TWI705813B - 含有ganetespib的粒子與含有該粒子的藥學組成物及其在抗癌治療上的用途 - Google Patents
含有ganetespib的粒子與含有該粒子的藥學組成物及其在抗癌治療上的用途 Download PDFInfo
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Abstract
本發明揭示一含有ganetespib的粒子,其包括一選自於下列的活性成分:ganetespib、ganetespib的一藥學上可接受的鹽類,以及它們的組合;以及一以兩親幾丁聚醣為基礎的載體,其攜帶該活性成分。本發明亦揭示一藥學組成物,其包括該含有ganetespib的粒子,以及該藥學組成物在治療癌症上的用途。
Description
本發明是有關於一種含有ganetespib的粒子,其中ganetespib、ganetespib的一藥學上可接受的鹽類或它們的組合是由兩親幾丁聚醣所攜帶,以及有關於一包含有該粒子的藥學組成物。本發明亦有關於該粒子與該藥學組成物在抗癌治療上的用途。
熱休克蛋白(Heat shock proteins)是保護客戶蛋白質(client proteins)免於降解(degradation)的分子伴護蛋白(molecular chaperones),特別是在諸如細胞壓力、氧化壓力以及經升高的溫度之情況下。這類蛋白質在癌症中經常被向上-調控(up-regulated)並且導致癌症的生長(growth)與轉移(metastasis)。熱休克蛋白90 (Heat shock protein 90, HSP90)是一特定的熱休克蛋白,其在蛋白質摺疊(protein folding)中扮演一重要的角色,並在不同類型的癌症中穩定許多重要的致癌蛋白質(oncogenic proteins),諸如表皮生長因子受體(epidermal growth factor receptor, EGFR)、表皮生長因子受體2 (HER2)、退行性淋巴瘤激酶(anaplastic lymphoma kinase, ALK)、蛋白質激酶B (protein kinase B, PKB)、絲裂原-活化的蛋白質激酶激酶(mitogen-activated protein kinase kinase, MEK)、雄性激素受體(androgen receptor)、***受體(estrogen receptor)等等
非-小細胞肺癌(Non-small cell lung cancer, NSCLC)是致命性的肺癌,其在所有的肺癌中佔了約85%。相較於小細胞癌(small cell carcinoma),NSCLC對化學療法(chemotherapy)相對地不敏感。而為了治療NSCLC,如果可行,則採用根治性目的(curative intent)之手術切除術(surgical resection)。儘管如此,自從對於HSP90的抑制已被顯示在治療NSCLC上是有希望的,HSP90抑制劑已被發展來提升針對NSCLC的療法之抗癌效用。
Ganetespib {4-[5-羥基-4-(1-甲基-1H-吲哚-5-基)-4H-1,2,4-***-3-基]-6-(丙-2-基)苯-1,3-二醇}{4-[5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl]-6-(propan-2-yl)benzene-1,3-diol}(亦被稱為STA-9090)是一以間苯二酚(resorcinol)為基礎的化合物,其結合至HSP90的ATP-結合口袋(ATP-binding pocket),因而導致HSP90的抑制作用。由於其抑制HSP90的能力,ganetespib能夠用來防止客戶蛋白質與HSP90結合,藉此導致細胞凋亡(cell apoptosis)。因此,ganetespib被認為能有效對抗NSCLC。
然而,ganetespib可能會誘導一非所欲的嚴重副作用(例如,呼吸困難、疲勞、發燒等等),因此高劑量的ganetespib應該被避免。即使以脂質為基礎以及以共聚物為基礎的載體(lipid-based and copolymer-based carriers)已被用來包覆與遞送ganetespib,這類藥物載體的藥物包覆率是令人不滿意的,且包覆ganetespib的製程亦相當複雜。此外,當被上述藥物載體包覆時,ganetespib的藥物效價(drug potency)[其能夠由ganetespib的半數最大抑制濃度(half maximal inhibitory concentration, IC
50)來表示]亦是令人不滿意的。
