TWI703990B - 具有核殼結構之複合物及其應用 - Google Patents
具有核殼結構之複合物及其應用 Download PDFInfo
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- TWI703990B TWI703990B TW108108701A TW108108701A TWI703990B TW I703990 B TWI703990 B TW I703990B TW 108108701 A TW108108701 A TW 108108701A TW 108108701 A TW108108701 A TW 108108701A TW I703990 B TWI703990 B TW I703990B
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Abstract
本發明係關於一種具有核殼結構之複合物及其用於製備治療血栓、治療癌症、或組織工程之藥物之用途,該具有核殼結構之複合物包含:一核心;及 一第一殼層,包覆該核心之一表面;其中,該核心係聚吡咯(polypyrrole)。
Description
本發明係關於一種複合物,尤指一種具有核殼結構之複合物。
聚吡咯(Polypyrrole,Ppy)是一種生物有機導電聚合物,由於其優異的穩定性、導電性和近紅外光(NIR)的高吸光度,長期以來一直被認為是一種多功能材料多用於面板、光電、半導體產業,然而,因為聚吡咯的疏水性而限制其在生物醫學領域之發展。
在目前醫療技術領域中,癌症治療主要為手術切除、傳統化學藥物治療等,其中,手術切除仍有無法企及之部位,且傳統化學藥物治療可能會引起許多副作用,例如導致腹瀉、便秘、營養吸收不良、毛髮掉落、免疫功能下降等,並且經口投與藥物治療無法僅散布至腫瘤所在區域,因此在腫瘤中或是在腫瘤附近難以獲得最有效的藥物濃度,因此,在治療癌症的同時,患者需要忍受各種化學藥物治療所帶來的不適。
其次,目前常用的創傷敷材多為傳統紗布,其雖最簡便且便宜,但易黏在傷口上,換藥疼痛,且其並非完全貼附破損之傷口表面,無法促進表皮細胞移行及傷口癒合。
此外,目前對於靜脈或動脈血栓的常見治療方法為給予血栓溶解劑(如鏈激酶),然而,血栓溶解劑的給予可引起危及生命的出血併發症,在治療血栓的同時帶給患者極大的風險。
有鑑於此,目前亟需發展一種可應用於生物醫學領域的多功能材料,有效改善癌症、血栓以及幫助傷口復原,使患者減少治療癌症所帶來的不適,幫助傷口復原,以及避免在治療血栓時引起的出血。
為了解決上述問題,本發明提供一種具有核殼結構之複合物,俾能有效改善癌症、血栓以及幫助傷口復原,使患者減少治療癌症所帶來的不適,幫助傷口復原,以及避免在治療血栓時引起的出血。
本發明提供一種具有核殼結構之複合物,包含:一核心;及一第一殼層,包覆該核心之一表面;其中,該核心係聚吡咯(polypyrrole,Ppy)。
在本發明之複合物中,較佳地,該第一殼層係兩親性(amphiphilic)高分子;更佳地,該第一殼層選自由聚乙烯亞胺(polyethylenimine,PEI)、肝素(heparin)、褐藻多醣(fucoidan)、玻尿酸(hyaluronic acid)、乙二醇幾丁聚醣(glyco chitosan)及其組合所組成之群組;再更佳地,該第一殼層係聚乙烯亞胺(polyethylenimine)。
在本發明之複合物中,該複合物之尺寸較佳為20nm至1000nm,更佳為20 nm至500nm。
本發明更提供一種具有核殼結構之複合物之製備方法,包含下列步驟:(A) 提供一聚乙烯亞胺溶於水中;(B) 加入一吡咯單體;及(C) 加入一催化劑形成一混合物。
在本發明之複合物之製備方法中,步驟(B)可在任何pH值之環境下進行攪拌;較佳地,該pH值小於1.2;更佳地,該pH值為0.5-1.2。
在本發明之複合物之製備方法中,該聚乙烯亞胺對該吡咯單體之比例不限,較佳為1500:500至80:4,更佳為300:50至100:5。
在本發明之複合物之製備方法中,可更包含步驟(D)利用一透析袋對該混合物進行透析。
本發明更提供一種具有核殼結構之複合物於製備治療血栓之藥物之用途,該核殼結構之複合物,包含:一核心;及一第一殼層,包覆該核心之一表面;其中,該核心係聚吡咯(Polypyrrole)。
在本發明之具有核殼結構之複合物於製備治療血栓之藥物之用途中,較佳地,該第一殼層係兩親性(amphiphilic)高分子;更佳地,該第一殼層選自由聚乙烯亞胺(polyethylenimine,PEI)、肝素(heparin)、褐藻多醣(fucoidan)、玻尿酸(hyaluronic acid)、乙二醇幾丁聚醣(glyco chitosan)及其組合所組成之群組;再更佳地,該第一殼層係聚乙烯亞胺(polyethylenimine)。
