涂艷陽，祁 婧，張永生,楊宏偉

(第四軍醫(yī)大學(xué)：1唐都醫(yī)院實(shí)驗(yàn)外科，2唐都醫(yī)院，陜西 西安 710038；3哈佛醫(yī)學(xué)院布列根與婦女醫(yī)院神經(jīng)外科，美國 波士頓 02115)

·述評·

膠質(zhì)瘤納米治療技術(shù)的研究現(xiàn)狀與發(fā)展前景

涂艷陽1，祁 婧1，張永生2,楊宏偉3

(第四軍醫(yī)大學(xué)：1唐都醫(yī)院實(shí)驗(yàn)外科，2唐都醫(yī)院，陜西 西安 710038；3哈佛醫(yī)學(xué)院布列根與婦女醫(yī)院神經(jīng)外科，美國 波士頓 02115)

神經(jīng)膠質(zhì)瘤是顱內(nèi)最常見的惡性腫瘤，占所有顱內(nèi)腫瘤的46%. 由于神經(jīng)膠質(zhì)瘤呈侵潤性生長，故僅通過傳統(tǒng)手術(shù)難以做到全部切除，因此，采用新技術(shù)手段提高現(xiàn)有早期診斷、療效預(yù)測以及有效治療策略是亟待解決的首要問題. 隨著納米生物醫(yī)學(xué)的飛速發(fā)展，納米技術(shù)已經(jīng)在膠質(zhì)瘤的預(yù)測、診斷、影像及治療等領(lǐng)域顯示出巨大的優(yōu)勢. 本研究綜述了納米載體、膠質(zhì)瘤納米治療機(jī)理以及膠質(zhì)瘤納米診斷和治療領(lǐng)域的主要研究進(jìn)展.

膠質(zhì)瘤;納米載體;化療藥物

0 引言

長期以來,惡性腫瘤的診斷和治療一直是醫(yī)學(xué)和生命科學(xué)研究領(lǐng)域的熱點(diǎn)和難點(diǎn). 神經(jīng)膠質(zhì)瘤是顱內(nèi)最常見的惡性腫瘤，約占所有顱內(nèi)腫瘤的46%，診斷后的膠質(zhì)瘤患者生存期僅有12～14個月. 由于神經(jīng)膠質(zhì)瘤呈侵潤性生長，故僅通過傳統(tǒng)手術(shù)無法有效治愈，難以做到腫瘤的全部切除，故多采用聯(lián)合治療，配以放療和化療來降低復(fù)發(fā)率，延長生存期[1]. 但是，目前的化療藥物和放療主要針對生長期細(xì)胞，而對處于非生長期的神經(jīng)膠質(zhì)瘤干癌細(xì)胞幾乎沒有作用[1]. 所以侵潤性極強(qiáng)的神經(jīng)膠質(zhì)瘤具有低治愈、高復(fù)發(fā)的特點(diǎn)，這也成為至今無法攻克的一大難題[1].

目前，對于惡性膠質(zhì)瘤，臨床上面臨的主要問題是腫瘤的診斷與治療的分離. 集多種性能于一體的診療劑(Theranostics)的設(shè)計和應(yīng)用有望解決這個難題[2]. 智能化的診療劑能有效提高治療疾病的選擇和特異性，達(dá)到高的局部毒性和低的副作用. 因此，針對膠質(zhì)瘤的診斷與治療分離這一臨床主要問題，能夠利用磁性納米粒子、金納米棒[3]實(shí)現(xiàn)惡性膠質(zhì)瘤的分子影像和個性化治療. 隨著納米生物醫(yī)學(xué)的快速發(fā)展，納米技術(shù)已經(jīng)在膠質(zhì)瘤的預(yù)防、診斷、影像和治療等領(lǐng)域作出巨大的貢獻(xiàn). 本研究綜述了納米載體、膠質(zhì)瘤納米治療機(jī)理以及膠質(zhì)瘤納米診斷和治療領(lǐng)域的主要研究進(jìn)展.

1 納米載體

納米載體來源于生物、有機(jī)和無機(jī)物，用以探究各種生物學(xué)機(jī)制和解決生物學(xué)問題. 納米載體多為脂類和聚合材料構(gòu)成，另外還開發(fā)出各種潛在新材料包括巨噬細(xì)胞特異的納米粒子[4]，靶向磁納米粒子[5-6]、金納米材料[7]、功能化的碳納米管[8]、二氧化硅顆粒[9-10]及修飾的植物病毒[11]等.

