隋芳茜,李杰雨,楊山景,姜海梅,楊詩(shī)宇,李凌軍,蔡曉青
基于刺激響應(yīng)及靶向因子修飾載多烯紫杉醇納米遞送系統(tǒng)的研究進(jìn)展
隋芳茜,李杰雨,楊山景,姜海梅,楊詩(shī)宇,李凌軍*,蔡曉青*
山東中醫(yī)藥大學(xué)藥學(xué)院,山東 濟(jì)南 250355
多烯紫杉醇是天然抗腫瘤藥物紫杉醇的衍生物,具有廣譜、高效的抗腫瘤活性,但其溶解性低、組織分布廣,限制了臨床應(yīng)用。刺激響應(yīng)型納米遞送系統(tǒng)憑借其載體材料結(jié)構(gòu)的多元性、環(huán)境敏感釋藥性,有效改善了多烯紫杉醇這些缺陷,在此基礎(chǔ)上,修飾靶向因子可使藥物靶向遞送,改變藥物的組織分布,進(jìn)一步提高抗腫瘤效果。綜述近年多烯紫杉醇刺激響應(yīng)型及靶向因子修飾納米遞送系統(tǒng)的研究進(jìn)展,提出其發(fā)展面臨的挑戰(zhàn)及未來(lái)趨勢(shì)等關(guān)鍵問(wèn)題,以期為多烯紫杉醇在抗腫瘤藥物的研究開(kāi)發(fā)方面提供參考。
多烯紫杉醇;刺激響應(yīng);靶向因子;抗腫瘤;納米遞送系統(tǒng)
世界衛(wèi)生組織國(guó)際癌癥研究機(jī)構(gòu)的最新數(shù)據(jù)顯示,2020年全球新發(fā)癌癥病例1929萬(wàn),其中死亡病例996萬(wàn),癌癥負(fù)擔(dān)不斷上升。結(jié)合調(diào)節(jié)免疫、未病先防、增效減毒等中醫(yī)藥基礎(chǔ)理論,多糖類(lèi)、萜類(lèi)、生物堿類(lèi)等天然抗腫瘤藥物通過(guò)抑制腫瘤增殖、誘導(dǎo)腫瘤細(xì)胞凋亡等發(fā)揮抗腫瘤作用,但很多天然抗腫瘤藥物存在選擇性差、易多藥耐藥、生物利用度低等問(wèn)題[1]。多烯紫杉醇(docetaxel,DTX)是萜類(lèi)抗腫瘤藥紫杉醇的衍生物,以其廣譜抗腫瘤活性備受研究者關(guān)注,但低溶低滲、生物分布廣、不良反應(yīng)大的特點(diǎn)限制其臨床應(yīng)用[2]。
靶向遞藥系統(tǒng)憑借其載體材料結(jié)構(gòu)的多元性、修飾因子的多樣性,可有效改善化療藥物缺陷,提高藥物療效,在腫瘤治療中顯示出巨大潛力。未經(jīng)修飾的脂質(zhì)體、納米粒、膠束、微囊等傳統(tǒng)遞藥系統(tǒng),主要借助非特異性的腫瘤高通透性和滯留效應(yīng)[3],使藥物富集于腫瘤部位,但藥物極易在肝、脾、腎等組織中蓄積。通過(guò)響應(yīng)腫瘤微環(huán)境內(nèi)源性刺激(低pH[4]、強(qiáng)還原性[5]、過(guò)表達(dá)的酶[6]等)及外源性刺激(光、超聲、溫度等)[7-8]設(shè)計(jì)納米遞送系統(tǒng)可以實(shí)現(xiàn)藥物在病灶部位快速釋放,此類(lèi)遞藥系統(tǒng)已有大量文獻(xiàn)報(bào)道。此外,將一些靶向因子(如抗體、配體及前體藥物等)利用物理或化學(xué)方法連接到載體表面可以進(jìn)一步使藥物定向輸送到靶點(diǎn)發(fā)揮藥效[9-10]。
當(dāng)前基于新型靶向遞藥系統(tǒng)的研究主要集中在創(chuàng)新性的載體材料[11]、不同刺激響應(yīng)[12]和不同修飾因子[13]等方面,故本文著重介紹DTX刺激響應(yīng)型納米藥物遞送系統(tǒng)(nanoparticles drug delivery system,NDDS)的研究進(jìn)展,分析其功能機(jī)制(圖1)及體內(nèi)外抗腫瘤效果,并對(duì)常用于修飾納米載體的靶向因子進(jìn)行總結(jié),以期為DTX新型制劑的研究開(kāi)發(fā)提供思路。
圖1 DTX-NDDS的刺激響應(yīng)行為
腫瘤細(xì)胞糖酵解產(chǎn)生大量乳酸[14],造成人體正常組織(pH 7.4)與腫瘤組織(pH 6.5~7.2)的pH環(huán)境差異,細(xì)胞內(nèi)細(xì)胞器中也存在pH梯度,如溶酶體的pH值在4.5~5.5[15],這種pH差異在提高納米制劑靶向性方面發(fā)揮了重要作用。pH響應(yīng)一方面可以利用基團(tuán)質(zhì)子化使納米材料化學(xué)構(gòu)象改變而釋放藥物,如聚(β-氨基酯)、殼聚糖等。聚(β-氨基酯)可在低pH條件下胺基質(zhì)子化釋放藥物,在pH響應(yīng)材料中應(yīng)用較早[16]。殼聚糖同樣具有氨基質(zhì)子化作用,且成本低,具有低免疫原性和良好的生物降解性[17]。還有報(bào)道基于兩親性材料聚乙二醇-聚(ω-十五內(nèi)酯-共--甲基二乙醇胺-共-2,2-硫代二乙醇)制備DTX膠束,在低pH刺激下,膠束核心中硫醚基團(tuán)質(zhì)子化而響應(yīng)性釋藥[18]。另一方面NDDS通過(guò)酸敏感的化學(xué)鍵斷裂實(shí)現(xiàn)pH響應(yīng),如腙鍵、肼鍵[19]等。有研究以低聚倍半硅氧烷為剛性核,將DTX通過(guò)腙鍵連接到接枝物上,繼而包載入剛性核中制備N(xiāo)DDS,在酸性溶酶體環(huán)境下,DTX被刺激釋放[20]。