在本發明之具有核殼結構之複合物於製備治療血栓之藥物之用途中,該複合物之尺寸較佳為1500:500至80:4,更佳為300:50至100:5。
本發明另外提供一種具有核殼結構之複合物於製備治療癌症之藥物之用途,該核殼結構之複合物,包含:一核心;及一第一殼層,包覆該核心之一表面;其中,該核心係聚吡咯(Polypyrrole)。
在本發明之具有核殼結構之複合物於製備治療癌症之藥物之用途中,較佳地,該第一殼層係兩親性(amphiphilic)高分子;更佳地,該第一殼層選自由聚乙烯亞胺(polyethylenimine,PEI)、肝素(heparin)、褐藻多醣(fucoidan)、玻尿酸(hyaluronic acid)、乙二醇幾丁聚醣(glyco chitosan)及其組合所組成之群組;再更佳地,該第一殼層係聚乙烯亞胺(polyethylenimine)。
在本發明之具有核殼結構之複合物於製備治療癌症之藥物之用途中,該複合物之尺寸較佳為1500:500至80:4,更佳為300:50至100:5。
在本發明之具有核殼結構之複合物於製備治療癌症之藥物之用途中,該癌症係任一癌症;較佳地,該癌症係肺癌。
本發明更再提供一種具有核殼結構之複合物之組成物,包含:一具有核殼結構之複合物,包含:一核心,該核心係聚吡咯(Polypyrrole);及一第一殼層,包覆該核心之一表面;以及一熱敏感型明膠。
本發明之具有核殼結構之複合物之組成物中,較佳地,該第一殼層係兩親性(amphiphilic)高分子;更佳地,該第一殼層選自由聚乙烯亞胺(polyethylenimine,PEI)、肝素(heparin)、褐藻多醣(fucoidan)、玻尿酸(hyaluronic acid)、乙二醇幾丁聚醣(glyco chitosan)及其組合所組成之群組;再更佳地,該第一殼層係聚乙烯亞胺(polyethylenimine)。
在本發明之具有核殼結構之複合物之組成物中,其中,該複合物之尺寸較佳為1500:500至80:4,更佳為300:50至100:5。
本發明另外再提供一種具有核殼結構之複合物之組成物於製備用於組織工程之藥物之用途,該具有核殼結構之複合物之組成物,包含:一具有核殼結構之複合物,包含:一核心,該核心係聚吡咯(Polypyrrole);及一第一殼層,包覆該核心之一表面;以及一熱敏感型明膠。
在本發明之具有核殼結構之複合物之組成物於製備用於組織工程之藥物之用途中,較佳地,該第一殼層係兩親性(amphiphilic)高分子;更佳地,該第一殼層選自由聚乙烯亞胺(polyethylenimine,PEI)、肝素(heparin)、褐藻多醣(fucoidan)、玻尿酸(hyaluronic acid)、乙二醇幾丁聚醣(glyco chitosan)及其組合所組成之群組;再更佳地,該第一殼層係聚乙烯亞胺(polyethylenimine)。
在本發明之具有核殼結構之複合物之組成物於製備用於組織工程之藥物之用途中,較佳地,係用於肌膚傷口。
本說明書用語「治療」、「治療中」、「療法」,係包含以治療或預防之方式緩和、減輕、或改善至少一項疾病症狀或生理狀況、預防新增之症狀、抑制疾病或生理狀況、阻止或減緩疾病發展、造成疾病或生理狀況之復原、減緩因疾病造成的生理狀況、停止疾病症狀或生理狀況。
以下係藉由特定的具體實施例說明本發明之實施方式,熟習此技藝之人士可由本說明書所揭示之內容輕易地了解本發明之其他優點與功效。本發明亦可藉由其他不同的具體實施例加以施行或應用,本說明書中的各項細節亦可針對不同觀點與應用,在不悖離本創作之精神下進行各種修飾與變更。
本發明之Ppy-PEI NC (polypyrrole- polyethylenimine nanocomplex)之製備係將PEI (600 Da,20-2000mg)溶在去離子水中,然後加入吡咯單體 (1-200μL),接著在特定pH值環境下攪拌該混合物0.2-3小時後,再加入氯化鐵六水合物(ferric chloride hexahydrate,0.0005- 0.1g/mL,0.1-10 mL)。在聚合反應進行0.1-2小時後,利用透析袋除去游離的PEI和鐵離子,之後用去離子水洗滌(3-30次) 再烘乾(約1-7天),得到含有Ppy-PEI NC(20-1000 nm) 的Ppy-PEI-NC。
[製備例1]-Ppy-PEI NC明膠的製備
圖1為本實施例所得之Ppy-PEI NC核殼結構示意圖。將PEI (600 Da,200mg,購自Sigma-Aldrich)溶在20mL去離子水中,然後加入吡咯單體 (12.5μL,購自Sigma-Aldrich),接著攪拌該混合物0.2-3小時後,再加入氯化鐵六水合物(ferric chloride hexahydrate,0.0125g/mL ,1 mL,購自Sigma-Aldrich)。在聚合反應進行0.1-2小時後,利用透析袋除去游離的PEI和鐵離子,之後用去離子水洗滌再烘乾,得到含有Ppy-PEI NC(20-1000 nm) 的Ppy-PEI-NC。