聚合物材料是納米材料中的最大的一類，包括許多亞型，如核-殼粒子、可生物降解的聚乳酸-共-羥基乙酸(PLGA)納米顆粒、水凝膠納米粒子. 聚合物膠束是非交聯(lián)粒子，涉及共聚物顆粒、單一聚合物鏈包含不止一個相同分子. 一個簡單的聚合物膠束包含許多二親聚合物，模擬膠束的尾巴和頭部. 這些聚合物在疏水性藥物周圍自發(fā)形成膠束. 具有受控尺寸和形狀的聚合物納米粒子允許細(xì)胞附著同時可以防止內(nèi)在化，從而使細(xì)胞對藥物的有效載荷攜帶到遞送第二個站點(diǎn). 因此針對循環(huán)腫瘤細(xì)胞，就可以使用具有長循環(huán)時間的聚合物. 水凝膠納米粒子，也被稱為納米凝膠，在親水環(huán)境中接觸水時交聯(lián)在接觸時膨脹[12]. 納米凝膠可以共價或非共價結(jié)合的藥物或靶向配體，還可以響應(yīng)于環(huán)境因素膨脹或縮小，如pH或溫度.

脂類是可以自組織囊泡(脂質(zhì)雙分子層和脂質(zhì)體)的二親性小分子、膠束或脂質(zhì)復(fù)合物(無定形顆粒[13]. 這些載體可以修飾為靶向遞送水溶性和不溶性的治療劑. 尺寸、承載能力和定位功能等屬性也可以被修飾. 再加上適當(dāng)?shù)哪繕?biāo)配體，如整聯(lián)蛋白結(jié)合肽，脂質(zhì)體可在血管生成過程在腫瘤血管系統(tǒng)積累[14]且可遞送有效治療載荷. 金納米顆粒已經(jīng)被用于熱燒蝕治療[15]，通過以熱的形式釋放能量至近紅外光響應(yīng)誘導(dǎo)腫瘤血管的凝結(jié)以及可協(xié)同增加其他靶向療法的治療效果[16]. 金納米顆粒也可以作為支架連接多個配體[17]. 其他納米材料類，如納米鐵顆粒和碳納米顆粒，也同樣應(yīng)用到藥物遞送治療[18].

2 治療機(jī)理

納米粒子治療劑從小分子藥物或生物大分子的載體(如蛋白質(zhì)或siRNA)[19-28]到成像和熱吸收載體. 納米顆粒裝載藥物的優(yōu)點(diǎn)包括疾病位點(diǎn)靶向藥物、觸發(fā)藥物在身體的特定位置釋放[29-30]以及改變藥物的藥代動力學(xué)特性以增加其在疾病部位的半衰期[31]. 這些能力會減少脫靶效應(yīng)和降低藥物劑量[32-33]. 納米粒子具備更多復(fù)雜的藥物遞送能力，例如遞送含有調(diào)節(jié)血管系統(tǒng)分子的藥物[34-35]，藥物前體以及其激活酶[36-37]或靶向配體免疫治療[38-41]. 同時，生理微環(huán)境[42-43]或可替代的外部刺激(超聲[44-46]、光[47-49]或射頻電磁場[50])也可以觸發(fā)局部藥物釋放.

納米粒子的治療作用不僅僅是藥物的封裝和遞送. Thermoablative治療(加熱組織以殺死腫瘤細(xì)胞)、磁場、紅外線和無線電頻率等技術(shù)可以通過激活納米材料局部增強(qiáng)對患病組織的作用[15,51-53]. 但是所有這些外部觸發(fā)作用既有優(yōu)點(diǎn)也有局限性. 例如，電磁場能深入(>15 cm)滲透，但它們難以聚焦. 高強(qiáng)度聚焦超聲(HIFU)能深入組織且可聚焦到幾個毫米的體積，但是當(dāng)應(yīng)用到骨骼或氣體填充的器官時其功能則會減弱[54]. 紅外燈的波長范圍為750～1300 nm，穿透組織且可達(dá)1 cm的深度，之后滲透大幅減小[55]. 因此紅外線主要適用于病變靠近皮膚表面的情況.