為進(jìn)一步利用pH響應(yīng)性增強(qiáng)NDDS靶向釋藥,研究者結(jié)合納米粒表面電性制備出基于pH響應(yīng)的可電荷反轉(zhuǎn)的NDDS[21]。Li等[22]以2,3-二甲基馬來(lái)酸酐改性-(2-羥丙基)甲基丙烯酰胺共聚物作為外殼,以正性介孔二氧化硅納米顆粒(mesoporous silica nanoparticle,MSN)為核,構(gòu)建逐級(jí)pH響應(yīng)的載DTX雜化納米粒,外殼上的氨基發(fā)生酰胺化反應(yīng)而形成的β-羧酰胺在生理pH下穩(wěn)定,當(dāng)pH值低于6.8時(shí)可水解,在共聚物屏蔽下,納米雜化材料的半衰期(1/2)達(dá)到裸MSN的1.93倍。還有研究依賴于聚合物的可逆質(zhì)子化/去質(zhì)子化實(shí)現(xiàn)pH響應(yīng)的電荷轉(zhuǎn)換以降低體內(nèi)免疫清除[23],為pH響應(yīng)的載DTX電荷反轉(zhuǎn)型納米粒研發(fā)提供一定參考。
癌細(xì)胞(2~10 mmol/L)和正常細(xì)胞基質(zhì)(2~20 μmol/L)之間的還原型谷胱甘肽(glutathione,GSH)濃度存在顯著差異,氧化還原電位成為細(xì)胞內(nèi)釋藥的有效刺激。近年來(lái),利用GSH響應(yīng)的NDDS展現(xiàn)出較好的發(fā)展前景[24-25]。
二硫鍵在高還原性腫瘤環(huán)境中會(huì)發(fā)生斷裂而迅速釋放藥物,目前關(guān)于二硫鍵載體的插入和合成方法已較為成熟[13,26],故二硫鍵已被廣泛應(yīng)用于構(gòu)建DTX還原響應(yīng)型納米載體。有報(bào)道顯示在β環(huán)糊精-杯芳烴巨型兩親分子中插入二硫鍵,自組裝成納米球或納米微囊用以包裹DTX,基于二硫鍵還原響應(yīng)的藥物釋放顯著增強(qiáng)了DTX對(duì)不同腫瘤細(xì)胞的毒性[27]。Li等[28]通過(guò)含有二硫鍵的半胱胺修飾DTX制備DTX前藥,而后進(jìn)一步以二硫鍵構(gòu)建兩親性聚合物硫酸軟骨素-ss-DTX對(duì)前藥進(jìn)行包載制備復(fù)合納米粒,其在還原和非還原條件下,DTX在96 h的體外累積釋藥量分別達(dá)到62.5%和50.0%,細(xì)胞攝取實(shí)驗(yàn)中,發(fā)現(xiàn)C-6標(biāo)記的復(fù)合納米粒主要存在于乳腺癌MCF-7細(xì)胞的胞漿中,說(shuō)明還原響應(yīng)改善了DTX靶向性,有助于提升DTX與微管蛋白的結(jié)合效率。
除二硫鍵外,還有其他化學(xué)鍵應(yīng)用于氧化還原響應(yīng),不同化學(xué)鍵對(duì)氧化還原響應(yīng)的敏感性及對(duì)腫瘤治療的潛力也有所不同。Zuo等[29]分別以二硒鍵、二硫鍵或碳化二鍵設(shè)計(jì)了3種DTX二聚體前藥,自組裝為納米粒。研究發(fā)現(xiàn)二硒鍵納米粒的體外氧化還原響應(yīng)釋放弱于二硫鍵納米粒,但以二硒鍵納米粒處理的乳腺癌4T1細(xì)胞內(nèi)活性氧(reactive oxygen species,ROS)水平更高,進(jìn)一步促進(jìn)DTX釋放,使其表現(xiàn)出比二硫鍵納米粒更強(qiáng)的細(xì)胞毒性。結(jié)合藥動(dòng)學(xué)研究,3種前藥納米粒組總DTX的藥-時(shí)曲線下面積分別是泰索帝組的28.2、12.2、23.3倍,說(shuō)明二硒鍵更能提高納米粒的膠體穩(wěn)定性,延長(zhǎng)血液循環(huán)時(shí)間,但目前關(guān)于二硒鍵的研究尚少,還需進(jìn)一步深入研究。