申請人意外地發現:兩親幾丁聚醣(amphiphilic chitosan){其是一含有β-(1,4)-連結的2-胺基-D-葡萄糖[β-(1,4)-linked 2-amino-D-glucose](D-葡萄糖胺)(D-glucosamine)以及2-乙醯胺基-D-葡萄糖(2-acetamido-D-glucose)(N-乙醯基-D-葡萄糖)(N-acetyl-D-glucose)單元的直鏈多醣(linear polysaccharide)]}能夠有效地包覆ganetespib以形成一有效治療癌症的粒子。特別地,與游離的ganetespib相較之下,由兩親幾丁聚醣所包覆時ganetespib的藥物效價能夠被改善。
發明概要
因此,在第一個方面,本發明提供一種含有ganetespib的粒子(ganetespib-containing particle),其包括一選自於由下列所構成之群組中的活性成分:ganetespib、ganetespib的一藥學上可接受的鹽類,以及它們的組合;以及一攜帶該活性成分之以兩親幾丁聚醣為基礎(amphiphilic chitosan-based)的載體。
在第二個方面,本發明提供一種藥學組成物,其包括如上所述之含有ganetespib的粒子。
在第三個方面,本發明提供一種如上所述的藥學組成物供應用於製備一用來治療一個體中的癌症之醫藥品的用途。
在第四個方面,本發明提供一種用來治療一個體中的癌症的方法,其包括對該個體投予如上所述的藥學組成物。
發明的詳細說明
要被瞭解的是:若有任何一件前案刊物在此被引述,該前案刊物不構成一個下述承認:在台灣或任何其他國家之中,該前案刊物形成本技藝中的常見一般知識之一部分。
為了這本說明書之目的,將被清楚地瞭解的是:文字“包含有(comprising)”意指“包含但不限於”,以及文字“包括(comprises)”具有一對應的意義。
除非另外有所定義,在本文中所使用的所有技術性與科學術語具有熟悉本發明所屬技藝的人士所共同瞭解的意義。一熟悉本技藝者會認知到許多與那些被描述於本文中者相似或等效的方法和材料,它們可被用於實施本發明。當然,本發明決不受到所描述的方法和材料之限制。
在下面的實施例中申請人意外地發現:ganetespib能夠被兩親幾丁聚醣(amphiphilic chitosan)包覆而形成一粒子,其藥物效價(drug potency)高於游離的ganetespib所具者,並且其能夠以一不複雜的方式來製備。
因此,本發明提供一種含有ganetespib的粒子(ganetespib-containing particle),其包括一選自於由下列所構成之群組中的活性成分:ganetespib、ganetespib的一藥學上可接受的鹽類,以及它們的組合;以及一攜帶該活性成分之以兩親幾丁聚醣為基礎的載體(amphiphilic chitosan-based carrier)。
在某些具體例中,該活性成分是ganetespib。
依據本發明,該以兩親幾丁聚醣為基礎的載體具有分別與疏水性(hydrophobic)以及親水性(hydrophilic)的分子交互作用(interact)之疏水性以及親水性的部分(moieties)。該以兩親幾丁聚醣為基礎的載體可以包括含有羧甲基(carboxymethyl)的幾丁聚醣和/或其衍生物。含有羧甲基的幾丁聚醣及其衍生物的實例包括,但不限於:羧甲基-己醯幾丁聚醣(carboxymethyl-hexanoyl chitosan, CHC)、(3-胺基丙基)三乙氧矽烷[(3-aminopropyl)triethoxysilane]-修飾的CHC、油醯羧甲基幾丁聚醣(oleoyl carboxymethyl chitosan, OCMC)、
N,
N-二甲基十六烷基羧甲基幾丁聚醣(
N,
N-dimethylhexadecyl carboxymethyl chitosan, DCMC)、去氧膽酸羧甲基幾丁聚醣(deoxycholic acid carboxymethyl chitosan, DACMC)、
N-辛基-
O,
N-羧甲基幾丁聚醣(
N-octyl-
O,
N-carboxymethyl chitosan, OCC)、以奧曲肽-Phe-聚乙二醇-硬酯酸(octreotide-Phe-polyethylene glycol-stearic acid)來標靶的OCC、
N-月桂基羧甲基幾丁聚醣(
N-lauryl carboxymethyl chitosan)、亞麻油醯基羧甲基幾丁聚醣(linoleyl carboxymethyl chitosan)、亞麻油酸聚(β-蘋果酸)幾丁聚醣[linoleic acid poly(β-malic acid) chitosan]、膽固醇-修飾的
O-羧甲基幾丁聚醣(cholesterol-modified
O-carboxymethyl chitosan)、
N-膽固醇琥珀醯基
O-羧甲基幾丁聚醣(
N-cholesterol succinyl