之後,將明膠(B型牛皮明膠,購自Sigma-Aldrich)加入溫的磷酸鹽緩衝生理鹽水(PBS)中直到濃度為200 mg/mL為止,再加入上述所得之Ppy-PEI NC攪拌均勻,得到一Ppy-PEI NC明膠,其中,Ppy-PEI NC濃度為0.1-100mg/mL。
[試驗例1]-Ppy-PEI NC明膠的形態
將製備例1所得之Ppy-PEI NC裝至1.5 mL之微量離心管中再將其倒置,將其置於室溫(22-25℃)之下,之後再將溫度升至高溫(39-45℃)。Ppy-PEI NC明膠在室溫環境下為膠狀因此可不受重力影響停留在倒置的微量離心管的上方,在高溫中為液狀而流至微量離心管的下方,且該Ppy-PEI NC明膠形態的轉換為可逆的,可隨著溫度升高從膠狀變化至液狀,之後可隨溫度降低再從液狀變化至膠狀,此外,該Ppy-PEI NC明膠係在溫度約為35℃時發生形態的轉換。
[試驗例2]-Ppy-PEI NC明膠的孔狀結構
圖2為本實施例之Ppy-PEI NC明膠之SEM圖。將製備例1所得之Ppy-PEI NC明膠經冷凍乾燥後之粉末,利用SEM觀察其結構。如圖2所示,和不含Ppy-PEI NC的明膠相比,Ppy-PEI NC明膠具有明顯的孔洞結構,該孔洞結構大小約為0.1~0.2 mm適合細胞生長,因此本發明之Ppy-PEI NC明膠適合作為生物支架。
[試驗例3]-Ppy-PEI NC明膠的光熱性質
圖3A為本實施例Ppy-PEI NC明膠經近紅外光照射後所得的熱影像圖,圖3B為圖3A溫度變化之量化圖。取製備例1所得之Ppy-PEI NC明膠以及不含有Ppy-PEI NC的明膠,將兩者皆暴露於遠距離的近紅外光照射源之下(808 nm),同時間利用熱影像儀進行觀察。如圖3B所示,在第180秒時,不含有Ppy-PEI NC的明膠(NIR組)之溫度經近紅外光照射後僅從起始的25℃略微上升至29℃,而本發明之Ppy-PEI NC明膠之溫度經近紅外光照射後從25℃上升至43℃,代表明膠中所含之Ppy-PEI NC在吸收近紅外光後確實可將所吸收之近紅外光轉換成熱能,使Ppy-PEI NC明膠之溫度上升。
圖4為本實施例之Ppy-PEI NC明膠應用於皮膚傷口之流程示意圖。本發明之Ppy-PEI NC明膠可應用於受試者之皮膚上,在施用前該Ppy-PEI NC明膠在室溫下為膠狀,經過近紅外光照射後明膠中的Ppy-PEI NC將所吸收之近紅外光轉換成熱能,使該Ppy-PEI NC明膠溫度上升而呈液狀,再將其塗覆至傷口上,由於其為液狀因此可緊密貼附傷口損壞之組織表面,提供細胞生長空間,幫助傷口復原。
[試驗例4]-Ppy-PEI NC明膠的細胞毒性測試
圖5為本實施例之Ppy-PEI NC明膠之MTT試驗之結果圖。分別取等體積的明膠和製備例1所得之Ppy-PEI NC明膠之後再分別加入96孔盤中,接著各自加入高葡萄糖DMEM(5 mL),置於培養箱(37℃,5%CO
2)中24小時,之後從每孔取10μl的液體培養基以進行間接MTT試驗。
將L929小鼠纖維母細胞(5000-50000個/孔,0.1mL)接種到一96孔盤中,然後培養約24至48小時以適當附著生長。接著,將上述液體培養基(10μl)加入至96孔盤中培養24小時。最後用MTT套組及微量盤分光光度計(Multiscan FC,MA,USA)檢測細胞存活率。
如圖5所示,Ppy-PEI NC明膠與作為對照組的明膠相比,在第1、3、6、24小時之細胞存活率皆沒有顯著差異。證實本實施例之Ppy-PEI NC明膠之生物相容性與明膠相似。
[試驗例5]-Ppy-PEI NC明膠用於動物傷口
圖6A為本實施例之Ppy-PEI NC明膠用於動物傷口所得之傷口圖,圖6B為圖6A量化後所得之傷口收縮率。
本實施例所進行之動物實驗係將大鼠(Wistar)分為控制組、Ppy-PEI NC NIR、及Ppy-PEI NC明膠NIR三組,每組各三隻。將大鼠麻醉後刮除其背部之毛髮後再用70%酒精消毒,接著畫出一直徑20 mm的圓形,並且依照所畫之圓形製造一個全皮層損傷傷口,然後馬上照相記錄該傷口。在該傷口形成之後,控制組之大鼠並未塗敷任何東西,Ppy-PEI NC NIR組之大鼠在該傷口上塗敷經近紅外光照射的Ppy-PEI NC,Ppy-PEI NC明膠NIR組之大鼠在該傷口上塗敷經近紅外光照射的Ppy-PEI NC明膠,接著觀察21天,在第0、3、7、14、及21天時記錄大鼠傷口尺寸、傷口面積和傷口收縮率,其中,傷口收縮率(W%)係經由以下算式計算:
W%=(W
d0-W
dn)/W
d0X 100
W
d0為在第0天時的傷口面積,W
dn為在第n天時的傷口面積(n=0、3、7、14、21)。
