TW201902465A - 醫藥組合物、製備方法及其用途 - Google Patents
醫藥組合物、製備方法及其用途 Download PDFInfo
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- TW201902465A TW201902465A TW107119564A TW107119564A TW201902465A TW 201902465 A TW201902465 A TW 201902465A TW 107119564 A TW107119564 A TW 107119564A TW 107119564 A TW107119564 A TW 107119564A TW 201902465 A TW201902465 A TW 201902465A
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Classifications
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
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Abstract
本發明提供一種醫藥組合物包括一個或多個金屬奈米顆粒及治療劑。每一金屬奈米顆粒包括內核及包覆於所述內核的表面的穩定劑。所述治療劑與金屬奈米顆粒上的穩定劑結合。所述治療劑是兩親化合物,每一治療劑具有至少一個與所述穩定劑相互作用的疏水鏈。所述醫藥組合物可進一步包括一包封金屬奈米顆粒和治療劑的聚合物外殼,所述聚合物外殼用於控制所述治療劑的釋放。所述的醫藥組合物具有雙重功能,可用於診斷及治療癌症。本發明還提供了一種應用該醫藥組合物的製備方法及其用途。
Description
本發明涉及一種醫藥領域,尤其涉及一種醫藥組合物、製備方法及其用途。
奈米技術已越來越廣地應用於腫瘤的臨床診斷與治療,以實現癌症的早期診斷與治療。電腦斷層掃描(Computed Tomography,CT)或核磁共振(Magnetic resonance imaging,MRI)可以使用奈米顆粒作為診斷的工具,其中奈米顆粒可以是氧化鐵顆粒(Iron Oxide)、金奈米顆粒(Nano-gold)、量子點顆粒(Quantum dots)及鐵鉑奈米顆粒(FePt),或是其他的組合合金等。由此,醫生就可以診斷病人是否患癌。
在現有的臨床應用中,病人在CT成像之前需要注射造影劑(如碘劑)或是在MRI成像之前注射其他類型的造影劑。之後,主治醫生可以診斷病人是否患癌,患何種類型的癌症,以及如何進行有效治療。例如,對於腫瘤的治療,可結合化學療法與放射療法來治療癌細胞。
然而,病人完成專門的療程可能需要5至10年連續不間斷的跟蹤治療,如此長時間的治療可能由診斷與治療之間的非同步性所導致的。另外,單一的造影劑可能只適用於對應的工具,因而,對於需要多種工具來進行診斷時,可能需要注射多種不同的對比劑到病人的體內,如此使得給診斷與治療帶來一定的不便。而在後續的治療中,化學治療或放射性治療並不與影像診斷同步,而藥物藥效的釋放也無法同步控制。因而,病人在治療的後期可能會產生不適或有副作用的產生。
有鑑於此,有必要提供一種醫藥組合物、製備方法及其用途,可以提高放射療法的治療效果。
一種醫藥組合物,包括:一個或多個金屬奈米顆粒及至少一依附於所述穩定劑的治療劑;每一金屬奈米顆粒包括:內核及塗覆於所述內核的表面的穩定劑;其中所述治療劑是兩親化合物,每一治療劑具有至少一個與所述穩定劑相互作用的疏水鏈。進一步地,所述醫藥組合物中,所述金屬奈米顆粒是FePt奈米顆粒。進一步地,所述醫藥組合物中,所述FePt奈米顆粒的平均直徑介於3奈米至13奈米之間。進一步地,所述醫藥組合物中,所述穩定劑包括油酸。進一步地,所述醫藥組合物中,所述治療劑包括至少一個抗癌藥物、抗炎劑、或其一種或多種的組合物。進一步地,所述醫藥組合物中,所述治療劑為2-氨基-2-[2-(4-辛基苯基)乙基] -1、3-丙二醇(FTY720)、FTY720之衍生物、2-氨基-N-(3-辛基苯基)-3-(磷醯氧基)-丙醯胺(VPC 23019)、VPC 23019之衍生物、[(3R)-3-氨基-4-[(3-己基苯基)氨基] -4-氧代丁基]磷酸(W146)、W146之衍生物、或以上任選之組合。進一步地,所述醫藥組合物中,所述金屬奈米顆粒與所述治療劑的質量比介於1:0.01至1:100之間。進一步地,所述醫藥組合物還包括一包封金屬奈米顆粒和治療劑的聚合物外殼。進一步地,所述醫藥組合中,所述聚合物外殼用於控制所述治療劑的釋放。進一步地,所述醫藥組合中,所述聚合物外殼的組成包括聚乙烯醇、聚乳酸聚甘醇酸、聚乙二醇、D-α-生育酚聚乙二醇1000琥珀酸酯、以上任選之共聚物、或以上任選之組合。進一步地,所述醫藥組合中,所述聚合物的含量占醫藥組合物總重量的比值介於0.1%至10%之間。進一步地,所述醫藥組合物還包括一用於將所述治療劑與所述金屬奈米顆粒的穩定劑連接的連接劑。進一步地,所述醫藥組合物還包括一用於將所述治療劑與所述金屬奈米顆粒的穩定劑連接的連接劑。
一種製備如上述所述的醫藥組合物的製備方法,包括:將所述金屬奈米顆粒溶解在有機溶劑中,以獲得金屬奈米顆粒溶液;將金屬奈米顆粒溶液與所述至少一兩親治療劑混合,以獲得混合物;及從混合物中除去有機溶劑。
一種如上述所述的醫藥組合物在製備用於診斷及治療癌症的雙重功能的藥物中的用途。進一步地,所述的用途中,所述癌症為肺癌或乳癌。