為進(jìn)一步增強(qiáng)DTX治療效果、發(fā)揮協(xié)同作用優(yōu)勢(shì),基于氧化還原響應(yīng)的聯(lián)合治療已有不少研究。Conte等[30]制備氧化還原響應(yīng)型納米粒用于DTX和核酸TUBB3 siRNA的聯(lián)合遞送,相比游離形式siRNA和非氧化還原響應(yīng)型納米粒,其在還原條件下表現(xiàn)出更高的siRNA細(xì)胞內(nèi)化能力,明顯降低β-微管蛋白的表達(dá),DTX納米粒與DTX/TUBB3納米粒的半數(shù)抑制濃度(IC50)分別為79、6.5 μg/mL,證實(shí)了共載納米粒良好的協(xié)同作用。Li等[31]以二硫鍵連接制備DTX-雙氫青蒿素納米復(fù)合物,由納米顆粒的溶脹和侵蝕以及共軛物二硫鍵的斷裂控制兩藥的釋放,其能顯著促進(jìn)細(xì)胞早期凋亡,誘導(dǎo)細(xì)胞阻滯于G0/G1期。
ROS是氧的不完全還原產(chǎn)物,包括羥基自由基、超氧陰離子、過(guò)氧化氫等,線粒體代謝是其主要來(lái)源[32]。由于腫瘤組織血管供應(yīng)氧氣含量不足以支撐腫瘤細(xì)胞正常代謝,致使腫瘤部位存在缺氧區(qū),繼而導(dǎo)致癌細(xì)胞(高達(dá)1×10?4mol/L)中的ROS水平遠(yuǎn)高于正常組織(≈20×10?9mol/L)[33]。利用腫瘤組織固有的高ROS環(huán)境,ROS敏感的連接物或強(qiáng)還原性載體,通過(guò)ROS響應(yīng)裂解選擇性快速釋藥[34-35]。研究表明,DTX本身可通過(guò)促進(jìn)ROS產(chǎn)生來(lái)誘導(dǎo)腫瘤細(xì)胞凋亡[36-37],輔以ROS響應(yīng),將有助于快速選擇性釋藥。Zhu等[38]開(kāi)發(fā)了基于維生素E的載DTX強(qiáng)還原納米系統(tǒng),體外釋藥實(shí)驗(yàn)顯示,其在腫瘤環(huán)境高ROS水平下DTX的釋放量接近29%(而生理?xiàng)l件下約10%);在體內(nèi)釋藥實(shí)驗(yàn)中,由F?rster共振能量轉(zhuǎn)移分析發(fā)現(xiàn),相比正常器官,該納米系統(tǒng)在腫瘤中可更快地釋藥,在腫瘤部位的DTX積聚明顯高于泰索帝組。
由于腫瘤細(xì)胞的惡性增殖、轉(zhuǎn)移及生理代謝紊亂,多數(shù)腫瘤的發(fā)生都伴隨著酶異常表達(dá),如基質(zhì)金屬蛋白酶(matrix metalloproteinases,MMPs)、組織蛋白酶B、透明質(zhì)酸酶、分泌性磷脂酶A2、堿性磷酸酶、氧化還原酶等,這些酶的表達(dá)異常使得腫瘤與正常組織之間存在失調(diào)酶的差異,為酶刺激響應(yīng)型治療提供了基礎(chǔ)[39-41]。酶刺激響應(yīng)機(jī)制可概括為酶底物片段通過(guò)物理化學(xué)作用插入NDDS中,經(jīng)血液循環(huán)到達(dá)腫瘤部位,暴露在高濃度酶環(huán)境中引發(fā)結(jié)構(gòu)改變,通過(guò)納米載體解體或偶聯(lián)鍵斷裂控制藥物釋放[42]。Zhang等[43]通過(guò)在-羥基丁二酰亞胺活化的甲氧基聚乙二醇與α-生育酚琥珀酸酯之間插入MMP-2/9可裂解寡肽,合成新型材料制備MMP-2/9敏感的DTX膠束。熒光共振能量轉(zhuǎn)移結(jié)果表明,該敏感膠束能被MMP-2/9成功切割,且與不敏感膠束相比,其在纖維肉瘤HT1080細(xì)胞(MMP-2/9過(guò)表達(dá))中的攝取量增加了1倍。
當(dāng)前外源性刺激響應(yīng)型NDDS已取得很大進(jìn)展,尤其光熱響應(yīng)、超聲響應(yīng)等具有高時(shí)空分辨率的刺激響應(yīng)型控釋NDSS備受關(guān)注。
腫瘤部位深層惡性細(xì)胞的不可及性和腫瘤復(fù)發(fā)的不可控性是傳統(tǒng)癌癥治療面臨的重大挑戰(zhàn)[44],光響應(yīng)型NDDS以光熱治療、等離子體光熱治療、光動(dòng)力療法等為前提,可用于局部治療惡性腫瘤,并且治療時(shí)間短、不良反應(yīng)小,更有助于增強(qiáng)藥物對(duì)腫瘤的靶向性,提高對(duì)腫瘤部位的穿透性。其常用載體材料包括Au、Ag、Pt等貴金屬納米顆粒,石墨烯、碳納米棒等碳類(lèi)材料,CuS、ZnS等金屬與非金屬化合物,吲哚菁綠、普魯士藍(lán)等有機(jī)染料物質(zhì)。DTX不是光敏性藥物,因此載DTX的光響應(yīng)型NDDS常與光熱治療、光動(dòng)力療法相結(jié)合發(fā)揮協(xié)同抗腫瘤作用[45-46]。
2.1.1 光熱療法 腫瘤細(xì)胞與正常細(xì)胞的熱耐受性不同,光熱療法作為一種非侵入性治療手段會(huì)導(dǎo)致腫瘤中的DNA損傷和蛋白質(zhì)變性,可利用具有光熱轉(zhuǎn)換效率的載體材料負(fù)載DTX,在近紅外激光刺激下,一方面使光能轉(zhuǎn)換為熱能,利用熱損傷引起腫瘤消融,另一方面控制腫瘤部位DTX的釋放以發(fā)揮藥效殺死細(xì)胞[47]。