如圖6A及6B所示,雖然在第21天時所有組別的大鼠的傷口接近完全閉合,但是在第3、7及14天時,Ppy-PEI NC明膠NIR組大鼠的傷口具有最佳的傷口收縮率,並且,在第21天時Ppy-PEI NC明膠NIR組與控制組之傷口收縮率具有顯著差異(
P<0.05),證實Ppy-PEI NC明膠可有效協助傷口的復原。
在第21天完成對三組大鼠的觀察記錄後,將大鼠麻醉進行犧牲,收集位在傷口的皮膚組織、心臟、肺臟、肝臟、腎臟以及脾臟器官,用2-50%福馬林固定前述的組織或器官後再用濃度漸增的酒精乾燥,再用石蠟包埋,將樣本切片後用蘇木精-伊紅染色以利觀察。
圖6C為Ppy-PEI NC明膠用於動物皮膚傷口後體內器官之組織切片圖。如圖6C所示,控制組、Ppy-PEI NC NIR組、Ppy-PEI NC明膠 NIR組之大鼠的體內器官(心臟、肺臟、肝臟、腎臟以及脾臟)皆未出現發炎及中毒反應。
圖6D為Ppy-PEI NC明膠用於動物皮膚傷口後之動物體重曲線。如圖6D所示,控制組、Ppy-PEI NC NIR組、Ppy-PEI NC明膠 NIR組之大鼠在第0天及第21天之動物體重保持穩定,並無體重顯著減少之情形。
因此,圖6C及圖6D證實本發明之Ppy-PEI NC明膠對於動物具有生物相容性。
在本實施例中,在第3、7及14天Ppy-PEI NC明膠 NIR組大鼠的傷口具有最佳的傷口收縮率,證明了含有Ppy-PEI NC的明膠比沒有包含Ppy-PEI NC的明膠更能促進細胞組織生長及傷口復原,其係因為Ppy-PEI NC明膠具有適合細胞生長的孔洞結構,以及Ppy-PEI NC具有將近紅外光轉換成能熱的能力可使Ppy-PEI NC明膠溫度升高後從膠狀轉變為液狀,而不含有Ppy-PEI NC的明膠在吸收近紅外光後仍為膠狀,因此塗敷於傷口時無法符合傷口凹凸不平的損傷表面導致無法有效提供促進細胞生長的支架。
[製備例2]- Ppy-PEI NC之製備
將PEI (600 Da,200mg,購自Sigma-Aldrich)溶在20mL去離子水中,然後加入吡咯單體 (12.5 μL,購自Sigma-Aldrich),接著攪拌該混合物0.2-3小時後,再加入氯化鐵六水合物(ferric chloride hexahydrate, 0.0125g/mL ,1 mL,購自Sigma-Aldrich)。在聚合反應進行0.1-2小時後,得到黑色的Ppy-PEI-NC溶液,再除去游離的PEI和鐵離子,之後用去離子水洗滌再烘乾,得到Ppy-PEI NC(20-1000 nm)。
上述Ppy-PEI NC可依照實驗需求而加入不同體積之溶劑以製備所需濃度之Ppy-PEI NC溶液。
[試驗例6]- Ppy-PEI NC之可溶性
圖7A為本實施例之Ppy-PEI NC水溶液之相片及利用穿透式電子顯微鏡(TEM)拍攝所得之影像圖。Ppy-PEI NC組係取製備例2所得之Ppy-PEI NC(0.1-1 mL)至微量離心管中,再加入水(0.1-1 mL)之後利用震盪器進行混合,然後利用一般相機拍攝及穿透式電子顯微鏡拍攝;而Ppy組係對照組,其係取聚吡咯 (5-200 μL,購自Sigma-Aldrich)至微量離心管中,再加入水(0.01-0.5 mL)之後利用震盪器進行混合,然後利用一般相機及穿透式電子顯微鏡(TEM)拍攝。由於Ppy的疏水特性,故其無法溶於水中穩定存在,在圖7A上列的相片及TEM圖中可觀察到在加入水後,Ppy無法溶於水而呈現沉澱及聚集;而圖7A下列的相片及TEM圖中可觀察到在加入水後,Ppy-PEI NC穩定存在於水溶液中且形成一黑色溶液。
圖7B為本實施例Ppy-PEI NC水溶液之SEM圖。如圖7B所示,Ppy-PEI NC在水溶液中為均勻分散的球形可能是因為其較小的尺寸以及每個Ppy-PEI NC之間較強互斥的陽離子電場。
由於Ppy分子在含水體系中具有不良的均質性,因此難以產生分散的奈米Ppy,因而限制其用途。塗覆聚合物的極性對Ppy的分散性質有影響,因此對於沒有極性基團塗覆的聚合物而言分散性更差。為了克服這種分散性的問題,必須要在Ppy表面覆上一層分散聚合物試劑,該分散聚合物試劑為一種讓Ppy聚合物分子可在水溶液中穩定存在的有機分子。本發明利用PEI覆蓋於Ppy表面,形成一Ppy-PEI奈米複合物之核殼結構,使其能溶於水中而增加可利用性。
[試驗例7]- Ppy-PEI NC之性質
圖8A為本實施例之Ppy-PEI NC與明膠A及明膠B作用後之共軛焦雷射掃描顯微鏡圖。取等量製備例2之Ppy-PEI NC(0.002-200 mg/mL),分別加入帶正電之明膠A(10-1000 μL,Sigma-Aldrich)以及帶負電之明膠B(10-1000 μL,Sigma-Aldrich),培養 (0.1-2 小時)之後用PBS洗滌,去除未與明膠結合之Ppy-PEI NC,再利用共軛焦雷射掃描顯微鏡(CLSM)檢測。如圖8所示,聚集在明膠B之Ppy-PEI NC大於明膠A聚集之Ppy-PEI NC。因此,可證實本實施例之Ppy-PEI NC係帶有正電,並且可受帶負電之明膠B的吸引。
