TWI719182B - 奈米組成物、其製造方法及其用途 - Google Patents

奈米組成物、其製造方法及其用途 Download PDF

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TWI719182B
TWI719182B TW106110485A TW106110485A TWI719182B TW I719182 B TWI719182 B TW I719182B TW 106110485 A TW106110485 A TW 106110485A TW 106110485 A TW106110485 A TW 106110485A TW I719182 B TWI719182 B TW I719182B
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黃唯婷
江俞謙
劉典謨
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國立交通大學
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Abstract

本發明提供一種奈米組成物、其製造方法及其用途。其製造方 法包含：混合雙性幾丁聚醣的第一溶液及含有抗癌成分的第二溶液，其中抗癌成分包含吉西他濱、薑黃素、其衍生物或其組合；使雙性幾丁聚醣藉由自組裝而包覆抗癌成分，以形成奈米粒子；以及將對一癌症具專一性的標靶分子與該奈米粒子進行嫁接，以得到奈米組成物。本發明之奈米組成物在乾燥後回溶於水相仍保有乾燥前的型態及性質，便於長期保存及運送。另外，本發明亦提供吉西他濱與去氧甲基薑黃素的較佳比例，藉其協同效應提升治療效果。

Description

奈米組成物、其製造方法及其用途
本發明係關於奈米組成物、其製造方法及其用途。具體而言，本發明係提供藉由選用較佳比例之雙藥組合製備對特定癌症具專一性的奈米組成物、其製造方法及其用於製備治療癌症之藥物的用途。
癌症，又稱惡性腫瘤，係生物體內控制細胞分裂的機制失常所引起的疾病。近代由於物質及生活習慣的改變，以及輻射或環境汙染因子的存在，使得全球整體的罹癌率較過去大幅提高。在2012年，全球約有1410萬人罹癌，並造成其中820萬人死亡(相當於全年總死亡人數的14.6%)(參照：World Cancer Report 2014,World Health Organization,2014,Chapter 1.1,ISBN 9283204298)，可見即便是在醫療技術逐漸發達的現在，癌症的治療仍為急需解決的問題。
現今，癌症可以藉由手術切除、化學治療、放射線治療、單株抗體治療、標靶治療等方式進行治療，其中標靶治療又屬其中副作用最低又具療效者，為本領域中的熱門研究項目。標靶治療多使用具專一性的小分子藥物或結合專一性分子的奈米粒子作為主要方法，其中又因奈米粒子通常具有可攜帶大量抗癌藥物的特性，使其除了具有比單獨 使用小分子藥物更高的療效，更能在特定位置釋放抗癌藥物，具有不遜於化學治療的治療效果且僅有低副作用。
奈米粒子雖具有上述的優點，然而其長期保存方法仍為需要解決的問題。奈米粒子通常以膠體溶液的形式保存(如：中華民國發明專利第I458833號、中華民國發明專利第I482782號、中華民國發明專利第I399214號等)，且需於其表面上修飾保護劑或在溶液中添加保護劑以避免聚集現象。再者，奈米粒子的膠體溶液對於溫度的變化較為敏感，因此在保存及運送上較為不易。雖可將奈米粒子乾燥成為粉末狀保存，惟將粉末回溶至水相以便於施用至病患時，在多數情況奈米粒子較難以回復成原本的粒徑，而是發生聚集的現象以致於無法施用。
