TW201912186A - 多功能探針及其用途 - Google Patents
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Abstract
在此揭示一種多功能探針及其用途。所述多功能探針的結構主要 如式(1)化學式所示,其能夠用以診斷和治療癌症。
Description
本發明關於多功能探針的領域,特別是關於能夠提供癌症治療和診斷多功能探針。
惡性腫瘤近年來為國人十大死因統計的首位,若能在癌症發生的初期診斷,並及早給予患者適當的治療,則能大幅度提升五年存活率。隨著全球各國罹癌人口的增加,癌症診斷與治療用藥之開發為生技製藥產業相當重要之一環。
目前臨床上對於原發性或轉移性腫瘤的處理,原則上以手術切除為主,但仍有許多狀況下是無法進行手術的。因此,發展出數種局部療法,其中以腫瘤熱消融治療(Thermal ablation)被證實是有效且安全的。腫瘤熱消融治療是腫瘤病患在不適合手術時,第一線之低侵入式治療模式。
腫瘤熱消融治療最大的挑戰在於如何提升對於需治療部位的標的,漸少對於正常組織的傷害。而光熱治療(Photothermal Therapy,PTT)是藉由特殊光源於腫瘤內產生熱能達到消融腫瘤組織的效果。藉由光敏劑的加入則可提升腫瘤組織對於特定波長光源的光敏感性,達到標的治療的目的。然而,在先前技術中,熱消融治療受限於治療中及治療後的 影像監測,無法進行同步監測。
有鑒於此,本領域亟需一種改良的診療探針,以改善先前技術的缺陷。
為了讓讀者了解本揭示內容的基本意涵,發明內容係提供本揭示內容的簡要說明。發明內容並非本揭示內容的完整描述,且其用意非界定本發明的技術特徵或權利範圍。
本揭示內容之一態樣有關於一種多功能探針,其具有式(1)所示結構:
其中R是或
依據本發明一具體的實施方式,本發明式(1)化合物的R基
依據本發明另一具體的實施方式,本發明式(1)化合物的R 基是。
依據本發明其他實施方式,本發明的多功能探針更包含一放射線核種標定於所述式(1)化合物上。在可任選的實施方式中,所述放射線核種是錸-188、鎝-99 m、銦-111、镥-177、鎵-68、釔90、氟-18、銅-64或釓。
本發明另一態樣是關於一種造影劑。具體而言,所述造影劑包含上述任一實施方式之多功能探針和一造影賦型劑。
本發明又一態樣是關於一種利用上述任一實施方式所示之多功能探針於製備診斷或治療癌症用之醫藥品的用途。在可任選的實施 方式中,所述癌症選自於以下所組成之群組中:血癌、淋巴瘤、骨幹骨肉瘤、多發性骨髓瘤、睾丸癌甲狀腺癌、前列腺癌、咽喉癌、子宮頸癌、鼻咽癌、乳癌、大腸癌、胰臟癌、胃癌、頭頸癌、食道癌、直腸癌、膀胱癌、腎癌、肺癌、肝癌、腦癌、黑色素癌、鱗狀細胞癌或皮膚癌。
本發明所屬技術領域中具有通常知識者參閱下文實施方式後,可充分瞭解本發明的中心概念、所採用的技術手段及各種實施態樣。
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,所述圖式說明如下:第1圖為依據本發明一實施方式所示製備本發明多功能探針DOTA-NIR790之流程圖;第2圖為依據本發明一實施方式所示製備本發明多功能探針DOTA-NIR780之流程圖;第3A圖為依據本發明一實施方式所示經施用本發明多功能探針銦-111-DOTA-NIR790的皮下腫瘤動物模型之單光子電腦斷層造影(SPECT)影像;第3B圖為經施用本發明多功能探針銦-111-DOTA-NIR780的皮下腫瘤動物模型之單光子電腦斷層造影(SPECT)結果;第3C圖為依據本發明一實施方式所示經施用本發明多功能探針銦-111-DOTA-NIR790的皮下腫瘤動物模型之近紅外螢光影像(NIRF)造影結果;第3D圖為依據本發明一實施方式所示經施用本發明多功 