一種如上述所述的醫藥組合物在製備用於治療癌症的藥物中的用途,其中向對象施用一治療有效量的醫藥組合物。進一步地,所述用途還包括向對象施用一有效量的放射劑量,所述有效量的放射劑量足以治療該對象的疾病。進一步地,所述用途還包括對對象進行核磁共振成像或CT掃描,確定對象是否患有癌症。進一步地,所述用途還包括對對象進行核磁共振成像或CT掃描,確定對象是否患有癌症;向對象施用一有效量的放射劑量,所述有效量的放射劑量足以治療該對象的疾病。
一種如上述所述的醫藥組合物在製備用於治療癌症的藥物中的用途,其中向對象施用一治療有效量的醫藥組合物。進一步地,所述用途還包括向對象施用一有效量的放射劑量,所述有效量的放射劑量足以治療該對象的疾病。進一步地,所述用途還包括對對象進行核磁共振成像或CT掃描,確定對象是否患有癌症。進一步地,所述用途還包括對對象進行核磁共振成像或CT掃描,確定對象是否患有癌症;向對象的癌細胞施用一放射劑量。進一步地,所述用途還包括向對象施用一有效量的放射劑量,所述有效量的放射劑量足以讓所述醫藥組合物中的治療劑被釋放。進一步地,所述的用途中,所述有效量的放射劑量足以治療該對象的疾病。進一步地,所述用途還包括對對象進行核磁共振成像或CT掃描,確定對象是否患有癌症;向對象施用一有效量的放射劑量,所述有效量的放射劑量足以讓所述醫藥組合物中的治療劑被釋放。進一步地,所述的用途中,所述有效量的放射劑量足以治療該對象的疾病。
上述醫藥組合物製備方法及用途中醫藥組合物包含金屬奈米顆粒(FePt NPs)和治療劑,該醫藥組合物可以同時用於診斷和治療癌症。另外,醫藥組合物可以是用於CT或MRI掃描的造影劑,用於通過產生自由基來破壞腫瘤細胞以提高放射療法的治療效果的增強劑和/或用於增強腫瘤細胞的敏感性的敏化劑輻射或化學療法。在FePt NPs中使用的含有FTY720藥物的醫藥組合物也可以明顯增加癌細胞的輻射敏感性,從而為癌細胞放射治療起到治療效果。
另外,所述醫藥組合物可包括金屬奈米顆粒(FePt NPs)、治療劑和聚合物外殼。所述聚合物外殼可由聚合物製成,並且覆蓋於所述醫藥組合物外側。因此,醫藥組合物的穩定性可以明顯增加,以避免治療劑在患者的正常組織中釋放。當施加輻射能量到腫瘤組織上,聚合物外殼的聚合度會降低,促進由金屬納米顆粒攜帶的治療劑在腫瘤組織中釋放,治療劑也可以積聚在腫瘤組織中。另外,聚合物外殼可以避免治療劑在正常組織釋放所引起的相關副作用。
下面將結合本發明實施例中的附圖,對本發明實施例中的技術方案進行清楚、完整地描述,顯然,所描述的實施例僅僅是本發明一部分實施例,而不是全部的實施例。基於本發明中的實施例,本領域普通技術人員在沒有做出創造性勞動前提下所獲得的所有其他實施例,都屬於本發明保護的範圍。
現在將說明貫穿本文適用的幾個定義。
如術語“基本上”意思是基本符合該術語修改的特定尺寸,形狀或其他特徵,使得該部件不必是精確的。當使用時,術語“包括”或“包含”意思是“包括但不一定限於”,它具體可表示在所描述的組合、組、系列等中的開放式包含或所屬的成員。
術語“施用”是指對一對象所進行的處置,該處置可以是一種治療,例如使該對象服用、施打特定藥物或進行放射治療,或者提供一診斷。
如本文所使用的,術語“對象”和“患者”可互換使用並且指哺乳動物,通常是人。
如本文所使用的術語“治療有效量”是指產生其給藥所需效果的劑量。確切的劑量可由本領域技術人員使用已知技術來確定,並且,功效可以常規方式測量。例如,對於癌症治療來說,可以通過評估退化或進展時間,確定治療反應率,復發時間,腫瘤大小等來測量功效。如本文所使用的術語“有效量”是指是指產生特定效果的劑量,所述劑量可以是一藥物的劑量或一放射線劑量,所述特定效果可以是治療效果、診斷效果、藥物釋放效果等。
如本文所用,術語“藥學上可接受的”意指由聯邦或州政府的管理機構批准或在美國藥典或其他公認的藥典中列出的用於動物且更具體地用於人的術語。
如本文所用,術語“第一、第二、第三、第四”等詞語用來表示名稱,而並不表示任何或用於限定特定的順序。
在一實施方式中,本發明提供了一種醫藥組合物。所述醫藥組合物可用於癌症的診斷與治療,所述醫藥組合物可包括若干種金屬奈米顆粒及至少一治療劑。每種金屬奈米顆粒可包括內核及塗覆於所述內核外的穩定劑,所述穩定劑可用于增加所述金屬奈米顆粒的穩定性。所述治療劑可以是兩親化合物,所述治療劑可具有至少一個與穩定劑相互作用的疏水鏈。
在可選的實施方案中,醫藥組合物還可包含用於將治療劑與金屬奈米顆粒的穩定劑連接的連接劑。
在一實施方式中,公開了醫藥組合物。該醫藥組合物可用於癌症的診斷與治療,所述醫藥組合物可包括多個金屬奈米顆粒、至少一治療劑和聚合物。每個金屬奈米顆粒包括內核及塗覆於所述內核外的穩定劑。所述穩定劑可以增加金屬奈米顆粒的穩定性。所述聚合物可包封金屬奈米顆粒和治療劑形成一聚合物外殼。所述治療劑可以是兩親化合物,可具有至少一個與穩定劑相互作用的疏水鏈。所述聚合物外殼可用於控制治療劑的特異性釋放並防止治療劑的非特異性釋放。
在一實施方式中,所述醫藥組合物還包含配置用於連接治療劑與金屬奈米顆粒的穩定劑連接的連接劑。
所公開的用於製備醫藥組合物的製備方法的一個實例可包括以下步驟:
將一個或多個金屬奈米顆粒溶解在有機溶劑中,以獲得金屬奈米顆粒溶液;
將金屬奈米顆粒溶液與兩親治療劑混合,以獲得混合物;
從混合物中除去有機溶劑。
在一實施方式中,用於製備醫藥組合物的方法還可包括在將金屬奈米顆粒溶液與治療劑混合之前加入連接劑以促進金屬奈米顆粒與治療劑之間的組合的步驟。
所公開的用於製備醫藥組合物的方法的另一個實例還可包括以下步驟:
將一個或多個金屬奈米顆粒溶解在有機溶劑中,以獲得金屬奈米顆粒溶液;