3 膠質(zhì)瘤納米治療技術(shù)

隨著納米技術(shù)在20世紀(jì)80年代的迅速發(fā)展，醫(yī)學(xué)領(lǐng)域便利用這一新的技術(shù)開發(fā)出新的治療劑. 對于腦腫瘤，納米技術(shù)方法可以通過血腦屏障便于藥物遞送[56-57]. 納米顆粒類似生物大分子，不能像生物小分子一樣隨意擴(kuò)散到組織[58]. 該納米粒子在腫瘤內(nèi)積累的能力是由于增強(qiáng)的滲透性和滯留效果. 增強(qiáng)的滲透性并且保留效果是由活躍的血管生成和血管結(jié)構(gòu)改變而部分介導(dǎo)的，這導(dǎo)致即使在血清水平下降的情況下，納米顆粒仍滯留在腫瘤組織[59]. 此外，納米顆粒可以“保護(hù)”遞送的目標(biāo)免于周圍環(huán)境的干擾而到達(dá)靶位. 例如，靜脈注射時亞甲藍(lán)很快會被高鐵血紅蛋白還原酶催化失活. 這種現(xiàn)象可以通過利用納米顆粒遞送亞甲藍(lán)到腫瘤組織的方法來避免[60-62]. 納米顆粒也可以用于遞送化療藥物穿過血腦屏障，如阿霉素[63-64]. 納米顆粒遞送阿霉素的療法具有降低毒性與改善多形性成膠質(zhì)細(xì)胞瘤的異種移植物模型中抗腫瘤細(xì)胞的功效[63-65].

在神經(jīng)外科領(lǐng)域，正在研究納米粒子用于腦成像[66]. 另外，氧化鐵納米顆?？裳b載熒光染料，實(shí)現(xiàn)腫瘤的可視化外科手術(shù)[58,67-69].

納米顆粒用于藥物遞送的能力是未來治療腦腫瘤的方向. 某些化療藥物，如阿霉素和紫杉醇，可利用固體脂質(zhì)納米粒封裝，對于腫瘤組織有較高的可利用性并盡量減少全身性毒性[70]. 由于病毒載體的免疫反應(yīng)以及脂質(zhì)體效率較低，研究人員也正在研究納米粒子用于基因治療[58]. 例如，含APO2/TRAIL質(zhì)粒裝載到納米顆粒可以在腫瘤組織中累積，增加C6膠質(zhì)瘤小鼠生存率[71].

4 展望

納米醫(yī)學(xué)開創(chuàng)了膠質(zhì)瘤早期診斷與靶向治療策略的新時代. 膠質(zhì)瘤的納米治療是利用納米材料靶向識別并殺滅惡性膠質(zhì)瘤細(xì)胞的個性化治療. 利用納米材料特性，同時結(jié)合腦膠質(zhì)瘤干細(xì)胞的特異靶點(diǎn)及其所特異的分子信號通路來設(shè)計納米治療探針已經(jīng)成為一個新的熱點(diǎn)研究. 但是膠質(zhì)瘤納米治療所面臨的許多問題還有待于進(jìn)一步的研究；如何構(gòu)建體內(nèi)靶向分子探針、放大信號、消除探針潛在毒性正是當(dāng)今膠質(zhì)瘤納米治療需要解決的關(guān)鍵問題；另外，納米探針作為小分子或多肽探針連接在納米粒子表面后，作為信號源的納米粒子較高的表面可能會改變其分子構(gòu)象或者屏蔽其結(jié)合基團(tuán)，所以兩者相互作用的長期機(jī)制還不明確，仍需進(jìn)一步的探究進(jìn)行驗(yàn)證. 因此，納米治療技術(shù)在人體應(yīng)用還有很多值得挖掘和深究的方向. 如今的膠質(zhì)瘤納米診斷和治療技術(shù)正飛速發(fā)展，納米科技也為攻克膠質(zhì)瘤提供了一種全新的治療策略.

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The current situation and prospect of treating glioma with nanotechnology

TUYan-Yang1,QIJing1,ZHANGYong-Sheng2，YANGHong-Wei3

The Fourth Military Medical University:1Department of Experimental Surgery,2Tangdu Hospital, Xi’an 710038, China;3Neurosurgerons, Brigham and Women’s Hospital, Haward Medical Shool, Boston 02115, America

Neuroglioma is the most common malignancy, accounting for nearly half of all human brain tumors. Operation is still difficult to completely remove because of its invasive growth. Thus, the introduction of new technology to improve current diagnosticis, curative effect forecast and treatment strategies is the major problems to be solved. With the rapid development of nano-biomedicine, nanotechnology has demonstrated its great advantages in the prevention, diagnosis, imaging and treatment of gliomas and other areas. This paper reviews the progress of major nanocarrier, nanoparticle therapy treatment mechanism and nanoparticle diagnostic and therapeutic areas for glioma.

glioma; nanocarrier; chemotherapy drugs

2016-07-18;接受日期:2016-08-04

國家自然科學(xué)基金資助項目(No.81572983,No.81272419)

涂艷陽. 博士,副教授,副主任醫(yī)師. Tel: 029-84777469 E-mail:tu.fmmu@gmail.com

張永生. 教授,主任醫(yī)師,院長. E-mail:zhangys@fmmu.edu.cn

2095-6894(2016)09-01-04

R739.4

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