TW202231299A - 肽連接之藥物遞送系統 - Google Patents
肽連接之藥物遞送系統 Download PDFInfo
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- TW202231299A TW202231299A TW110148008A TW110148008A TW202231299A TW 202231299 A TW202231299 A TW 202231299A TW 110148008 A TW110148008 A TW 110148008A TW 110148008 A TW110148008 A TW 110148008A TW 202231299 A TW202231299 A TW 202231299A
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Abstract
本揭示案係關於一種全身性投與之肽遞送平台,其生物分佈至腎或泌尿道。本揭示案進一步關於治療有需要之個體之腎或泌尿道疾病的方法。
Description
關於聯邦政府贊助研究之聲明本發明係在政府支持下在由美國國家衛生研究院(the National Institutes of Health)授予之授權號CA222802下進行。政府對本發明具有一定權利。
腎臟及泌尿道的疾病引起顯著的發病率及死亡率。舉例而言,尿道上皮癌係最常見的膀胱癌(BC)類型,其為美國主要癌症之一。大部分BC係非肌層侵襲性及淺表性的。標準治療涉及在初始手術切除腫瘤之後,在膀胱中滴注化學治療劑/免疫治療劑。此等藥物通常經由尿道導管插入膀胱中來投與,亦稱為膀胱內療法(ITT)。儘管有證據證明ITT之臨床功效,但疾病復發率仍舊較高,高達50%。此可能由藥物遞送不完全引起,因為所投與之藥物僅能在膀胱中保持有限時間。此外,尿道上皮癌可在整個尿道上皮(腎盂、輸尿管及膀胱)中復發。由於ITT僅將藥物遞送至膀胱,所以無法達至輸尿管或腎盂中之任何腫瘤。ITT亦需要侵襲性導管插入術,此會引起疼痛、感染、泌尿道症狀、不良患者順應性且最終引起治療中斷。仍然需要鑑別會克服當前ITT之藥物遞送障礙之系統,以便無需侵入性程序或手術即可治療腎臟及泌尿道的疾病。此類系統應將全身性投與之療法遞送至泌尿系統,無全身毒性,且延長藥物與泌尿系統之間的接觸時間,從而更有效地治療諸如尿道上皮癌之疾病。
在某些態樣中,本揭示案提供一種治療癌症之方法,其包含向有需要之患者投與本揭示案之化合物或組合物。
已提出不同方法來改良膀胱內化學療法(ITC)治療。為延長治療持續時間,熱敏性水凝膠UGN-102經設計以在膀胱內部轉化為半固體藥物儲槽且緩慢釋放絲裂黴素(MIT)。亦已研發出含有吉西他濱(gemcitabine,GEM)之半滲透矽管GemRis,其充當滲透泵,以控制GEM之釋放。關於對BCG無反應之患者,當前其他治療正處於臨床試驗中。莫托珠單抗(Oportuzumab Monatox)係一種靶向表現EpCAM之腫瘤細胞的抗體-蛋白質結合物。阿德斯拉曲(Adstiladrin)係一種編碼人類IFNα-2b基因之非複製型腺病毒載體。大量合成及表現而得到之IFNα-2b蛋白質經由在人類膀胱癌細胞中抑制血管生成及誘發細胞凋亡而顯示出抗腫瘤活性。然而,所有上述方法均為侵入性的,需要插入導管及/或手術程序。或者,可腎臟清除之奈米粒子可用作藥物載劑。然而,已知網狀內皮系統非特異性地捕捉該等奈米粒子,導致其在肝中大量脫靶累積。
噬菌體呈現之發展已引起許多靶向泌尿系統(URS)之生物活性肽的發現。舉例而言,已使用半乳糖凝集素-3靶向肽G3-C12遞送卡托普利(captopril),卡托普利係一種血管收縮素轉化酶抑制劑。另一種肽(KKEEE)
3K用於運載環丙沙星(ciprofloxacin)。此等肽具有藥理學活性。其主要經由結合於細胞表面受體靶向腎,且已延長遞送後局部滯留。其尚未應用於BC治療。實際上,在無化學修飾之情況下,肽並非良好的候選藥物或載劑。其顯示不利之藥物動力學(PK),由蛋白酶快速降解,且可藉由腎過濾消除。
本發明利用肽之快速腎臟清除將治療劑排入URS。在某些實施例中,本揭示案提供一種小型(例如12個胺基酸)帶負電肽(例如Bdd),其可繞過網狀內皮系統及其他器官且優先(例如完全)排泄至尿液中,使得再吸收程度極低。在某些實施例中,本揭示案提供ITC之替代方案,其使其他器官中之脫靶累積減至最少,促進藥物遞送至URS且延長膀胱滯留時間,從而提供對BC之全面且更有效之治療(圖1a)。
本揭示案係關於一種全身性投與之肽遞送平台,其生物分佈至腎或泌尿道。在某些實施例中,活性部分連接至肽遞送平台。本揭示案進一步關於治療有需要之個體之腎或泌尿道疾病的方法。在一些實施例中,疾病為急性腎病。在一些實施例中,疾病為慢性腎病。
在某些實施例中,肽遞送平台包含一種帶負電肽,其可暫時累積於腎中,不會脫靶遞送至其他器官。因為肽在尿液中逐漸消除,所以其適用作一種藥物遞送平台,以提供用於治療腎或泌尿道疾病(諸如BC)之連續藥物流。該肽將全身性投與之藥物遞送至泌尿系統,同時延長膀胱滯留時間,從而提供更有效之治療。
在某些態樣中,肽具有多個負電荷,此可促進快速腎臟清除。因此,經由腎臟清除向膀胱遞送藥物為連續事件。與經由導管插入來投與藥物相比,肽可增強療法對整個泌尿系統之浸潤,且在膀胱中之停留時間更長,從而引起更有效之無創治療。在某些態樣中,肽用作使用美登素(mertansine,DM1)(一種高度細胞毒性微管抑制劑)之BC治療的藥物遞送系統。DM1毒性太強而不能單獨使用,但經批准作為抗體-藥物結合物(諸如T-DM1)中之藥效基團。在某些態樣中,肽用於遞送DM1以治療BC以及其他泌尿道癌症。
在某些態樣中,肽用作例如用抗生素治療泌尿道感染之藥物遞送系統。在某些態樣中,肽用作治療腎結石之藥物遞送系統。在某些態樣中,肽用作治療膀胱過動症之藥物遞送系統。在某些態樣中,肽用作治療尿失禁之藥物遞送系統。在某些態樣中,肽用作治療間質性膀胱炎之藥物遞送系統。在某些態樣中,肽用於將顯影劑遞送至膀胱。
在某些態樣中,肽為水溶性、生物惰性及非免疫原性的。在IV注射之後,肽可完全經由腎臟清除來消除,最低程度地累積在包括心、肝及脾在內的其他器官中。
在某些實施例中,旨在腎臟清除之肽包含如下序列:
,
其中X、Y及Z中之一者為β-胺基酸殘基,X、Y及Z中之兩者獨立地為各具有至少一個包含羧酸基之側鏈的α-胺基酸殘基,各α-胺基酸殘基可獨立地為D或L立體化學且m為2至10。
在某些實施例中,肽在生理pH值下具有約-30 mV至+20 mV之ζ電位。在某些實施例中,肽在生理pH值下具有約-20 mV至0 mV之ζ電位。在某些實施例中,肽在生理pH值下具有約-5 mV至0 mV之ζ電位。
在某些實施例中,連接子包含選自以下之一個或多個基團:醯胺、醯亞胺、硫脲、硫醚、二硫基、烷基、芳基、聚醚、腙、酯、碳酸酯、縮酮及矽烷基醚。在某些實施例中,活性部分為治療劑或顯影劑。
在某些實施例中,旨在腎臟清除之肽包含如下序列:
,
其中X、Y及Z中之一者為β-胺基酸殘基,X、Y及Z中之兩者獨立地為各具有至少一個包含羧酸基之側鏈的α-胺基酸殘基,各α-胺基酸殘基可獨立地為D或L立體化學,m為2至10,連接子包含選自以下之一個或多個基團:醯胺、醯亞胺、硫脲、硫醚、二硫基、烷基、芳基、聚醚、腙、酯、碳酸酯、縮酮及矽烷基醚;且
活性部分為治療劑或顯影劑。
在某些實施例中,β-胺基酸殘基不包含可電離側鏈。在某些實施例中,β-胺基酸殘基為β-丙胺酸殘基。在某些實施例中,X為β-丙胺酸殘基。在某些實施例中,各α-胺基酸殘基獨立地選自天冬胺酸殘基及麩胺酸殘基。在某些實施例中,至少一個α-胺基酸殘基為非天然胺基酸殘基。在某些實施例中,非天然α-胺基酸殘基具有至少兩個側鏈羧酸基。在某些實施例中,非天然α-胺基酸殘基係選自2-胺基乙烷-1,1,2-三甲酸殘基及2-胺基丙烷-1,2,3-三甲酸殘基。在某些實施例中,各Y及Z為天冬胺酸殘基。在某些實施例中,各Y及Z為D-天冬胺酸殘基。在某些實施例中,X、Y及Z各自獨立地選自β-丙胺酸殘基、天冬胺酸殘基及麩胺酸殘基。在某些實施例中,m為4。
在某些實施例中,連接子包含衍生自N-丁二醯亞胺基3-(2-吡啶基二硫基)丙酸酯或丁二醯亞胺基4-(N-順丁烯二醯亞胺基甲基)環己烷-1-甲酸酯之基團。
在某些實施例中,活性部分為治療劑。在某些實施例中,治療劑係選自抗癌劑、抗生素、治療膀胱過動症之藥劑、治療尿失禁之藥劑、治療間質性膀胱炎之藥劑及治療腎結石之藥劑。在某些實施例中,治療劑係選自13-順維他命A酸(13-cis-Retinoic Acid)、2-氯去氧腺苷(2-Chlorodeoxyadenosine)、5-阿紮胞苷(5-Azacitidine)、5-氟尿嘧啶(5-Fluorouracil)、6-巰嘌呤(6-Mercaptopurine)、6-硫鳥嘌呤(6-Thioguanine)、放射菌素-D(actinomycin-D)、阿德力黴素(adriamycin)、阿地介白素(aldesleukin)、阿侖妥珠單抗(alemtuzumab)、阿利維甲酸(alitretinoin)、全反維他命A酸(all-transretinoic acid)、α干擾素(alpha interferon)、六甲蜜胺(altretamine)、胺甲喋呤(amethopterin)、阿米福汀(amifostine)、阿那格雷(anagrelide)、阿那曲唑(anastrozole)、阿拉伯糖基胞嘧啶(arabinosylcytosine)、三氧化二砷(arsenic trioxide)、安吖啶(amsacrine)、胺基喜樹鹼(aminocamptothecin)、胺麩精(aminoglutethimide)、天冬醯胺酸酶(asparaginase)、阿紮胞苷(azacytidine)、卡介苗(bacillus calmette-guerin,BCG)、苯達莫司汀(bendamustine)、貝伐單抗(bevacizumab)、貝沙羅汀(bexarotene)、比卡魯胺(bicalutamide)、硼替佐米(bortezomib)、博萊黴素(bleomycin)、硫酸布他卡因(busulfan)、甲醯四氫葉酸鈣(calcium leucovorin)、嗜橙菌因子(citrovorum factor)、卡培他濱(capecitabine)、卡奈替尼(canertinib)、卡鉑(carboplatin)、雙氯乙基亞硝脲(carmustine)、西妥昔單抗(cetuximab)、氯芥苯丁酸(chlorambucil)、順鉑(cisplatin)、克拉屈濱(cladribine)、可體松(cortisone)、環磷醯胺(cyclophosphamide)、阿糖胞苷(cytarabine)、阿法達貝泊汀(darbepoetin alfa)、達沙替尼(dasatinib)、柔紅黴素(daunomycin)、地西他濱(decitabine)、地尼介白素(denileukin diftitox)、地塞米松(dexamethasone)、地沙松(dexasone)、右雷佐生(dexrazoxane)、放線菌素D(dactinomycin)、道諾黴素(daunorubicin)、達卡巴嗪(decarbazine)、多西他賽(docetaxel)、多柔比星(doxorubicin)、多希(doxil)、阿多比欣(aldoxorubicin)、去氧氟尿苷(doxifluridine)、依決洛單抗(edrecolomab)、恩尿嘧啶(eniluracil)、表柔比星(epirubicin)、阿法依泊汀(epoetin alfa)、埃羅替尼(erlotinib)、依維莫司(everolimus)、伊析美斯坦(exemestane)、雌莫司汀(estramustine)、依託泊苷(etoposide)、非格司亭(filgrastim)、氟羥甲基睪酮(fluoxymesterone)、氟維司群(fulvestrant)、夫拉平度(flavopiridol)、氟尿苷(floxuridine)、氟達拉濱(fludarabine)、氟尿嘧啶(fluorouracil)、氟他胺(flutamide)、吉非替尼(gefitinib)、吉西他濱(gemcitabine)、吉妥珠單抗奧唑米星(gemtuzumab ozogamicin)、戈舍瑞林(goserelin)、顆粒球群落刺激因子、顆粒球巨噬細胞群落刺激因子、六甲三聚氰胺(hexamethylmelamine)、氫化可體松(hydrocortisone)羥基脲(hydroxyurea)、布突默單抗(ibritumomab)、替伊莫單抗(ibritumomab tiuxetan)、干擾素α(interferon alpha)、介白素-2(interleukin-2)、介白素-11(interleukin-11)、異維甲酸(isotretinoin)、伊沙匹隆(ixabepilone)、艾達黴素(idarubicin)、甲磺酸伊馬替尼(imatinib mesylate)、依弗醯胺(ifosfamide)、伊立替康(irinotecan)、拉帕替尼(lapatinib)、來那度胺(lenalidomide)、利妥唑(letrozole)、甲醯四氫葉酸(leucovorin)、亮丙立德(leuprolide)、脂質體Ara-C(liposomal Ara-C)、洛莫司汀(lomustine)、甲基二(氯乙基)胺(mechlorethamine)、甲地孕酮(megestrol)、黴法蘭(melphalan)、巰嘌呤(mercaptopurine)、美登素、美司鈉(mesna)、胺甲喋呤(methotrexate)、甲基普賴蘇穠(methylprednisolone)、絲裂黴素C(mitomycin C)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、奈拉濱(nelarabine)、尼魯米特(nilutamide)、奧曲肽(octreotide)、奧普瑞介白素(oprelvekin)、奧沙利鉑(oxaliplatin)、紫杉醇(paclitaxel)、帕米膦酸鹽(pamidronate)、培美曲塞(pemetrexed)、帕尼單抗(panitumumab)、PEG干擾素、培門冬酶(pegaspargase)、派非格司亭(pegfilgrastim)、PEG-L-天冬醯胺酸酶、噴司他丁(pentostatin)、普卡黴素(plicamycin)、普賴蘇穠(prednisolone)、普賴松(prednisone)、丙卡巴肼(procarbazine)、雷洛昔芬(raloxifene)、利妥昔單抗(rituximab)、羅米司亭(romiplostim)、雷替曲塞(ralitrexed)、沙帕他濱(sapacitabine)、沙格司亭(sargramostim)、賽特鉑(satraplatin)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、司莫司汀(semustine)、鏈脲菌素(streptozocin)、他莫昔芬(tamoxifen)、喃氟啶(tegafur)、喃氟啶-尿嘧啶(tegafur-uracil)、坦羅莫司(temsirolimus)、替莫唑胺(temozolamide)、替尼泊苷(teniposide)、沙利多邁(thalidomide)、硫鳥嘌呤(thioguanine)、噻替哌(thiotepa)、拓樸替康(topotecan)、托瑞米芬(toremifene)、托西莫單抗(tositumomab)、曲妥珠單抗(trastuzumab)、曲妥珠單抗恩他新(trastuzumab emtansine)、視網酸(tretinoin)、三甲曲沙(trimitrexate)、阿魯比辛(alrubicin)、長春新鹼(vincristine)、長春花鹼(vinblastine)、長春地辛(vindestine)、長春瑞賓(vinorelbine)、伏立諾他(vorinostat)及唑來膦酸(zoledronic acid)。