將金屬奈米顆粒溶液與兩親治療劑混合,以獲得混合物;
在混合物中加入聚合物;
從混合物中除去有機溶劑。
在一個可替代實施方案中,用於製備醫藥組合物的方法還包括在將金屬奈米顆粒溶液與治療劑混合之前加入配置劑以促進金屬奈米顆粒與治療劑之間的組合的步驟。
在一實施方式中,醫藥組合物在製備可用於診斷及治療癌症的雙重功能的藥物中的用途。所述癌症,較佳的,可以為肺癌或乳癌。
較佳地,請參閱圖1A,本發明醫藥組合物100的第一較佳實施方式可包括若干金屬奈米複合材料10及藥物載體(圖未示)。本實施方式中,所述醫藥組合物100的微粒直徑可介於10奈米至1000奈米之間,較佳地,所述醫藥組合物100的微粒直徑大約在10奈米至200奈米之間。所述醫藥組合物的細微性可適應于奈米藥物的臨床應用,可使其具有更好的生物吸收性和安全性。所述醫藥組合物100可通過口服、靜脈注射、皮下注射或肌肉注射等方式進入體內。
請參閱圖1B,每一金屬奈米複合材料10可包括金屬奈米顆粒11及至少一治療劑13。所述金屬奈米顆粒11可包括內核111及塗覆於所述內核111表面的穩定劑112。所述穩定劑112可用于增加所述金屬奈米顆粒11的穩定性。所述至少一治療劑13可依附於所述金屬奈米顆粒11的穩定劑112,以與所述穩定劑112進行交互作用。
在第一較佳實施方式中,所述醫藥組合物100可包括若干金屬奈米複合材料11及位於每一金屬奈米顆粒11表面上的所述治療劑13。本實施方式中,所述金屬奈米顆粒11與所述治療劑13之間質量比可介於1:0.01至1:100之間。
可以理解地,所述金屬奈米顆粒11的內核11可由對應的材質得到,所述材質包括但不限於金屬、合金、金屬氧化物、類金屬(Metalloid)、類金屬氧化物(Metalloid Oxide)、磁性奈米顆粒(Magnetic Nanoparticle)或其組合。
可以理解地,當所述金屬奈米顆粒11的材質為金屬時,所述金屬包括但不限於金、銀、銅、鈦、鎳、鉑、鈀或者及其組合;所述金屬亦可包括但不限於鑭系元件;當所述金屬奈米顆粒11的材質為金屬氧化物時,所述金屬氧化物包括但不限於TiO2。當所述金屬奈米顆粒11的材質為磁性奈米顆粒時,所述磁性奈米顆粒包括但不限於鐵奈米顆粒、鐵複合材料的奈米顆粒或者及其組合。所述鐵複合材料的奈米顆粒包括但不限於Fe2O3、 Fe3O4、 FePt、FeCo、 FeAl,、FeCoAl、 CoFe2O4、 MnFeO4、CoPt或者及其組合。
在第一較佳實施方式中,所述金屬奈米顆粒11可為FePt奈米顆粒(以下簡稱FePt NPs)。
所述FePt奈米顆粒的晶體結構可為面心立方(face-centered cubic, FCC)結構。所述FePt奈米顆粒的平均直徑可介於3奈米(nanometer,nm)至13奈米之間,優選的平均直徑約6奈米至7奈米。所述FePt奈米顆粒的一般式為Fe58Pt42。
所述FePt奈米顆粒可同時用於癌症的診斷與治療,特別是針對於惡性腫瘤;所述癌症,較佳的,可以為肺癌或乳癌。所述FePt奈米顆粒可用於為CT或MRI掃描的造影劑,也就是說,所述FePt奈米顆粒擁有CT/MRI的雙造影特徵。另外,所述FePt奈米顆粒可具有在腫瘤組織累和積吸收放射線能量的功能,因此,所述FePt奈米顆粒可通過吸收放射線能量進而在體內達到放射線聚焦,從而更有效地殺死腫瘤組織的效果。
可以理解地,所述FePt奈米顆粒可用作藥物載體,如用於運載癌症藥物,因此,通過攜帶癌症治療藥物,進而達到放射線與藥物治療的加乘效果。
當所述FePt奈米顆粒吸收放射線能量時,所述FePt奈米顆粒可分裂其附近的水分子,之後通過產生自由基來摧毀腫瘤細胞。因此,所述FePt奈米顆粒可用作放射治療的增強劑。
所述金屬奈米顆粒11的穩定劑112可用於穩定所述金屬奈米顆粒,所述穩定劑可為表面活性劑(Surfactant)。所述表面活性劑包括但不限於陰離子型表面活性劑、中性表面活性劑或陽離子型表面活性劑。所述陰離子型表面活性劑可包括但不限於鹵化烷基三甲銨(alkyl trimethylammonium halide)。所述中型表面活性劑可包括但不限於飽和脂肪酸(saturated fatty acid)或不飽和脂肪酸,如油酸,月桂酸或十二烷酸,三烷基磷化合物或三烷基磷氧化物如三辛基氧化磷(TOPO),三辛基磷(TOP)或三丁基磷,烷基胺如十二烷基胺,油胺,三辛胺或辛胺,或烷基硫醇。所述陰離子表面活性劑可以包括但不限於烷基磷酸鈉。
為保持所述金屬奈米顆粒11的穩定性及較統一的大小,所述表面活性劑可優選為包括但不限於飽和脂肪酸,不飽和脂肪酸和/或烷基胺。
所述穩定劑112可優選為油酸,以根據需要金屬奈米顆粒的疏水性來選用。
所述至少一治療劑13可以是兩親化合物。所述至少一種治療劑13具有至少一個與穩定劑112相互作用的疏水鏈。
所述治療劑13可以包括但不限於抗代謝藥,抗真菌藥,抗炎劑,抗腫瘤藥,抗感染藥,抗生素,營養素,激動劑和拮抗劑。
所述至少一種治療劑13可以優選地包括抗癌藥物,抗炎劑和它們的組合。
所述治療劑13可優選包括2-氨基-2- [2-(4-辛基苯基)乙基] -1、3-丙二醇(FTY720)、2-氨基-N-(3-辛基苯基)-3- (磷醯氧基) - 丙醯胺(VPC 23019)、[(3R)-3-氨基-4 - [(3-己基苯基)氨基] -4-氧代丁基] 磷酸(W146)及其衍生物(如FTY720之衍生物、VPC 23019之衍生物、W146之衍生物)、或以上任選之組合。
由於FTY720可以作為敏化劑,其可以增強腫瘤細胞對輻射的易感性,因此,所述治療劑13也可以優選為FTY720。