CuS納米粒子是一種新興的光熱劑,具有生物相容性、易制備性、不溶性和低成本等特點(diǎn),其由于Cu2+離子的d-d能帶躍遷而具有穩(wěn)定的近紅外吸收特性。Poudel等[48]構(gòu)建了CuS納米平臺(tái)負(fù)載DTX,并進(jìn)一步包裹共軛聚合物-多肽用于靶向化療-光療。體內(nèi)外研究表明,該納米系統(tǒng)的增強(qiáng)吸收和近紅外響應(yīng)行為可增強(qiáng)藥物釋放效率、促進(jìn)光熱消融并增強(qiáng)ROS的產(chǎn)生,并且該系統(tǒng)表現(xiàn)出較高的生物安全性。Su等[49]報(bào)道了一種附著于脂質(zhì)雙層上的海綿狀碳材料,其中脂質(zhì)雙層以石墨烯納米片為支撐,在近紅外光照射下可釋放出DTX、氣化的全氟己烷和高熱,抗腫瘤效果顯著。進(jìn)一步通過(guò)蛋白質(zhì)/紅細(xì)胞膜封端的碳/二氧化硅納米微球(red blood cell-membrane enveloped nanosponge,RBC@NS)遞送石墨烯量子點(diǎn)和DTX,在遠(yuǎn)程運(yùn)動(dòng)蛋白質(zhì)/紅細(xì)胞膜的介導(dǎo)下,經(jīng)紅外處理的RBC@NS在靶點(diǎn)的DTX有效聚集量約是未經(jīng)紅外處理的NS的8倍。抑瘤率實(shí)驗(yàn)中發(fā)現(xiàn),單純化療或光熱治療組易出現(xiàn)腫瘤復(fù)發(fā),而靶向RBC@NS結(jié)合紅外照射組前10 d內(nèi)顯著抑制腫瘤生長(zhǎng),且56 d內(nèi)無(wú)腫瘤復(fù)發(fā)[50]。
2.1.2 等離子體光熱治療 等離子體納米結(jié)構(gòu)由于等離子體共振而具有強(qiáng)光吸收,金基納米結(jié)構(gòu)屬于等離子體納米結(jié)構(gòu),其穩(wěn)定性高、毒性低且有助于腫瘤攝取[51]。Villar-Alvarez等[52]以人血清白蛋白/殼聚糖納米粒包裹游離DTX和阿霉素修飾的金納米棒,嵌入的金納米棒在近紅外光刺激下,可對(duì)DTX進(jìn)行獨(dú)立的部分釋放控制,結(jié)合等離子體光熱治療,DTX納米粒使單次低劑量照射后對(duì)腫瘤細(xì)胞的殺傷率接近90%。Zhao等[53]將DTX和NH4HCO3負(fù)載到表面包覆有金納米殼的熱敏脂質(zhì)體中,在808 nm激光照射下實(shí)現(xiàn)了藥物的時(shí)空可控釋放。
2.1.3 光動(dòng)力療法 光動(dòng)力療法的選擇性主要依賴于光敏劑在腫瘤微環(huán)境中的選擇性積聚和局部照射。光敏劑主要通過(guò)接受特定波長(zhǎng)的激光照射產(chǎn)生ROS,利用化學(xué)損傷抑制腫瘤。光動(dòng)力療法尤其適應(yīng)于對(duì)抗多藥耐藥及缺氧相關(guān)的腫瘤治療[54-55],Jiang等[56]在改進(jìn)的納米組裝體中共載DTX和光敏劑維替泊芬,同時(shí)修飾腫瘤血管生成靶向肽以提高腫瘤靶向效率,激光作用下由靶向納米粒處理的細(xì)胞幾乎無(wú)管狀結(jié)構(gòu)形成,更能有效抑制血管生成。
相比pH響應(yīng)型與氧化還原響應(yīng)型NDDS而言,目前載DTX的光響應(yīng)NDDS研究較少,具有較大發(fā)掘潛力。經(jīng)過(guò)一系列初步研究可知,以光響應(yīng)為基礎(chǔ)的化療方法是一種較為可行的腫瘤消融方式,有助于提高抗腫瘤效果,降低腫瘤穿透難度,但高功率激光也會(huì)造成正常組織的光損傷,其安全性需進(jìn)一步深入研究。
當(dāng)超聲刺激作用于體內(nèi)組織時(shí),機(jī)體會(huì)產(chǎn)生熱效應(yīng)、機(jī)械效應(yīng)與化學(xué)效應(yīng),基于此,超聲響應(yīng)型NDDS憑借其高時(shí)空性、高穿透性、非侵入性滲透腫瘤組織和經(jīng)濟(jì)便捷的特點(diǎn)而被逐漸探索。