在某些實施例中,治療劑為抗癌劑。在某些實施例中,抗癌劑係選自美登素、多柔比星、達沙替尼、順鉑、絲裂黴素、吉西他濱及紫杉醇。
在某些實施例中,X為β-丙胺酸殘基,且Y及Z為D-天冬胺酸殘基。在某些實施例中,X為β-丙胺酸殘基,Y及Z為D-天冬胺酸殘基且m為4。在某些實施例中,X為β-丙胺酸殘基,Y及Z為D-天冬胺酸殘基,m為4,連接子包含二硫基;且活性部分為美登素。
在某些實施例中,本揭示案提供一種醫藥組合物,其包含本發明之化合物。在某些實施例中,組合物經調配用於靜脈內投與。
在某些實施例中,本揭示案提供一種治療癌症、泌尿道感染、膀胱過動症、尿失禁、間質性膀胱炎或腎結石之方法,其包含向有需要之患者投與本發明之化合物或組合物。在某些實施例中,本揭示案提供一種治療癌症之方法,其包含向有需要之患者投與本發明之化合物或組合物。在某些實施例中,癌症係腎癌或泌尿道癌。在某些實施例中,癌症係膀胱癌。在某些實施例中,膀胱癌係非肌層侵襲性膀胱癌。在某些實施例中,膀胱癌係尿道上皮癌。在某些實施例中,組合物經靜脈內投與。
醫藥組合物 本揭示案之組合物及方法可用於治療有需要之個體。在某些實施例中,個體為哺乳動物,諸如人類,或非人類哺乳動物。當向諸如人類之動物投與時,較佳投與呈醫藥組合物形式之組合物或化合物,該醫藥組合物包含例如本揭示案之化合物及醫藥學上可接受之載劑。醫藥學上可接受之載劑為此項技術中所熟知,且包括例如水溶液,諸如水或生理緩衝食鹽水,或其他溶劑或媒劑,諸如二醇、丙三醇、油(諸如橄欖油)或可注射有機酯。在較佳實施例中,當此類醫藥組合物用於投與人類、尤其用於侵入性投藥途徑(亦即,避開經由上皮障壁傳輸或擴散之途徑,諸如注射或植入)時,水溶液無熱原,或實質上無熱原。可選擇例如實現藥劑之延遲釋放或選擇性靶向一種或多種細胞、組織或器官的賦形劑。醫藥組合物可呈單位劑型,諸如錠劑、膠囊(包括分散型膠囊及明膠膠囊)、顆粒、復原用凍乾物、散劑、溶液、糖漿、栓劑、注射劑或其類似物。組合物亦可存在於經皮遞送系統(例如皮膚貼片)中。組合物亦可存在於諸如洗劑、乳膏或軟膏之適用於局部投與之溶液中。
醫藥學上可接受之載劑可含有生理學上可接受之試劑,其例如用以穩定諸如本揭示案化合物之化合物、增加其溶解度或增加其吸收。此類生理學上可接受之試劑包括例如碳水化合物,諸如葡萄糖、蔗糖或聚葡萄糖;抗氧化劑,諸如抗壞血酸或麩胱甘肽;螯合劑,低分子量蛋白質或其他穩定劑或賦形劑。醫藥學上可接受之載劑(包括生理學上可接受之試劑)的選擇例如視組合物之投與途徑而定。製劑或醫藥組合物可為自乳化藥物遞送系統或自2微乳化藥物遞送系統。醫藥組合物(製劑)亦可為脂質體或其他聚合物基質,其中可併入例如本揭示案之化合物。脂質體(例如其包含磷脂或其他脂質)係生理學上可接受且可代謝之無毒載劑,其可相對簡單地製備及投與。
片語「醫藥學上可接受」在本文中用於指在合理醫學判斷範圍內,適合與人類及動物之組織接觸使用而無過度毒性、刺激、過敏反應或其他問題或併發症,與合理益處/風險比相匹配之彼等化合物、物質、組合物及/或劑型。
如本文所用,片語「醫藥學上可接受之載劑」意謂醫藥學上可接受之物質、組合物或媒劑,諸如液體或固體填充劑、稀釋劑、賦形劑、溶劑或囊封材料。在與調配物之其他成分相容且對患者無害的意義上,各載劑必須為「可接受的」。可用作醫藥學上可接受之載劑之物質的一些實例包括:(1)糖,諸如乳糖、葡萄糖及蔗糖;(2)澱粉,諸如玉米澱粉及馬鈴薯澱粉;(3)纖維素及其衍生物,諸如羧甲基纖維素鈉、乙基纖維素及乙酸纖維素;(4)粉末狀黃蓍膠;(5)麥芽;(6)明膠;(7)滑石;(8)賦形劑,諸如可可脂及栓劑蠟;(9)油,諸如花生油、棉籽油、紅花油、芝麻油、橄欖油、玉米油及大豆油;(10)二醇,諸如丙二醇;(11)多元醇,諸如甘油、山梨糖醇、甘露糖醇及聚乙二醇;(12)酯,諸如油酸乙酯及月桂酸乙酯;(13)瓊脂;(14)緩衝劑,諸如氫氧化鎂及氫氧化鋁;(15)海藻酸;(16)無熱原水;(17)等張生理食鹽水;(18)林格氏溶液(Ringer's solution);(19)乙醇;(20)磷酸鹽緩衝溶液;以及(21)醫藥調配物中所採用之其他無毒相容物質。
可藉由包括例如以下之多種投藥途徑中之任一者向個體投與醫藥組合物(製劑):經口(例如,如呈水溶液或非水溶液或水性或非水性懸浮液形式之大劑量藥液、錠劑、膠囊(包括分散型膠囊及明膠膠囊)、食團(bolus)、散劑、顆粒、施加至舌部之糊劑);經由口腔黏膜(例如,舌下)吸收;皮下;經皮(例如,呈施加至皮膚之貼片形式);及局部(例如,呈施加至皮膚之乳膏、軟膏或噴霧形式)。化合物亦可經調配用於吸入。在某些實施例中,化合物可簡單地溶解或懸浮於無菌水中。適當投與途徑及適合該投與途徑之組合物的細節可見於例如美國專利第6,110,973號、第5,763,493號、第5,731,000號、第5,541,231號、第5,427,798號、第5,358,970號及第4,172,896號中,以及其中所引用之專利中。
調配物宜以單位劑型呈遞且可藉由藥劑學技術中熟知之任何方法來製備。可與載劑物質組合以產生單一劑型之活性成分之量將視所治療之宿主、特定投藥模式而定。可與載劑物質組合以產生單一劑型之活性成分之量一般將為化合物產生治療作用之量。以100%計,此量通常在約1%至約99%活性成分,較佳約5%至約70%,最佳約10%至約30%之範圍內。
製備此等調配物或組合物之方法包括使活性化合物(諸如本揭示案之化合物)與載劑及視情況一種或多種輔助成分締合在一起之步驟。一般而言,藉由將本揭示案之化合物與液體載劑或細粉狀固體載劑或二者均一且緊密地締合且必要時接著使產物成形來製備調配物。
本揭示案之適於口服之調配物可呈膠囊(包括分散型膠囊及明膠膠囊)、扁囊劑、丸劑、錠劑、口含錠(使用調味基質,通常為蔗糖及阿拉伯膠或黃蓍膠)、凍乾物、散劑、顆粒形式,或呈水性或非水性液體中之溶液或懸浮液形式,或呈水包油或油包水之液體乳液形式,或呈酏劑或糖漿形式,或呈丸粒(使用惰性基質,諸如明膠及甘油,或蔗糖及阿拉伯膠)形式及/或呈漱口水形式及其類似形式,其各含有預定量的本揭示案之化合物作為活性成分。組合物或化合物亦可呈食團、舐劑或糊劑之形式投與。
為製備供經口投與之固體劑型(膠囊(包括分散型膠囊及明膠膠囊)、錠劑、丸劑、糖衣錠、散劑、顆粒及其類似物),將活性成分與一種或多種醫藥學上可接受之載劑(諸如檸檬酸鈉或磷酸二鈣)及/或以下中之任一者混合:(1)填充劑或增量劑,諸如澱粉、乳糖、蔗糖、葡萄糖、甘露糖醇及/或矽酸;(2)黏合劑,諸如羧甲基纖維素、海藻酸鹽、明膠、聚乙烯吡咯啶酮、蔗糖及/或阿拉伯膠;(3)保濕劑,諸如丙三醇;(4)崩解劑,諸如瓊脂-瓊脂、碳酸鈣、馬鈴薯或木薯澱粉、海藻酸、某些矽酸鹽及碳酸鈉;(5)溶解阻滯劑,諸如石蠟;(6)吸收促進劑,諸如四級銨化合物;(7)潤濕劑,諸如鯨蠟醇及單硬脂酸甘油酯;(8)吸收劑,諸如高嶺土及膨潤土;(9)潤滑劑,諸如滑石、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、月桂基硫酸鈉以及其混合物;及(10)錯合劑,諸如經改質及未經改質之環糊精;及(11)著色劑。在膠囊(包括分散型膠囊及明膠膠囊)、錠劑及丸劑之情況下,醫藥組合物亦可包含緩衝劑。亦可使用諸如乳糖(lactose/milk sugar)以及高分子量聚乙二醇及其類似物之賦形劑將相似類型之固體組合物用作軟填充及硬填充明膠膠囊中之填充劑。
錠劑可藉由視情況與一種或多種輔助成分一起壓縮或模製來製造。可使用黏合劑(例如明膠或羥丙基甲基纖維素)、潤滑劑、惰性稀釋劑、防腐劑、崩解劑(例如羥基乙酸澱粉鈉或交聯羧甲基纖維素鈉)、表面活性劑或分散劑來製備壓縮錠劑。可藉由在適合機器中模製用惰性液體稀釋劑濕潤之粉末狀化合物之混合物來製造模製錠劑。
醫藥組合物之錠劑及其他固體劑型(諸如糖衣錠、膠囊(包括分散型膠囊及明膠膠囊)、丸劑及顆粒)可視情況刻痕或製備成具有包衣及殼層(諸如腸溶衣及醫藥調配技術中熟知之其他包衣)。其亦可使用例如不同比例以提供所要釋放特徵之羥丙基甲基纖維素、其他聚合物基質、脂質體及/或微球體來調配,以便提供其中活性成分之緩慢或控制釋放。其可藉由例如經由細菌截留過濾器過濾來滅菌,或在呈臨用前可溶解於無菌水或一些其他無菌可注射介質中之無菌固體組合物形式時藉由併入滅菌劑來滅菌。此等組合物亦可視情況含有失透劑且可為視情況以延遲方式,僅或優先在胃腸道某一部分中釋放活性成分之組合物。可使用之包埋組合物之實例包括聚合物質及蠟。活性成分亦可在適當時與一種或多種上述賦形劑一起呈微囊封形式。
適用於經口投與之液體劑型包括醫藥學上可接受之乳液、用於復原之凍乾物、微乳液、溶液、懸浮液、糖漿及酏劑。除了活性成分之外,液體劑型可含有此項技術中常用之惰性稀釋劑,諸如水或其他溶劑、環糊精及其衍生物、增溶劑及乳化劑,諸如乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、油(特定言之,棉籽油、花生油、玉米油、胚芽油、橄欖油、蓖麻油及芝麻油)、丙三醇、四氫呋喃醇、聚乙二醇以及脫水山梨糖醇之脂肪酸酯,以及其混合物。
除惰性稀釋劑之外,口服組合物亦可包括佐劑,諸如潤濕劑、乳化劑及懸浮劑、甜味劑、調味劑、著色劑、芳香劑及防腐劑。
除了活性化合物之外,懸浮液可含有懸浮劑,例如乙氧基化異硬脂醇、聚氧化乙烯山梨糖醇及脫水山梨糖醇酯、微晶纖維素、偏氫氧化鋁、膨潤土、瓊脂-瓊脂及黃蓍膠以及其混合物。
用於局部或經皮投與之劑型包括散劑、噴霧劑、軟膏、糊劑、乳膏、洗劑、凝膠、溶液、貼片及吸入劑。活性化合物可在無菌條件下與醫藥學上可接受之載劑且與可能需要之任何防腐劑、緩衝劑或推進劑混合。
除活性化合物之外,軟膏、糊劑、乳膏及凝膠亦可含有賦形劑,諸如動物及植物脂肪、油、蠟、石蠟、澱粉、黃蓍膠、纖維素衍生物、聚乙二醇、矽酮、膨潤土、矽酸、滑石及氧化鋅或其混合物。
除活性化合物之外,散劑及噴霧劑可含有賦形劑,諸如乳糖、滑石、矽酸、氫氧化鋁、矽酸鈣及聚醯胺粉末或此等物質之混合物。噴霧劑可另外含有習用推進劑,諸如氯氟烴及揮發性未經取代之烴,諸如丁烷及丙烷。
經皮貼片具有控制本揭示案之化合物向身體之遞送的額外優勢。此類劑型可藉由將活性化合物溶解或分散於適當介質中來製備。亦可使用吸收強化劑來增加化合物之透皮量。此流動之速率可藉由提供速率控制膜或使化合物分散於聚合物基質或凝膠中來控制。
如本文所用,片語「非經腸投藥(parenteral administration)」及「非經腸投與(administered parenterally」意謂除經腸及表面投與以外通常藉由注射進行之投與模式,且包括(不限於)靜脈內、肌肉內、動脈內、鞘內、囊內、眶內、心內、皮內、腹膜內、經氣管、皮下、表皮下、關節內、囊下、蛛膜下、脊柱內及胸骨內注射及輸注。適合於非經腸投與之醫藥組合物包含一種或多種活性化合物以及一種或多種醫藥學上可接受之無菌等張水性或非水性溶液、分散液、懸浮液或乳液,或可在即將使用時復原成無菌可注射溶液或分散液之無菌粉末,其可含有抗氧化劑、緩衝劑、抑菌劑、使調配物與預期接受者之血液等張之溶質或者懸浮劑或增稠劑。
可用於本揭示案之醫藥組合物中之適合水性及非水性載劑的實例包括水、乙醇、多元醇(諸如丙三醇、丙二醇、聚乙二醇及其類似物)及其適合混合物、植物油(諸如橄欖油)及可注射有機酯(諸如油酸乙酯)。可例如藉由使用包衣材料(諸如卵磷脂),在分散液之情況下維持所需粒度及藉由使用界面活性劑來維持適當流動性。
此等組合物亦可含有佐劑,諸如防腐劑、潤濕劑、乳化劑及分散劑。可藉由包括各種抗細菌及抗真菌劑,例如對羥基苯甲酸酯、氯丁醇、苯酚山梨酸及其類似物來預防微生物作用。組合物中亦可能需要包括等張劑,諸如糖、氯化鈉及其類似物。另外,可注射醫藥形式之延長吸收可藉由包括吸收延遲劑(諸如單硬脂酸鋁及明膠)來達成。
在一些情況下,為延長藥物作用,需要減緩皮下或肌肉內注射之藥物吸收。此可藉由使用具有水溶性差之結晶或非晶形物質之液體懸浮液來實現。藥物之吸收速率則視其溶解速率而定,而溶解速率又可視晶體大小及結晶形式而定。或者,非經腸投與之藥物形式藉由將藥物溶解或懸浮於油性媒劑中來實現延遲吸收。
可注射儲槽形式係藉由在諸如聚丙交酯-聚乙交酯之可生物降解聚合物中形成目標化合物之微囊封基質而製造。視藥物與聚合物之比率及所用的特定聚合物之性質而定,可控制藥物釋放速率。其他可生物降解聚合物之實例包括聚(原酸酯)及聚(酸酐)。可注射儲槽調配物亦藉由將藥物截留於與身體組織相容之脂質體或微乳液中來製備。
為在本揭示案之方法中使用,活性化合物可單獨或以含有例如0.1至99.5%(更佳0.5至90%)活性成分以及醫藥學上可接受之載劑的醫藥組合物之形式給予。