由於在腫瘤周圍組織的嗜中性球表面被帶正電的胜肽/物質覆蓋而帶正電,而所有種類癌細胞中大量乳酸產生的陰離子電荷,因此這種表面具有不同帶電特徵差異可為癌症標靶治療提供標的。本實施例之Ppy-PEI NC表面覆蓋帶正電之PEI,因此可瞄準帶有大量陰離子之癌細胞進行治療。
圖8B為本實施例之Ppy-PEI NC之傅利葉轉換紅外光譜(FTIR)。為了進一步證明本發明之Ppy-PEI NC中PEI確實與PEI形成共價鍵形成一核殼結構,利用傅立葉轉換紅外光譜儀分析製備例2所得之Ppy-PEI NC。如圖8B所示,Ppy-PEI NC在波數約為1444~1459 cm
-1處可觀察到吡咯(pyrrol)之波峰特徵(出自於pyrrol中芳香環的伸縮震動),且在約為3454 cm
-1處可觀察到聚乙烯亞胺(PEI)之波峰特徵(出自於PEI的一級胺)。
[試驗例8]- 細胞對於Ppy-PEI-NC之胞吞作用及Ppy-PEI-NC在細胞內經近紅外光照射後增加細胞中ROS及H
2O
2含量
圖9A為本實施例之細胞對於Ppy-PEI-NC胞吞作用及ROS含量之共軛焦雷射掃描顯微鏡(CLSM)圖;圖9B為圖11A之ROS螢光強度統計圖;圖9C為本實施例之細胞對於Ppy-PEI-NC胞吞作用及H
2O
2含量之共軛焦雷射掃描顯微鏡(CLSM)圖;圖9D為圖9C之H
2O
2螢光強度統計圖;其中,NIR組為經近紅外光照射組別,Heat組為經加熱之組別,NC組為加入Ppy-PEI-NC但未經近紅外光照射之組別,NC/NIR組為加入Ppy-PEI-NC且經近紅外光照射組別。
在本實施例中,將肺癌細胞株NCI-H460接種在共軛焦培養皿中,然後放置在37℃和5%CO
2的細胞培養箱中過夜。之後培養於Hank's平衡鹽溶液(HBSS)中1小時,然後分別加入或未加入經Cy5標示的NC(即Cy5-Ppy-PEI-NC,0.002-200 mg/mL)至培養皿中培養1小時。其中,為了製造Heat組的高溫環境,將培養皿放置於水浴培養箱中(0.1-4 小時)培養。接著用PBS洗滌三次,再加入4',6-二脒基-2-苯基吲哚(DAPI)、二氯螢光素二乙酸酯(DCFH-DA,ROS染劑)及Amplex Red(過氧化氫染劑)染色,之後再利用CLSM檢測螢光,並利用ImageJ軟體將螢光訊號強度定量。
如圖9A至9D所示,僅照射近紅外光之NIR組以及僅添加Ppy-PEI-NC但未經近紅外光照射之NC組的肺癌細胞僅生產少量的ROS,但可明顯觀察到H
2O
2之存在;然而,在經加熱之Heat組或是在加入Ppy-PEI-NC且經近紅外光照射之NC/NIR組中,肺癌細胞中的ROS以及H
2O
2的含量顯著增加。
在本實施例中可觀察到Ppy-PEI-NC透過依賴網格蛋白的(clathrin-dependent)胞吞作用進入癌細胞中,其中由於本發明之Ppy-PEI-NC之顆粒大小平均為10nm~1000nm,其在利於胞吞作用的進行的尺寸範圍內(60~400 nm),並且本發明之Ppy-PEI-NC之顆粒表面帶正電,利於附著在帶大量負電的癌係胞表面,因此癌細胞可順利進行胞吞作用,本發明之Ppy-PEI-NC可用於癌症治療之用途。
[試驗例9]- Ppy-PEI-NC之MTT試驗
圖10A為本實施例之Ppy-PEI-NC之MTT試驗統計圖,圖10B為本實施例之細胞SEM圖。在本實施例中,將NCI-H460細胞培養於96孔盤中,每孔之細胞數為0.1-10X10
4個,放置於37℃、5%CO
2的培養箱中培養過夜,接著利用HBSS洗滌兩次之後培養於含有200μL的Ppy或是Ppy-PEI-NC的HBSS(0.15-150 mg/mL)中一小時,再照射/不照射近紅外光(2 W/cm
2,0-60分鐘)。接著再用PBS洗滌兩次,再加入20μL /well的MTT溶液(5 mg/ml,Sigma-Aldrich),之後放置於37℃、5%CO
2的培養箱中培養1-4小時。然後,取出細胞,移去96孔盤內培養基的混合液,再加入DMSO到細胞中培養20分鐘,再利用ELISA測讀機測量在490-570 nm的吸光值。
如圖10A所示,控制組為未加入Ppy或是Ppy-PEI-NC的組別,在照射近紅外光後並未減少其細胞存活率,證明近紅外光的照射對於細胞並沒有細胞毒性;在加入Ppy-PEI-NC的組別中,在未照射近紅外光的情形下,其細胞存活率仍超過80%,證明Ppy-PEI-NC對於細胞的毒性相對較低;而在加入Ppy的組別中,因為細胞對於Ppy的附著性不佳,在洗滌及照射近紅外光後對於細胞較無毒性,因此有較佳的細胞存活率。
圖10A為本實施例之Ppy-PEI-NC附著於細胞表面之SEM圖。如圖10A所示,在加入Ppy-PEI-NC後,細胞進行胞吞作用,因此可在細胞表面觀察到Ppy-PEI-NC顆粒(如10B所示)。