O-carboxymethyl chitosan)、羧甲基幾丁聚醣-接枝-磷脂醯乙醇胺(carboxymethyl chitosan-graft- phosphatidylethanolamine)、葉酸-修飾的羧甲基幾丁聚醣(folate-modified carboxymethyl chitosan)以及順-3-(9H-嘌呤-6-基硫)-丙烯酸-接枝-羧甲基幾丁聚醣[
cis-3-(9H-purin-6-ylthio)-acrylic acid-graft-carboxymethyl chitosan]。在一示範性具體例中,該以兩親幾丁聚醣為基礎的載體是CHC。
依據本發明,該含有ganetespib的粒子可以進一步包含有一額外的活性成分(additional active ingredient),其是由該以兩親幾丁聚醣為基礎的載體所攜帶的。該額外的活性成分的實例包括,但不限於:吉西他濱(gemcitabine)[2’-去氧-2’,2’-二氟胞核苷-單鹽酸鹽(β-異構物) ] [2’-deoxy-2’,2’-difluorocytidine-monohydrochloride (betaisomer)]、去甲氧基薑黃素(demethoxycurcumin)[1,6-庚二烯-3,5-二酮,1-(4-羥基-3-甲氧苯基)-7-(4-羥苯基)][1,6-heptadiene-3,5-dione,1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)]、17-丙烯胺基去甲氧基格爾德黴素(17-allylamino demethoxygeldanamycin, 17-AAG)、厄洛替尼(erlotinib)[N-(3-乙炔基苯基)-6,7-雙(2-甲氧乙氧基)喹唑啉-4-胺][N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine]、瑞他黴素(retaspimycin)以及微小RNA (miRNA)調節子[microRNA (miRNA) regulator]。
依據本發明,適合的miRNA調節子包括,但不限於:miRNA向上調控子(miRNA upregulators)[例如,miRNA仿效物(miRNA mimics)]以及miRNA向下調控子(miRNA downregulators)[例如,miRNA抑制劑(miRNA inhibitors)]。適合的miRNA仿效物包括,但不限於:針對miRNA-183家族的仿效物、針對miRNA-200家族的仿效物、針對miRNA-34家族的仿效物、針對miRNA-126家族的仿效物,以及針對miRNA-30-5-p家族的仿效物。適合的miRNA抑制劑包括,但不限於:針對miRNA-21家族的抑制劑以及針對miRNA-155家族的抑制劑。
依據本發明,該含有ganetespib的粒子可以進一步包含一生物功能性分子(biologically functional molecule),其綴合(conjugated)至該活性成分以及該以兩親幾丁聚醣為基礎的載體中之一者。該生物功能性分子的實例包括,但不限於:抗-表皮生長因子受體(EGFR)抗體[anti-epidermal growth factor receptor (EGFR) antibodies]、抗-表皮生長因子受體2 (HER2)抗體[anti-epidermal growth factor receptor 2 (HER2) antibodies]、抗-退行性淋巴瘤激酶(ALK)抗體[anti-anaplastic lymphoma kinase (ALK) antibodies]、抗-蛋白質激酶B (PKB)抗體[anti-protein kinase B (PKB) antibodies]、抗-絲裂原-活化的蛋白質激酶激酶(MEK)抗體[anti-mitogen-activated protein kinase kinase (MEK) antibodies]、抗-雄性激素受體抗體(anti-androgen receptor antibodies)以及抗-***受體抗體(anti-estrogen receptor antibodies)。在某些具體例中,該生物功能性分子是一抗-EGFR抗體。
依據本發明,該含有ganetespib的粒子具有一範圍落在30 nm至500 nm內的粒徑。在某些具體例中,該含有ganetespib的粒子具有一範圍落在50 nm至200 nm內的粒徑。在其他具體例中,該含有ganetespib的粒子具有一範圍落在50 nm至100 nm內的粒徑。
此外,本發明提供一種藥學組成物,其包含有一如上所述的含有ganetespib的粒子。
此外,本發明提供一種如上所述的藥學組成物供應用於製備一用來治療一個體中的癌症的醫藥品的用途。
依據本發明,該癌症是選自於由下列所構成之群組:肺癌(lung cancer)、肝癌(liver cancer)、胰臟癌(pancreatic cancer)、乳癌(breast cancer)、結腸直腸癌(colorectal cancer),以及它們的組合。在某些具體例中,該癌症是肺癌。在一示範性具體例中,該癌症是非-小細胞肺癌(non-small cell lung cancer)。