在本實施方式中,FTY720可以作為治療劑13。FTY720可形成於每個FePt奈米顆粒的表面,以形成醫藥組合物100(在此表示為:FePt@FTY720 NPs)。可以理解地,所述 FePt 奈米顆粒與FTY720的質量比在1:0.01至1:100的範圍內。
請參閱圖2A,在第二較佳實施方式中,醫藥組合物200可包括多個金屬奈米複合材料20和藥物載體(圖未示)。
可以理解地,所述醫藥組合物200中的顆粒直徑可以在10奈米至1000奈米的範圍內。所述醫藥組合物200的粒徑可以優選在約10奈米至200奈米的範圍內。所述醫藥組合物的細微性可適應于奈米藥物的臨床應用,可使其具有更好的生物吸收性和安全性。
請參閱圖2B,每一金屬奈米複合材料20可包括金屬奈米顆粒21和至少一種治療劑23。所述金屬奈米顆粒21可包括內核211和塗覆在所述內核211的表面上的穩定劑212。所述穩定劑212可用于增加所述金屬奈米顆粒21的穩定性。所述金屬奈米顆粒21及至少一治療劑23在結構上與第一較佳實施方式大致相同。在與第一較佳實施方式中不在之處在於,第二較佳實施方式的金屬奈米複合材料20還包括連接穩定劑212與治療劑23的連接劑25。
可以理解地,所述連接劑25可以是但不限於聚合物。例如,所述連接劑25可包括但不限於纖維素,聚乙二醇(PEG),聚(N-乙烯基吡咯烷酮),聚(氰基丙烯酸烷基酯),聚-ε-己內酯,其衍生物及其組合。
在第二實施例中,所述醫藥組合物200可包括多個金屬奈米顆粒21。所述治療劑23可形成在每個金屬奈米顆粒21的表面,所述連接劑25可使得所述金屬奈米顆粒21與治療劑23連接。所述金屬奈米顆粒21與治療劑23的質量比可以介於1:0.01至1:100之間。
較佳地,所述金屬奈米顆粒21可以選擇FePt NPs(FePt奈米顆粒),所述治療劑23可以選擇FTY720,所述連接劑25可以選擇PEG,所述PEG可形成於所述FePt奈米顆粒的表面上,以形成親水性FePt奈米顆粒(在此表示為FePt@PEG NPs);更進一步地,所述FTY720可形成於FePt@PEG NPs的表面,以形成醫藥組合物200(在此表示為FePt@PEG-FTY720 NPs)。
請參閱圖3,在第三較佳實施方式中,所述醫藥組合物300包括多個金屬奈米顆粒31及至少一治療劑33。每個金屬奈米顆粒31可包括內核311和塗覆於所述內核311的表面上的穩定劑312。所述穩定劑312可用于增加所述金屬奈米顆粒31的穩定性。所述金屬奈米顆粒31及至少一治療劑33在結構上與第一較佳實施方式大致相同。與第一較佳實施方式相比,第三較佳實施中,所述醫藥組合物300還可包括包封所述金屬奈米顆粒31及至少一治療劑33的聚合物外殼301。
可以理解地,所述聚合物外殼301可以優選由可生物降解的聚合物製成。所述聚合物外殼301由選自但不限於聚乙烯醇(PVA),聚乳酸聚甘醇酸(PLGA),聚乙二醇(PEG),D-α-生育酚聚乙二醇1000琥珀酸酯(TPGS),以及以上任選的組合。所述醫藥組合物300中聚合物外殼301的含量的範圍可在0.1%至10%之間。所述醫藥組合物300中聚合物外殼301的含量可以優選在0.25%至5%之間。
在本實施實施方式中,所述聚合物外殼301的材料可優選聚乙烯醇。
所述聚合物外殼301可用於控制所述治療劑33在腫瘤部位的釋放,並且還可以防止藥物發生非特異性釋放,從而有效避免由於治療劑33釋放到正常組織時而產生的副作用。
可以理解地,所述醫藥組合物300的顆粒直徑可以在10奈米至1000奈米的範圍內。
較佳地,所述醫藥組合物300的粒徑可以優選在10奈米至200奈米的範圍內。所述醫藥組合物的細微性可適應于奈米藥物的臨床應用,可使其具有更好的生物吸收性和安全性。
在第三較佳實施方式中,所述金屬奈米顆粒31可以選擇FePt NPs(FePt奈米顆粒),所述治療劑33可以選擇FTY720,所述聚合物可以選擇聚乙烯醇(PVA)。 可以理解地,所述PVA可形成於在所述FePt@FTY720 NPs的表面,進而形成醫藥組合物300(在此表示為:FePt@FTY720-PVA NP)。 較佳地,所述FePt奈米顆粒與FTY720的質量比可在1:0.01至1:100的範圍內。所述醫藥組合物300中PVA的含量占在總重量的比值可在0.1%至10%的範圍內。本實施方式中,所述醫藥組合物300中PVA的優選的含量占總重量比較約在0.25%至5%的範圍內。
請參閱圖4,在第四較佳實施方式中,所述醫藥組合物400可包括多個金屬奈米顆粒41及至少一治療劑43。每個金屬奈米顆粒41包括內核411和塗覆在內核411的表面上的穩定劑412。所述穩定劑412可用于增加金屬奈米顆粒41的穩定性。所述金屬奈米顆粒41及至少一治療劑43在結構上與第二較佳實施方式大致相同。與第二較佳實施方式的不同之處在於,第四較佳實施方式中的醫藥組合物400還可包括包封所述金屬奈米顆粒41及至少一種治療劑43的聚合物外殼401。
第四較佳實施方式中的聚合物外殼401與第三較佳實施方式中的聚合物外殼301的構造基本相同。
在第四較佳實施方式,所述聚合物外殼401的材料可優選為聚乙烯醇。所述醫藥組合物400中聚乙烯醇的含量占總重量比值可在0.1%至10%的範圍內。本實施方式中,所述醫藥組合物400的聚乙烯醇中的優選含量占總重量的比值可在0.25%至5%的範圍內。
可以理解地,所述醫藥組合物400的顆粒直徑(粒徑)可以在10奈米至1000奈米的範圍內。
較佳地,所述醫藥組合物400的粒徑可以優選在10奈米至200奈米的範圍內。所述醫藥組合物的細微性可適應于奈米藥物的臨床應用,可使其具有更好的生物吸收和安全性。