[試驗例10]- Ppy-PEI-NC之胞殺作用
圖11為本實施例之Ppy-PEI-NC之細胞螢光顯微鏡圖。在本實施例中,將NCI-H460細胞培養於培養皿中,放置於37℃、5%CO
2的培養箱中培養過夜,接著利用HBSS洗滌兩次之後培養於含有0-200μL的Ppy或是Ppy-PEI-NC (0.15-150 mg/mL ) 的HBSS中一小時,再照射/不照射近紅外光(2 W/cm
2,1-100分鐘)。接著再用PBS洗滌兩次,然後利用活死細胞染色試劑盒(Molecular Probes)進行30分鐘的細胞染色,最後利用細胞螢光顯微鏡檢測活/死細胞。
如圖11所示,僅經近紅外光照射之細胞仍有良好的存活率,加入Ppy之細胞經紅外光照射之後亦有良好的存活率,而加入本發明之Ppy-PEI-NC的細胞經紅外光照射之後呈現低存活率,證實本發明之Ppy-PEI-NC可有效殺死癌細胞,可應用於癌症治療之用途。
[製備例3] - Ppy-PEI-NC之製備3
將PEI (600 Da,200mg,購自Sigma-Aldrich)溶在20mL去離子水中,然後加入吡咯單體(12.5 μL,購自Sigma-Aldrich),接著攪拌該混合物0.2-3小時後,再加入氯化鐵六水合物(ferric chloride hexahydrate, 12.5 mg/mL,1 mL,購自Sigma-Aldrich)。在聚合反應進行0.2-3小時後,再去游離的PEI和鐵離子,之後用去離子水洗滌再烘乾,得到含有Ppy-PEI NC(20-1000 nm)之Ppy-PEI NC。為了便於觀察,將Cy5 N-羥基琥珀醯亞胺螢光染料(Cy5)與前述Ppy-PEI NC (0.1-200 mg/mL )在pH值為7.4以及溫度為4-37 ℃的環境下混合4-24小時,之後在去離子水中透析2-7天移除未標示的Cy5衍生物,得到經標示的Cy5-Ppy-PEI NC(0.1-200 mg/mL )。
[試驗例11]- Ppy-PEI NC在體外對血栓之作用
圖12為本實施例之Ppy-PEI NC在體外對血栓作用之CLSM圖。
在本實施例中,為了測試體外抗凝塊的光熱效應,將有螢光標示(Alex Fluor 647)的人類血纖維蛋白原(fibrinogen,Sigma-Aldrich)在pH7.4的環境下溶解在Tris-HCl (5-500 mM) – NaCl (0.14-100 mM)緩衝液中形成血纖維蛋白原溶液(0.1-100 mg/mL),接著先加入Ppy-PEI NC (0.0005- 0.1g/mL ) 凝血酶(0.1-5 U/mL)之後再加入CaCl
2(0.25-100 mM)至該血纖維蛋白原溶液(0.01-1000 mg/mL, 0.9-100 μL)中,然後攪拌均勻,之後在37℃下置於共軛焦培養皿之蓋玻片上培養1小時以形成血栓。之後為了模擬血栓在生物體血管內之環境,在平行之培養皿上製造流動的PBS產生一剪切力,在此狀態下用近紅外光 (2 W/cm
2)照射含有Cy5-Ppy-PEI NC血纖維蛋白的血栓0.1-3小時,並用共軛焦顯微鏡觀察血纖維蛋白密度的變化。
如圖12所示,在未經近紅外光照射 (0分鐘) 時,即使在剪切力的作用下可觀察到高密度的血栓結構,而在經過近紅外光照射(20、40、60分鐘)後,血栓結構的密度下降,從緊密血栓結構變為疏鬆血栓結構。
[試驗例12]- Ppy-PEI-NC在動物活體中藉由巨噬細胞在血栓處的聚集
圖14為本實施例之動物實驗中Ppy-PEI-NC分布於血栓形成處之IVIS圖。將體重約為250-350克重的大鼠(Wistar,BioLASCO)分為控制組、及Ppy-PEI NC兩組。使用2-4%異氟烷將大鼠麻醉之後進行手術將股靜脈(femur vein)露出,然後將具有0-50%氯化鐵的濾紙覆蓋在該股靜脈上0-30分鐘,之後注射/不注射製備例3所得之Cy5-Ppy-PEI NC(0.1-200 mg/mL)至心臟使其能在大鼠全身中循環。在心臟注射0-60分鐘後犧牲大鼠,利用活體成像系統(in vivo imaging system,IVIS)觀察股靜脈中血栓處。
如圖14所示,該活體成像系統清楚偵測到Cy5-Ppy-PEI NC之螢光,特別是在被施與氯化鐵而形成血栓處(thrombus site)的股靜脈中觀察到大量聚集的Cy5-Ppy-PEI NC,代表Cy5-Ppy-PEI NC藉由心臟注射循環全身時,被巨噬細胞偵測到且進行了胞吞作用,並且由於免疫反應故巨噬細胞累積在血栓處,因此在血栓處觀察到大量聚集的Cy5-Ppy-PEI NC。由於巨噬細胞會累積在血栓處,故可作為光熱抗血栓治療的血栓標靶運輸系統。
[試驗例13]- Ppy-PEI-NC在活體中的光熱性質