依據本發明的藥學組成物可利用熟習此技藝者所詳知的技術而被製造成一適合於非經腸道的(parenteral)或口服(oral)投藥之劑型(dosage form),這包括,但不限於:注射品(injections)[例如,無菌的水性溶液(sterile aqueous solutions)或分散液(dispersions)]、無菌的粉末(sterile powder)、錠劑(tablets)、片劑(troches)、丸劑(pills)、膠囊(capsules)以及類似之物。
依據本發明的藥學組成物能夠藉由一或多個下面的途徑來被非經腸道地投藥:靜脈內注射(intravenous injection)、肌肉內注射(intramuscular injection)以及皮下注射(subcutaneous injection)。
在某些具體例中,該藥學組成物是被製造成一適合於口服投藥(oral administration)的劑型。
依據本發明的藥學組成物能夠額外地包含有一被廣泛地使用於藥物製造技術之藥學上可接受的載劑(pharmaceutically acceptable carrier)。例如,該藥學上可接受的載劑可包括一或多種下面的試劑:溶劑(solvents)、乳化劑(emulsifiers)、懸浮劑(suspending agents)、分解劑(decomposers)、黏結劑(binding agents)、賦形劑(excipients)、安定劑(stabilizing agents)、螯合劑(chelating agents)、稀釋劑(diluents)、膠凝劑(gelling agents)、防腐劑(preservatives)、潤滑劑(lubricants)、吸收延遲劑(absorption delaying agents)、塑化劑(plasticizer)、填充劑(filling agents)、崩散劑(disintegrants)、界面活性劑(surfactants)、增稠劑(thickening agents)、脂質體(liposomes)以及類似之物。
本發明亦提供一種用來治療一個體中的癌症的方法,其包括對該個體投予如上所述的藥學組成物。
依據本發明的藥學組成物的投藥劑量與頻率可視下面因素而變化:要被治療的疾病之嚴重性,投藥途徑,以及要被治療的個體之體重、年齡、身體狀況與反應。舉例來說,依據本發明的藥學組成物的每日劑量可以是每m
2的身體表面積50 mg至150 mg,並且可以單一劑量或數個劑量而被投藥。
較佳實施例之詳細說明
本發明將透過下面的實施例而被進一步說明。然而,應瞭解的是:下面的實施例僅是意欲供例示說明之用,而不應被解釋為本發明於實施上的限制。
實施例 一般實驗材料: 1. 非-小細胞肺癌(NSCLC)細胞株[Non-small cell lung carcinoma (NSCLC) cell lines]
在實施例中所使用的下面的細胞株是得自於台灣的財團法人食品工業發展研究所(Food Industry Research and Development Institute, FIRDI)的生物資源保存及研究中心(Bioresource Collection and Research Center, BCRC)和/或美國的美國類型培養物收集中心(American Type Culture Collection, ATCC):人類肺癌細胞株A549 (ATCC CCL-185; BCRC 60074)以及人類肺癌細胞株H1299 (ATCC CRL-5803)。
各個細胞株的細胞是使用顯示於表1中之各自的培養基以及培養皿(petri dish)而在一培養箱中(37℃以及5% CO
2)進行培育。培養基的更換是約每兩天被進行。當達到大約80-90%的匯聚(confluence)時,進行培養基的移除,繼而以磷酸鹽緩衝生理鹽水(phosphate buffered saline, PBS)予以清洗細胞兩次。胰蛋白酶-EDTA (trypsin-EDTA)被添加俾以使細胞自培養皿的底部脫離。隨後,新鮮的培養基被添加以中和胰蛋白酶的活性,並藉由以量吸管(pipette)反覆地吸沖來充分打散細胞。所形成的細胞懸浮液被移至培養瓶中,繼而在培養箱中進行培養。
表1
實施例 1. 依據本發明的含有 ganetespib 的粒子之分析
NSCLC細胞株 | 培養基 |
A549 | 補充有10%胎牛血清(Fetal Bovine Serum, FBS)的杜貝可氏改良的依格氏培養基(Dulbecco’s Modified Eagle’s Medium, DMEM) |
H1299 | 補充有10% FBS的RPMI 1640培養基 |