以下,將提供示例來說明本公開的實施例。以下實施例旨在為本領域普通技術人員提供關於如何製造和使用該方法以及使用本文所述的方法和組合物的完整公開和描述,並且不旨在限制。
請參閱圖5,實施例一,本發明金屬奈米顆粒的製備方法的第一較佳實施方式可包括以下步驟:
步驟S110,將含鉑化合物、含鐵化合物和穩定劑混合,並溶解在有機溶劑中以獲得反應溶液。
步驟S120,從反應溶液中除去有機溶劑以分離沉澱物。
步驟S130,洗滌沉澱物並離心,以分離並得到期望的金屬奈米顆粒。
在一較佳的實施方式中,所述含鐵化合物可以是Fe(CO)5。所述穩定劑可以是油酸。所述有機溶劑可以是二辛基醚、1,2-十六烷二醇和油胺。所述含鉑化合物可以是Pt(acac)2。
在第一種方式中,製備粒徑為3奈米至4奈米的FePt奈米顆粒的製備方法可以包括:將97mg Pt(acac)2、195mg 1,2-十六烷二醇和10mL二辛基醚混合並在氮氣環境下10分鐘內加熱至100℃。在100℃下,注入66μL Fe(CO)5、80μL油胺和80μL油酸。將反應混合物以15℃/分鐘的加熱速率加熱至297℃。 30分鐘後,移除加熱源並讓產物冷卻至室溫。用己烷/乙醇洗滌顆粒三次,並通過離心收集以分離出粒徑為3奈米至4奈米的FePt 奈米顆粒。
在第二種方式中,製備粒徑為6奈米至7奈米的FePt奈米顆粒的製備方法可以包括:採用化學還原法製備FePt奈米顆粒。具體地說,將97mg Pt(acac)2、4mL二辛基醚、66μL Fe(CO)5、195mg 1,2-十六烷二醇、100μL油胺和100μL油酸在氮氣下混合。將反應混合物以15℃/分鐘的加熱速率加熱至240℃。在240℃以15℃/分鐘的加熱速率加熱反應混合物。30分鐘後,移除加熱源,然後使產物冷卻至室溫。用己烷/乙醇洗滌顆粒三次,並通過離心收集以分離出粒徑為6奈米至7奈米的FePt 奈米顆粒。
在第三種方式中,製備粒徑為12奈米至13奈米的FePt奈米顆粒的製備方法可以包括:將195mg Pt(acac)2、1.05g 1,2-十六烷二醇、4mL二辛基醚、66μL Fe(CO)5、4mL油胺和4mL油酸在氮氣下混合,然後將混合物在15℃/分鐘的加熱速率下加熱至240℃。之後,將混合物在240℃保持60分鐘。然後,移除加熱源,將反應混合物冷卻至室溫。用己烷/乙醇洗滌顆粒三次,並通過離心收集以分離出粒徑為12奈米至13奈米的FePt 奈米顆粒。
參閱圖6,根據第一較佳實施方式製備奈米顆粒的製備方法的較佳實施方式可包括以下步驟:
步驟S210,將金屬奈米顆粒溶解在有機溶劑中,以獲得金屬奈米顆粒溶液。
步驟S220,將金屬奈米顆粒溶液與至少一兩親性的治療劑混合,以獲得混合物。
步驟S230,從混合物中除去有機溶劑以獲得沉澱物。
步驟S240,洗滌沉澱物並離心,以分離得到期望的醫藥組合物。
參閱圖7,根據第三較佳實施方式製備金屬奈米顆粒的製備方法的較佳實施方式可包括以下步驟:
步驟S310,將金屬奈米顆粒溶解在有機溶劑中,以獲得金屬奈米顆粒溶液。
步驟S320,將金屬奈米顆粒溶液與兩親治療劑混合,以獲得混合物。
步驟S330,在混合物中加入聚合物。
步驟S340,從混合物中除去有機溶劑,以獲得沉澱物。
步驟S350,洗滌沉澱物並離心,以分離得到所期望的醫藥組合物。
參閱圖8,以FePt@FTY720 NPs及FePt@FTY720-PVA NPs為例的醫藥組合物的製備方法中,所述醫藥組合物可通過奈米沉澱法合成的。具體而言,將5mg粒徑為6奈米的FePt NPs溶解於100ul 二氯甲烷(dichloromethane methylene chloride,DCM)溶液中,以製備第一反應溶液;將3mg FTY720溶解于900ul水中,以製備第二反應溶液。然後,將第一反應溶液和第二反應溶液通過吸液混合方式進行混合,直到混合物均勻化。之後,將混合物注入9ml水中或含有1%PVA溶液的水中,並通過超聲波震盪處理5分鐘,然後將經超聲波處理後混合物放置真空中15分鐘以蒸發DCM溶液。由於溶劑疏水性的突然降低,從而可以使得FTY720和包封所述FePt奈米顆粒的疏水片段的聚集,從而生成載有FTY720的金屬奈米顆粒的沉澱。之後,可使用離心機分離多餘的FTY720和PVA,並用水溶液洗滌兩次,以獲得最終產物FePt@FTY720 NPs和FePt@FTY720-PVA NPs。
於上述實施例中,所述FePt奈米顆粒與FTY720的質量比可介於在1:0.01至1:100之間。所述醫藥組合物中聚乙烯醇的含量可以占總重量的0.1%至10%之間。較佳地,所述 FePt@FTY720-PVA NPs中聚乙烯醇的優選含量占總重量的0.25%至5%之間;更佳地,所述FePt@FTY720-PVA NPs中聚乙烯醇的含量約為1%。在有機溶劑的真空蒸發過程中,由於溶劑疏水性的突然降低導致FTY720和包封金屬奈米顆粒的疏水片段的聚集,進而可以使得所述治療劑載入在金屬醫藥組合物上。
請一併參閱圖9A至9D,根據上述實施例的步驟所製備的FePt@FTY720 NPs可通過透射電子顯微鏡(TEM)及低溫電子顯微鏡(Cryo-EM)進行觀察與測定。此處的測定結果顯示,FePt@FTY720 NPs的平均直徑基本上在84.4±12.3奈米的範圍內。
請一併參閱圖10A至圖10D,根據上述實施例的步驟所製備的FePt@FTY720-PVA NPs可通過透射電子顯微鏡及低溫電子顯微鏡進行觀察與測定。此處的測定結果顯示,FePt@FTY720-PVA NPs的平均直徑基本上在71.7±23.6奈米的範圍內。