圖15A為本實施例之動物實驗之IVIS圖;圖15B為本實施例之動物實驗之熱影像圖;圖15C為本實施例之動物實驗之足部組織切片染色圖;圖15D為本實施例之動物實驗之器官切片染色圖。
本實施例將體重約為250-350克重的大鼠(Wistar,BioLASCO)分為控制組(NIR)、及Ppy-PEI NC兩組,其中,Ppy-PEI NC組係將製備例3所得之Cy5-Ppy-PEI NC(0.1-200 mg/mL,0.01-1 mL)經由皮下注射至大鼠足部,之後照射近紅外光0-60分鐘(2 W/cm
2),而控制組(NIR)僅照射近紅外光並沒有注射Cy5-Ppy-PEI NC,之後再利用活體成像系統(IVIS)以及熱影像儀觀察該足部皮下注射處;在進行皮下注射2-7天後犧牲大鼠,收集位在足部皮下注射處的皮膚組織以及大鼠的心臟、肺臟、肝臟、腎臟以及脾臟器官,用2-50%福馬林固定前述的組織或器官後再用濃度漸增的酒精乾燥,再用石蠟包埋,將樣本切片後用蘇木精-伊紅染色(HE Stain)再利用光學顯微鏡觀察。
如圖15A所示,活體成像系統清楚偵測到Ppy-PEI NC組在足部皮下注射處之螢光,而控制組(NIR)則無。如圖15B所示,藉由熱影像儀觀察可知,Ppy-PEI NC組在足部皮下注射Cy5-Ppy-PEI NC處經由近紅外光照射之後,該區域之溫度上升至高溫(42-45℃),而控制組(NIR)經由近紅外光照射之後,該區域之溫度仍維持在33℃左右,並無顯著提升溫度。
如圖15C所示,Ppy-PEI NC組在足部皮下注射Cy5-Ppy-PEI NC處經由近紅外光照射2-7天之後,發現該區域具有巨噬細胞聚集之現象,而控制組(NIR)則無。如圖15D所示,控制組(NIR)及Ppy-PEI NC組的體內器官(心臟、肺臟、肝臟、腎臟以及脾臟)皆未出現發炎等不良反應。
因此本實施例可證明所施用之Cy5-Ppy-PEI NC比起控制組(NIR)對生物體並沒有顯著差異。此外,這種局部的光熱治療應不會對血管內皮和血管壁造成傷害,因為血栓附近的血流可能會減弱局部形成的熱反應並阻止其擴散到血管壁,因此本發明之Ppy-PEI NC可應用於血栓的治療而不會對患者血栓處的血管內皮和血管壁造成傷害。
本發明之導電性高分子材料亦可作為熱療相關的物理治療領域技術平台,例如光熱熱療貼布搭配醫用紅外光源,可用於刺激穴道,產生類似中醫拔罐、針灸、飛針治療等療效。由於此導電性高分子價格便宜、具生物降解性、經過無數次反覆照射亦能進行穩定光熱效應,增進目前物理治療效果並取代現有器材可以且更經濟環保。
上述實施例僅係為了方便說明而舉例而已,本發明所主張之權利範圍自應以申請專利範圍所述為準,而非僅限於上述實施例。
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圖1為本發明之一較佳實施例所得之Ppy-PEI NC核殼結構示意圖。
圖2為本發明之一較佳實施例之Ppy-PEI NC明膠(Gelatin)之SEM圖。
圖3A為本發明之一較佳實施例之Ppy-PEI NC明膠經近紅外光照射後所得的熱影像圖;圖3B為圖3A溫度變化之量化圖。
圖4為本發明之一較佳實施例之Ppy-PEI NC明膠應用於皮膚傷口之流程示意圖。
圖5為本發明之一較佳實施例之Ppy-PEI NC明膠之MTT試驗之結果圖。
圖6A為本發明之一較佳實施例之Ppy-PEI NC明膠用於動物傷口所得之傷口圖;圖6B為圖6A量化後所得之傷口收縮率;圖6C為Ppy-PEI NC明膠用於動物皮膚傷口後體內器官之組織切片圖;圖6D為Ppy-PEI NC明膠用於動物皮膚傷口後之動物體重曲線。
圖7A為本發明之一較佳實施例之Ppy-PEI NC水溶液之相片及利用穿透式電子顯微鏡(TEM)拍攝所得之影像圖;圖7B為本發明之一較佳實施例之Ppy-PEI NC水溶液之SEM圖。
圖8A為本發明之一較佳實施例之Ppy-PEI NC與明膠A及明膠B作用後之共軛焦雷射掃描顯微鏡圖;圖8B為本發明之一較佳實施例之Ppy-PEI NC之傅利葉轉換紅外光譜(FTIR)。
圖9A為本發明之一較佳實施例之細胞對於Ppy-PEI-NC胞吞作用及ROS含量之共軛焦雷射掃描顯微鏡(CLSM)圖;圖9B為圖9A之ROS螢光強度統計圖;圖9C為本實施例發明之一較佳之細胞對於Ppy-PEI-NC胞吞作用及H
2O
2含量之共軛焦雷射掃描顯微鏡(CLSM)圖;圖9D為圖9C之H
2O
2螢光強度統計圖。
圖10A為本發明之一較佳實施例之Ppy-PEI-NC之MTT試驗統計圖;圖10B為本實施例之細胞SEM圖。
圖11為本發明之一較佳實施例之Ppy-PEI-NC之細胞螢光顯微鏡圖。
圖12為本發明之一較佳實施例之Ppy-PEI NC在體外對血栓作用之CLSM圖。
圖13為本發明之一較佳實施例之巨噬細胞與Ppy-PEI-NC之SEM圖。
圖14為本發明之一較佳實施例之動物實驗中Ppy-PEI-NC分布於血栓形成處之IVIS圖。