另外，在上述奈米粒子搭配的藥物選用方面，近年來，熱門的研究對象轉為複數種藥物的合併療法，例如：美國食品藥物管理局(FDA)在2005年11月核准使用標靶藥物厄洛替尼(Erlotinib)與吉西他濱合併治療晚期胰臟癌；2007年的美國臨床腫瘤學會會議(ASCO Annual Meeting)上亦揭露了伊立替康(Irinotecan)/歐洲紫杉醇(Docetaxel)及貝伐單抗(Bevacizumab)/西妥昔單抗(Cetuximab)的合併療法；而在2012年亦有文獻提供了厄洛替尼與吉西他濱合併治療非小細胞肺癌的臨床三期研究(參照：DOI：10.1200/JCO.2011.39.9782 Journal of Clinical Oncology 30,no.28(October 2012)3516-3524)，雖有治療效果，但皆無法在臨床上顯示可增加五年內存活率。
綜上述，目前確有針對特定癌症的有效藥物組合、可供長期保存且便於運輸的奈米粒子標靶藥物的需求或兩者之組合的需求。
鑒於以上習知技藝的問題，本發明之目的係提供一種奈米組成物、其製造方法及其用途。
在本發明之一目的中，提供奈米組成物的製造方法，其包含：混合雙性幾丁聚醣的第一溶液及含有抗癌成分的第二溶液，其中抗癌成分包含吉西他濱、薑黃素、其衍生物或其組合；使雙性幾丁聚醣藉由自組裝而包覆抗癌成分，以形成奈米粒子；以及將對癌症具專一性的標靶分子與奈米粒子進行嫁接，以得到奈米組成物。
較佳地，雙性幾丁聚醣包含具釓元素的親水端。
較佳地，相對於第一溶液總重計，雙性幾丁聚醣的濃度介於0.001%~10%(w/w)之間。
較佳地，相對於第二溶液總體積計，抗癌成分的濃度介於1mg/mL~1000mg/mL之間。
較佳地，薑黃素及其衍生物：吉西他濱及其衍生物的重量比介於1：1~1：60之間。
本發明的另一目的係提供由上述製造方法所製得的奈米組成物。
較佳地，當奈米組成物溶於水相時，奈米組成物的粒徑介於5奈米~500奈米之間。
較佳地，奈米組成物進一步藉由包含冷凍乾燥、減壓濃縮、真空乾燥、噴霧乾燥或其組合的方式去除其溶劑，以形成粒徑係為0.5微米~20微米的一乾燥微米粉體。
較佳地，當乾燥微米粉體回溶於水相時，乾燥微米粉體分散為粒徑介於5奈米~500奈米之間的奈米組成物。
本發明之另一目的係提供一種奈米組成物用於製備治療癌症之藥物的用途，包含藉由所述之製造方法所製得之奈米組成物製備治療癌症之藥物，以及施予藥物至個體。
本發明之特徵僅藉由參照附圖之例示性結果使本發明更易於本領域具通常知識者理解，而非限定本發明。
第1圖係為本發明的奈米組成物之製造步驟的示意圖。
第2圖係為本發明的奈米組成物之型態的TEM圖。
第3圖(A)部分及(B)部分係為吉西他濱(GEM)之釋放百分比對時間的關係圖。
第4圖(A)部分及(B)部分係為去氧甲基薑黃素(DMC)之釋放百分比對時間的關係圖。
第5圖係為以A549-ON細胞株的細胞存活率計算而得之藥物合併指數(combination index，CI)對致效率(Fa)之對比圖。
第6圖係為腫瘤大小對施予後天數的關係圖。
第7圖係呈現以A549細胞株的的細胞存活率計算而得之CI對Fa之對比圖。
第8圖係為A549異位腫瘤大小對施予後天數的關係圖，圖中箭頭代表施予時點。
第9圖係為A549異位腫瘤的抑制效率比較圖。
第10圖(A)部分係為本發明的乾燥微米粉體於肉眼所見的型態；(B)部分係為乾燥微米粉體的粒子型態；(C)部分係為乾燥微米粉體回溶於水 相後的型態。
為使上述目的、技術特徵及實際實施後之效益更易於使本領域具通常知識者理解，將於下文中的實施例來進行更詳細之說明。
本發明說明書中之用語縮寫及中文的對照係列於下表1：
Figure 106110485-A0305-02-0007-1
本文中「雙性幾丁聚醣(CHC)」乙詞係指經化學方法將幾丁聚醣改質使其具有疏水基團，並保有部分原始親水端及部分功能性改質的親水端以形成同時具親水端及疏水端的改質幾丁聚醣。
本文中「包覆」乙詞係指利用奈米粒子內部的空間攜載添 加的內容物，例如：包覆GEM的CHC奈米粒子係指在內部空間攜載GEM的CHC奈米粒子。
