporation | Compositions and methods for the treatment of cancer |
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TR201905612T4 (tr) * | 2012-12-05 | 2019-05-21 | Univ Heidelberg Ruprecht Karls | Proteinlerin ve çok değerlikli, hücreye nüfuz eden peptitlerin konjugatları ve bunların kullanımları. |
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TWI770396B (zh) | 2022-07-11 |
CN110655585A (zh) | 2020-01-07 |
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