請參閱圖11,根據第二較佳實施方式製備FePt@PEG-FTY720 NPs奈米顆粒的製備方法的較佳實施方式可包括以下步驟:
步驟S410,將金屬奈米顆粒溶解在有機溶劑中,以獲得金屬奈米顆粒溶液。
步驟S420,向金屬奈米顆粒溶液添加連接劑,以獲得親水性的金屬奈米顆粒溶液。
步驟S430,將親水性的金屬奈米顆粒溶液與至少一兩親性治療劑混合,以獲得混合物。
步驟S440,從混合物中除去有機溶劑,以獲得沉澱物。
步驟S450,洗滌沉澱物並離心,以分離得到所期望的醫藥組合物。
據上述實施例的步驟製備的醫藥組合物(FePt@PEG-FTY720 NPs)中可包括金屬奈米顆粒、至少一治療劑和連接劑。較佳地,所述金屬奈米顆粒的粒徑可為6奈米。所述至少一治療劑可以是FTY720,其可以溶于水中。所述連接劑可由PEG的材料製成。所述FePt奈米顆粒與FTY720的質量比可介於1:0.01至1:100之間。
請參閱圖12,根據第四較佳實施方式製備FePt@PEG-FTY720-PVA NPs的製備方法的較佳實施方式可包括以下步驟:
步驟S510,將金屬奈米顆粒溶解在有機溶劑中,以獲得金屬奈米顆粒溶液。
步驟S520,向金屬奈米顆粒溶液添加連接劑,以獲得親水性金屬奈米顆粒溶液。
步驟S530,將親水性金屬奈米顆粒溶液與至少一兩親性治療劑混合,以獲得混合物。
步驟S540,在混合物中添加聚合物。
步驟S550,從混合物中除去有機溶劑,以獲得沉澱物。
步驟S560,洗滌沉澱物並離心,以分離得到所期望的醫藥組合物。
上述實施例的步驟製備的醫藥組合物(FePt@PEG-FTY720-PVA NPs)中可包括金屬奈米顆粒、至少一治療劑、連接劑及聚合物外殼。較佳地,所述金屬奈米顆粒平均粒徑可為6奈米。所述種治療劑可為FTY720,其可以溶于水中。所述連接劑可由PEG的材料製成。所述聚合物外殼可由PVA材料製成。 所述FePt NPs與FTY720的質量比可介於1:0.01至1:100之間。所述醫藥組合物中PVA的含量占總重量的比值可介於0.1%至10%之間。所述 FePt@FTY720-PVA NP中PVA的含量占總重量的比值可優選為0.25%至約5%之間。
請參閱圖13,使用根據第一至第四較佳實施方式製備的醫藥組合物(如FePt@FTY720 NPs,FePt@FTY720-PVA NPs,FePt@PEG-FTY720 NPs或FePt@PEG-FTY720-PVA NPs)的較佳實施方式可包括以下步驟:
步驟S610,向對象施用一治療有效量的醫藥組合物。所述醫藥組合物可以口服、靜脈注射、皮下注射或肌肉注射等方式給予一對象。可以理解地,在向一對象施用醫藥組合物之前,可以進一步包括配置醫藥組合物的步驟,例如將醫藥組合物與藥物載體結合。
在一個實例中,上述使用方法進一步包含步驟S620,對對象進行核磁共振成像或CT掃描,以診斷該對象是否患有癌症;或者步驟S630,向對象施用一有效量的放射劑量,所述有效量的放射劑量足以治療該對象的疾病。在另一個實例中,上述使用方法進一步包含步驟S620以及步驟S630,因此可同時針對對象的癌細胞組織進行診斷與治療。
請參閱圖14,在另一實施方式中,使用根據第三至第四較佳實施方式製備的醫藥組合物(如FePt@FTY720-PVA NPs或FePt@PEG-FTY720-PVA NPs)的較佳實施方式可包括以下步驟:
步驟S710,向對象施用一治療有效量的醫藥組合物。所述醫藥組合物可以口服、靜脈注射、皮下注射或肌肉注射等方式給予一對象。可以理解地,在向一對象施用醫藥組合物之前,可以進一步包括配置醫藥組合物的步驟,例如將醫藥組合物與藥物載體結合。
在一個實例中,上述使用方法進一步包含步驟S720,對對象進行核磁共振成像或CT掃描,以診斷該對象是否患有癌症。在另一實施方式中,上述醫藥組合物之使用方法,可進一步包含步驟S730,向醫藥組合物提供一有效量的放射劑量,所述有效量的放射劑量足以讓所述醫藥組合物中的治療劑被釋放。所述有效量的放射劑量可能同時足以治療該對象的疾病,因此可利用所述治療劑與放射劑量同時治療癌症。在另一實施方式中,上述使用方法進一步包含步驟S720以及步驟S730,因此可同時針對對象的癌細胞組織進行診斷與治療。
請一併參閱圖15A及圖15B,其顯示了施用不同FePt 奈米顆粒醫藥組合物對癌細胞的治療效果。具體而言,實驗分別將兩種醫藥組合物,FePt@FTY720 NPs和FePt@FTY720-PVA NPs,依不同濃度施用於人類肺癌細胞SR3A-13,在未施用或施用放射能量(圖中以IR表示有施用放射能量)的情況下,分析不同醫藥組合物對癌細胞存活率之影響。將SR3A-13癌細胞與濃度範圍從0、0.25、0.5及1.0mg / ml的FePt@FTY720 NPs或FePt@FTY720-PVA NPs醫藥組合物於體外進行培養,並持續進行25小時後,將SR3A-13癌細胞分為2組,其中一組進一步以6Gy輻射劑量進行照射。最後,將SR3A-13癌細胞利用胰蛋白酶懸浮,並在10cm大小培養皿中以不同細胞密度(500〜10000個細胞/培養皿)再培養10-14天,以形成細胞群落。計算每個實驗組的細胞群落後計算得到存活率(Surviving Fraction,SF),從而可以觀察如圖15A及圖15B所述的細胞存活結果。
如圖15A及圖15B所示,FePt@FTY720 NPs具有治療癌症的加乘作用。具體而言,以FePt@FTY720 NPs處理的SR3A-13癌細胞經由輻射能量照射後,其癌細胞的存活率明顯地下降。在FePt@FTY720 NPs濃度為0.25mg / ml時,照射輻射能量後癌細胞存活率大約降低至30%-50%。由以上結果可知FePt@FTY720 NPs對癌症放射治療具有一加乘治療效果。