綜合各方面文獻(xiàn)資料發(fā)現(xiàn),MSN等介孔納米材料比表面積大、孔徑均勻,可負(fù)載治療藥物,在超聲響應(yīng)的生物醫(yī)學(xué)領(lǐng)域中應(yīng)用廣泛。作為經(jīng)典介孔納米材料,MSN本身無(wú)刺激響應(yīng)性,當(dāng)介孔體系引入藥物后,若不及時(shí)加以封端,在體內(nèi)循環(huán)時(shí),極易造成藥物泄漏而過(guò)早釋放。因此,常在MSN孔隙入口處用適宜分子進(jìn)行封端,一方面可避免藥物過(guò)早釋放,另一方面封端分子可響應(yīng)某些刺激從MSN中脫落,進(jìn)而實(shí)現(xiàn)藥物的按時(shí)、按需釋放[57]。超聲響應(yīng)型NDDS進(jìn)行封端的分子通常具有幾種特點(diǎn):(1)利用熱效應(yīng),在溫度刺激下發(fā)生結(jié)構(gòu)變化而脫落;(2)在超聲刺激下間接產(chǎn)生大量ROS,刺激ROS敏感接頭斷裂而控釋藥物;(3)利用機(jī)械效應(yīng)釋放藥物。目前基于DTX/MSN的超聲響應(yīng)型納米粒研究較少,其對(duì)于DTX的利用價(jià)值有待進(jìn)一步探索。
介孔二氧化鈦納米材料(mesoporous titania nanoparticle,MTN)同MSN類(lèi)似,目前已應(yīng)用到DTX-NDDS中。Shi等[58]開(kāi)發(fā)了一種超聲觸發(fā)的β-環(huán)糊精封端的DTX-MTN藥物釋放系統(tǒng),將β-環(huán)糊精通過(guò)ROS敏感接頭連接到MTN外表面,發(fā)揮“門(mén)控”作用。一旦受到超聲激發(fā),MTN可產(chǎn)生大量ROS,一方面導(dǎo)致ROS敏感接頭斷裂,使β-環(huán)糊精分離釋放DTX,通過(guò)檢測(cè)超聲誘導(dǎo)的DTX在腫瘤中的釋放發(fā)現(xiàn),納米粒組超聲前DTX質(zhì)量濃度很低,而超聲后DTX質(zhì)量濃度顯著升高,且較長(zhǎng)時(shí)間高于1 μg/mL;另一方面,ROS誘導(dǎo)腫瘤細(xì)胞凋亡以協(xié)同發(fā)揮抗腫瘤作用。另已有多項(xiàng)研究證實(shí),聲動(dòng)力療法與DTX結(jié)合,在超聲刺激下誘導(dǎo)ROS產(chǎn)生,利用ROS誘導(dǎo)一系列生化反應(yīng)亦可抑制腫瘤細(xì)胞[59-62]。
除光熱、超聲等外源性刺激響應(yīng)外,還有溫度[63]、磁場(chǎng)[64]等外源性刺激型響應(yīng)系統(tǒng),也為DTX提供了有潛力的納米平臺(tái)。有研究合成了一種溫敏型磁性水凝膠,其包載阿霉素(doxorubicin,DOX)、DTX及用于磁熱刺激響應(yīng)的氧化鐵,該載藥磁性水凝膠對(duì)三重陰性乳腺癌細(xì)胞株具有顯著抗腫瘤活性[65]。
相比傳統(tǒng)未功能化的NDDS,單一刺激響應(yīng)NDDS的靶向性已得到一定增強(qiáng),但其響應(yīng)靈敏度、響應(yīng)速度、物理化學(xué)靶向效果仍然有限,故研究者趨向于利用各種納米材料或修飾組裝,開(kāi)發(fā)出不同功能組合的多響應(yīng)型NDDS[18,66]。Chen等[67]制備了具有pH和氧化還原雙重響應(yīng)的載DTX納米粒,其在PBS緩沖液(pH 6.5,10 mmol/L GSH)中藥物釋放顯著增加,在增強(qiáng)肝癌HepG2細(xì)胞和SMMC 7721細(xì)胞藥物攝取的同時(shí),帶正電的納米粒子還促進(jìn)細(xì)胞周期阻滯于G2/M期,增加細(xì)胞凋亡率。部分多響應(yīng)型DTX-NDDS的載體結(jié)構(gòu)與功能機(jī)制見(jiàn)表1。
盡管多重刺激響應(yīng)型NDDS在一定程度上增加了藥物靶向性,但單純刺激響應(yīng)型NDDS仍然是半選擇性靶向病灶,為進(jìn)一步增強(qiáng)靶向性,基于刺激響應(yīng)的NDDS結(jié)合適宜靶向因子實(shí)現(xiàn)多重靶向性,成為近年來(lái)靶向制劑領(lǐng)域的研究熱點(diǎn)[74-75]。目前一些配體,如糖類(lèi)、配體、受體、適配子、肽、抗體等已被廣泛用于腫瘤靶向。例如,葉酸是一種常見(jiàn)靶向因子,葉酸受體在癌細(xì)胞(乳腺、子宮和肺癌等)中過(guò)表達(dá)而在健康細(xì)胞中的表達(dá)降低,在兼具刺激響應(yīng)及體內(nèi)血液長(zhǎng)循環(huán)等多功能的NDDS中,輔以葉酸修飾將大大增加其靶向性。Nie等[76]用氨基-聚乙二醇-葉酸和硼替佐米對(duì)載DTX的星形共聚物膽酸-聚丙交酯-聚乙交酯納米粒進(jìn)行包覆,形成靶向復(fù)合物,實(shí)現(xiàn)了NDDS主動(dòng)靶向、pH響應(yīng)、體內(nèi)長(zhǎng)循環(huán)和雙重載藥的多功能一體化。透明質(zhì)酸是CD44受體的特異性配體,其修飾的納米粒子可以通過(guò)CD44受體介導(dǎo)的內(nèi)吞作用提高腫瘤細(xì)胞對(duì)納米粒子的攝取效率。此外,透明質(zhì)酸還是一種帶負(fù)電的聚陰離子,可用于屏蔽正電性NDDS的正電荷,一定程度上減少NDDS的體內(nèi)清除。Bai等[77]以聚酰胺-胺型樹(shù)枝狀大分子為藥物載體,阿侖膦酸鈉為骨靶向配體和破骨細(xì)胞抑制劑,透明質(zhì)酸為腫瘤細(xì)胞靶向配體,制備了破骨細(xì)胞和腫瘤細(xì)胞雙靶向納米粒子,在治療肺癌骨轉(zhuǎn)移方面顯示出巨大潛力。應(yīng)用于DTX-NDDS的靶向因子見(jiàn)表2。