本文中「釋放」乙詞係指奈米粒子包覆的藥物移動到奈米粒子外部的過程，此過程中奈米粒子可被破壞或可不被破壞。
本文中「藥物合併指數(CI)」乙詞係指藉藥物合併指數定理(The Combination Index Theorem)計算而得之數值。依照藥物合併指數所得之值可推知複方藥物中藥物之間的互相影響，例如藥物之間具有協同作用(CI<1)、相加作用(CI=1)，或拮抗作用(CI>1)。
本文中「致效率(Fa)」乙詞係指質量作用中效定理(Median-Effect Principle)中的藥物致效程度，可與CI做成對比圖以定義不同藥物間之協同或拮抗關係。
本文中提及之DMC與GEM之間的比例係重量比。
在本發明的一態樣中，奈米組成物以一鍋合成方式製備，其步驟如第1圖所示。
在一實施例中，一鍋合成所加入的雙性幾丁聚醣於合成前以雙性幾丁聚醣粉末及二次水預先配製成第一溶液，其中相對於第一溶液總重計，雙性幾丁聚醣可為介於0.001%~10%(w/w)之間、較佳地介於0.005%~7.5%(w/w)之間、更佳地介於0.01%~5%(w/w)之間、再更佳地介於0.025%~2.5%(w/w)之間、最佳地為0.05%(w/w)的濃度。
在一實施例中，抗癌成分可包含吉西他濱、薑黃素、兩者之衍生物及兩者及其衍生物之組合，較佳地為吉西他濱(GEM)及去氧甲基薑黃素(DMC)。在一實施例中，去氧甲基薑黃素粉末及吉西他濱粉末可預先以介於1：1~1：500之間、較佳地為1：5、較佳地為1：10、較佳地為1：20、較佳地為1：25、較佳地為1：50、較佳地為1：100、 較佳地為1：150、較佳地為1：200的比例混合，並較佳地以二甲基亞碸或醇類溶解以配製成第二溶液，其中相對於第二溶液總體積計，抗癌成分的總濃度介於1mg/mL~1000mg/mL之間，較佳地介於100mg/mL~900mg/mL之間、較佳地介於300mg/mL~700mg/mL之間、較佳地介於400mg/mL~600mg/mL之間。在一較佳實施例中，GEM及DMC係溶於二甲基亞碸或醇類。
在一實施例中，混合0.05%(w/w)的第一溶液及DMC：GEM=1：5的第二溶液後，在4℃攪拌24小時後以形成CHC/DMC-GEM。在一實施例中，混合CHC/DMC-GEM、交聯劑及標靶分子以結合標靶分子與CHC/DMC-GEM並得到CHC/DMC-GEM/標靶分子，其中交聯劑較佳地可為1-乙基-(3-二甲基氨基丙基)碳醯二亞胺(3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine，EDC)，標靶分子較佳地可為anti-EGFR、anti-CD133、anti-CD166或anti-PD-L1。在一較佳實施例中，CHC/DMC-GEM/標靶分子可為CHC/DMC-GEM/anti-CD133。
在本發明的實施例中，奈米組成物的粒徑介於5奈米~500奈米之間、較佳地介於50奈米~400奈米之間、更佳地介於100~250奈米之間、最佳地介於150奈米到200奈米之間，且表面電位較佳地為負電位。
在一實施例中，CHC/DMC-GEM/標靶分子可以動態光散射(DLS)測量粒徑及表面電位，並以穿透式電子顯微鏡觀測其形態。在一較佳實施例中，發明人分別以動態光散射測量未包覆抗癌成分的CHC奈米粒子、CHC/DMC-GEM及CHC/DMC-GEM/anti-CD133，並將結果列於以下表2。在一較佳實施例中，CHC/DMC-GEM/anti-CD133的型態可以穿透式電子顯微鏡(TEM)觀察，其照片呈現於第2圖。
Figure 106110485-A0305-02-0009-2
Figure 106110485-A0305-02-0010-3