為了研究依據本發明之含有ganetespib的粒子的特性並且驗證這類粒子是否能夠攜帶一用於提升抗癌效用的生物功能性分子(biologically functional molecule),下面的實驗被進行。
A. 依據本發明的含有 ganetespib 的粒子之製備
10 mg的ganetespib粉末(購自於Selleckchem)被溶於0.5 mL的二甲亞碸(dimethyl sulfoxide, DMSO)溶液中以配製成一具有一為20 mg/mL的ganetespib濃度之ganetespib儲備溶液(stock solution)。5 μL的ganetespib儲備溶液被添加至95 μL的DMSO溶液中以得到一具有一為1 mg/mL的ganetespib濃度之經稀釋的ganetespib溶液。
0.5 mg的羧甲基己醯幾丁聚醣(carboxymethyl hexanoyl chitosan, CHC)[亦即,兩親幾丁聚醣(amphiphilic chitosan)]粉末(購自於Advanced Delivery Technologies, Inc.)被添加至一微量離心管中,繼而添加50 μL的經稀釋的ganetespib溶液。0.95 mL的1X PBS溶液被添加至所形成的混合物中俾以形成一具有一為0.5 mg/mL的初始CHC濃度以及一為50 μg/mL的初始游離ganetespib濃度之1 mL的混合溶液(pH 7.4)。上述操作程序被重複一次以形成另一個具有相同的初始CHC濃度以及相同的初始游離ganetespib濃度之混合溶液。隨後,該二個混合溶液在4℃下分別被進行攪拌歷時12小時以及24小時,而使得兩個CHC-ganetespib粒子溶液(亦即,含有ganetespib的粒子的溶液)被形成。
B. 含有 ganetespib 的粒子的溶液之藥物包覆率 (drug encapsulation efficiency) 的測定
在本實施例的第A項中所得到的CHC-ganetespib粒子溶液被進行藥物包覆率的測定如下。
該ganetespib儲備溶液被進行連續稀釋(serial dilution)以得到分別具有下面的游離ganetespib濃度的標準ganetespib溶液:10
5ng/mL、10
4ng/mL、10
3ng/mL、500 ng/mL、250 ng/mL以及125 ng/mL。標準ganetespib溶液是使用一圓二色性(CD)分光光度計[circular dichroism (CD) spectrophotometer](Model J-1700, Jasco)來進行在275 nm下之吸光值(OD
275)的測定。標準曲線是根據標準ganetespib溶液的濃度以及OD
275而被建立。
進一步地,各個CHC-ganetespib粒子溶液在4℃下以10,000 rpm予以離心歷時10分鐘。500 μL之所形成的上澄液被得到並被添加至500 μL的甲醇溶液中俾以形成1 mL的試驗溶液(test solution)。之後,該試驗溶液是使用CD分光光度計來進行OD
275的測定。將該試驗溶液的OD
275拿來與該標準曲線進行比對俾以測得未被包覆的ganetespib濃度(亦即,殘餘的游離ganetespib濃度)。該試驗溶液的藥物包覆率是使用下面的公式(1)而被計算出:
A=[(B-C)/B]×100 (1)
A=藥物包覆率(%)
B=初始游離ganetespib濃度(50 μg/mL)
C=各試驗溶液之未被包覆的ganetespib濃度
結果:
所得到的實驗數據是以平均值±SD [標準誤差(standard deviation)]或平均值來表示。
由分別攪拌12小時以及24小時所製得的CHC-ganetespib粒子溶液具有51.4±0.61%以及60±0.25%的藥物包覆率。換言之,由分別攪拌12小時以及24小時所製得的CHC-ganetespib粒子溶液具有大約25.7 μg/mL以及30 μg/mL的CHC-ganetespib粒子濃度(亦即,被包覆的ganetespib濃度)。
C. 依據本發明的含有 ganetespib 的粒子之物理性質 (physical properties) 的測定
適量之在本實施例的第A項中所使用的CHC粉末被溶於1 mL的去離子(DI)溶液[deionized (DI) solution]中以形成一具有一為0.5 mg/mL的CHC濃度的CHC粒子溶液。