表1 多響應(yīng)型DTX-NDDS的響應(yīng)機(jī)制與體內(nèi)外評(píng)價(jià)
Table 1 Response mechanism and in vitro and in vivo evaluation of multi responsive DTX-NDDS
納米藥物遞送系統(tǒng)響應(yīng)機(jī)制體內(nèi)外評(píng)價(jià)文獻(xiàn) Au/Fe3O4/PVA-DTX(1)pH;(2)溫度;(3)光(1)對(duì)乳腺癌MCF-7模型小鼠的抑瘤率達(dá)70%,安全性高;(2)有助于增強(qiáng)CT成像對(duì)比度68 DSPE-PEG-SS-PCL/DTX(1)ROS;(2)GSH(1)細(xì)胞毒性增強(qiáng),誘導(dǎo)細(xì)胞凋亡,抑制細(xì)胞遷移和侵襲;(2)在荷前列腺癌的小鼠體內(nèi),抑制腫瘤生長(zhǎng),對(duì)主要器官無(wú)明顯損傷69 PEG-PPMD/PEG-PCMD-DTX(1)pH;(2)GSH(1)低pH與GSH條件下,細(xì)胞毒性增強(qiáng);(2)抑瘤實(shí)驗(yàn)中,顯著抑制腫瘤生長(zhǎng)70 PEG-PPMT/DTX(1)pH;(2)ROS(1)細(xì)胞對(duì)納米粒的攝取效率增加;(2)納米粒對(duì)荷CT-26腫瘤小鼠的抑瘤率在90%以上,同時(shí)對(duì)肝臟和腎臟等正常器官的毒性較小71 HA-DTX(1)酶;(2)pH;(3)GSH(1)表現(xiàn)出較高的細(xì)胞攝取率和腫瘤細(xì)胞凋亡率;(2)在荷瘤裸鼠體內(nèi),顯著抑制腫瘤生長(zhǎng),循環(huán)時(shí)間長(zhǎng),藥動(dòng)學(xué)時(shí)間長(zhǎng),對(duì)器官毒性低19 CSCD-DTX(1)氧化還原;(2)酶(1)誘導(dǎo)細(xì)胞凋亡;(2)減少轉(zhuǎn)移促進(jìn)蛋白的表達(dá)(3)減少原位腫瘤體積和肺轉(zhuǎn)移形成72 SP-DTX(1)pH;(2)氧化還原(1)細(xì)胞毒性增強(qiáng),引起顯著的微管聚集、G2/M細(xì)胞期停滯和細(xì)胞凋亡;(2)對(duì)PC-3/3T3移植瘤小鼠的抑瘤率達(dá)78.9%20 DTX/CA-PLGA@PDA/DOX-PEG-APT(1)pH;(2)溫度;(3)光熱(1)細(xì)胞毒性增大,細(xì)胞對(duì)納米粒攝取顯著增加;(2)延長(zhǎng)藥物半衰期,抑制腫瘤生長(zhǎng)73
PVA-聚乙烯醇 DSPE-1,2-二硬脂酰-sn-甘油-3-磷酸乙醇胺 PEG-聚乙二醇 SS-二硫鍵 PCL-聚己內(nèi)酯 PPMD-聚(ω-五癸內(nèi)酯-co--甲基二乙胺-co-3,3′-二硫代二丙酸酯) PCMD-聚(己內(nèi)酯-co--甲基二乙胺-co-3,3′-二硫代二丙酸酯) PPMT-聚(鄰十五內(nèi)酯-co--甲基二亞乙基胺-共-3,30-硫代二丙酸酯) HA-透明質(zhì)酸 CSCD-硫酸軟骨素-二硫鍵-脫氧膽酸 SP-雙刺激響應(yīng)型雜化聚合物納米粒 CA-碳酸酐酶 PLGA-聚(乳酸-乙醇酸) PDA-聚多巴胺 APT-適配子AS1411
PVA-poly(vinyl alcohol) DSPE-1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) PEG-polyethylene glycol SS-disulfide bond PCL-poly(caprolactone) PPMD-poly(pentadecalactone-co--methyldiethyleneamine-co-3,3′-dithiodipropionate) PCMD-poly(caprolactone-co--methyldiethyleneamine-co-3,3′-dithiodipropionate) PPMT-poly(-pentadecalactone-co--methyldiethyleneamine-co-3,30-thiodipropionate) HA- hyaluronic acid CSCD-chondroitin sulfate-ss-deoxycholic acid SP-dual stimuli-responsive hybrid polymeric nanoparticles CA-carbonic anhydrase PLGA-poly(lactic-co-glycolic acid) PDA-polydopamine APT-aptamer AS1411