亦可藉由可再裝填或生物可降解裝置提供引入方法。近年來已研發及活體內測試用於控制藥物(包括蛋白質生物藥物)遞送之多種緩慢釋放聚合物裝置。包括可生物降解及不可降解聚合物之多種生物相容性聚合物(包括水凝膠)可用於形成在特定目標位點持續釋放化合物之植入物。
醫藥組合物中活性成分之實際劑量濃度可變化,以獲得有效達成特定患者、組合物及投與模式之所要治療反應而對患者無毒性的活性成分之量。
所選劑量濃度將視多種因素而定,該等因素包括所採用之特定化合物或化合物之組合、或其酯、鹽或醯胺之活性;投藥途徑;投藥時間;待採用之特定化合物之排泄速率;治療持續時間;與所採用特定化合物組合使用之其他藥物、化合物及/或材料;接受治療患者之年齡、性別、體重、病狀、一般健康狀況及先前病史;及醫學技術中熟知之類似因素。
一般技術之醫師或獸醫可容易確定及規定所需醫藥組合物之治療有效量。舉例而言,醫師或獸醫可以低於實現所要治療作用所需之水準開始醫藥組合物或化合物給藥,且逐漸增加劑量直至實現所要作用。「治療有效量」意謂足以引起所要治療效果之化合物濃度。一般理解化合物之有效量將根據個體之體重、性別、年齡及病史而變化。影響有效量之其他因素可包括(但不限於)患者病狀之嚴重程度、所治療之病症、化合物之穩定性及必要時與本揭示案之化合物一起投與的另一類型治療劑。可藉由多次投與藥劑來遞送較大總劑量。確定功效及劑量之方法為熟習此項技術者已知(Isselbacher等人.(1996)Harrison's Principles of Internal Medicine 第13版, 1814-1882,以引用的方式併入本文中)。
一般而言,用於本揭示案之組合物及方法中之活性化合物的適合日劑量將為有效產生治療效果之最低劑量的化合物之量。此類有效劑量將一般視上述因素而定。
需要時,活性化合物之有效日劑量可視情況呈單位劑型,一天內呈以適當時間間隔分開投與之一個、兩個、三個、四個、五個、六個或更多個子劑量投與。在本揭示案之某些實施例中,活性化合物可每日投與二次或三次。在較佳實施例中,活性化合物將每日投與一次。
接受此治療之患者為任何有需要之動物,包括靈長類動物,尤其是人類;及其他哺乳動物,諸如馬、牛、豬、綿羊、貓及狗;家禽;且一般為寵物。
在某些實施例中,本揭示案之化合物可單獨投與或與另一類型之治療劑結合投與。
本揭示案包括在本揭示案之組合物及方法中使用本揭示案化合物之醫藥學上可接受之鹽。在某些實施例中,本揭示案考慮之鹽包括但不限於烷基、二烷基、三烷基或四烷基銨鹽。在某些實施例中,本揭示案考慮之鹽包括(但不限於)L-精胺酸、苯乙苄胺(benethamine)、苯乍生(benzathine)、甜菜鹼、氫氧化鈣、膽鹼、丹醇、二乙醇胺、二乙胺、2-(二乙胺基)乙醇、乙醇胺、乙二胺、N-甲基葡糖胺、海卓胺(hydrabamine)、1H-咪唑、鋰、L-離胺酸、鎂、4-(2-羥基乙基)
啉、哌
、鉀、1-(2-羥基乙基)吡咯啶、鈉、三乙醇胺、緩血酸胺及鋅鹽。在某些實施例中,本揭示案考慮之鹽包括(但不限於)Na、Ca、K、Mg、Zn或其他金屬鹽。在某些實施例中,本揭示案考慮之鹽包括但不限於1-羥基-2-萘甲酸、2,2-二氯乙酸、2-羥基乙磺酸、2-側氧基戊二酸、4-乙醯胺基苯甲酸、4-胺基柳酸、乙酸、己二酸、l-抗壞血酸、l-天冬胺酸、苯磺酸、苯甲酸、(+)-樟腦酸、(+)-樟腦-10-磺酸、羊脂酸(癸酸)、羊油酸(己酸)、羊羶酸(辛酸)、碳酸、肉桂酸、檸檬酸、環己胺磺酸、十二烷基硫酸、乙-1,2-二磺酸、乙磺酸、甲酸、反丁烯二酸、半乳糖二酸、龍膽酸、d-葡糖庚酸、d-葡糖酸、d-葡糖醛酸、麩胺酸、戊二酸、甘油磷酸、乙醇酸、馬尿酸、氫溴酸、鹽酸、異丁酸、乳酸、乳糖酸、十二酸、順丁烯二酸、l-蘋果酸、丙二酸、杏仁酸、甲磺酸、萘-1,5-二磺酸、萘-2-磺酸、菸鹼酸、硝酸、油酸、乙二酸、棕櫚酸、雙羥萘酸、磷酸、丙酸、l-焦麩胺酸、水楊酸、癸二酸、硬脂酸、丁二酸、硫酸、l-酒石酸、硫氰酸、對甲苯磺酸、三氟乙酸及十一碳烯酸之酸鹽。
醫藥學上可接受之酸加成鹽亦可呈諸如與水、甲醇、乙醇、二甲基甲醯胺及其類似物的各種溶劑合物之形式存在。亦可製備此類溶劑合物之混合物。此類溶劑合物之來源可來自結晶之溶劑,係製備或結晶之溶劑中所固有的或外加於此類溶劑中的。
潤濕劑、乳化劑及潤滑劑(諸如月桂基硫酸鈉及硬脂酸鎂)以及著色劑、脫模劑、包衣劑、甜味劑、調味劑及芳香劑、防腐劑及抗氧化劑亦可存在於組合物中。
醫藥學上可接受之抗氧化劑之實例包括:(1)水溶性抗氧化劑,諸如抗壞血酸、半胱胺酸鹽酸鹽、硫酸氫鈉、偏亞硫酸氫鈉、亞硫酸鈉及其類似物;(2)油溶性抗氧化劑,諸如抗壞血酸棕櫚酸酯、丁基化羥基甲氧苯(BHA)、丁基化羥基甲苯(BHT)、卵磷脂、沒食子酸丙酯、α-生育酚及其類似物;以及(3)金屬螯合劑,諸如檸檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸及其類似物。
定義
除非本文中另外定義,否則本申請案中所用之科學及技術術語應具有一般熟習此項技術者通常所理解之含義。一般而言,與本文所述之化學、細胞及組織培養、分子生物學、細胞及癌症生物學、神經生物學、神經化學、病毒學、免疫學、微生物學、藥理學、遺傳學及蛋白及核酸化學結合使用之命名法及其技術為此項技術中熟知且一般使用的命名法及技術。
除非另外指示,否則本揭示案之方法及技術通常根據此項技術中熟知之習知方法且如本說明書通篇所引用及論述之各種一般及更特定參考文獻中所描述來進行。參見例如「Principles of Neural Science」, McGraw-Hill Medical, New York, N.Y.(2000);Motulsky, 「Intuitive Biostatistics」, Oxford University Press, Inc.(1995);Lodish等人, 「Molecular Cell Biology, 第4版」, W. H. Freeman & Co., New York(2000);Griffiths等人, 「Introduction to Genetic Analysis, 第7版」, W. H. Freeman & Co., N.Y.(1999);及Gilbert等人, 「Developmental Biology, 第6版」 Sinauer Associates, Inc., Sunderland, MA(2000)。
除非本文中另外定義,否則本文中所用之化學術語係根據此項技術中之習知用法使用,如「The McGraw-Hill Dictionary of Chemical Terms」, Parker, S.編, McGraw-Hill, San Francisco(1985)所例示。
本申請案中所提及之所有上述及任何其他公開案、專利及公開專利申請案特定以引用之方式併入本文中。在有衝突之情況下,將以本說明書(包括其特定定義)為凖。
術語「藥劑」在本文中用以表示化合物(諸如有機或無機化合物、化合物之混合物)、生物大分子(諸如核酸、抗體(包括其部分)以及人類化抗體、嵌合抗體及人類抗體以及單株抗體、蛋白質或其部分,例如肽、脂質、碳水化合物)或由生物材料(諸如細菌、植物、真菌或動物(尤其哺乳動物)細胞或組織)製成之提取物。藥劑包括例如結構已知之藥劑及結構未知之藥劑。此類藥劑抑制AR或促進AR降解之能力可使得其適用作本揭示案之方法及組合物中之「治療劑」。
「患者」、「個體(subject)」或「個體(individual)」可互換使用且係指人類或非人類動物。此等術語包括哺乳動物,諸如人類、靈長類動物、家畜動物(包括牛科動物、豬科動物等)、伴侶動物(例如犬科動物、貓科動物等)及嚙齒動物(例如小鼠及大鼠)。
「治療」病狀或患者係指採取措施獲得有益或期望結果,包括臨床結果。如本文所用及此項技術中充分瞭解,「治療」係用於獲得有益或期望結果(包括臨床結果)之方法。有益或期望臨床結果可包括但不限於一種或多種症狀或病狀緩解或改善、疾病程度減弱、疾病狀態穩定(亦即不惡化)、疾病擴散預防、疾病發展延遲或減緩、疾病狀態改善或緩和以及緩解(無論部分還是完全),無論可偵測還是不可偵測。「治療」亦可意謂相比於未接受治療時之預期存活期會延長存活期。
術語「預防」係此項技術中公認的,且在關於諸如局部復發(例如疼痛)之病狀、諸如癌症之疾病、諸如心臟衰竭之複雜症候群或任何其他醫學病狀使用時,為此項技術中充分瞭解,且包括投與相對於未接受組合物之個體,降低個體之醫學病狀之症狀的頻率或延遲其發作的組合物。因此,預防癌症包括例如相對於未經治療之對照群體,減少接受防治性治療之患者群體中可偵測癌性生長之數目;及/或相對於未經治療之對照群體,延緩經治療之群體中可偵測癌性生長之出現,例如達統計學上及/或臨床上顯著量。
可使用熟習此項技術者已知之多種方法中之一種向個體「投與(Administering/administration of)」物質、化合物或藥劑。舉例而言,可靜脈內、動脈、皮內、肌內、腹膜內、皮下、經眼、舌下、經口(藉由攝食)、鼻內(藉由吸入)、脊椎內、顱內及經皮(藉由吸收,例如經由皮膚管道)投與化合物或藥劑。亦可藉由可再裝填或可生物降解之聚合物裝置或其他裝置(例如貼片及泵或調配物,其提供化合物或藥劑之經延長、緩慢或控制釋放)適當地引入化合物或藥劑。投與亦可例如執行一次、複數次及/或經一個或多個延長之週期。
向個體投與物質、化合物或藥劑之適當方法亦將視例如個體之年齡及/或身體狀況及化合物或藥劑之化學及生物特性(例如,溶解性、可消化性、生物可用性、穩定性及毒性)而定。在一些實施例中,例如藉由攝食向個體經口投與化合物或藥劑。在一些實施例中,經口投與之化合物或藥劑呈延長釋放或緩慢釋放調配物形式,或使用用於此類緩慢釋放或延長釋放之裝置投與。
如本文所用,片語「聯合投與」係指投與兩種或更多種不同治療劑,使得在先前已投與之治療劑在體內仍有效的同時投與第二藥劑(例如,兩種藥劑在患者體內同時生效,此可包括兩種藥劑之協同效應)之任何形式。舉例而言,不同治療性化合物可呈同一調配物或呈單獨調配物形式同時或依序投與。因此,接受此類治療之個體可受益於不同治療劑之組合作用。
藥物或藥劑之「治療有效量」或「治療有效劑量」係藥物或藥劑在向個體投與時將具有預期治療作用之量。全面的治療效果在投與一個劑量時未必會發生,且可能僅在投與一系列劑量之後發生。因此,可在一次或多次投藥中投與治療有效量。個體所需之精確有效量將視例如個體之體型、健康及年齡以及諸如癌症或MDS之所治療病狀之性質及程度而定。熟習此項技術者可藉由常規實驗容易地確定既定情況之有效量。
如本文所用,術語「視情況存在」或「視情況」意謂隨後描述之事件或情形可能發生或可能不發生,且該描述包括其中該事件或情形發生之情況以及不發生之情況。舉例而言,「視情況經取代之烷基」係指可經取代之烷基以及烷基未經取代之情況。
應瞭解,一般熟習此項技術者可選擇本揭示案化合物之取代基及取代模式,以產生可易於藉由此項技術中已知之技術以及下文闡述之彼等方法自容易獲得之起始物質合成之化學穩定化合物。若取代基自身經超過一個基團取代,則應瞭解,此等多個基團可在同一碳上或不同碳上,只要產生穩定結構即可。
如本文所用,術語「視情況經取代」係指既定結構中之一至六個氫基經指定取代基之基團置換,指定取代基包括但不限於:羥基、羥基烷基、烷氧基、鹵素、烷基、硝基、矽烷基、醯基、醯氧基、芳基、環烷基、雜環基、胺基、胺基烷基、氰基、鹵烷基、鹵烷氧基、-OCO-CH
2-O-烷基、-OP(O)(O-烷基)
2或-CH
2-OP(O)(O-烷基)
2。較佳地,「視情況經取代」係指既定結構中之一至四個氫基經上文所提及之取代基置換。更佳地,一至三個氫基經如上文所提及之取代基置換。應理解,取代基可進一步經取代。
如本文所用,術語「烷基」係指包括但不限於C
1-C
10直鏈烷基或C
1-C
10分支鏈烷基之飽和脂族基團。較佳地,「烷基」係指C
1-C
6直鏈烷基或C
1-C
6分支鏈烷基。最佳地,「烷基」係指C
1-C
4直鏈烷基或C
1-C
4分支鏈烷基。「烷基」之實例包括(但不限於)甲基、乙基、1-丙基、2-丙基、正丁基、二級丁基、三級丁基、1-戊基、2-戊基、3-戊基、新戊基、1-己基、2-己基、3-己基、1-庚基、2-庚基、3-庚基、4-庚基、1-辛基、2-辛基、3-辛基或4-辛基及其類似基團。「烷基」可視情況經取代。
術語「醯基」為此項技術中公認的且係指由通式烴基C(O)-、較佳烷基C(O)-表示之基團。
術語「醯胺基」為此項技術中公認的且係指經醯基取代之胺基,且可例如由式烴基C(O)NH-表示。
術語「醯氧基」為此項技術中公認的且係指由通式烴基C(O)O-、較佳烷基C(O)O-表示之基團。
術語「烷氧基」係指附接有氧之烷基。代表性烷氧基包括甲氧基、乙氧基、丙氧基、三級丁氧基及其類似基團。
術語「烷氧基烷基」係指經烷氧基取代之烷基且可由通式烷基-O-烷基表示。
術語「烷基」係指飽和脂族基團,包括直鏈烷基、分支鏈烷基、環烷基(脂環族)基團、經烷基取代之環烷基及經環烷基取代之烷基。在較佳實施例中,直鏈或分支鏈烷基在其主鏈中具有30個或更少碳原子(例如直鏈C
1-C
30、分支鏈C
3-C
30),且更佳20個或更少。
此外,如整個說明書、實例及申請專利範圍中所用之術語「烷基」意欲包括未經取代之烷基及經取代之烷基,後者係指具有置換烴主鏈之一個或多個碳上之氫的取代基的烷基部分,包括諸如三氟甲基及2,2,2-三氟乙基之鹵烷基等。
術語「C
x-y」或「C
x-C
y」當與諸如醯基、醯氧基、烷基、烯基、炔基或烷氧基之化學部分結合使用時意在包括鏈中含有x至y個碳之基團。C
0烷基在基團處於末端位置中之情況下指示氫,若處於內部,則指示鍵。C
1-6烷基例如在鏈中含有一至六個碳原子。
如本文所用,術語「烷基胺基」係指經至少一個烷基取代之胺基。
如本文所用,術語「烷基硫基」係指經烷基取代之硫醇基且可由通式烷基S-表示。
術語「胺」及「胺基」為此項技術中公認的且係指未經取代與經取代之胺及其鹽,例如可由
表示,
其中R
9、R
10及R
10'各獨立地表示氫或烴基,或R
9及R
10與其附接之N原子一起構成在環結構中具有4至8個原子之雜環。
如本文所用,術語「胺基烷基」係指經胺基取代之烷基。
如本文所用,術語「芳烷基」係指經芳基取代之烷基。