將在本實施例的第A項中所得到之藥物包覆率為60%以及CHC-ganetespib粒子濃度為30 μg/mL的CHC-ganetespib粒子溶液中的CHC-ganetespib粒子拿來與抗-表皮生長因子受體(EGFR)抗體[anti-epidermal growth factor receptor (EGFR) antibody]綴合。具體而言,1 μL的抗-小鼠EGFR抗體(1 mg/mL,配於二次蒸餾水中)被添加至CHC-ganetespib粒子溶液,繼而在4℃下攪拌歷時1小時。0.05 mL的EDC {1-乙基-3-(3-二甲基胺基丙基)碳二亞胺[1-ethyl-3-(3-dimethylaminopropyl)carbodiimide]}溶液(0.1%, w/v)被添加至所形成的溶液中,繼而被靜置歷時超過4小時。因此,一含有抗-EGFR的CHC-ganetespib粒子(亦即,經抗-EGFR抗體綴合的CHC-ganetespib粒子)之經抗-EGFR抗體綴合的粒子溶液被形成。該經抗-EGFR抗體綴合的粒子溶液大體上是依據本實施例的第B項中所述的方法來進行藥物包覆率的測定。
CHC粒子、CHC-ganetespib粒子以及抗-EGFR的CHC-ganetespib粒子的流體動力學直徑(hydrodynamic diameter)是藉由在BI-200SM測角計(BI-200SM Goniometer, Brookhaven Inc., Holtsville, NY)上的動態光散射(dynamic light scattering, DLS)於二次蒸餾水中被測量。
CHC粒子、CHC-ganetespib粒子以及抗-EGFR的CHC-ganetespib粒子的ζ電位(zeta potential)是在一雷射都卜勒測速儀系統(laser Doppler anemometry system, Beckman Coulter Inc., USA)上於二次蒸餾水中被測量,俾以研究這些粒子的表面電位(surface potential)。
此外,CHC-ganetespib粒子以及抗-EGFR的CHC-ganetespib粒子是使用Jeol 2100穿透式電子顯微鏡(Jeol 2100 Transmission Electron Microscope, Jeol Ltd., Japan)在20,000倍的放大倍率下來觀察,俾以測定這些粒子的粒徑,並且確認CHC對ganetespib的包覆以及抗-EGFR抗體的綴合。
結果:
所得到的實驗數據是以平均值±SD或平均值來表示。
該抗體-綴合的粒子溶液具有43%的藥物包覆率。換言之,該抗體-綴合的粒子溶液大約具有一為21.5 μg/mL之抗-EGFR的CHC-ganetespib粒子濃度(亦即,一被包覆的ganetespib濃度)。
CHC粒子、CHC-ganetespib粒子以及抗-EGFR的CHC-ganetespib粒子的流體動力學直徑與ζ電位被顯示於下面的表2中。
表2
粒子 | 流體動力學直徑(nm) | ζ電位(mV) |
CHC | 65.69±7.31 | 45±0.33 |
CHC-ganetespib | 158.29±20.20 | 50.31±0.43 |
抗-EGFR的CHC-ganetespib | 207.71±27.97 | 40.17±1.43 |
如表2中所示,CHC-ganetespib粒子的流體動力學直徑是大於CHC粒子所具者,其顯示:藥物ganetespib是成功地被藥物載體CHC包覆而形成一粒子。此外,抗-EGFR的CHC-ganetespib粒子的流體動力學直徑是大於CHC-ganetespib粒子所具者,其顯示:抗-EGFR抗體是成功地綴合至具有被CHC包覆的ganetespib之粒子。
此外,可藉由ζ電位確認的是:具有CHC包覆的ganetespib之CHC-ganetespib粒子以及抗-EGFR的CHC-ganetespib粒子帶有正表面電荷(positive surface electric charge),因而在水溶液中是穩定的。
轉而藉由穿透式電子顯微術(transmission electron microscopy)來觀察,抗-EGFR的CHC-ganetespib粒子的粒徑(約為200 nm)是大於CHC-ganetespib粒子的粒徑(約為50至100 nm),其顯示:抗-EGFR抗體是成功地綴合至具有被CHC包覆的ganetespib之粒子。此外,藉由穿透電子顯微術所顯示的是:藥物ganetespib是成功地被藥物載體CHC包覆而形成一粒子,而抗-EGFR抗體透過綴合在具有被CHC包覆的ganetespib的粒子上形成一殼結構(shell structure)(數據未顯示)。
基於上述,兩親幾丁聚醣能夠包覆ganetespib而形成一粒子,而一生物功能性分子能夠進一步地綴合至其上。
實施例 2. 依據本發明的含有 ganetespib 的粒子之抗癌效用的評估
在下面的實驗中,依據本發明的含有ganetespib的粒子對抗NSCLC細胞的抗癌效用被評估,俾以研究兩親幾丁聚醣是否供作為一能夠提升ganetespib的抗癌效用的藥物載體。
A. 製備由游離的 ganetespib 或含有 ganetespib 的粒子所組成的試驗溶液