能探針銦-111-DOTA-NIR780的皮下腫瘤動物模型之近紅外螢光影像(NIRF)造影結果;第4A圖為依據本發明一實施方式所示經施用本發明多功能探針銦-111-DOTA-NIR790的腦轉移動物模型之單光子電腦斷層造影(NanoSPECT/CT)影像,其中圖左半部顯示小鼠全身造影結果,圖右半部為頭部局部擷取結果;第4B圖為依據本發明一實施方式所示經施用本發明多功能探針銦-111-DOTA-NIR790的腦轉移動物模型之近紅外螢光影像(NIRF)造影結果;第4C圖為依據本發明一實施方式所示經施用本發明多功能銦-111-DOTA-NIR790的腦轉移動物模型,其腦部組織之近紅外螢光影像(NIRF)造影結果;第5A圖為依據本發明一實施方式所示本發明多功能探針銦-111-DOTA-NIR790對於結腸直腸癌動物模型生體分布分析的直條圖;第5B圖為依據本發明一實施方式所示本發明多功能探針銦-111-DOTA-NIR790對於大腸癌動物模型生體分布分析的直條圖;第5C圖為依據本發明一實施方式所示本發明多功能探針銦-111-DOTA-NIR790對於頭頸癌動物模型生體分布分析的直條圖;以及第5D圖為依據本發明一實施方式所示本發明多功能探針 銦-111-DOTA-NIR790對於肺癌動物模型生體分布分析的直條圖。
為使本揭示內容的敘述更加詳盡與完備,下文針對本發明實施態樣與具體實施例提出說明性的文字敘述;但本發明的實施態樣及具體實施例並非僅限於此。
除非另有說明,本說明書所用的科學與技術專有名詞之含義與本技術領域中具有通常知識者所理解與慣用的意義相同。再者,本說明書所用的名詞均涵蓋該名詞的單數型及複數型,除非另有指明。
所述「個體」或「患者」一詞係指能接受本發明熱敏感載體的動物。在一較佳的實施方式中,所述動物為哺乳類,且特別是人類。
所述「癌症」可以是非固態腫瘤或固態腫瘤。舉例而言,所述癌症包含,但不限於血癌、淋巴瘤、骨幹骨肉瘤、多發性骨髓瘤、睾丸癌甲狀腺癌、前列腺癌、咽喉癌、子宮頸癌、鼻咽癌、乳癌、大腸癌、胰臟癌、胃癌、頭頸癌、食道癌、直腸癌、膀胱癌、腎癌、肺癌、肝癌、腦癌、黑色素癌、鱗狀細胞癌或皮膚癌等。
在本說明書所述,「約」一詞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。「約」一詞在本文中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。除了實驗例外,或除非另有明確的說明,當可理解此處所用的範圍、數量、數值與百分比均經過「約」的修飾。因此,除非另有說明,本說明書與附隨申請專利範圍所揭示的數值或參數皆為約略的數值,且可視需求而更動。
為解決先前技術所存在的問題,在此本案發明人首次提出一種多功能單一探針分子,其不同先前技術的探針在於本發明之探針具有近紅外螢光與核子醫學影像之腫瘤診斷能力、腫瘤光熱治療(Photothermal Therapy)以及同位素標的放射治療能力。具體而言,本發明的化合物結構主要由二部分所組成,其中一部分為紅外螢光染劑-花菁染料(Heptamethine cyanine dye),此一化合物具有獨特近紅外光波段強吸收的光學特性與腫瘤標的性,能夠提升腫瘤組織對於特定波長光源的光敏感性;經特殊光源的激發後,於腫瘤內產生熱能達到消融腫瘤組織的效果,另一部分為螯合基(如,DOTA),用以同時藉由標誌放射線核種進行治療。
下文揭示多個實施例以闡述本發明各種不同的實施態樣,以使本發明所屬技術領域中具有通常知識者依據本說明書的揭示能夠實施本發明所揭示技術內容。因此,以下所揭示的各實施例不可用以限制本發明的權利範圍。再者,本說明書所引述的所有文獻,皆視為完全引用成為本說明書的一部分。
實施例1 合成本發明之多功能探針
1.1 DOTA-NIR790的合成。