如本文所用,術語「芳基」包括經取代或未經取代之單環芳族基,其中環之各原子為碳。環較佳為5員至7員環,更佳為6員環。術語「芳基」亦包括具有兩個或更多個環之多環環系統,其中兩個或更多個碳為兩個鄰接環所共用,其中至少一個環為芳族的,例如其他環可為環烷基、環烯基、環炔基、芳基、雜芳基及/或雜環基。芳基包括苯、萘、菲、酚、苯胺及其類似物。
如本文所用,術語「碳環基烷基」係指經碳環基取代之烷基。
術語「碳環」包括5-7員單環及8-12員雙環。雙環碳環之各環可選自飽和、不飽和及芳族環。碳環包括雙環分子,其中兩個環之間共用一個、兩個或三個或超過三個原子。術語「稠合碳環」係指一種雙環碳環,其中各環與另一環共用兩個相鄰原子。稠合碳環之每一環可選自飽和、不飽和及芳族環。在一例示性實施例中,芳環(例如苯基)可與飽和或不飽和環,例如環己烷、環戊烷或環己烯稠合。飽和、不飽和及芳族雙環之任何組合在價數准許時均包括於碳環之定義中。例示性「碳環」包括環戊烷、環己烷、雙環[2.2.1]庚烷、1,5-環辛二烯、1,2,3,4-四氫萘、雙環[4.2.0]辛-3-烯、萘及金剛烷。例示性稠合碳環包括十氫萘、萘、1,2,3,4-四氫萘、雙環[4.2.0]辛烷、4,5,6,7-四氫-1H-茚及雙環[4.1.0]庚-3-烯。「碳環」可在能夠載有氫原子之任一個或多個位置處經取代。
如本文所用,術語「碳環基烷基」係指經碳環基取代之烷基。
術語「碳酸酯」為此項技術中公認的,且係指基團-OCO
2-。
如本文所用,術語「羧基」係指由式-CO
2H表示之基團。
如本文所用,術語「酯」係指基團-C(O)OR
9,其中R
9表示烴基。
如本文所用,術語「醚」係指經氧連接於另一烴基之烴基。因此,烴基之醚取代基可為烴基-O-。醚可為對稱或不對稱的。醚之實例包括(但不限於)雜環-O-雜環及芳基-O-雜環。醚包括「烷氧基烷基」,其可由通式烷基-O-烷基表示。
如本文所用,術語「鹵基」及「鹵素」意謂鹵素且包括氯、氟、溴及碘。
如本文所用,術語「雜芳烷基(hetaralkyl)」及「雜芳烷基(heteroaralkyl)」係指經雜芳基取代之烷基。
術語「雜芳基(heteroaryl)」及「雜芳基(hetaryl)」包括經取代或未經取代之芳族單環結構,較佳5至7員環,更佳5至6員環,其環結構包括至少一個雜原子,較佳一至四個雜原子,更佳一個或兩個雜原子。術語「雜芳基」亦包括具有兩個或更多個環狀環之多環環系統,其中兩個或更多個碳為兩個鄰接環所共用,其中至少一個環為雜芳環,例如,其他環可為環烷基、環烯基、環炔基、芳基、雜芳基及/或雜環基。雜芳基包括例如吡咯、呋喃、噻吩、咪唑、
唑、噻唑、吡唑、吡啶、吡
、噠
及嘧啶及其類似基團。
如本文所用,術語「雜原子」意謂除碳或氫之外的任何元素之原子。較佳雜原子為氮、氧及硫。
如本文所用,術語「雜環基烷基」係指經雜環基取代之烷基。
術語「雜環基」、「雜環(heterocycle)」及「雜環(heterocyclic)」係指經取代或未經取代之非芳族環結構,較佳3至10員環,更佳3至7員環,其環結構包括至少一個雜原子,較佳一至四個雜原子,更佳一或兩個雜原子。術語「雜環基」及「雜環」亦包括具有兩個或更多個環之多環環系統,其中兩個或更多個碳為兩個鄰接環所共用,其中至少一個環為雜環,例如,其他環可為環烷基、環烯基、環炔基、芳基、雜芳基及/或雜環基。雜環基包括例如哌啶、哌
、吡咯啶、
啉、內酯、內醯胺及其類似基團。
如本文所用,術語「烴基」係指經由碳原子鍵結之基團,該基團不具有=O或=S取代基且通常具有至少一個碳-氫鍵及主要為碳之主鏈,但可視情況包括雜原子。因此,出於本申請案之目的,認為如甲基、乙氧基乙基、2-吡啶基及甚至三氟甲基之基團為烴基,但諸如乙醯基(其在鍵聯之碳上具有=O取代基)及乙氧基(其經氧而非碳鍵聯)之取代基並非烴基。烴基包括(但不限於)芳基、雜芳基、碳環、雜環基、烷基、烯基、炔基及其組合。
如本文所用,術語「羥基烷基」係指經羥基取代之烷基。
術語「低碳」當與諸如醯基、醯氧基、烷基、烯基、炔基或烷氧基之化學部分結合使用時,意謂包括取代基中存在十個或更少,較佳六個或更少原子之基團。「低碳烷基」例如係指含有十個或更少、較佳六個或更少碳原子之烷基。在某些實施例中,本文所定義之醯基、醯氧基、烷基、烯基、炔基或烷氧基取代基分別係低碳醯基、低碳醯氧基、低碳烷基、低碳烯基、低碳炔基或低碳烷氧基,不管其單獨出現還是與其他取代基組合出現,諸如在敍述羥基烷基及芳烷基中(在此情形中,例如,當計數烷基取代基中之碳原子時不計數芳基內之原子)。
術語「多環基」、「多環(polycycle)」及「多環(polycyclic)」係指兩個或更多個環(例如,環烷基、環烯基、環炔基、芳基、雜芳基及/或雜環基),其中兩個或更多個原子為兩個鄰接環所共用,例如,該等環為「稠環」。多環之各環可經取代或未經取代。在某些實施例中,多環之各環在環中含有3至10個,較佳5至7個原子。
術語「亞碸」為此項技術中公認的且係指基團-S(O)-。
術語「磺酸酯基」為此項技術中公認的且係指基團SO
3H或其醫藥學上可接受之鹽。
術語「碸」為此項技術中公認的且係指基團-S(O)
2-。
術語「經取代」係指部分具有置換主鏈之一個或多個碳上之氫的取代基。應瞭解「取代」或「經取代」包括隱含限制條件,亦即此類取代與經取代原子及取代基之允許價態一致,且取代產生穩定化合物,例如其不會自發地諸如藉由重排、環化、消除等進行轉化。如本文所用,考慮術語「經取代」包括有機化合物之所有可容許取代基。在一廣泛態樣中,可容許取代基包括有機化合物之非環狀及環狀、分支鏈及非分支鏈、碳環及雜環、芳族及非芳族取代基。對於合適之有機化合物,可容許取代基可為一個或多個及相同或不同的。出於本揭示案之目的,諸如氮之雜原子可具有氫取代基及/或本文所述的滿足雜原子價數之有機化合物之任何可容許取代基。取代基可包括本文所述之任何取代基,例如鹵素、羥基、羰基(諸如羧基、烷氧基羰基、甲醯基或醯基)、硫羰基(諸如硫酯基、硫乙酸酯基或硫甲酸酯基)、烷氧基、磷醯基、磷酸酯基、膦酸酯基、亞膦酸酯基、胺基、醯胺基、脒、亞胺、氰基、硝基、疊氮基、硫氫基、烷硫基、硫酸酯基、磺酸酯基、胺磺醯基、磺醯胺基、磺醯基、雜環基、芳烷基或芳族或雜芳族部分。熟習此項技術者應瞭解,取代在烴鏈上之部分本身在適當時可經取代。
如本文所用,術語「硫烷基」係指經硫醇基取代之烷基。
如本文所用,術語「硫酯」係指基團-C(O)SR
9或-SC(O)R
9,其中R
9表示烴基。
如本文所用,術語「硫醚」等同於醚,其中氧經硫置換。
如本文所用,術語「調節」包括抑制或遏制功能或活性(諸如細胞增殖)以及增強功能或活性。
片語「醫藥學上可接受」為此項技術中公認的。在某些實施例中,該術語包括在合理醫學判斷範圍內,適合與人類及動物之組織接觸使用而無過度毒性、刺激、過敏反應或其他問題或併發症,與合理益處/風險比相匹配之組合物、賦形劑、佐劑、聚合物及其他材料及/或劑型。
「醫藥學上可接受之鹽」或「鹽」在本文中用於指適用於治療患者或與該治療相容的酸加成鹽或鹼加成鹽。
如本文所用,術語「醫藥學上可接受之酸加成鹽」意謂由式I表示之任何鹼化合物之任何無毒的有機或無機鹽。形成適合鹽之例示性無機酸包括鹽酸、氫溴酸、硫酸及磷酸,以及諸如正磷酸一氫鈉及硫酸氫鉀之金屬鹽。形成適合鹽之例示性有機酸包括單羧酸、二羧酸及三羧酸,諸如乙醇酸、乳酸、丙酮酸、丙二酸、丁二酸、戊二酸、反丁烯二酸、蘋果酸、酒石酸、檸檬酸、抗壞血酸、順丁烯二酸、苯甲酸、苯乙酸、肉桂酸及柳酸,以及磺酸,諸如對甲苯磺酸及甲磺酸。可形成單酸鹽或二酸鹽,且此類鹽可呈水合、溶合或實質上無水形式存在。一般而言,式I化合物之酸加成鹽更可溶於水及各種親水性有機溶劑中,且通常展現與其游離鹼形式相比更高的熔點。適當鹽之選擇為熟習此項技術者所已知。其他非醫藥學上可接受之鹽,例如乙二酸鹽,可用於例如分離式I化合物以供實驗室使用,或用於隨後轉化成醫藥學上可接受之酸加成鹽。
如本文所用,術語「醫藥學上可接受之鹼加成鹽」意謂由式I表示之任何酸化合物或其任一中間物之任何無毒的有機或無機鹼加成鹽。形成適合鹽之例示性無機鹼包括氫氧化鋰、氫氧化鈉、氫氧化鉀、氫氧化鈣、氫氧化鎂或氫氧化鋇。形成適合鹽之例示性有機鹼包括脂族、脂環或芳族有機胺,諸如甲胺、三甲胺及甲吡啶或氨。適當鹽之選擇為熟習此項技術者所已知。
許多適用於本揭示案之方法及組合物之化合物在其結構中具有至少一個立體異構源中心。此立體異構源中心可呈R或S組態存在,該R及S符號係根據Pure Appl. Chem.(1976), 45, 11-30中所描述之規則使用。本揭示案考慮所有立體異構形式,諸如化合物、鹽、前藥之對映異構形式及非對映異構形式或其混合物(包括立體異構體之所有可能混合物)。參見例如WO 01/062726。
此外,含有烯基之某些化合物可呈Z(同側)或E(異側)異構體之形式存在。在各情況下,本揭示案包括混合物及單獨的個別異構體兩者。
一些化合物亦可呈互變異構形式存在。儘管本文中所描述之式中未明確指示,但此類形式意欲包括於本揭示案之範疇內。
「前藥」或「醫藥學上可接受之前藥」係指在投與之後在宿主中代謝,例如水解或氧化以形成本揭示案之化合物(例如式I化合物)的化合物。前藥之典型實例包括在活性化合物之官能性部分上具有生物學不穩定或可裂解(保護)基團的化合物。前藥包括可經氧化、還原、胺化、脫胺化、羥基化、脫羥基化、水解、脫水解、烷基化、去烷基化、醯化、去醯化、磷酸化或去磷酸化以產生活性化合物之化合物。使用酯或胺基磷酸酯作為生物學不穩定或可裂解(保護)基團之前藥之實例揭示於美國專利6,875,751、7,585,851及7,964,580中,該等專利之揭示內容以引用的方式併入本文中。本揭示案之前藥經代謝以產生式I化合物。本揭示案在其範疇內包括本文所述之化合物之前藥。用於選擇及製備適合前藥之習知程序描述於例如「Design of Prodrugs」, H. Bundgaard編, Elsevier, 1985中。
如本文所用,片語「醫藥學上可接受之載劑」意謂諸如適用於調配用於醫學或治療用途之藥物之液體或固體過濾器、稀釋劑、賦形劑、溶劑或囊封材料的醫藥學上可接受之材料、組合物或媒劑。
如本文所用,術語「溶解度之Log」、「LogS」或「logS」在此項技術中用於定量化合物之水溶性。化合物之水溶性顯著影響其吸收及分佈特徵。低溶解度通常與不良吸收相關聯。LogS值為以莫耳/公升為單位所量測之溶解度之單位剝離對數(底數10)。
實例 現已大體描述本揭示案,參考以下實例將更容易理解本揭示案,該等實例僅為說明本揭示案之某些態樣及實施例而包括在內,且不意欲限制本揭示案。
材料與方法
化學物質及供應品-六氟磷酸2(1
H-苯并三唑-1-基)-1,1,3,3-四甲基
(HBTU)及
N-羥基苯并三唑(HOBt)係購自Vivitide(Gardner, MA)。所有經保護之胺基酸、rink醯胺MBHA樹脂及
N-甲基
啉(NMM)均由Gyros Protein Technologies(Tucson, AZ)供應。聚乙二醇(PEG
3)由Creative PEGWorks(Durham, NC)獲得。三氟乙酸(TFA)、哌啶、大茴香硫醚、大茴香醚、1,2-乙二硫醇、甲基-三級丁基醚、
N,N-二異丙基乙胺(DIPEA)、二甲基甲醯胺(DMF)、乙腈(ACN)、
N-甲基-2-吡咯啶酮(NMP)、碳酸鈉、Sephadex G25、還原L-麩胱甘肽(GSH)、脂多醣(LPS)及順式-二氯二氨鉑(II)(順鉑)係購自Sigma Aldrich(Saint-Louis, MO)。丁二醯亞胺基3-(2-吡啶基二硫基)丙酸酯(SPDP)由Invitrogen(Carlsbad, CA)供應。對-SNC-去鐵胺(DFO)來自Macrocyclics Inc.(Plato, TX)。
N2'-去乙醯基-
N2 '-(3-巰基-1-側氧基丙基)-美登素(DM1)及阿多比欣鹽酸鹽(aldoxorubicin HCl,aldox)來自MedKoo Biosciences(Morrisville, NC)。多柔比星(DOX)及吉西他濱(GEM)自LC Laboratories(Woburn, MA)獲得。絲裂黴素(MIT)由Selleckchem(Houston, TX)供應。花青5.5 NHS酯係購自Lumiprobe Corporation(Hallandale Beach, FL)且螢光素來自Caliper LifeScience(Hopkinton, MA)。
肽合成-所有肽均在固相肽合成器(PS3, Gyros Protein Technologies, Tucson, AZ)上使用
N-
α-Fmoc方法在如先前所述之Rink醯胺樹脂上來合成。藉由使用NMM作為基質、HBTU/HOBt作為偶合試劑及哌啶(DMF中20% v/v)作為去保護劑逐步伸長,將側鏈保護之胺基酸(0.4 mmol)連接至樹脂(385 mg,0.1 mmol)。在肽N端併入β-丙胺酸作為間隔子,以用於在肽裂解之前進一步結合所需部分,包括螢光團(花青5.5)、螯合劑(DFO)或連接子(SPDP)。
免疫原性分析-經由尾靜脈注射用單次劑量之Bdd或LPS(5 mg/kg)處理雌性BALB/c小鼠(n=3/組)。投與PBS之小鼠用作陰性對照。在4小時後經由眶後竇穿刺技術收集血液樣品,且用商業夾心酶聯免疫吸附分析套組量測血漿中先天性免疫及發炎性細胞介素IL1β、IL2、IL6、IL10、TNF-α及INF-γ之濃度。根據製造商說明書(Invitrogen, Carlsbad, CA)進行ELISA分析。
將不同官能基併入肽之方法-將含花青5.5 NHS酯(50 mg,1.4當量)之DMF(4 mL)、含DFO(25 mg,1當量)之DMSO(4 mL)或含SPDP(25 mg,1當量)之NMP(4 mL)添加至樹脂(0.05 mmoL,1當量)中且使其在室溫下反應隔夜。對於螢光團及螯合劑結合,在有機鹼(DIPEA,1 mL)存在下進行反應。接著使用含有TFA/大茴香硫醚/1,2-乙二硫醇/大茴香醚(90:5:3:2)之裂解混合液(5 mL)自樹脂移除肽,歷時4小時,且將該等肽在甲基-三級丁基醚中沈澱。使用逆相高效液相層析法(rp-HPLC, Agilent, Santa Clara, CA)將所得到之肽(Cy-肽、DFO-肽及SPDP-肽)純化至>98%純度,且藉由MALDI-TOF分析(Tufts Medical School, Boston, MA)表徵以證實其分子量。