圖15A為本發明之一較佳實施例之動物實驗之IVIS圖;圖15B為本發明之一較佳實施例之動物實驗之熱影像圖;圖15C為本發明之一較佳實施例之動物實驗之足部組織切片染色圖;圖15D為本發明之一較佳實施例之動物實驗之器官切片染色圖。
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Claims (22)
- 一種具有核殼結構之複合物,包含:一核心;及一第一殼層,包覆該核心之一表面;其中,該核心係聚吡咯(polypyrrole);且該第一殼層係選自由聚乙烯亞胺(polyethylenimine,PEI)、褐藻多醣(fucoidan)及其組合所組成之群組。
- 如申請專利範圍第1項所述之複合物,其中,該第一殼層係聚乙烯亞胺(polyethylenimine)。
- 如申請專利範圍第1項所述之複合物,其中,該複合物之尺寸為20nm至500nm。
- 一種具有核殼結構之複合物之製備方法,包含下列步驟:(A)提供一聚乙烯亞胺溶於水中;(B)加入一吡咯單體;及(C)加入一催化劑形成一混合物。
- 如申請專利範圍第4項所述之方法,其中,步驟(B)更包含在一pH值小於1.2的環境中進行攪拌。
- 如申請專利範圍第5項所述之方法,其中,該pH值為0.5-1.2。
- 如申請專利範圍第4項所述之方法,其中,該聚乙烯亞胺對該吡咯單體之比例為300:50至100:5。
- 如申請專利範圍第4項所述之方法,其中,更包含步驟(D)利用一透析袋對該混合物進行透析。
- 一種具有核殼結構之複合物於製備治療血栓之藥物之用途,該核殼結構之複合物,包含: 一核心;及一第一殼層,包覆該核心之一表面;其中,該核心係聚吡咯(Polypyrrole)。
- 如申請專利範圍第9項所述之用途,其中,該第一殼層係選自由聚乙烯亞胺(polyethylenimine,PEI)、肝素(heparin)、褐藻多醣(fucoidan)、玻尿酸(hyaluronic acid)、乙二醇幾丁聚醣(glyco chitosan)及其組合所組成之群組。
- 如申請專利範圍第9項所述之用途,其中,該第一殼層係聚乙烯亞胺(polyethylenimine)。
- 如申請專利範圍第9項所述之用途,其中,該複合物之尺寸為20nm至500nm。
- 一種具有核殼結構之複合物於製備治療癌症之藥物之用途,該核殼結構之複合物,包含:一核心;及一第一殼層,包覆該核心之一表面;其中,該核心係聚吡咯(Polypyrrole);且該第一殼層係選自由聚乙烯亞胺(polyethylenimine,PEI)、褐藻多醣(fucoidan)及其組合所組成之群組。
- 如申請專利範圍第13項所述之用途,其中,該第一殼層係聚乙烯亞胺(polyethylenimine)。
- 如申請專利範圍第13項所述之用途,其中,該複合物之尺寸為20nm至500nm。
- 如申請專利範圍第13項所述之用途,其中,該癌症係肺癌。
- 一種具有核殼結構之複合物之組成物,包含: 一具有核殼結構之複合物,包含:一核心,該核心係聚吡咯(Polypyrrole);及一第一殼層,包覆該核心之一表面;以及一熱敏感型明膠。
- 如申請專利範圍第17項所述之組成物,其中,該第一殼層係選自由聚乙烯亞胺(polyethylenimine,PEI)、肝素(heparin)、褐藻多醣(fucoidan)、玻尿酸(hyaluronic acid)、乙二醇幾丁聚醣(glyco chitosan)及其組合所組成之群組。
- 如申請專利範圍第17項所述之組成物,其中,該第一殼層係聚乙烯亞胺(polyethylenimine)。
- 如申請專利範圍第17項所述之組成物,其中,該複合物之尺寸為20nm至500nm。
- 一種具有核殼結構之複合物之組成物於製備用於組織工程之藥物之用途,該具有核殼結構之複合物之組成物,包含:一具有核殼結構之複合物,包含:一核心,該核心係聚吡咯(Polypyrrole);及一第一殼層,包覆該核心之一表面;以及一熱敏感型明膠。
- 如申請專利範圍第21項所述之組成物,其中,該第一殼層係聚乙烯亞胺(polyethylenimine)。
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Manivasagan P ETAL:"Multifunctional biocompatible chitosan-polypyrrole nanocomposites as novel agents for photoacoustic imaging-guided photothermal ablation of cancer", Sci Rep., Vol 14, 20170302, 7:43593。 |
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