在實施例1的第A項中所得到的ganetespib儲備溶液被進行連續稀釋以得到分別具有下面的游離ganetespib濃度的游離ganetespib試驗溶液:25 ng/mL、20 ng/mL、12.5 ng/mL、6.25 ng/mL、3.125 ng/mL以及1.5625 ng/mL。此外,於實施例1的第A項中所得到之藥物包覆率為60%以及CHC-ganetespib粒子濃度為30 μg/mL的CHC-ganetespib粒子溶液被進行連續稀釋以得到分別具有下面的CHC-ganetespib粒子濃度的CHC-ganetespib試驗溶液:20 ng/mL、10 ng/mL、5 ng/mL、2.5 ng/mL、1.25 ng/mL以及0.625 ng/mL。
B. 對抗 A549 細胞株的活體外抗癌效用之測定
將在實驗材料的第1項中所述的A549細胞以一1×10
4細胞/井的數量平盤培養於一24-井培養盤(24-well culture plate)中,繼而在37℃以及5% CO
2下以補充有10% FBS的DMEM來進行培育。在井中的A549細胞各自被處理以該游離ganetespib試驗溶液以及該CHC-ganetespib試驗溶液。具體而言,200 μL的各自的試驗溶液被添加至一對應的含有A549細胞的井中。沒有被處理以該游離ganetespib試驗溶液以及該CHC-ganetespib試驗溶液的A549細胞供作為一正常對照組(normal control)。在處理之後,在37℃以及5% CO
2下來進行培育歷時48小時。
移除井中的液體之後,所形成的各個培養物以PBS予以清洗兩次,接著藉由3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物(MTT)分析[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay]來進行細胞可活性(cell viability)的測定。具體而言,適量的MTT溶液(具有一為1.9 mg/mL的MTT濃度)被添加至各個培養物中,繼而進行培育歷時4小時。井中的液體被移除,接著二甲亞碸被添加至井中以溶解甲䐶(formazan)染料。井中的混合物在450 nm下的吸光值(OD
450)是使用微量培養盤讀取儀(microplate reader, Tecan Sunrise, Switzerland)來測量。細胞可活性(%)是將吸光值代入至下面的公式(2)而被計算出:
D=(E/F)×100 (2)
D=細胞可活性(%)
E=各個培養物的OD
450F=正常對照組的OD
450
游離的ganetespib以及CHC-ganetespib粒子對抗A549細胞株的IC
50(半數最大抑制濃度)分別是根據游離ganetespib濃度與CHC-ganetespib粒子濃度以及這些濃度所得到的細胞可活性而被測得。
結果:
不同的游離ganetespib濃度以及不同的CHC-ganetespib粒子濃度所得到的細胞可活性以及由此所測得的IC
50被顯示於下面的表3中。
表3
游離ganetespib試驗溶液 | CHC-ganetespib試驗溶液 | ||
濃度 (ng/mL) | 細胞可活性 (%, A549) | 濃度 (ng/mL) | 細胞可活性 (%, A549) |
1.5625 | 98 | 0.625 | 90 |
3.125 | 70 | 1.25 | 72 |
6.25 | 52 | 2.5 | 48 |
12.5 | 40 | 5 | 40 |
25 | 30 | 10 | 25 |
IC 50(ng/mL) = 8.8 | IC 50(ng/mL) = 1.95 |
如表3中所示,CHC-ganetespib粒子對抗A549細胞株的IC
50低於游離的ganetespib所具者約4.5倍,其顯示:當ganetespib被兩親幾丁聚醣包覆時,ganetespib對抗NSCLC細胞的抗癌效用會被顯著地提升。此外,CHC-ganetespib粒子之明顯較低的IC
50顯示:當ganetespib被兩親幾丁聚醣包覆時,有效治療NSCLC細胞所需的藥物劑量會被大幅地降低,因而大幅地降低ganetespib的副作用。
C. 對抗 H1299 細胞株的活體外抗癌效用之測定
游離的ganetespib以及CHC-ganetespib粒子對抗H1299細胞株的活體外抗癌效用大體上是依據本實施例的第B項中所述的方法來測定,除了在實驗材料的第1項中所述的H1299細胞是以一5×10
4細胞/井的數量平盤培養於一24-井培養盤中,繼而在補充有10% FBS的RPMI培養基中來進行培育。
結果:
不同的游離ganetespib濃度以及不同的CHC-ganetespib粒子濃度所得到的細胞可活性以及由此所測得的IC
50被顯示於下面的表4中。
表4
游離ganetespib試驗溶液 | CHC-ganetespib試驗溶液 | ||
濃度 (ng/mL) | 細胞可活性 (%, H1299) | 濃度 (ng/mL) | 細胞可活性 (%, H1299) |
1.5625 | 93 | 1.25 | 80 |