可裂解藥物-肽結合物之合成-將DM1(1 mg,1當量)添加至含SPDP-肽(10 mg,3當量)之NMP(100 μL)與磷酸鹽緩衝鹽水(PBS;10 mM,pH 7,100 μL)之共溶劑中,且使其在室溫下反應2天。接著藉由rp-HPLC純化DM1-肽。為結合aldox,將硫醇反應性側(半胱胺酸)引入肽N端。將aldox(2 mg,1當量)添加至含肽(10 mg,3當量)之PBS(10 nM,1 mL,pH 7.4)中,且使其反應30分鐘。所獲得之藥物-肽對pH敏感且藉此藉由rp-HPLC在中性條件(移動相A:PBS,移動相B:PBS中90% ACN)下純化。使用尺寸排阻層析法(TipTop C-18管柱)移除鹽內含物。所有最終藥物-肽結合物均使用MALDI-TOF分析來表徵,且根據預先確定之DM1(ε = 3,700 cm
-1M
-1)或aldox(ε = 13,000 cm
-1M
-1)在含5%(v/v)PBS之甲醇中之消光係數,用UV吸光度進行定量。
放射化學-
89鋯(
89Zr)由3DImaging LLC(Little Rock, AR)供應。首先將
89Zr-乙二酸鹽(500 μCi)用同等體積之碳酸鈉溶液(2 M)中和,且接著添加至DFO-肽(0.2 mg,250 μL)中。在室溫下培育1.5小時之後,藉由尺寸排阻層析法使用Sephadex G-25凝膠來純化經放射性標記之肽(
89Zr-肽)以移除游離鋯。
藥物動力學研究-經由尾靜脈注射向BALB/c小鼠(Jackson Laboratory, Bar Harbor, ME)投與
89Zr-肽或游離
89Zr(20 μCi,100 μL)(n=4/條件)。在多個時間間隔使用眶後竇穿刺技術收集血液樣品(20 μL)。在Wallac Wizard 2 γ計數器(Perkin-Elmer, Waltham, MA)上量測放射性。藉由使用PKSolver 2.0軟體擬合隔室模型選擇之資料來估計
89Zr-肽及游離
89Zr之藥物動力學模型及參數,包括血清半衰期及血漿清除率。
μPET/CT成像及生物分佈研究-BALB/c小鼠經靜脈內注射不同
89Zr-肽類似物(20 μCi,100 μL)。在動物中在第一次成像之前在收集尿液及不收集尿液的情況下進行μPET/CT成像(n=4/類似物/條件)。在注射之後1小時、4小時及24小時使用Inveon μPET/CT掃描儀(Siemens Medical Solutions, Malvern, PA)獲取全身影像。使用Amide v1.0.4及Inveon Research Workplace軟體處理μPET/CT最大能量投影。確定不同感興趣區域(ROI)之放射性。對於終點生物分佈研究,在用
89Zr-肽處理之後0.17、1、2、5及7天處死小鼠(n=3/肽類似物/時間點)。使用Wallac Wizard 2 γ計數器來量測所採集器官之放射性。結果根據放射衰變校正,且表示為注射劑量百分比(% ID)或每公克組織之注射劑量百分比(% ID/g)。
螢光成像-經由尾靜脈注射向雌性SHO小鼠(Charles River Laboratories, Wilmington, MA)投與含游離花青5.5或Cy-肽類似物(藉由在680 nm下UV吸光度測得花青5.5含量為0.5 nmol)之PBS(150 μL)(n=4/組)。使用活體內Xtreme成像系統(Bruker, Billerica, MA)進行即時螢光成像。在注射之後1小時及4小時使用適當激發(670 nm)及發射(750 nm)濾光片獲取全身螢光影像。接著處死動物。切除器官以進行離體螢光成像。亦在靜脈內注射游離染料或Cy-肽類似物之後1小時對自單獨動物收集之尿液樣品(50 μL)進行成像(n=4/處理)。使用Bruker MI軟體處理螢光/亮光影像且量測不同ROI中之螢光強度。校正所有資料以消除器官或流體自體螢光。
細胞株-MB49由EMD Millipore Corporation(Temecula, CA)供應。UMUC-3、T24及Renca係自ATCC(Manassas,VA)獲得。各細胞株根據公司之說明書進行培養。週期性進行黴漿菌屬(Mycoplasma)測試(Lonza, Basel, Switzerland)以確保無污染。UMUC-3與Renca細胞株均進一步經攜帶螢火蟲螢光素酶與綠色螢光蛋白(GFP)基因二者之GlowCell 16 FLuc-F2A-GFP慢病毒(Biosettia, San Diego, CA)轉導。簡言之,將細胞接種於6孔盤中(0.25×10
6個細胞/孔)且與病毒(2×10
7IU/孔)一起在聚凝胺(10 μg/mL)存在下培育3天。為確保超過95%之細胞純度,分析細胞株且使用流動式細胞測量術針對GFP表現進行分選。藉由使用EVOS FL自動螢光顯微鏡(Life Technology, Carlsbad, CA)成像進一步證實成功轉導。
細胞活力及細胞毒性分析-將癌細胞(3×10
3/孔)接種在平底96孔盤上隔夜。接著將不同濃度之DM1、吉西他濱(GEM)、絲裂黴素(MIT)、順鉑(CIS)、多柔比星(DOX)、阿多比欣(aldox)或負載藥物之肽(DM1-肽及aldox-肽)添加至細胞中,歷時72小時,且接著用PBS(400 μL)洗滌2次。將CellTiter Glo試劑(Promega, Madison, WI)添加在各孔(50 μL)中。使用微定量盤式讀取器(Tecan US Inc., Morrisville, NC)記錄所產生之發光。使用Graph Pad Prism 6.0軟體繪製劑量反應曲線且計算半最大抑制濃度(IC
50值)。
活體外藥物釋放研究-將DM1-肽結合物(10 μM藥物含量)在PBS緩衝液(800 μL)中在還原劑GSH(1 mM)存在下培育。在不同時間間隔(0、2、4、6、8、12、24及48小時),取出少量溶液(100 μL),供使用C18分析管柱進行HPLC分析。量測隨著時間推移釋放之DM1活性代謝物之量(在254 nm下偵測吸光度)且接著定量。實驗獨立地重複進行三次。進行類似實驗以定量aldox之釋放。在玻璃小瓶中將aldox-肽結合物(100 μM藥物含量)在具有不同pH值(7.4及5.5)之PBS緩衝液(800 μL)中培育,該玻璃小瓶塗有二氧化矽以避免反應容器表面上之非特異性吸附。接著如上所述量測隨著時間推移釋放之藥物之量(在480 nm下偵測吸光度)。為準確定量,將所有結果與在類似條件下培育之DOX對照相比進行歸一化。
動物護理-將此項目所使用之所有動物圈養於無病原體隔離室中,維持在控制溫度(72±2℉)下,每日12小時光照與黑暗循環。對小鼠進行之所有程序均經威爾康奈爾醫學中心機構動物護理及使用委員會(Weill Cornell Medical Center Institutional Animal Care and Use Committee)(方案#2019-0003)批准,且與美國獸醫協會(the American Veterinary Medical Association)及美國國立衛生研究院(the National Institutes of Health)實驗動物護理與使用指南之建議相符。在進行任何實驗之前至少7天使小鼠適應新環境。免疫功能不全之NSG小鼠容易受到感染。因此,用含有磺胺甲啶(sulfatrim)抗生素(Envigo, Indianapolis, IN)之飲食餵養動物。用AING93非螢光飲食(Envigo, Indianapolis, IN)餵養用於螢光成像之動物。
藥物-Bdd結合物治療BC之治療功效-如先前描述,將腫瘤原位植入動物。簡言之,經由無菌24 G兒科靜脈導管(Dublin, Ireland)移出7至9週齡雌性NSG小鼠(Jackson Laboratory, Bar Harbor, ME)之尿液。接著將胰蛋白酶溶液(0.125%,80 μL)遞送至膀胱中。隨後,將培養基(50 μL)中之UMUC-3/GFP-Luc細胞(4×10
4個細胞)轉移至膀胱中且使之進行接種。藉由生物發光成像監測腫瘤進展。在進行成像之前15分鐘,向動物(經由腹膜內注射)提供含螢光素(3 mg)之PBS(100 μL)。一旦證實膀胱中腫瘤進展(基於生物發光信號),則隨機分配動物,每週經由尾靜脈注射用含PBS、DM1或DM1-Bdd(0.75 mg/kg藥物含量)之鹽水(150 μL)治療3週(n=14/組)。不同的動物組被分配用含DM1、DM1-Bdd(0.75 mg/kg藥物含量)或MIT(1 mg/mL)之鹽水(50 μL)進行膀胱內處理(n=14/組)。基於腫瘤生長抑制(生物發光成像)及長期存活率來評估治療功效。募集額外小鼠進行組織病理學分析(n=4/組)。在處理時程結束之後1週立即處死此等動物。採集膀胱且將其保存在中性緩衝福馬林(10%)中。使用相同實驗條件來比較經由尾靜脈注射或膀胱內投與用PBS、aldox或aldox-Bdd處理之動物中的處理結果(5 mg/kg藥物含量)。
評估DM1-Bdd對腎癌之治療-如先前描述,將含Renca/GFP-Luc細胞(4×10
3個細胞)之PBS(3 μL)原位植入7至9週齡雌性BALB/c小鼠(Jackson Laboratory, Bar Harbor, ME)之腎被膜中。藉由生物發光成像證實腫瘤進展。將動物隨機分配成4組,每週經由尾靜脈注射用PBS、DM1或DM1-Bdd(0.75 mg/kg藥物含量)處理,或經由膀胱內投與用DM1-Bdd(0.75 mg/kg藥物含量)處理(n=14/處理)。如上所述對動物之腫瘤生長抑制及存活率進行監測。使用額外小鼠進行組織病理學分析(n=4/組)。
組織學分析-將組織樣品固定在福馬林中,經乙醇脫水,且包埋於石蠟中。將組織切片(5 μm)用蘇木精及伊紅Y(H&E)染色。對於免疫組織化學,使膀胱切片脫蠟,且接著復水,隨後與抗Ki67或抗GFP抗體(Abcam, Cambridge, UK)一起培育隔夜。接著將載片用蘇木精複染。使用Aperio 9數位病理學載片掃描器(Leica Biosystems, Weltzar, Germany)獲取高解析度影像。
屍檢-每週經由尾靜脈注射(150 μL)用PBS、DM1、DM1-肽(0.75 mg/kg藥物含量)或順鉑(10 mg/kg)處理七至9週齡雌性BALB/c小鼠(n=4/組)。在3週處理結束時,處死小鼠。採集器官/組織,將其固定於10%中性緩衝福馬林中2天。將骨在甲酸溶液中脫鈣(Surgipath脫鈣劑I;Leica Biosystems, Weltzar, Germany)。接著將樣品包埋於石蠟中,切片(5 μm),且用H&E染色,以由ACVP委員會認證之解剖病理學家來檢查。
腎毒性研究-經由尾靜脈向BALB/c小鼠投與PBS、DM1、DM1-肽、MIT、GEM、CIS(0.75 mg/kg藥物含量)或高劑量CIS(10 mg/kg)(n=3/組)。使用ELISA分析,根據製造商說明書(R&D Systems, Minneapolis, MN)來量測尿液樣品中之急性腎損傷生物標記物,亦即嗜中性球明膠酶相關脂質運載蛋白(NGAL)及腎損傷分子-1(KIM-1)之含量。對用PBS、DM1、DM1-Bdd(0.75 mg/kg藥物含量)或高劑量CIS(10 mg/kg)處理之動物腎進行補充組織病理學分析。在處理結束時將所有動物(n=3/組)處死,且收集腎並將該等腎固定於10%中性緩衝福馬林中。接著處理組織,將其包埋於石蠟中,切片且用H&E染色。亦進行腎損傷(NGAL及KIM -1)之免疫組織化學(IHC)。
血液學及生物化學-經由心臟穿刺收集血液樣品。使用IDEXX Procyte DX血液學分析器(iDEXX, Westbrook, ME)進行全血球計數,包括紅血球、白血球、網狀紅血球及血小板計數,以及自動化白血球分類計數。製備血液塗片,用經改良之賴德染色劑(Wright's stain)染色,由委員會認證之獸醫學臨床病理學家(T.S.)盲法檢查,且使用配備有photometrics CoolSNAP HQ
2相機之Nikon Eclipse TE2000-U螢光顯微鏡(Nikon Corporation, Tokyo, Japan)成像。亦將血液(1,500×G)離心15分鐘以獲得血清,用於使用Beckman Coulter AU680分析器(Beckman Coulter, Brea, CA)進行生物化學分析。
統計分析-使用Graph Pad Prism 7.0軟體及R v4.0.5(R Foundation for Statistical Computing, Vienna, Austria)軟體進行統計分析。所有數據均呈現為平均值±標準差且顯著性分配為*p<0.05、**p<0.01及***p<0.001。使用雙尾斯圖登氏t檢驗確定組之間的顯著差異。為評估存活率,進行曼特爾-考克斯對數秩檢驗以將用靜脈內DM1-Bdd或aldox-Bdd處理之動物之存活率曲線與其他處理進行比較。使用本傑明與霍赫貝格方法調整p值以進行多重比較。所有p值均為雙側的,在0.05 α水準下評估統計顯著性。計算所有參數之百分之九十五(準確)信賴區間以評估所獲得之估計值的精確度。
實例1:Bdd可完全經由腎臟清除作用來消除
Bdd以
D-組態設計,以避免在血液循環中由蛋白酶降解。其由多個
D-天冬胺酸(d)及β-丙胺酸(B)殘基構成(圖1b)。天冬胺酸促成總體負電荷,此可防止重要器官之非特異性攝取且促進肽之腎臟清除。B殘基充當連接子以避免形成二級結構。為研究電荷如何影響Bdd之活體內行為,亦合成一組呈
L-組態(BDD)、中性(BKD)、攜有正電荷(BKK)及聚乙二醇化形式(PEG
3DD)之Bdd類似物,用於比較研究。肽經89-鋯(
89Zr,一種長壽命放射性同位素(t
1/2=78小时))標記,此允許使用微型正電子發射及電腦化斷層掃描(μPET/CT)成像來研究藥物動力學(PK)及長期生物分佈(BD)。藉由在胺基酸伸長之後,首先在固相中將去鐵胺(DFO)螯合劑與肽結合來合成經放射性標記之肽(
89Zr-肽)。接著在溶液中在鹼性條件下
89Zr與所得到之DFO-肽結合物錯合(圖1c)。
結果顯示,
89Zr-Bdd及
