魏向娟 秦靖雯 張劉源 陳貴梅 南文濱 陳紅麗

453003新鄉(xiāng)醫(yī)學(xué)院生命科學(xué)技術(shù)學(xué)院，新鄉(xiāng)醫(yī)學(xué)院納米生物醫(yī)用材料研究所

用于腫瘤聯(lián)合治療的基因和化療藥物納米共載體系的研究進(jìn)展

魏向娟 秦靖雯 張劉源 陳貴梅 南文濱 陳紅麗

453003新鄉(xiāng)醫(yī)學(xué)院生命科學(xué)技術(shù)學(xué)院，新鄉(xiāng)醫(yī)學(xué)院納米生物醫(yī)用材料研究所

化學(xué)藥物治療（化療）或基因治療單獨(dú)使用治療腫瘤均具有較多缺陷，而將兩者聯(lián)合應(yīng)用能協(xié)同治療腫瘤，克服單一療法的不足。納米載體既能包載化療藥物又能遞送基因，其用于腫瘤的聯(lián)合治療，可減少化療藥物的劑量，增加藥物在靶器官的分布量，減輕毒副作用，從而提高抗腫瘤效果；同時(shí)保護(hù)攜帶基因的穩(wěn)定性和完整性，一定程度上提高基因的轉(zhuǎn)染效率，以達(dá)到減輕毒副作用及提高療效的協(xié)同目的?；蚝突熕幬锛{米共載體系用于腫瘤的聯(lián)合治療是近年來腫瘤治療的研究熱點(diǎn)。就基因和化療藥物納米共載體系的類型及負(fù)載基因類型，特別是納米共載體系用于腫瘤聯(lián)合治療的研究進(jìn)行總結(jié)和展望。

納米載體； 基因； 化療藥物； 腫瘤治療

Fund program：National Natural Science Foundation of China(U1304819,81401519);National Training Programs of Innovation and Entrepreneurship for Undergraduates(201410472030)

0 引 言

化學(xué)藥物治療（化療）是常用和有效的腫瘤治療方法之一[1]，但長期化療易導(dǎo)致腫瘤細(xì)胞產(chǎn)生多藥耐藥性（multiple drug resistance，MDR）；此外化療具有較強(qiáng)的組織器官毒副作用，且安全劑量的化療藥物不能達(dá)到有效治療腫瘤的目的，這些缺陷均限制了化療的應(yīng)用[2-3]。隨著對(duì)參與腫瘤發(fā)生和發(fā)展過程中相關(guān)分子、細(xì)胞和生理機(jī)制的進(jìn)一步認(rèn)識(shí)，腫瘤的治療趨于多元化，治療方式也更具有針對(duì)性[4]。近年來，人們認(rèn)識(shí)到腫瘤的發(fā)生與多種基因的突變密切相關(guān)，因此期待通過基因治療即將外源基因?qū)氚屑?xì)胞，抑制腫瘤生長甚至殺傷腫瘤細(xì)胞，達(dá)到治療腫瘤的目的，并在一定程度上取得了顯著進(jìn)展[5-6]；但基因易降解、細(xì)胞轉(zhuǎn)染效率低、病毒載體的不安全性以及人體的免疫反應(yīng)等均極大限制了腫瘤基因治療的廣泛應(yīng)用[7]。因此，需借助合適的遞送載體提高療效。

化療或基因治療單獨(dú)使用均具有較多缺陷，而將兩者聯(lián)合應(yīng)用能發(fā)揮協(xié)同作用，克服單一治療手段的缺陷，提高抗腫瘤效果[8-9]。納米輸送體系是一種屬于納米級(jí)微觀范疇的藥物載體輸送系統(tǒng)。其既能攜帶化療藥物又可負(fù)載基因片段，可減少化療藥物的使用劑量，增加藥物在靶器官的分布量，顯著降低機(jī)體的不良反應(yīng)，減輕毒副作用，從而提高抗腫瘤效果；同時(shí)保護(hù)攜帶基因的穩(wěn)定性和完整性，一定程度上提高基因的轉(zhuǎn)染效率，以達(dá)到減輕毒副作用及提高療效的協(xié)同目的。相對(duì)于傳統(tǒng)單一載體，基因和化療藥物納米共載體系具有廣闊的應(yīng)用前景。本文就基因和化療藥物納米共載體系的類型、負(fù)載基因類型及其近年來用于腫瘤聯(lián)合治療的研究進(jìn)行總結(jié)。