本實施例化學合成的主要流程示於第1圖。合成步驟如下:將NIR-790(2-[2-[2-(4-aminobenzenethio)-3-[(1,3-dihydro-3,3-dimethyl-1-(4-sulfobutyl)-2H-indol-2-ylidene)-ethylidene]-1-cycloxen-1-yl]-ethynyl]-3,3-dimethyl-1-(4-sulfobutyl)-3H-indolium,innersalt,monosodium)(83.8毫克,100微摩爾)溶於5毫升無水DMF中,並加入三乙胺(20毫克,200微摩爾)。然後再將DOTA-NHS(153毫克,200微摩爾)溶於1毫升DMF中的 溶液加入上述反應混合物中,並將該混合物在室溫下攪拌3天。將得到的粗產物用C-18的HPLC管柱純化,以60%ACN和40%H2O內含有0.1%TFA作為流動相,以獲得純的目標產物,烘乾後為綠色固體(21毫克,17.2%),經HPLC分析、核磁共振光譜儀和質譜儀鑑定,確定本發明多功能探針的結構。
1.2 DOTA-NIR780的合成
本實施例化學合成的主要流程示於第2圖。合成步驟如下:將IR780 iodide(2-[2-[2-Chloro-3-(1,3-dihydro-3,3-dimethyl-1-propyl-2H-indol-2-ylidene)ethylidene]-1-cyclohexen-1-yl]ethenyl]-3,3-dimethyl-1-propylindolium iodide)(120毫克,143.2微摩爾)與4-Aminothiophenol(300毫克,958微摩爾)溶於5毫升無水DMF中,室溫反應過夜。將得到的粗產物用製備級HPLC配合C-18管柱純化,以獲得純的目標產物IR780-NH2,烘乾後為綠色固體(120毫克,79.4%),經HPLC分析、核磁共振光譜儀和質譜儀鑑定。將IR780-NH2(75.5毫克,100微摩爾)溶於5毫升無水DMF中,並加入三乙胺(20毫克,200微摩爾)。然後再將DOTA-NHS(153毫克,200微摩爾)溶於1毫升DMF中的溶液加入上述反應混合物中,並將該混合物在室溫下攪拌3天。將得到的粗產物用用製備級HPLC配合C-18管柱純化,以60%ACN和40%H2O內含有0.1%TFA,15分鐘後梯度升至100%ACN作為流動相,以獲得純的目標產物,烘乾後為綠色固體(21毫克,17.2%),經HPLC分析、核磁共振光譜儀和質譜儀鑑定,確定本發明多功能探針的結構。
實施例2 製備標誌放射性核種之多功能探針:銦-111-DOT
A-NIR790或銦-111-DOTA-NIR780
將111InCl3(370活度)加入到含有1毫克DOTA-NIR790(或DOTA-NIR780)的300微升的0.2M乙酸鈉緩衝液(pH5.5)中。將混合物在37℃下振盪反應1小時。反應後將銦-111-DOTA-NIR790(或DOTA-NIR780)經由RP-18管柱加以吸附,以生理食鹽水作為洗滌液和乙醇作為洗脫緩衝液進行純化。以Radio-HPLC評估銦-111-DOTA-NIR790(或DOTA-NIR780)的放射化學純度,經純化後其放化純度可達95%以上。
實施例3 本發明多功能探針能診斷和治療癌症
3.1 動物模式的建立
3.1.1 皮下腫瘤動物模型
本實驗例所採用的實驗動物是雌性BALB/c裸鼠(5至6週齡),分別於右和左腿側翼皮下接種老鼠乳癌4T1(ATCC®CRL-2539TM)細胞(1×106)。實驗期間定時測量腫瘤大小和體重,每三天測量一次。腫瘤體積計算為π ab2/6,其中a是腫瘤的長度,和b是腫瘤的寬度。當腫瘤體積到達至約150-200mm3後,進行後續試驗。
3.1.2 腦轉移動物模型
本實驗例所採用的實驗動物是雌性BALB/c小鼠(8週齡)。在腫瘤植入前,將小鼠通過暴露麻醉為1%至3%的isoflurane。將4T1-luc乳癌細胞(2×104)懸浮於PBS(2μL)中,由距硬腦膜3.7毫米深度緩慢注入,前後歷時3分鐘。將針留在原處進行5分鐘,然後慢慢取出。頭皮傷口用6-0縫線縫合。本動物模型接受癌細胞接種10日後,進行後續試驗。
3.1.3 人類大腸癌動物模型之建立
本實驗例所採用的實驗動物是雌性BALB/c Nude小鼠(8週齡)。將HCT-116大腸癌細胞(3×106)懸浮於PBS(100μL)中,皮下注射於大腿至背部之間。本動物模型接受癌細胞接種14日後,進行後續試驗。