89Zr-BDD顯示最小脫靶遞送(圖1d)。除腎以外,未能在重要器官中偵測到任何放射性(肽)。如在成像之前插入導管且排空之膀胱中不存在放射性所證實,兩種肽均在靜脈內投與之後1小時內快速排泄至尿液中。結果亦顯示,高達80%總注射劑量(ID)在自注射
89Zr-Bdd之動物收集的第一尿液樣品中(圖1e),此表明該肽經由腎小球過濾,具有最低程度之再吸收。另一方面,除URS之外,帶正電荷之
89Zr-BKK亦遞送至肝臟(圖1d)。亦在肽類似物當中比較腎攝取。除PEG
3DD初始增加以外,均顯示在腎臟中隨著時間推移累積減少(圖1f)。為確定PK概況,將實驗資料擬合成雙室模型。結果顯示,與游離
89Zr相比,所有肽類似物均顯示較短半衰期(圖1g)。
89Zr-Bdd具有0.53小时之終末半衰期及快速血漿清除率(圖7a)。進一步進行
89Zr-Bdd之終點生物分佈研究。結果與成像及PK研究非常一致。如所預期,在靜脈內注射之後4小時,未在重要器官或血液循環中偵測到任何肽(圖1h及圖7b)。儘管清除快速,但在腎臟中仍發現15.1%
89Zr-Bdd,在7天之後減少至2.1%。
實例2:作為疏水性分子之載劑
大部分化學治療劑係呈現不利PK及BD,引起脫靶遞送及不當毒性之疏水性分子。預測Bdd之快速腎臟清除可有利於促進藥物遞送至URS。為證實此點,將疏水性花青5.5螢光團(Cy)作為藥物模型共價附接至肽類似物(圖2a)且比較所得結合物(Cy-肽)之活體內遞送。Cy-Bdd與Cy-BDD均可經由腎臟清除作用迅速地消除。其在靜脈內注射之後1小時到達動物膀胱(圖2b),尿液中呈現高達70-75% ID(圖2c)。另一方面,Cy-BKD、Cy-BKK、Cy-PEG
3DD及游離Cy主要由肝臟吸收。亦對所採集之器官進行離體成像(圖2d)。如所預期,與其他結合物相比,腎中之Cy-Bdd及Cy-BDD之累積最少(圖2e)。然而,不同於
89Zr-Bdd,胃、肝及腸吸收痕量之Cy-Bdd及Cy-BDD。生物分佈差異可能歸因於疏水性Cy對帶負電之
89Zr-DFO的置換。總體而言,Bdd可用於將諸如Cy之疏水性分子遞送至URS,同時維持全面UDD特性。
實例3:作為化學治療劑之載劑
Bdd之優良UDD特性促使對遞送化學治療劑用於治療NMIBC作進一步研究。許多肽為免疫原性的。首次證實Bdd肽未觸發先天性免疫反應。在靜脈內注射之後4小時BALB/c小鼠之血漿中的發炎性細胞介素含量(IL-1β、IL-2、IL-6、IL-10、TNF-α及INF-γ)未增加(圖3a)。使用螢光Cy-Bdd,進一步證實肽可能由人類BC(UMUC-3)及鼠類腎癌(Renca)細胞吸收(圖3b)。觀測到肽(紅色)及溶酶體(綠色)螢光重疊,此表明肽之細胞攝取主要經由胞吞作用發生。作為原理驗證,選擇恩他新(emtansine,DM1)作為候選藥物,其為一種有效微管抑制劑。與其他習知化學治療劑相比,DM1比順鉑(CIS)、多柔比星(DOX)及絲裂黴素(MIT)更有效,且與吉西他濱(GEM)同等有效地針對UMUC-3,其中IC
50值在奈莫耳(nM)範圍內(圖3c)。該藥物亦有效地針對Renca細胞株。接著,DM1-Bdd結合物藉由經由可裂解二硫基連接子將DM1附接至Bdd來合成(圖3d),使得能夠在還原環境中,諸如在細胞內麩胱甘肽(GSH)存在下釋放藥物(圖3e)。亦建立將諸如阿多比欣(aldox)之其他化學治療劑與Bdd結合之化學(圖3f)。aldox係一種經腙連接子修飾之DOX衍生物,已知其對酸性溶酶體及腫瘤微環境敏感。藥物自aldox-Bdd結合物之釋放依賴於pH值(圖3g)。在細胞毒性方面,DM1-Bdd及aldox-Bdd均展現與對應游離藥物類似的針對不同鼠類(MB49)及人類(UMUC-3及T24)BC細胞株之效能(圖3h-i)。
實例4:習知ITC之更有效替代物
不同於膀胱內(i.t.)投與,動物無需在靜脈內注射之後不久進行排泄(圖4a)。經由靜脈內注射投與之DM1-Bdd將延長藥物之膀胱停留時間。此連同獨特UDD特性一起,在使用Bdd作為藥物載劑時將提供更有效(與ITC相比)且安全(與全身性化學療法相比)之治療選擇。然而,Bdd可暫時累積在腎臟中(圖1d及h)。因此,在評估DM1-Bdd之治療功效之前,評估健康小鼠中腎臟對單次可注射劑量之耐受性。結果顯示,在注射之後1天,DM1-Bdd略微增加尿液中泌尿系統小管損傷標記物,亦即腎損傷分子-1(KIM-1)及嗜中性球明膠酶相關脂質運載蛋白(NGAL)之含量(圖4b)。增加極少且短暫,在3天內恢復至基礎含量。藥物投與之後3天進行的組織學檢查未顯示腎臟之任何異常,與PBS相比,組織切片對KIM-1及NGAL之免疫反應性未升高(圖4c)。相比之下,包括DM1、MIT、CIS及GEM之其他靜脈內化學治療劑顯示在該時間點對KIM-1及/或NGAL之持續誘發。亦發現在用高劑量靜脈內CIS(陽性對照)處理之動物中小管上皮細胞之擴張及退化(圖4c)。
接著評估DM1-Bdd對負載原位人類UMUC-3腫瘤之小鼠的治療。在將UMUC-3細胞植入動物膀胱之前,其經雙重螢光素酶及GFP報導體穩定地轉導(圖4d)。此允許利用生物發光成像來監測疾病進展。亦證實在固有層中生長之所建立之腫瘤係本質非侵入性的且限於膀胱黏膜下層(圖4e)。與臨床上使用之ITC(膀胱內MIT)相比,靜脈內DM1與DM1-Bdd均更有效地抑制腫瘤生長(圖4f-g及圖8a-e)且延長動物存活期(圖4h)。與膀胱內投與相比,靜脈內注射DM1-Bdd提供更佳治療結果。根據在每週一次之3次處理過程中獲取的成像資料,靜脈內DM1-Bdd及DM1之抗腫瘤活性相似(圖4f)。然而,用靜脈內DM1-Bdd處理之彼等動物顯示總存活率顯著提高(在100天之後存活36%對比0%)。在單獨實驗中,藉由組織學證實對減小腫瘤之治療作用。用靜脈內DM1-Bdd處理之動物的腫瘤較小(圖4i)。免疫組織化學顯示GFP陽性細胞較少且表現增生標記物(Ki67)之細胞的比例較低,此證實對腫瘤細胞生長及增生之抑制(圖4j及圖8f)。更重要地,DM1-Bdd處理可治癒21%動物。存活小鼠缺乏總體及組織學腫瘤證據(使用GFP及Ki67免疫染色),此表明其在210天之後無病(圖8g)。Bdd為一種可運載不同化學治療劑之通用遞送平台。與PBS及游離DOX相比,aldox-Bdd亦能夠延長動物存活率(圖9a-c)。然而,其在提高總存活期方面不如DM1-Bdd有效(圖9c)。意外地,用游離DOX處理之動物的預期壽命比PBS對照短,其中在DOX處理期間所有動物體重均不斷減輕(圖9d及e)。其最終在接受最終劑量之前死亡,表明藥物誘發之毒性及死亡率。
實例5:解剖靈活性
該等研究使用同基因型小鼠模型來評估DM1-Bdd對腎癌之治療,其涉及經手術將Renca細胞(經GFP及Luc穩定地轉導)植入BALB/c小鼠之右腎之腎被膜中(圖5a)。腫瘤生長為侵襲性的。早在植入之後1週即出現很大尺寸之腫瘤塊(圖5b)。成像研究顯示,靜脈內DM1-Bdd不僅能夠抑制腫瘤進展(圖5c及d),且如大部分動物在處理期間生物發光信號減少所示,亦減小腫瘤尺寸(圖5e)。在160天之後存活率為50%(圖5f及g)。另一方面,所有用靜脈內或膀胱內DM1處理之動物均死亡。在單獨實驗中,在完成處理過程之後一週對動物腎臟進行組織學檢查(圖5h)。在經靜脈內DM1-Bdd處理之動物中存在極少腫瘤,而用DM1或PBS對照處理之動物的腫瘤很大且伴有單核細胞浸潤。總體而言,UDD方法在解剖學上係靈活的且可用於治療位於上泌尿道處之腫瘤。
實例6:毒性概況
在完成每週一次共3週之處理之後評估DM1-Bdd在健康動物中之毒性概況。DM1-Bdd未影響紅血球、白血球或血小板計數或形態學特徵(圖6a-b及圖10)。另一方面,DM1誘發網狀紅血球增多,無明顯貧血,及發炎反應,該發炎反應之特徵在於嗜中性球、單核球及血小板之比例增加。如血小板減少及淋巴球減少所證明,陽性對照CIS亦具有毒性。亦進行血清生化分析以評估肝損傷及腎功能。DM1-Bdd不具有肝毒性,ALP、ALT及AST之釋放無顯著改變(圖6c及圖11)。重要地,尿素氮/肌酐比率正常,此表明DM1-Bdd未影響含氮廢物之腎臟清除。組織病理學研究進一步證實用DM1-Bdd處理之動物的肝、脾、心、肺或腎中形態學上無損傷之證據(圖6d及圖12)。相比之下,生化測試顯示,DM1與CIS均誘發肝及腎毒性,如ALT及AST活性以及BUN/肌酐比率增加所示(圖6c)。其亦誘發肌肉損傷(CK活性),此將在一定程度上解釋AST活性之增加。組織學檢查亦顯示,CIS引起近端腎小管之退化及壞死、肺部炎症及脾中紅血球與髓外造血(EMH)之耗盡(圖6d及圖12)。用DM1處理之動物顯示相似腎損傷,但程度較小。在DM1下亦觀測到脾及肝EMH增加,此可解釋在經處理之動物中觀測到之網狀紅血球增多。
論述
大部分化學治療劑對健康及癌細胞有毒性,其藉由輸注給予,以使得其可在較高總劑量下在較長時段內不斷投與。目標係藉由將藥物血漿濃度維持在某一水準且延長腫瘤暴露於藥物來達成更有效之治療,以改善患者對脫靶毒性之耐受性。在本發明之研究中,旨在促進而非減少藥物之清除,作為ITC之非侵入性替代方案。已批准許多生物活性肽用於治療各種疾病,包括癌症、糖尿病及心血管疾病。在無化學修飾下,肽具有數分鐘之短循環半衰期。其迅速由蛋白酶降解且藉由腎過濾消除。在本發明之研究中認識到,作為藥物載劑,肽之快速腎臟清除可為有利的,其將大部分全身性投與之藥物處置於尿液中以治療NMIBC及減少不必要之全身副作用。在本發明中,藉由使用生物惰性之帶負電肽(Bdd)引入UDD方法,網狀內皮系統及其他器官對該肽之攝取極少且其完全排泄至尿液中。Bdd用於遞送DM1(一種微管抑制劑)。選擇DM1之原因在於其對一組BC細胞株之效力比包括MIT、DOX及CIS之常用ITC藥物高100倍。此外,將藥物與Bdd肽結合不損害細胞毒性。
在治療功效方面,與習知膀胱內MIT相比,靜脈內投與之肽-DM1結合物(DM1-Bdd)使具有BC之小鼠的總存活率提高(圖4h)。與藉由膀胱內給予之相同處理相比,其亦更有效(圖4f-i)。考慮到動物無需在靜脈內注射之後不久排泄,預期功效提高(圖4a)。促進腎臟清除可降低藥物之脫靶毒性。DM1-Bdd未誘發不必要之毒性(圖6)。相比之下,用DM1或CIS處理之動物顯示肝損傷及腎損傷之證據。藉由使用aldox-Bdd來治療BC,亦展示UDD方法降低藥物誘導之毒性的靈活性。不同於引起死亡之游離DOX,觀測到用aldox-Bdd處理之彼等動物中存活率提高(圖9)。然而,與DM1-Bdd相比,aldox-Bdd處理僅減緩癌症進展且未消除個別動物中之腫瘤。結果並不意外,因為DM1比DOX更有效力(圖3c)。
ITC係一種僅覆蓋膀胱中之腫瘤的局部治療,因為藥物溶液無法到達上泌尿道。DM1-Bdd經由靜脈內注射投與。此連同快速腎臟清除一起將允許藥物沖洗整個URS。應用DM1-Bdd來治療腎癌,且發現與游離藥物相比,DM1-Bdd提供顯著存活率益處。實際上,完成處理過程後一週,大約50%之動物缺乏總體或組織學腫瘤證據。因此,當用於治療BC時靜脈內藥物投與將允許更全面地覆蓋URS,因為腫瘤可能延伸、遷移至整個尿道上皮中或在其中復發,包括腎盂及輸尿管,其中8-12%尿道上皮癌來源於腎盂及輸尿管。當前,當治療患有腎盂或輸尿管腫瘤之患者時,為防止URS腫瘤之疾病復發,醫師通常除了移除整個腎臟及輸尿管外別無選擇(即使當腫瘤為非侵襲性時)。DM1-Bdd可能成為上尿道上皮癌患者之保留腎臟之治療選擇。
ITC之一個缺點為患者順應率較差(16-30%)。接受ITC之患者需要每週由醫院/臨床之經培訓之人員插入導管。相比之下,靜脈內DM1-Bdd治療為非侵入性的,此可避免與導管插入程序相關之併發症且提高患者生活品質及順應性。BC之壽命管理成本高,因為其復發率高,所以需要反覆治療。諸如DM1-Bdd之化學治療劑的全身性投與將可能降低住院成本。
總體而言,已研發出UDD方法,其可使其他器官中之非特異性累積降至最低且藉由向整個URS供應藥物而提供全面治療,成為ITC之更有效替代方案。所研發之DM1-Bdd係可在臨床上轉化的。FDA已批准許多肽用於治療不同癌症。所採用之DM1係一種已用於抗體-藥物結合物,諸如赫賽汀(Herceptin)-DM1(T-DM1)中進行乳癌治療之活性藥效基團。
以引用的方式併入 本文所提及之所有公開案及專利均以全文引用的方式併入本文中,其引用的程度如同特定且個別地指示各個別公開案或專利以引用的方式併入一般。在有衝突之情況下,將以本申請案(包括本文中之任何定義)為凖。
同等物
儘管已論述本揭示案之特定實施例,但以上說明書為例示性而非限制性的。當回顧本說明書及隨附申請專利範圍時,對於熟習此項技術者而言,本揭示案之許多變化形式將變得顯而易見。本揭示案之完整範疇以及其同等物及本說明書以及此類變化形式之完整範疇,應參照申請專利範圍來確定。
無
圖 1.Bdd顯示顯著之泌尿道處置特性。(A)習知膀胱內化學療法(ITC)係侵入性的,且藥物遞送限於膀胱。Bdd經設計以攜帶多個負電荷,該等負電荷將脫靶遞送降至最低且在靜脈內(i.v.)投與之後促進腎排泄。當用作藥物載劑時,Bdd促進藥物沈積至整個尿道上皮系統中且提供連續藥物排泄,實現更全面之治療。(B)展示BDD之組分及淨電荷以及其
D-組態(Bdd)、不帶電荷(BKD)、帶正電荷(BKK)及聚乙二醇化(PEG
3DD)對應物的表。(C)展示用
89Zr對肽進行放射性標記以用於比較PK及生物分佈研究之合成流程。(D)在經由尾靜脈注射投與不同的經
89Zr放射性標記之肽(20 μCi,20 μg,在100 μL PBS中)後1小時、4小時及24小時獲取之BALB/c小鼠的代表性μPET/CT影像(n=4/組)。在排空或不排空動物膀胱下獲取全身影像。(E)展示在投與
89Zr-Bdd之後不同時間間隔自動物(n=5)收集之尿液樣品(20 μL)中放射性之量的長條圖。(F)比較經放射性標記之肽之腎臟清除。曲線圖展示隨著時間推移動物腎臟(每cc)中注射劑量之百分比(% ID)。根據在所獲取之PET影像之感興趣區域(ROI)量測之放射性計算ID/cc百分比。(G)比較經放射性標記之肽的藥物動力學(PK)概況(n=4/類似物)。在將肽或游離
89Zr注射至動物之後多個時間間隔收集血液樣品(20 μL)。將結果(在血液樣品中量測之放射性)擬合成雙室模型,用於確定t
1/2α(分佈相半衰期)及t
1/2β(消除相半衰期)。圖7a中可利用其他PK參數。(H)