1 基因和化療藥物納米共載體類型

1.1 納米脂質(zhì)體

脂質(zhì)體是由磷脂和膽固醇有序排列形成的類生物膜的雙分子脂質(zhì)囊泡。脂質(zhì)體具有低毒、無免疫原性、藥物緩釋性和降低藥物毒副作用等優(yōu)點(diǎn)[10]。目前，常用于基因和化療藥物共載的脂質(zhì)體主要是陽離子脂質(zhì)體[11]。陽離子脂質(zhì)體通常由陽離子脂質(zhì)和中性脂質(zhì)組成，能包封化療藥物并與DNA形成復(fù)合物。

Kato等[12]研制了新型陽離子脂質(zhì)體（LipoTrust EX Oligo）用于共載O6-甲基鳥嘌呤-DNA甲基轉(zhuǎn)移酶（MGMT）基因的小干擾RNA（smallinterferingRNA, siRNA）和化療藥物替莫唑胺，進(jìn)行神經(jīng)膠質(zhì)瘤體內(nèi)動(dòng)物實(shí)驗(yàn)治療發(fā)現(xiàn)，經(jīng)MGMT siRNA誘導(dǎo)后的膠質(zhì)瘤干細(xì)胞對(duì)替莫唑胺敏感性有所增加。由于脂質(zhì)體在體內(nèi)實(shí)驗(yàn)中表現(xiàn)出較差的特異性，研究人員發(fā)現(xiàn)通過多肽等對(duì)其修飾能增強(qiáng)陽離子脂質(zhì)體遞送基因和化療藥物的效果[13]。Jiang等[14]用精氨酸-甘氨酸-天冬氨酸（RGD）多肽來修飾陽離子脂質(zhì)體，共載抑制P-糖蛋白（P-glycoprotein,P-gp）的siRNA和阿霉素（doxorubicin,DOX）用于耐阿霉素乳腺癌（MCF7/ADR）治療發(fā)現(xiàn)，經(jīng)修飾后的脂質(zhì)體不僅能顯著抑制P-gp的表達(dá)，提高化療效果，還具有良好的腫瘤靶向作用。

1.2 納米粒

納米粒是一類由天然或合成高分子材料制成的固體微粒，粒徑約為10～1 000 nm。納米粒的粒徑小、穩(wěn)定性高，可改變藥物在體內(nèi)的分布，增加藥物在靶器官的生物分布，延長藥物在體內(nèi)的循環(huán)時(shí)間，提高療效的同時(shí)還能降低藥物的毒副作用[15]。目前，常用作基因和化療藥物共載體的納米粒有聚合物納米粒和無機(jī)納米粒。

聚合物納米粒多由生物可降解材料制備，包括高聚物如聚乙烯亞胺（polyethyleneimine,PEI）[16-17]、聚賴氨酸（PLL）[18-20]、樹枝狀高分子類（dendrimers）（如聚酰胺-胺（polyamidoamine，PAMAM）[21-23]）等人工合成聚合物和殼聚糖（chitosan，CS）[24-25]等天然陽離子大分子。Liu等[26]通過聚乙烯亞胺-聚乙二醇（PEI-PEG）共聚物制備了多功能納米粒共載DNA和化療藥物DOX，發(fā)現(xiàn)該體系具有較高的轉(zhuǎn)染效率和良好的抗腫瘤活性。