在一實施例中，發明人比較CHC/DMC、CHC/GEM、CHC/DMC-GEM及其結合抗體後的樣本在不同酸鹼值的緩衝溶液下內含的GEM及DMC的釋放情形。第3圖(A)部分及(B)部分為上述樣本釋放GEM的累積釋放量與時間的關係圖；第4圖(A)部分及(B)部分為上述樣本釋放DMC的累積釋放量與時間的關係圖(累積釋放率=累積釋放量/原始包覆量x100%)。由第3圖及第4圖可知，抗癌成分DMC及GEM在前10小時的釋放速率皆較高，但在10小時後的釋放速率趨緩，且在40小時後累積釋放率仍未超過40%。而在上述樣本中，又屬CHC/GEM-DMC/anti-CD133的累積釋放量最低，因而較適合作為藥物載體於體內循環。
在本發明的實施例中，本發明的奈米組成物可對應需求個體的癌症種類選擇不同的標靶分子，其中癌症種類可包含非小細胞肺癌、小細胞肺癌、卵巢癌、胰腺癌、膀胱癌、乳癌及腦癌。
在一較佳實施例中，發明人選用A549-ON作為癌症細胞模型，並將DMC、GEM、CHC/DMC以及CHC/GEM與A549-ON共培養，觀察A549-ON在共培養後的細胞存活率，其結果列於以下表3。由表3可得知DMC及GEM藉由CHC包覆之後其IC50皆小於單獨使用之IC50，證實抗癌成分經CHC包覆之後可具有較佳的細胞毒殺效果。
Figure 106110485-A0305-02-0010-4
Figure 106110485-A0305-02-0011-5
在一實施例中，加入DMC：GEM=1：1.2、1：5、1：12及1：25的CHC/DMC-GEM至A549-ON並共培養，以找出DMC及GEM具有較佳協同效應(synergistic effect)的藥物比例。所計算出的CI及Fa對比圖係呈現於第5圖。由第5圖的結果可得知，當CHC/DMC-GEM中的DMC：GEM=1：5時，其CI值小於1，亦即以DMC：GEM=1：5比例製備的CHC/DMC-GEM中的兩種藥物具有協同效應，可使治療效果提升。
在一實施例中，發明人在小鼠體內種殖A549-ON的極惡性異位腫瘤並施予PBS、DMC及GEM的混合物、本發明的CHC/DMC-GEM及CHC/DMC-GEM/anti-CD133的樣品至小鼠體內，紀錄施予藥物後11天內的腫瘤大小變化，其結果如第6圖所示。由第6圖可知，經CHC/DMC-GEM/anti-CD133施予的小鼠體內腫瘤體積與僅施予PBS的控制組在11天時相差約7倍，顯示在上述各樣品中CHC/DMC-GEM/anti-CD133對於小鼠體內的A549-ON及惡性異位腫瘤具有較佳的抑制效果。
在另一較佳實施例中，發明人選用A549作為癌症細胞模型，將DMC、GEM、CHC/DMC以及CHC/GEM與A549共培養，並觀察A549在共培養後的細胞存活率，其結果列於以下表4。由表4可得知DMC及GEM藉由CHC包覆之後其IC50皆小於單獨使用之IC50，證實抗癌成分經CHC包覆之後可具有較佳的細胞毒殺效果。
Figure 106110485-A0305-02-0011-6
Figure 106110485-A0305-02-0012-7
在一實施例中，加入DMC：GEM=1：2.5、1：5、1：10及1：20的CHC/DMC-GEM至A549並共培養，以找出DMC及GEM具有較佳協同效應(synergistic effect)的藥物比例。藉A549細胞在共培養後的存活率所計算出的CI及Fa對比圖係呈現於第7圖。由第7圖可得知，當CHC/DMC-GEM中的DMC：GEM=1：5時，其CI值小於1，亦即DMC：GEM=1：5時製備的CHC/DMC-GEM中的兩種藥物具有協同效應，可使治療效果提升。
在一實施例中，發明人在小鼠體內種殖A549的異位腫瘤並施予生理食鹽水、CHC/anti-EGFR以及CHC/DMC-GEM/anti-EGFR的樣品至小鼠體內以觀察腫瘤治療效果。