89Zr-Bdd之終點生物分佈研究。在投與肽(20 μCi,20 μg,在100 μL PBS中)之後不同時間間隔(n=4/時間點)處死動物。確定所採集之器官中之肽的量(放射性)。結果(根據衰變校正)表示為% ID。(斯圖登氏t檢驗(Student's t-test);**p<0.01,及***p<0.001)。
圖 2.Bdd有效地使結合之花青5.5螢光團分佈至泌尿系統。(A)經花青5.5標記之肽(Cy-肽)類似物的合成流程。(B)在尾靜脈注射不同Cy-肽類似物(0.5 nmol,150 μL)或游離花青5.5之後1小時及4小時獲取的SCID小鼠之代表性合併螢光/白光影像(n=4/組)。(C)基於量測之螢光比較尿液中螢光團之量(注射劑量%)的圖。(下圖)在投與肽或螢光團之後1小時自動物收集之尿液樣品(20 μL)的螢光影像。(D)在尾靜脈注射不同Cy-肽之後4小時自動物採集之器官的代表性離體合併螢光/亮光影像(n=4/組)。(E)基於總螢光強度比較所採集器官(n=4/組)中之肽分佈的長條圖。(斯圖登氏t檢驗;*p<0.05,**p<0.01及***p<0.001)。
圖 3.Bdd作為化學治療劑之載劑。(A)Bdd未觸發任何先天性免疫反應。在靜脈內投與Bdd肽(5 mg/kg)之後24小時在雌性BALB/c小鼠(n=3/組)之血漿中未偵測到發炎性細胞介素濃度增加。LPS用作陽性對照且藉由ELISA套組量測各細胞介素之濃度。(B)經花青5.5標記之Bdd(Cy-Bdd)之細胞攝取。與Cy-Bdd(0.5 nmol)一起培育6小時及24小時之人類UMUC-3 BC細胞及鼠類Renca腎腺癌細胞的代表性螢光顯微影像。Dapi(9 μM)及LysoTracker-GFP(1 μM)分別用於進行細胞核(藍色)及細胞器(綠色)染色,且在成像之前30分鐘添加至細胞中。比例尺為25 μm。(C)比較不同化學治療劑(DM1、GEM、MIT、CIS及DOX)之效力。將UMUC-3及Renca細胞與藥物一起在多種濃度下培育72小時,然後量測細胞活力。使用Graph Pad Prism 6.0軟體繪製劑量反應曲線且計算各藥物之半最大抑制濃度(IC
50值)。(D)DM1與Bdd之結合。可裂解連接子SPDP首先在固相中結合於肽N端。接著在PBS與NMP之溶液混合物中將DM1添加至裂解之肽中。(E)展示在缺乏及存在GSH(1 mM)下PBS中隨著時間推移自DM1-Bdd釋放之累積DM1之百分比的圖。使用HPLC分析來定量所釋放之藥物之量(在254 nm下偵測吸光度)。(F)aldox與Bdd結合。將補充有N端半胱胺酸之肽與含aldox之PBS(pH = 7.4)一起培育30分鐘,隨後藉由HPLC在中性條件下純化。(G)展示具有不同pH值之PBS緩衝液中隨著時間推移自aldox-Bdd(100 μM)釋放之累積DOX活性代謝物之百分比的圖。使用HPLC分析來定量所釋放之藥物之量(在480 nm下偵測吸光度)。(H)DM1-Bdd顯示與游離藥物相比相似的針對鼠類膀胱(MB49)、人類膀胱(UMUC-3及T24)及鼠類腎臟(Renca)癌細胞株之細胞毒性。相對細胞活力針對藥物濃度之曲線圖。(I)aldox-Bdd比游離aldox更有效。相對細胞活力針對藥物濃度之曲線圖。
圖 4.DM1-Bdd治療膀胱癌之治療功效。(A)比較在靜脈內(i.v.)或膀胱內(i.t.)投與PBS(80 μL)之後BALB/c小鼠(n=20/組)自然排泄所需之時間的長條圖。在開始實驗之前將膀胱排空。將各動物隔離以監測排尿模式。(B)比較DM1-Bdd與其他化學治療劑之腎毒性。展示在經由尾靜脈注射用PBS、DM1(0.75 mg/kg)、DM1-Bdd(0.75 mg/kg藥物含量)、MIT(0.75 mg/kg)、CIS(0.75及10 mg/kg)或GEM(0.75 mg/kg)處理後1天、3天及7天,自動物收集之尿液中腎損傷生物標記物NGAL及KIM-1之濃度的長條圖。(斯圖登氏t檢驗;*p<0.05,**p<0.01及***p<0.001)。(C)亦針對NGAL及KIM1進行免疫染色。來自經靜脈內投與PBS、DM1(0.75 mg/kg)、DM1-Bdd(0.75 mg/kg藥物含量)或作為陽性對照之CIS(10 mg/kg)之BALB/c小鼠的腎切片之代表性顯微影像。在藥物處理之後3天採集器官且用H&E染色。黑色箭頭指示用CIS處理後腎小管上皮細胞之多灶性退化。紅色及綠色箭頭分別指示在CIS處理之後對NGAL及KIM-1具有免疫反應性之腎小管上皮細胞。比例尺為50 μm。(D)經攜帶GFP與螢火蟲螢光素酶基因二者之慢病毒穩定轉導的UMUC-3/GFP-Luc細胞之明視野及螢光影像。比例尺為80 μm。(E)原位異種移植模型。在植入UMUC-3/GFP-Luc細胞(4×10
4個細胞/動物)之後1週自雌性NSG小鼠(n=3)收集之膀胱的代表性影像。黑色箭頭指示在固有層中生長之腫瘤。比例尺為500 μm。(F)在每週用靜脈內PBS(150 μL)、靜脈內DM1(0.75 mg/kg,150 μL)、靜脈內DM1-Bdd(0.75 mg/kg藥物含量,150 μL)、膀胱內MIT(1 mg/mL,50 μL)、膀胱內DM1(0.75 mg/kg,50 μL)或膀胱內DM1-Bdd(0.75 mg/kg,50 μL)處理一次歷時3週之後,負載腫瘤動物之代表性合併生物發光/明視野影像(n=10/組)。每週獲取影像以監測且比較各處理組中之腫瘤生長。(G)在完成治療週期之後1週自各動物組(額外募集n=3/處理組)切除之膀胱的代表性圖片。(H)投與不同藥物之動物的卡普蘭-邁耶累積存活率圖(Kaplan-Meier cumulative survival plot)(n=14/組)。使用曼特爾-考克斯對數秩檢驗(Mantel-Cox log-rank test)及本傑明霍赫貝格調整之p值(Benjamini Hochberg adjusted p-value)評估用靜脈內DM1-Bdd處理之動物與其他組之間存活率之顯著差異。(i-j)來自各處理組中之動物之膀胱切片的代表性影像(n=3/組)。在3週處理結束時採集器官且接著進行石蠟包埋,切片且經(I)H&E及(J)Ki67(增生標記物)染色。
圖 5.DM1-Bdd治療腎癌之治療功效。(A)經攜帶GFP與螢火蟲螢光素酶基因二者之慢病毒穩定轉導的Renca細胞之明視野及螢光影像。比例尺為80 μm。(B)同基因型異種移植模型。在腎被膜(renal capsule)(黑色箭頭)中植入鼠類Renca細胞(4×10
3個細胞/動物)之後1週,自雌性BALB/c小鼠(n=3)收集之腎臟的組織學分析之代表性影像。比例尺1 mm。(C)在每週用靜脈內PBS(150 μL)、靜脈內DM1(0.75 mg/kg,150 μL)、靜脈內DM1-Bdd(0.75 mg/kg藥物含量,150 μL)或膀胱內DM1(0.75 mg/kg,50 μL)處理一次歷時3週後負載Renca/GFP-Luc腫瘤之動物的代表性合併生物發光/明視野影像(n=10/組)。(D)完成治療週期後自動物切除之腎臟的代表性相片(額外n=4/組)。在接受不同處理之動物(n=14/組)當中縱向比較(E)感興趣區域(ROI=腎臟)之生物發光信號、(F)體重及(G)存活率。使用曼特爾-考克斯對數秩檢驗及本傑明霍赫貝格調整之p值評估用靜脈內DM1-Bdd及藥物處理之動物之間存活率之顯著差異。(H)來自各處理組之動物的代表性腎切片(額外n=4/組)。將切片用H&E染色。綠色、黃色、黑色及藍色箭頭分別指示負載色素之巨噬細胞、病灶性礦化、間質纖維化及單核細胞浸潤之存在。比例尺為2 mm及50 μm。
圖 6.DM1-Bdd顯示安全毒性概況。(A)在每週靜脈內投與PBS、DM1(0.75 mg/kg)、DM1-Bdd(0.75 mg/kg藥物含量)或作為陽性對照之CIS(10 mg/kg)一次歷時3週之後自雌性BALB/c小鼠收集之血液抹片的代表性顯微影像。黑色箭頭指示多染性大紅血球。比例尺為10 μm。(B)在完成不同處理過程之後一週獲得的選定血液結果。(RBC=紅血球及WBC=白血球)。(斯圖登氏t檢驗;*p<0.05,**p<0.01及***p<0.001)。(C)比較選定血清生化分析物,包括肝臟酶活性(ALP、ALT及AST)、肌肉酶活性(AST及CK)及含氮廢物之清除率(BUN/CREA比率)。(ALP = 鹼性磷酸酶;ALT = 丙胺酸轉胺酶;AST = 天冬胺酸轉胺酶;CK = 肌酸激酶;BUN = 血尿素氮;CREA = 肌酸)。(D)來自投與不同藥物處理之動物的重要器官(肝、脾、心、肺及腎)之組織病理學分析。黑色箭頭指示肝臟中肝細胞有絲分裂活性增加。藍色箭頭顯示增強之肝及脾髓外造血(EMH)。白色箭頭之間的區域指示脾之紅髓中紅血球及EMH要素之耗乏。紅色箭頭突出顯示肺泡中大巨噬細胞及泡沫狀巨噬細胞之存在。黃色及綠色箭頭分別指示內腔內所含之扁平腎小管細胞及瀕死細胞之壞死脫落碎片。比例尺為30 μm。
圖 7.(A)比較經放射性標記之肽的藥物動力學參數(n=4/類似物)的表。在經尾靜脈將肽或游離
89Zr(20 μCi,20 μg,100 μL PBS中)注射至動物之後多個時間間隔收集血液樣品(20 μL)。將結果(在血液樣品中量測之放射性)擬合成雙室模型以確定PK參數。(k
10= 消除速率常數;k
12及k
21= 轉移速率常數;t
1/2α= 分佈相半衰期;t
1/2β= 消除相半衰期;C
0= 藥物濃度之消除閾值;V
d= 表觀分佈體積;CL = 總清除率;AUC = 曲線下面積;MRT = 平均滯留時間;及V
ss= 穩態分佈體積)。(B)
89Zr-Bdd之終點生物分佈研究。在投與肽之後不同時間間隔處死動物(n=4/時間點)。確定所採集之器官中之肽的量(放射性)。結果(根據衰變校正)表示為每公克組織之注射劑量%(% ID/g)。(斯圖登氏t檢驗;*p<0.05及***p<0.001)。
圖 8.(A)負載膀胱腫瘤且每週用靜脈內PBS(150 μL)、靜脈內DM1(0.75 mg/kg,150 μL)、靜脈內DM1-Bdd(0.75 mg/kg藥物含量,150 μL)、膀胱內MIT(1 mg/mL,50 μL)、膀胱內DM1(0.75 mg/kg,50 μL)或膀胱內DM1-Bdd(0.75 mg/kg,50 μL)處理一次歷時3週的NSG小鼠之體重變化。(B)不同藥物當中感興趣區域(ROI=膀胱)之生物發光信號的比較。(C)自投與不同藥物處理之3隻動物切除的膀胱之代表性影像。(d-e)比較膀胱之體積(D)及重量(E)之圖。(斯圖登氏t檢驗;*p<0.05,**p<0.01及***p<0.001)。(F)來自各處理組中之動物之膀胱切片的代表性影像(n=3/組)。在3週處理結束時採集器官且接著進行石蠟包埋,切片且用抗GFP抗體染色以鑑別表現GFP之腫瘤細胞。(G)來自在靜脈內DM1-Bdd處理之後缺乏總體及組織學腫瘤證據的3隻動物之膀胱切片的代表性影像。在腫瘤植入之後210天處死動物且採集器官,進行石蠟包埋,切片,且經H&E、Ki67(增生標記物)及抗GFP抗體染色。
圖 9.(A)在每週用靜脈內PBS(150 μL)、靜脈內DOX(5 mg/kg,150 μL)、靜脈內aldox-Bdd(5 mg/kg藥物含量,150 μL)或膀胱內DOX(5 mg/kg,50 μL)處理一次歷時3週後,負載原位植入之UMUC-3/GFP-Luc膀胱腫瘤之NSG小鼠的代表性合併生物發光/明視野影像(n=10/組)。每週獲取影像以監測且比較各處理組中之腫瘤生長。(B)不同處理組當中感興趣區域(ROI=膀胱)之生物發光信號的比較。(C)投與不同藥物之動物的卡普蘭-邁耶累積存活率圖(n=10/組)。使用曼特爾-考克斯對數秩檢驗及本傑明霍赫貝格調整之p值評估用靜脈內aldox-Bdd處理之動物與其他組之間存活率之顯著差異。(D)負載膀胱腫瘤且每週用PBS、靜脈內DOX、靜脈內aldox-Bdd或膀胱內DOX處理一次歷時3週的NSG小鼠之體重變化。(E)用靜脈內DOX(5 mg/kg)處理之小鼠在僅投與2劑藥物之後的代表性圖片。
圖 10.全血球計數分析之延伸結果。展示在BALB/c小鼠中每週靜脈內投與PBS、DM1(0.75 mg/kg)、DM1-Bdd(0.75 mg/kg藥物含量)或用作陽性對照之CIS(10 mg/kg)一次歷時3週之後的血液結果之表。(RBC = 紅血球;HGB = 血紅素;HCT = 血容比;MCV = 平均紅血球體積;MCH = 平均紅血球血紅素;MCHC = 平均紅血球血紅素濃度;RDW = 紅血球分佈寬度;RET = 網狀紅血球;PLT = 血小板;PDW = 血小板分佈寬度;MPV = 平均血小板體積;WBC = 白血球;NEUT = 嗜中性球;LYMPH = 淋巴球;MONO = 單核球;EO = 嗜酸性球;及BASO = 嗜鹼性球)。
圖 11.血清生化分析之延伸結果。展示在BALB/c小鼠中每週靜脈內投與PBS、DM1(0.75 mg/kg)、DM1-Bdd(0.75 mg/kg藥物含量)或用作陽性對照之CIS(10 mg/kg)一次歷時3週之後量測的所有生化分析物結果之表。(BUN = 血尿素氮;CREA = 肌酐;ALP = 鹼性磷酸酶;ALT = 丙胺酸轉胺酶;AST = 天冬胺酸轉胺酶;GGT = γ-麩胺醯基轉移酶;BIL = 膽紅素;TP = 總蛋白;ALB = 白蛋白;GLOB = 球蛋白;A/G = 白蛋白/球蛋白;P = 磷酸酯;Ca = 鈣;GLU = 葡萄糖;CHOL = 膽固醇;TRIG = 三酸甘油酯;CK = 肌酸激酶;TCO2 = 總二氧化碳;Na = 鈉;K = 鉀;及CL = 氯離子)。
圖 12.來自每週投與靜脈內DM1(0.75 mg/kg)及作為陽性對照之靜脈內CIS(10 mg/kg)一次歷時3週之動物的重要器官切片(肝、脾、肺及腎)之高放大率影像。將切片用H&E染色。黑色箭頭指示肝臟中肝細胞有絲分裂活性增加。藍色箭頭顯示增強之肝及脾髓外造血(EMH)。白色箭頭之間的區域指示脾之紅髓中紅血球及EMH要素之耗乏。紅色箭頭突出顯示肺泡中大巨噬細胞及泡沫狀巨噬細胞之存在。黃色及綠色箭頭分別指示內腔內所含之扁平腎小管細胞及瀕死細胞之壞死脫落碎片。比例尺為10 μm。
Claims (41)