3.1.4 人類頭頸癌腫瘤動物模型之建立
本實驗例所採用的實驗動物是雌性SCID小鼠(8週齡)。將FaDu頭頸部癌細胞(5×106)懸浮於PBS(100μL)中,皮下注射於大腿至背部之間。本動物模型接受癌細胞接種21日後,進行後續試驗。
3.1.5人類肺癌腫瘤動物模型之建立
本實驗例所採用的實驗動物是雌性SCID小鼠(8週齡)。將A549肺癌細胞(3×106)懸浮於PBS(100μL)中,注射於胸部側邊皮下。本動物模型接受癌細胞接種21日後,進行後續試驗。
3.1.6老鼠大腸癌動物模型之建立
本實驗例所採用的實驗動物是雌性BALB/c小鼠(8週齡)。將CT26大腸癌細胞(1×106)懸浮於PBS(100μL)中,皮下注射於大腿至背部之間。本動物模型接受癌細胞接種14日後,進行後續試驗。
3.2 本發明多功能探針銦-111-DOTA-NIR790和銦-111-DOTA-NIR780對於皮下腫瘤動物模型之生體分布分析
本實驗例以單光子電腦斷層掃描(SPECT)與近紅外螢光影像(NIRF)進行造影。評估標定有放射線核種之多功能探針(即,銦-111-DOTA-NIR790或銦-111-DOTA-NIR780)於皮下腫瘤動物模型體內分布情形。
首先,將銦-111-DOTA-NIR790和銦-111-DOTA-NIR780(約37MBq的銦-111)分別靜脈注射至實施例3.1.1之皮下腫瘤動物模型,再以N anoSPECT/CT造影,於第1、4、24和48小時取得本發明多功能探針於小鼠活體影像,待小鼠犧牲後摘取各臟器組織以加馬射線計數分析儀(γ-counter)、放射顯像法(Autoradiography)進行定量與定性分析,結果分別示於第3A圖和第3B圖。舉例而言,如第3A圖所示,小鼠經本發明多功能探針銦-111-DOTA-NIR790注射後24小時大量聚積在腫瘤處(1.78±0.37%ID/g),經48小時候於腫瘤處的聚積量仍達1.67±0.21%ID/g,且本藥物易代謝,不會累積在其他器官中。另,本發明的多功能探針銦-111-DOTA-NIR790和銦-111-DOTA-NIR780經注射後24小時,其腫瘤與肌肉聚積比(tumor/muscle ratio)分別為12.84±0.65和2.97±0.96,由此可見本發明多功能探針在腫瘤部位的具聚積量遠高於肌肉組織。
另外,於近紅外螢光影像部分,將本發明的多功能探針銦-111-DOTA-NIR790和銦-111-DOTA-NIR780(約100~300μg的DOTA-NIR790)靜脈注射至皮下腫瘤動物模型後,於第1、4、24和48小時經IVIS影像系統進行拍攝與影像定量,所使用的激發波長/螢光波長分別為ex 710-760nm/em 810-875nm(ICG filter set),結果分別示於第3C圖和3D,如圖所示,本發明多功能探針銦-111-DOTA-NIR790於近紅外光影像部分的結果與單光子電腦斷層掃描相符,本發明的多功能探針具有腫瘤專一性。
3.2 本發明多功能探針銦-111-DOTA-NIR790對於腦轉移動物模型之生體分布分析
本實驗例以單光子電腦斷層掃描(SPECT)與近紅外螢光影像(NIRF)進行造影。評估標定有放射線核種之多功能探針(即,銦-111-DO TA-NIR790)於腦轉移動物模型體內分布情形。
首先,將銦-111-DOTA-NIR790(約37MBq的銦-111)分別靜脈注射至實施例3.1.2之腦轉移模型,再以NanoSPECT/CT造影,取得藥物於小鼠活體影像,待小鼠犧牲後摘取其腦部組織以加馬射線計數分析儀(γ-counter)、放射顯像法(Autoradiography)進行定量與定性分析,結果分別示於第4A圖。另外,於近紅外螢光影像部分,將本發明的多功能探針銦-111-DOTA-NIR790(約100~300μg的DOTA-NIR790)靜脈注射至腦轉移皮下腫瘤動物模型後,經IVIS影像系統進行拍攝與影像定量,所使用的激發波長/螢光波長分別為ex 710-760nm/em 810-875nm(ICG filter set),另小鼠犧牲後摘取其腦部組織同前步驟進行分析,結果分別示於第4B和第4C圖。由結果可以得知,本發明多功能探針同樣能夠專一性結合至腦腫瘤組織,於SPECT和近紅外光影像造影中有類似的結果。