在一較佳實施例中，CHC/DMC-GEM/anti-EGFR選用1：5的DMC：GEM比例，以DMC的量作為劑量指標施予小鼠5mg/kg、10mg/kg、20mg/kg、30mg/kg及40mg/kg的劑量。此外，由第一次施予上述樣本起算，又於第8天、第15天及第22天再次施予相同樣本至小鼠體內，並於29天內觀察A549異位腫瘤的體積變化，其結果如第8圖所示，圖中箭頭代表樣本施予時點。接著，經上述各樣本施予的小鼠在第29天時的腫瘤體積相對於施予生理食鹽水的小鼠腫瘤體積差計算出腫瘤抑制率，並以柱狀圖呈現，如第9圖所示。由第9圖可得知，當以DMC量作為劑量指標時，施予40mg/kg、30mg/kg、20mg/kg劑量之組別的腫瘤抑制率與施予生理食鹽水組別的腫瘤抑制率有顯著差 異。另外，藉由上述腫瘤抑制率可計算出CHC/DMC-GEM/anti-EGFR對A549的ED50為GEM=98.98mg/kg及DMC=19.67mg/kg。
在一實施例中，本發明的奈米組成物可經由冷凍乾燥、減壓濃縮、真空乾燥、噴霧乾燥或其組合的方式去除其溶劑，製成介於0.5微米~20微米、較佳地介於0.5微米~10微米、更佳地介於0.5微米~5微米、最佳地介於0.5微米~2微米的乾燥微米粉體。在一較佳實施例中，本發明的奈米組成物可經由噴霧造粒的方式製成乾燥微米粉體，其外觀如第10圖(A)部分所示；乾燥微米粉體的顆粒型態及粒徑可由掃描式電子顯微鏡測得，直徑約為1微米，其照片如第10圖(B)部分所示。另外，當乾燥微米粉體回溶於水相時，可快速恢復成乾燥前的奈米組成物型態，由掃描式電子顯微鏡可測得回溶後的奈米組成物粒徑約100奈米，其照片如第10圖(C)部分所示。可見本發明之奈米組成物不需以膠體溶液形式保存，而可經乾燥後以粉末形式保存，便於長期儲藏及運送且不易受保存溫度影響。
在一實施例中，奈米組成物係水溶液針劑、口服錠劑，以及吸劑的形式。
在另一實施例中，本發明的奈米組成物亦可藉其包含之雙性幾丁聚醣所改質修飾的釓元素發揮作為T1磁振造影顯影劑的用途。
雖然本發明已以例示性實施例具體描述本發明之奈米組成物用於製備治療癌症之藥物的用途，然而具本發明所屬技術領域之通常知識者應理解，可在不違背本發明之技術原理及精神下，對實施例作修改與變化。因此本發明之權利保護範圍應如後述之申請專利範圍所述。

Claims (10)

  1. 一種奈米組成物的製造方法，其包含：混合一雙性幾丁聚醣的一第一溶液及含有一抗癌成分的一第二溶液；使該雙性幾丁聚醣藉由自組裝而一次性包覆該抗癌成分，以形成一奈米粒子；以及將對一癌症具專一性的一標靶分子與該奈米粒子進行嫁接，而得到一奈米組成物；其中該抗癌成分包含吉西他濱及去氧甲基薑黃素，其中該製造方法不包含調配混合後之該第一溶液及該第二溶液的pH值的步驟。
  2. 如請求項1所述之製造方法，其中該雙性幾丁聚醣包含具釓元素的親水端。
  3. 如請求項1所述之製造方法，其中相對於該第一溶液總重計，該雙性幾丁聚醣的濃度係為0.001%~10%(w/w)。
  4. 如請求項1所述之製造方法，其中相對於該第二溶液總體積計，該抗癌成分的濃度係為1mg/mL~1000mg/mL。
  5. 如請求項1所述之製造方法，其中去氧甲基薑黃素：吉西他濱的重量比係為1：1~1：60。
  6. 一種奈米組成物，其係藉由如請求項1所述之製造方法所製得。
  7. 如請求項6所述之奈米組成物，其中當該奈米組成物溶於水相時，該奈米組成物的粒徑係為5奈米~500奈米。
  8. 如請求項6所述之奈米組成物，其中該奈米組成物進一步藉由包含冷凍乾燥、減壓濃縮、真空乾燥、噴霧乾燥或其組合的方式去除其溶劑，以形成粒徑係為0.5微米~20微米的一乾燥微米粉體。
  9. 如請求項6所述之奈米組成物，其中當該乾燥微米粉體回溶於水相時，該乾燥微米粉體分散為粒徑介於5奈米~500奈米之間的該奈米組成物。
  10. 一種奈米組成物用於製備治療癌症之藥物的用途，其中該奈米組成物係藉由請求項1所述之製造方法所製得；以及施予該藥物至一個體。
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