- 如前述請求項中任一項所述之化合物,其中該肽在生理pH值下具有約-30 mV至+20 mV之ζ電位。
- 如請求項3所述之化合物,其中該肽在生理pH值下具有約-20 mV至0 mV之ζ電位。
- 如請求項4所述之化合物,其中該肽在生理pH值下具有約-5 mV至0 mV之ζ電位。
- 如請求項2至5中任一項所述之化合物,其中該連接子包含選自以下之一個或多個基團:醯胺、醯亞胺、硫脲、硫醚、二硫基、烷基、芳基、聚醚、腙、酯、碳酸酯、縮酮及矽烷基醚。
- 如請求項2至6中任一項所述之化合物,其中該活性部分為治療劑或顯影劑。
- 如請求項2至9中任一項所述之化合物,其中該β-胺基酸殘基不包含可電離側鏈。
- 如請求項2至10中任一項所述之化合物,其中該β-胺基酸殘基為β-丙胺酸殘基。
- 如請求項2至11中任一項所述之化合物,其中X為β-丙胺酸殘基。
- 如請求項2所述之化合物,其中各α-胺基酸殘基獨立地選自天冬胺酸殘基及麩胺酸殘基。
- 如請求項2所述之化合物,其中至少一個α-胺基酸殘基為非天然胺基酸殘基。
- 如請求項14所述之化合物,其中該非天然α-胺基酸殘基具有至少兩個側鏈羧酸基。
- 如請求項15所述之化合物,其中該非天然α-胺基酸殘基係選自2-胺基乙烷-1,1,2-三甲酸殘基及2-胺基丙烷-1,2,3-三甲酸殘基。
- 如請求項13所述之化合物,其中各Y及Z為天冬胺酸殘基。
- 如請求項17所述之化合物,其中各Y及Z為D-天冬胺酸殘基。
- 如請求項2所述之化合物,其中X、Y及Z各自獨立地選自β-丙胺酸殘基、天冬胺酸殘基及麩胺酸殘基。
- 如請求項2至19中任一項所述之化合物,其中m為4。
- 如請求項2至21中任一項所述之化合物,其中該連接子包含衍生自N-丁二醯亞胺基3-(2-吡啶基二硫基)丙酸酯或丁二醯亞胺基4-(N-順丁烯二醯亞胺基甲基)環己烷-1-甲酸酯之基團。
- 如前述請求項中任一項所述之化合物,其中該活性部分為治療劑。
- 如前述請求項中任一項所述之化合物,其中該治療劑係選自抗癌劑、抗生素、治療膀胱過動症之藥劑、治療尿失禁之藥劑、治療間質性膀胱炎之藥劑及治療腎結石之藥劑。
- 如請求項23所述之化合物,其中該治療劑係選自13-順維他命A酸(13-cis-Retinoic Acid)、2-氯去氧腺苷(2-Chlorodeoxyadenosine)、5-阿紮胞苷(5-Azacitidine)、5-氟尿嘧啶(5-Fluorouracil)、6-巰嘌呤(6-Mercaptopurine)、6-硫鳥嘌呤(6-Thioguanine)、放射菌素-D(actinomycin-D)、阿德力黴素(adriamycin)、阿地介白素(aldesleukin)、阿侖妥珠單抗(alemtuzumab)、阿利維甲酸(alitretinoin)、全反維他命A酸(all-transretinoic acid)、α干擾素(alpha interferon)、六甲蜜胺(altretamine)、胺甲喋呤(amethopterin)、阿米福汀(amifostine)、阿那格雷(anagrelide)、阿那曲唑(anastrozole)、阿拉伯糖基胞嘧啶(arabinosylcytosine)、三氧化二砷(arsenic trioxide)、安吖啶(amsacrine)、胺基喜樹鹼(aminocamptothecin)、胺麩精(aminoglutethimide)、天冬醯胺酸酶(asparaginase)、阿紮胞苷(azacytidine)、卡介苗(bacillus calmette-guerin,BCG)、苯達莫司汀(bendamustine)、貝伐單抗(bevacizumab)、貝沙羅汀(bexarotene)、比卡魯胺(bicalutamide)、硼替佐米(bortezomib)、博萊黴素(bleomycin)、硫酸布他卡因(busulfan)、甲醯四氫葉酸鈣(calcium leucovorin)、嗜橙菌因子(citrovorum factor)、卡培他濱(capecitabine)、卡奈替尼(canertinib)、卡鉑(carboplatin)、雙氯乙基亞硝脲(carmustine)、西妥昔單抗(cetuximab)、氯芥苯丁酸(chlorambucil)、順鉑(cisplatin)、克拉屈濱(cladribine)、可體松(cortisone)、環磷醯胺(cyclophosphamide)、阿糖胞苷(cytarabine)、阿法達貝泊汀(darbepoetin alfa)、達沙替尼(dasatinib)、柔紅黴素(daunomycin)、地西他濱(decitabine)、地尼介白素(denileukin diftitox)、地塞米松(dexamethasone)、地沙松(dexasone)、右雷佐生(dexrazoxane)、放線菌素D(dactinomycin)、道諾黴素(daunorubicin)、達卡巴嗪(decarbazine)、多西他賽(docetaxel)、多柔比星(doxorubicin)、多希(doxil)、阿多比欣(aldoxorubicin)、去氧氟尿苷(doxifluridine)、依決洛單抗(edrecolomab)、恩尿嘧啶(eniluracil)、表柔比星(epirubicin)、阿法依泊汀(epoetin alfa)、埃羅替尼(erlotinib)、依維莫司(everolimus)、伊析美斯坦(exemestane)、雌莫司汀(estramustine)、依託泊苷(etoposide)、非格司亭(filgrastim)、氟羥甲基睪酮(fluoxymesterone)、氟維司群(fulvestrant)、夫拉平度(flavopiridol)、氟尿苷(floxuridine)、氟達拉濱(fludarabine)、氟尿嘧啶(fluorouracil)、氟他胺(flutamide)、吉非替尼(gefitinib)、吉西他濱(gemcitabine)、吉妥珠單抗奧唑米星(gemtuzumab ozogamicin)、戈舍瑞林(goserelin)、顆粒球群落刺激因子、顆粒球巨噬細胞群落刺激因子、六甲三聚氰胺(hexamethylmelamine)、氫化可體松(hydrocortisone)羥基脲(hydroxyurea)、布突默單抗(ibritumomab)、替伊莫單抗(ibritumomab tiuxetan)、干擾素α(interferon alpha)、介白素-2(interleukin-2)、介白素-11(interleukin-11)、異維甲酸(isotretinoin)、伊沙匹隆(ixabepilone)、艾達黴素(idarubicin)、甲磺酸伊馬替尼(imatinib mesylate)、依弗醯胺(ifosfamide)、伊立替康(irinotecan)、拉帕替尼(lapatinib)、來那度胺(lenalidomide)、利妥唑(letrozole)、甲醯四氫葉酸(leucovorin)、亮丙立德(leuprolide)、脂質體Ara-C(liposomal Ara-C)、洛莫司汀(lomustine)、甲基二(氯乙基)胺(mechlorethamine)、甲地孕酮(megestrol)、黴法蘭(melphalan)、巰嘌呤(mercaptopurine)、美登素(mertansine)、美司鈉(mesna)、胺甲喋呤(methotrexate)、甲基普賴蘇穠(methylprednisolone)、絲裂黴素C(mitomycin C)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、奈拉濱(nelarabine)、尼魯米特(nilutamide)、奧曲肽(octreotide)、奧普瑞介白素(oprelvekin)、奧沙利鉑(oxaliplatin)、紫杉醇(paclitaxel)、帕米膦酸鹽(pamidronate)、培美曲塞(pemetrexed)、帕尼單抗(panitumumab)、PEG干擾素、培門冬酶(pegaspargase)、派非格司亭(pegfilgrastim)、PEG-L-天冬醯胺酸酶、噴司他丁(pentostatin)、普卡黴素(plicamycin)、普賴蘇穠(prednisolone)、普賴松(prednisone)、丙卡巴肼(procarbazine)、雷洛昔芬(raloxifene)、利妥昔單抗(rituximab)、羅米司亭(romiplostim)、雷替曲塞(ralitrexed)、沙帕他濱(sapacitabine)、沙格司亭(sargramostim)、賽特鉑(satraplatin)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、司莫司汀(semustine)、鏈脲菌素(streptozocin)、他莫昔芬(tamoxifen)、喃氟啶(tegafur)、喃氟啶-尿嘧啶(tegafur-uracil)、坦羅莫司(temsirolimus)、替莫唑胺(temozolamide)、替尼泊苷(teniposide)、沙利多邁(thalidomide)、硫鳥嘌呤(thioguanine)、噻替哌(thiotepa)、拓樸替康(topotecan)、托瑞米芬(toremifene)、托西莫單抗(tositumomab)、曲妥珠單抗(trastuzumab)、曲妥珠單抗恩他新(trastuzumab emtansine)、視網酸(tretinoin)、三甲曲沙(trimitrexate)、阿魯比辛(alrubicin)、長春新鹼(vincristine)、長春花鹼(vinblastine)、長春地辛(vindestine)、長春瑞賓(vinorelbine)、伏立諾他(vorinostat)及唑來膦酸(zoledronic acid)。
- 如請求項2至25中所述任一項之化合物,其中該治療劑為抗癌劑。
- 如請求項26所述之化合物,其中該抗癌劑係選自美登素、多柔比星、達沙替尼、順鉑、絲裂黴素、吉西他濱及紫杉醇。
- 如請求項2所述之化合物,其中, X為β-丙胺酸殘基;且 Y及Z為D-天冬胺酸殘基。
- 如請求項2所述之化合物,其中, X為β-丙胺酸殘基; Y及Z為D-天冬胺酸殘基;且 m為4。
- 如請求項2所述之化合物,其中, X為β-丙胺酸殘基; Y及Z為D-天冬胺酸殘基; m為4; 該連接子包含二硫基;且 該活性部分為美登素。
- 一種醫藥組合物,其包含如前述請求項中任一項所述之化合物。
- 如請求項33所述之醫藥組合物,其中該組合物經調配用於靜脈內投與。
- 一種治療癌症、泌尿道感染、膀胱過動症、尿失禁、間質性膀胱炎或腎結石之方法,其包含向有需要之患者投與如前述請求項中任一項所述之化合物或組合物。
- 一種治療癌症之方法,其包含向有需要之患者投與如前述請求項中任一項所述之化合物或組合物。
- 如請求項36所述之方法,其中該癌症係腎癌或泌尿道癌。
- 如請求項37所述之方法,其中該癌症係膀胱癌。
- 如請求項38所述之方法,其中該膀胱癌係非肌層侵襲性膀胱癌。
- 如請求項39所述之方法,其中該膀胱癌係尿道上皮癌。
- 如請求項35至40中任一項所述之方法,其中該化合物係靜脈內投與。
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US5541231A (en) | 1993-07-30 | 1996-07-30 | Glaxo Wellcome Inc. | Stabilized Pharmaceutical |
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US5358970A (en) | 1993-08-12 | 1994-10-25 | Burroughs Wellcome Co. | Pharmaceutical composition containing bupropion hydrochloride and a stabilizer |
US6110973A (en) | 1998-01-29 | 2000-08-29 | Sepracor | Methods for treating obesity and weight gain using optically pure (-)-bupropion |
GB9929801D0 (en) | 1999-12-16 | 2000-02-09 | Btg Int Ltd | Anti-cancer agents iii |
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JP4696079B2 (ja) | 2003-12-17 | 2011-06-08 | ヤンセン アルツハイマー イミュノセラピー | Aβ免疫原性ペプチド担体結合物およびそれの製造方法 |
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WO2009151687A2 (en) | 2008-03-12 | 2009-12-17 | The Regents Of The University Of Michigan | Dendrimer conjugates |
US8889635B2 (en) | 2008-09-30 | 2014-11-18 | The Regents Of The University Of Michigan | Dendrimer conjugates |
US8852599B2 (en) | 2011-05-26 | 2014-10-07 | Bristol-Myers Squibb Company | Immunoconjugates, compositions for making them, and methods of making and use |
WO2014152460A2 (en) | 2013-03-15 | 2014-09-25 | Indiana University Research And Technology Corporation | Prodrugs with prolonged action |
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