3.2 本發明多功能探針銦-111-DOTA-NIR790對於其他癌症動物模型之生體分布分析
本實驗例以單光子電腦斷層掃描(SPECT))進行造影。評估本發明標定有放射線核種之多功能探針(即,銦-111-DOTA-NIR790)於3.1.3至3.1.6各種癌症動物模型體內分布情形。
將各該癌症動物模型以銦-111-DOTA-NIR790(約37MBq的銦-111)靜脈注射後,於第1、4、24和48小時測定放射活性,結果請參見第5A至第5D圖。
於人類大腸癌(HCT-116)小鼠模式下的生體分布結果,於腫瘤的積聚量,於注射24小時和48小時分別為1.62±0.29%和0.94±0.15%ID /g,於第48小時腫瘤與肌肉積聚比為7.66±1.13。於老鼠大腸癌(CT26)小鼠模式下的生體分布結果,於腫瘤的積聚量,於注射24小時和48小時分別為5.39±0.40%和3.19±0.49%ID/g,於第48小時腫瘤與肌肉積聚比為15.18±2.13。於人類頭頸癌(FaDu)小鼠模式下的生體分布結果,於腫瘤的積聚量,於注射24小時和48小時分別為0.87±0.02%和0.46±0.02%ID/g,於第48小時腫瘤與肌肉積聚比為4.27±0.19。於人類肺癌(A549)小鼠模式下的生體分布結果,於腫瘤的積聚量,於注射24小時和48小時分別為2.65±0.21%和2.31±0.15%ID/g,於第48小時腫瘤與肌肉積聚比為18.98±3.35
綜合以上結果可以得知,本發明多功能探針經由動物系統性循環能夠準確聚積在腫瘤處,證實本發明所提出的多功能探針能夠合併近紅外螢光與核醫影像,同時提供診斷及治療癌症和/或腫瘤的功效,。
實施例4 本發明多功能探針對於結腸直腸癌於光熱治療上的效果
施打標誌多功能腫瘤診治探針(DOTA-NIR790,約100~300μg)至實施例3.1.3的HCT-116腫瘤動物模型,注射後24小時,以808nm雷射進行照射,腫瘤組織溫度量測的結果示於第6A圖。再者,腫瘤體積大小量測示於第6B圖。依據第6A圖的結果可以得知,本發明的多功能探針倔近紅外光波段強吸收的光學特性,能夠於腫瘤組織內產生熱能,進行光熱治療。再者,依據第6B圖的結果顯示,在施用本發明多功能探針高濃度的組別(300ug)能夠有效控制腫瘤體積,能夠有效抑制腫瘤生長。
以上所揭示的具體實施例非用以限定本發明的權利範圍,本技術領域中具有通常知識者,於本發明原理與精神所涵蓋的範圍 內,一罩其通常經驗當可進行修改,因此本發明所主張的權利範圍係以申請專利範圍所界定的為準。
Claims (8)
- 一種多功能探針,其具有式(1)所示結構:
- 如請求項1所述之多功能探針,其中R是 。
- 如請求項1所述之多功能探針,其中該R是 。
- 如請求項1所述之多功能探針,更包含一放射線核種標定於該式(1)化合物上。
- 如請求項4所述之多功能探針,其中該放射線核種是錸-188、鎝-99 m、銦-111、镥-177、鎵-68、釔90、氟-18、銅-64或釓。
- 一種造影劑,包含:如請求項1至5任一項所示之多功能探針;以及一造影賦型劑。
- 一種多功能探針於製備診斷或治療癌症用之醫藥品的用途,其中該多功能探針如請求項1至5任一項所示。
- 如請求項7所述之用途,其中該癌症選自於以下所組成之群組中:血癌、淋巴瘤、骨幹骨肉瘤、多發性骨髓瘤、睾丸癌甲狀腺癌、前列腺癌、咽喉癌、子宮頸癌、鼻咽癌、乳癌、大腸癌、胰臟癌、胃癌、頭頸癌、食道癌、直腸癌、膀胱癌、腎癌、肺癌、肝癌、腦癌、黑色素癌、鱗狀細胞癌和皮膚癌。
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