3.125 | 85 | 2.5 | 68 |
6.25 | 55 | 5 | 52 |
10 | 48 | 10 | 30 |
20 | 23 | 20 | 12 |
IC 50(ng/mL) = 10.3 | IC 50(ng/mL) = 4.3 |
如表4中所示,CHC-ganetespib粒子對抗H1299細胞株的IC
50低於游離的ganetespib所具者約2.5倍,其顯示:當ganetespib被兩親幾丁聚醣包覆時,ganetespib對抗NSCLC細胞的抗癌效用會被顯著地提升。此外,CHC-ganetespib粒子之明顯較低的IC
50顯示:當ganetespib被兩親幾丁聚醣包覆時,有效治療NSCLC細胞所需的藥物劑量會被大幅地降低,因而大幅地降低ganetespib的副作用。
於本說明書中被引述之所有專利和文獻以其整體被併入本案作為參考資料。若有所衝突時,本案詳細說明(包含界定在內)將佔上風。
雖然本發明已參考上述特定的具體例被描述,明顯地在不背離本發明之範圍和精神之下可作出很多的修改和變化。因此意欲的是,本發明僅受如隨文檢附之申請專利範圍所示者之限制。
Claims (20)
- 一種含有ganetespib的粒子,其包含有: 一選自於下列的活性成分:ganetespib、ganetespib的一藥學上可接受的鹽類,以及它們的組合;以及 一以兩親幾丁聚醣為基礎的載體,其攜帶該活性成分。
- 如請求項1的含有ganetespib的粒子,其中該以兩親幾丁聚醣-為基礎的載體包括一選自於由下列所構成之群組中的分子:羧甲基-己醯幾丁聚醣、(3-胺基丙基)三乙氧矽烷-修飾的羧甲基-己醯幾丁聚醣、油醯羧甲基幾丁聚醣、 N, N-二甲基十六烷基羧甲基幾丁聚醣、去氧膽酸羧甲基幾丁聚醣、 N-辛基- O, N-羧甲基幾丁聚醣、以奧曲肽-Phe-聚乙二醇-硬酯酸來標靶的 N-辛基- O, N-羧甲基幾丁聚醣、 N-月桂基羧甲基幾丁聚醣、亞麻油醯基羧甲基幾丁聚醣、亞麻油酸聚(β-蘋果酸)幾丁聚醣、膽固醇-修飾的 O-羧甲基幾丁聚醣、 N-膽固醇琥珀醯基 O-羧甲基幾丁聚醣、羧甲基幾丁聚醣-接枝-磷脂醯乙醇胺、葉酸-修飾的羧甲基幾丁聚醣、順-3-(9H-嘌呤-6-基硫)-丙烯酸-接枝-羧甲基幾丁聚醣,以及它們的組合。
- 如請求項2的含有ganetespib的粒子,其中該以兩親幾丁聚醣為基礎的載體是羧甲基-己醯幾丁聚醣。
- 如請求項1的含有ganetespib的粒子,其進一步包含有一由該以兩親幾丁聚醣為基礎的載體所攜帶之額外的活性成分。
- 如請求項4的含有ganetespib的粒子,其中該額外的活性成分是選自於由下列所構成之群組:吉西他濱、去甲氧基薑黃素、17-丙烯胺基去甲氧基格爾德黴素、厄洛替尼、瑞他黴素、微小RNA調節子,以及它們的組合。
- 如請求項1的含有ganetespib的粒子,其進一步包含有一綴合至該活性成分以及該以兩親幾丁聚醣-為基礎的載體中之一者的生物功能性分子。
- 如請求項6的含有ganetespib的粒子,其中該生物功能性分子是選自於由下列所構成之群組:抗-表皮生長因子受體抗體、抗-表皮生長因子受體2抗體、抗-退行性淋巴瘤激酶抗體、抗-蛋白質激酶B抗體、抗-絲裂原-活化的蛋白質激酶激酶抗體、抗-雄性激素受體抗體、抗-***受體抗體,以及它們的組合。
- 如請求項6的含有ganetespib的粒子,其中該生物功能性分子為一抗-表皮生長因子受體抗體。
- 如請求項1的含有ganetespib的粒子,其具有一範圍落在30 nm至500 nm內的粒徑。
- 如請求項9的含有ganetespib的粒子,其具有一範圍落在50 nm至200 nm內的粒徑。
- 一藥學組成物,其包含有一如請求項1的含有ganetespib的粒子。
- 如請求項11的藥學組成物,其中該以兩親幾丁聚醣為基礎的載體是羧甲基-己醯幾丁聚醣。
- 如請求項12的藥學組成物,其進一步包含有一由該以兩親幾丁聚醣為基礎的載體所攜帶之額外的活性成分
- 如請求項11的藥學組成物,其中該額外的活性成分是選自於由下列所構成之群組:吉西他濱、去甲氧基薑黃素、17-丙烯胺基去甲氧基格爾德黴素、厄洛替尼、瑞他黴素、微小RNA調節子,以及它們的組合。
- 如請求項11的藥學組成物,其進一步包含有一綴合至該活性成分以及該以兩親幾丁聚醣-為基礎的載體中之一者的生物功能性分子。
- 如請求項15的藥學組成物,其中該生物功能性分子為一抗-表皮生長因子受體抗體。
- 一種如請求項11的藥學組成物供應用於製備一用來治療癌症之醫藥品的用途。
- 如請求項17的用途,其中該癌症是選自於由下列所構成之群組:肺癌、肝癌、胰臟癌、乳癌、結腸直腸癌,以及它們的組合。
- 如請求項18的用途,其中該癌症為肺癌。
- 如請求項19的用途,其中該癌症為非-小細胞肺癌。
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