表2 應(yīng)用于DTX-NDDS的靶向因子
Table 2 Targeting factors applied to DTX-NDDS
靶向因子靶向部位文獻(xiàn) 甘露糖配體四聚體植物凝集素刀豆蛋白A(concanavalin A,Con A)78 半乳糖配體去唾液酸糖蛋白(asialoglycoprotein,ASGP)受體79 T細(xì)胞受體人類(lèi)白細(xì)胞抗原(human leukocyte antigens,HLAs)80 乙酸單羧酸轉(zhuǎn)運(yùn)蛋白1(monocarboxylic acid transporter 1,MCT1)81 S2.2適配子黏蛋白(mucin-1,MUC-1)53 適配子AS1411核仁素73,82 小分子靶向配體ACUPA; DUPA前列腺特異性膜抗原(prostate specific membrane antigen,PSMA)83-84 腫瘤血管生成靶向肽腫瘤血管內(nèi)皮細(xì)胞的氨基肽酶N(aminopeptidase N,APN/CD13)56 T7肽血管生成素2(angiopoietin-2,Ang 2)、轉(zhuǎn)鐵蛋白受體(transferrin receptor,TfR)85-87 環(huán)狀五肽FC131趨化因子受體4型(C-X-C chemokine receptor type 4,CXCR4)88 RVG29肽尼古丁乙酰膽堿受體(nicotinic acetylcholine receptor,NAchR)89 胃泌素釋放肽胃泌素釋放肽受體(gastrin-releasing peptide receptor,GRPR)90 AE147肽尿激酶型纖溶酶原激活劑受體(urokinase-type plasminogen activator receptor,uPAR)91 精氨酸-甘氨酸-天冬氨酸三肽序列整聯(lián)蛋白avb392-93 西妥昔單抗表皮生長(zhǎng)因子受體(epidermal growth factor receptor,EGFR)50,94-95 曲妥珠單抗人表皮生長(zhǎng)因子受體2型(human epidermal growth factor receptor 2,HER2)96-97 嵌合小鼠/人抗體Tn抗原(N-乙酰葡萄糖胺-O-絲氨酸/蘇氨酸,GalNAc-O-serine/threonine)98
多功能刺激響應(yīng)型納米粒具有粒徑小,藥物體內(nèi)清除少、可控釋放、靶向性高等優(yōu)勢(shì)。DTX作為天然藥物紫杉醇的衍生物,抗腫瘤作用顯著,關(guān)于其納米制劑的研究從未停止,其制劑的研究方向是在“盡可能減少DTX體內(nèi)清除、實(shí)現(xiàn)長(zhǎng)效循環(huán)”的基礎(chǔ)上,進(jìn)一步提高DTX靶向性,增強(qiáng)藥物入胞效率,以降低全身毒性。當(dāng)前DTX納米制劑結(jié)合納米技術(shù)的基本理論及腫瘤組織生理代謝的新進(jìn)展,聚焦于刺激響應(yīng)的或靶向修飾的NDDS,可顯著改善DTX溶解性低、靶向性差等理化缺陷,在增強(qiáng)DTX抗腫瘤活性,擴(kuò)大其臨床應(yīng)用方面,具有顯著優(yōu)越性。
但刺激響應(yīng)型納米遞藥系統(tǒng)及有關(guān)修飾因子還存在許多亟待解決的問(wèn)題:(1)功能化脂質(zhì)體、聚合物納米粒等雖然在納米材料的輔助下提高了藥物靶向性,但由于材料自身的限制性,載藥量通常低于10%;(2)刺激響應(yīng)型納米制劑的響應(yīng)速度低,限制了藥物釋放,導(dǎo)致藥物療效降低;(3)目前發(fā)現(xiàn)并研究應(yīng)用的靶向因子類(lèi)型眾多,但大都存在靶向因子受體非腫瘤部位獨(dú)有這一關(guān)鍵問(wèn)題,降低了NDDS的主動(dòng)靶向效率;(4)目前各類(lèi)NDDS多停留在基礎(chǔ)研究階段,亟需更深入的制劑穩(wěn)定性、安全性及毒理學(xué)研究為臨床研究奠定基礎(chǔ);(5)在創(chuàng)新的DTX-NDDS成果轉(zhuǎn)化方面,還需注意復(fù)雜材料、工藝帶來(lái)的成本問(wèn)題以及工業(yè)生產(chǎn)方面出現(xiàn)的設(shè)備及技術(shù)問(wèn)題。