除此之外,以FePt@FTY720 NPs處理的實驗組別顯示了隨著增加醫藥組合物的濃度,不論有沒有照射輻射能量,癌細胞存活率都顯著的下降;相對的,以FePt@FTY720-PVA NPs處理的實驗組別隨著增加醫藥組合物的濃度,癌細胞存活率的下降只在有照射輻射能量時較為顯著。此外,以FePt@FTY720-PVA NPs處理的實驗組別在照射輻射能量後,對癌細胞所產生的毒殺作用與FePt@FTY720 NPs相似。如此,可以說明了,金屬奈米顆粒醫藥組合物被聚乙烯醇包封時(FePt@FTY720-PVA NPs),聚乙烯醇(PVA)外殼可抑止FTY720藥物的釋放,使得FTY720藥物的釋放速率明顯降低;並且所述聚乙烯醇外殼可透過輻射能量照射來控制FTY720藥物釋放。
請參閱圖16,其顯示了不同緩衝液系統對醫藥組合物的治療劑釋放度的測定結果。實驗中的所述醫藥組合物分別使用FePt@FTY720 NPs和FePt@FTY720-PVA NPs,分別以水和細胞質模擬緩衝液(CMB)進行測試,其中所述CMB由KCl(120mM),CaCl2(0.15mM),K2HPO4 / KH2PO4(10mM),HEPES(25mM),EGTA(2mM),MgCl2(5mM),ATP(2mM)和谷胱甘肽(5mM)組合。所述 CMB的pH值可基本上為7.6。可以理解,醫藥組合物分散在CMB緩衝系統中的環境條件與分散在腫瘤組織的環境條件相類似。所述醫藥組合物在不同緩衝液系統中被靜置於室溫24小時,再分別觀察各組的FePt奈米顆粒的聚集程度
如圖16所示,當FePt@FTY720 NPs和FePt@FTY720-PVA NPs被放至於水中時,在試管中沒有沉澱形成,表示在水中FePt@FTY720 NPs和FePt@FTY720-PVA NPs的FTY720不會被釋放。相對的,當FePt@FTY720 NPs被放至於CMB環境時,在試管中有金屬顆粒沉澱物形成,表示在CMB環境中FePt@FTY720 NPs中的FTY720被釋放;然而,當FePt@FTY720-PVA NPs被放至於CMB環境時,在試管中沒有沉澱形成,說明了FePt@FTY720-PVA NPs在未被輻射能量照射的情形下,FTY720的釋放會受到抑止。
本公開的醫藥組合物包含金屬奈米顆粒(FePt NPs)和治療劑(FTY720),因此該醫藥組合物可以同時用於診斷和治療癌症。另外,醫藥組合物可以是用於CT或MRI掃描的造影劑,用於通過產生自由基來破壞腫瘤細胞以提高放射療法的治療效果的增強劑和/或用於增強腫瘤細胞的敏感性的敏化劑輻射或化學療法。在FePt NPs中使用的含有FTY720藥物的醫藥組合物也可以明顯增加癌細胞的輻射敏感性,從而為癌細胞放射治療起到治療效果。
根據本公開的另一種醫藥組合物,包括金屬奈米顆粒(FePt NPs)、治療劑(FTY720)和聚合物外殼。所述聚合物外殼可由聚合物組成,並且覆蓋於所述醫藥組合物外側。因此,醫藥組合物的穩定性可以明顯增加,以避免治療劑(FTY720)在患者的正常組織中釋放。當施加輻射能量到腫瘤組織上,聚合物外殼的聚合度會降低,促進由金屬納米顆粒攜帶的治療劑在腫瘤組織中釋放,治療劑也可以積聚在腫瘤組織中。另外,聚合物外殼可以避免治療劑在正常組織釋放所引起的相關副作用。
以上示出和描述的實施例僅是示例。本領域經常會發現許多細節,例如醫藥組合物的其他特徵,以及製備和使用該醫藥組合物的方法。因此,許多這樣的細節既沒有示出也沒有描述。儘管在前面的描述中已經闡述了本技術的眾多特徵和優點以及本公開的結構和功能的細節,但是本公開僅僅是說明性的,並且可以在細節上做出改變,特別是在事項 在本公開內容的原理範圍內的部件的形狀,尺寸和佈置,直到並且包括由權利要求中使用的術語的廣泛一般含義所確定的全部範圍。因此可以理解,上述實施例可以在權利要求的範圍內進行修改。
對於本領域的普通技術人員來說,可以根據本發明的技術構思做出其它各種相應的改變與變形,而所有這些改變與變形都應屬於本發明權利要求的保護範圍。
100、200、300、400‧‧‧醫藥組合物
10、20‧‧‧金屬奈米複合材料
11、21、31、41‧‧‧金屬奈米顆粒
13、23、33、43‧‧‧治療劑
112、212、312、412‧‧‧穩定劑
111、211、311、411‧‧‧內核
25、45‧‧‧連接劑
301、401‧‧‧聚合物外殼
圖1A提供了本發明醫藥組合物的第一較佳實施方式的示意圖。 圖1B是圖1A中醫藥組合物中單一顆金屬奈米複合材料的較佳實施方式的示意圖。 圖2A提供了本發明醫藥組合物的第二較佳實施方式的示意圖。 圖2B是圖2A中醫藥組合物中單一顆金屬奈米複合材料的較佳實施方式的示意圖。 圖3提供了本發明醫藥組合物的第三較佳實施方式的示意圖。 圖4提供了本發明醫藥組合物的第四較佳實施方式的示意圖。 圖5是本發明醫藥組合物中金屬奈米颗粒製備方法的一較佳實施方式的流程圖。 圖6提供了一種根據第一較佳實施方式的醫藥組合物製備的較佳實施方式流程圖。 圖7提供了一種根據第三較佳實施方式的醫藥組合物製備的較佳實施方式流程圖。 圖8是以FePt@FTY720 NPs及FePt@FTY720-PVA NPs為例的醫藥組合物的製備過程的較佳實施方式示意圖。 圖9A和圖9B示出了一示例性對應FePt@FTY720 NPs的透射電子顯微鏡(TEM)照片。 圖9C和圖9D示出了一示例性對應FePt@FTY720 NPs的低溫電子顯微鏡(Cryo-EM)照片。 圖10A和圖10B示出了示例三的FePt@FTY720-PVA NPs的TEM圖。 