本文對(duì)DTX刺激響應(yīng)型納米藥物遞送系統(tǒng)及其修飾因子進(jìn)行總結(jié)與分析,希望為DTX遞藥系統(tǒng)的進(jìn)一步發(fā)展提供可行思路,相信隨著納米科技、高分子材料及靶向修飾因子的深入發(fā)展,NDDS將進(jìn)一步提高腫瘤特異性響應(yīng)程度,向高效低毒、高度靶向、功能一體化的方向發(fā)展。
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Research progress on docetaxel loaded nano delivery system based on stimulus response and targeting factors
SUI Fang-qian, LI Jie-yu, YANG Shan-jing, JIANG Hai-mei, YANG Shi-yu, LI Ling-jun, CAI Xiao-qing
College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
Docetaxel, a derivative of natural antitumor drug paclitaxel, has broad-spectrum and highly effictive antitumor activity, but its low solubility and wide tissue distribution limit its clinical application. The stimulation responsive nano delivery system effectively improves the above defects by diversity of carrier material structure and environment sensitive drug release. On this basis, modifying the targeting factor can make the drug targeted delivery, change the organization distribution of the drug and further improve the antitumor effect. This paper reviews the research progress on stimulation responsive and modifier modified nano delivery system of docetaxel in recent years, and puts forward the key problems such as its development challenges and future trend, in order to provide reference for the research and development of docetaxel in antitumor drugs.
docetaxel; stimulus response; targeting factor; antitumor activity;nano delivery system
R283
A
0253 - 2670(2022)19 - 6296 - 10
10.7501/j.issn.0253-2670.2022.19.034
2022-03-20
國(guó)家自然科學(xué)基金資助項(xiàng)目(81803474);山東中醫(yī)藥大學(xué)藥學(xué)院“藥苑育研”優(yōu)秀研究生創(chuàng)新基金(2021-0027)
隋芳茜(1997—),女,碩士研究生,主要研究方向?yàn)橹兴幮轮苿?、新劑型研究及藥物體內(nèi)過(guò)程。Tel: 18340077520 E-mail: 18340077520@163.com
李凌軍(1966—),男,博士生導(dǎo)師,教授,從事中藥新制劑、新劑型研究及藥物體內(nèi)過(guò)程研究。Tel: 13853157076 E-mail: sdzyylilingjun@163.com
蔡曉青(1982—),女,碩士生導(dǎo)師,副教授,從事智能靶向給藥系統(tǒng)研究。Tel: 18753103526 E-mail: caixiaoqing0901@163.com
[責(zé)任編輯 潘明佳]