圖10C和圖10D示出了示例三的FePt@FTY720-PVA NPs的Cryo-EM圖。 圖11提供了一種根據第二較佳實施方式的醫藥組合物製備的較佳實施方式流程圖。 圖12提供了一種根據第四較佳實施方式的醫藥組合物製備的較佳實施方式流程圖。 圖13示出了一示例性實施方式中的醫藥組合物在製備用於遞送治療劑至一對象的藥物中的用途的流程圖。 圖14示出了一示例性實施方式中的醫藥組合物在製備用於治療癌症的藥物中的用途的流程圖。 圖15A示出了通過使用不具或具有聚合物外殼的醫藥組合物和每種醫藥組合物的特定濃度所對應腫瘤細胞的存活部分的測定結果的示意圖。 圖15B示出了通過使用不具或具有聚合物外殼的醫藥組合物和每種醫藥組合物的特定濃度並施加輻射所對應腫瘤細胞的存活部分的測定結果的示意圖。 圖16示出了細胞質模擬緩衝系統對治療劑釋放程度的測定結果的示意圖。
Claims (28)
- 一種醫藥組合物,其特徵在於,所述醫藥組合包括: 一個或多個金屬奈米顆粒,每一金屬奈米顆粒包括: 內核;及 包覆於所述內核的表面的穩定劑;及 至少一依附於所述穩定劑的治療劑; 其中所述治療劑是兩親化合物,每一治療劑具有至少一個與所述穩定劑相互作用的疏水鏈。
- 如申請專利範圍第1項所述的醫藥組合物,其中所述金屬奈米顆粒是FePt奈米顆粒。
- 如申請專利範圍第2項所述的醫藥組合物,其中所述FePt奈米顆粒的平均直徑介於3奈米至13奈米之間。
- 如申請專利範圍第1項所述的醫藥組合物,其中所述穩定劑包括油酸。
- 如申請專利範圍第1項所述的醫藥組合物,其中所述治療劑包括至少一個抗癌藥物、抗炎劑、或其一種或多種的組合。
- 如申請專利範圍第5項所述的醫藥組合物,其中所述治療劑為2-氨基-2-[2-4-辛基苯基)乙基] -1、3-丙二醇(FTY720)、FTY720之衍生物、2-氨基-N-(3-辛基苯基)-3-(磷醯氧基)-丙醯胺(VPC 23019)、VPC 23019之衍生物、[(3R)-3-氨基-4-[(3-己基苯基)氨基] -4-氧代丁基]磷酸(W146)、W146之衍生物、或以上任選之組合。
- 如申請專利範圍第1項所述的醫藥組合物,其中所述金屬奈米顆粒與所述治療劑的質量比介於1:0.01至1:100之間。
- 如申請專利範圍第1項所述的醫藥組合物,其中所述醫藥組合物進一步包括一包覆金屬奈米顆粒和治療劑的聚合物外殼。
- 如申請專利範圍第8項所述的醫藥組合物,其中所述聚合物外殼可用於控制所述治療劑的釋放。
- 如申請專利範圍第8項所述的醫藥組合物,其中所述聚合物外殼的組成包括聚乙烯醇、聚乳酸聚甘醇酸、聚乙二醇、D-α-生育酚聚乙二醇1000琥珀酸酯、以上任選之共聚物、或以上任選之組合。
- 如申請專利範圍第8項所述的醫藥組合物,其中所述聚合物的含量占醫藥組合物總重量的比值介於0.1%至10%之間。
- 如申請專利範圍第8項所述的醫藥組合物,其中所述醫藥組合物進一步包括一用於將所述治療劑與所述金屬奈米顆粒的穩定劑連接的連接劑。
- 如申請專利範圍第1項所述的醫藥組合物,其中所述醫藥組合物進一步包括一用於將所述治療劑與所述金屬奈米顆粒的穩定劑連接的連接劑。
- 一種製備如申請專利範圍第1至13項中任一項所述的醫藥組合物的方法,其中所述製備方法包括: 將所述金屬奈米顆粒溶解在有機溶劑中,以獲得金屬奈米顆粒溶液; 將金屬奈米顆粒溶液與所述至少一兩親治療劑混合,以獲得混合物;及 從混合物中除去有機溶劑。
- 一種如申請專利範圍第1項所述的醫藥組合物之用途,其用於製造用於診斷及治療癌症的雙重功能藥劑。
- 如申請專利範圍第15項所述的用途,其中所述癌症為肺癌或乳癌。
- 一種如申請專利範圍第1項所述的醫藥組合物之用途,其用於製造用於治療癌症的藥劑,其中 向對象施用一治療有效量的醫藥組合物。
- 如申請專利範圍第17項所述的用途,其中進一步 向對象施用一有效量的放射劑量,所述有效量的放射劑量足以治療該對象的疾病。
- 如申請專利範圍第17項所述的用途,其中進一步 對對象進行核磁共振成像或CT掃描,確定對象是否患有癌症。
- 如申請專利範圍第17項所述的用途,其中進一步 對對象進行核磁共振成像或CT掃描,確定對象是否患有癌症; 向對象施用一有效量的放射劑量,所述有效量的放射劑量足以治療該對象的疾病。
- 一種如申請專利範圍第8項所述的醫藥組合物之用途,其用於製造用於治療癌症的藥劑,其中 向對象施用一治療有效量的醫藥組合物。
- 如申請專利範圍第21項所述的用途,其中進一步 向對象施用一有效量的放射劑量,所述有效量的放射劑量足以治療該對象的疾病。
- 如申請專利範圍第21項所述的用途,其中進一步 對對象進行核磁共振成像或CT掃描,確定對象是否患有癌症。
- 如申請專利範圍第21項所述的用途,其中進一步 對對象進行核磁共振成像或CT掃描,確定對象是否患有癌症; 向對象的癌細胞施用一放射劑量。
- 如申請專利範圍第21項所述的用途,其中進一步 向對象施用一有效量的放射劑量,所述有效量的放射劑量足以讓所述醫藥組合物中的治療劑被釋放。
- 如申請專利範圍第25項所述的用途,其中所述有效量的放射劑量足以治療該對象的疾病。
- 如申請專利範圍第21項所述的用途,其中進一步 對對象進行核磁共振成像或CT掃描,確定對象是否患有癌症; 向對象施用一有效量的放射劑量,所述有效量的放射劑量足以讓所述醫藥組合物中的治療劑被釋放。
- 如申請專利範圍第27項所述的用途,其中所述有效量的放射劑量足以治療該對象的疾病。
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