在無機(jī)納米粒中，介孔二氧化硅納米顆粒（mesoporoussilicananoparticles,MSNPs）尤為常用。MSNPs是一種多孔納米粒，多孔內(nèi)可負(fù)載化療藥物，延長藥物作用時(shí)間；經(jīng)陽離子多聚物修飾后又可負(fù)載基因，用于聯(lián)合治療腫瘤。Chen等[27]用二代聚酰胺-胺（G2-PAMAM）修飾MSNPs來呈遞Bcl-2 siRNA和DOX。Pakunlu等[28-29]研究發(fā)現(xiàn)，與脂質(zhì)體呈遞siRNA逆轉(zhuǎn)耐藥性相比，經(jīng)修飾后的MSNPs能靶向定位在細(xì)胞核周區(qū)域，誘導(dǎo)細(xì)胞凋亡，降低泵耐藥性，提高DOX的腫瘤殺傷作用，其殺傷效果遠(yuǎn)高于DOX游離藥物，并具有較低的毒副作用。Meng等[30-31]制備了PEI MSNPs和PEI-PEG MSNPs共遞送P-gp siRNA和DOX，用于人口腔表皮樣癌細(xì)胞系KB-V1腫瘤治療發(fā)現(xiàn)，與只負(fù)載DOX的納米粒相比，共載體系能明顯降低耐藥性，顯著減少用藥劑量，提高抗腫瘤效果。

此外，量子點(diǎn)（QDs）也是一種有效的基因和化療藥物的納米載體。Li等[32]制備了由β-環(huán)糊精（βcyclodextrin,β-CD）和L-精氨酸或L-組氨酸修飾的硒化鎘/硒化鋅量子點(diǎn)，通過疏水性β-CD腔包埋DOX，P-gp siRNA則絡(luò)合于陽離子氨基酸上；該體系不僅能明顯逆轉(zhuǎn)腫瘤細(xì)胞的耐藥性，還能提高化療藥物的抗腫瘤效果。

層層自組裝納米粒（layer-by-layer self-assembly nanoparticles,LbL NPs）是近年來研究的新型基因和化療藥物的納米載體。Deng等[33]通過交替沉積的方法制備了LbL NPs，該體系表面的一個(gè)雙分子層能有效負(fù)載3 500個(gè)siRNA分子；LbL NPs的半衰期延長至28 h，能使靶蛋白P-gp的表達(dá)降低80%，從而顯著逆轉(zhuǎn)腫瘤細(xì)胞的耐藥性，增強(qiáng)化療藥物DOX的抑瘤效果。動(dòng)物實(shí)驗(yàn)結(jié)果表明，其能使腫瘤體積減少87.5%且無明顯毒副作用。

1.3 納米膠束

聚合物膠束是由兩親性聚合物自組裝形成的超分子聚集體或具有核-殼結(jié)構(gòu)的納米載藥體系[34]。兩親性嵌段聚合物膠束由親水性片段（如PEG）和疏水性片段（如聚己內(nèi)酯（polycaprolactone,PCL）、聚乳酸-羥基乙酸共聚物（poly（lactic-co-glycolic acid）, PLGA）等）組成，聚陽離子PEI則用于負(fù)載基因，以實(shí)現(xiàn)共遞送化療藥物和基因，提高治療效果。

Zou等[35]制備了葉酸（FA）-PEG-PEI-PCL聚合物膠束，用其共載抗凋亡基因Bcl-2 siRNA和化療藥物DOX用于卵巢癌的治療發(fā)現(xiàn)，當(dāng)DOX的質(zhì)量濃度為10 μg/ml時(shí)，該共載體系能抑制85%的人卵巢癌細(xì)胞SKOV-3的生長，與包載等劑量DOX的單一納米載體相比，細(xì)胞凋亡率約增加35%，抑瘤效果顯著。Cheng等[36]用葉酸修飾的聚乙二醇-聚谷酰胺（FA-PEG-PGA）聚合物膠束共載Bcl-2siRNA和DOX進(jìn)行C6神經(jīng)膠質(zhì)瘤治療發(fā)現(xiàn)，與單獨(dú)給予化療藥物相比，共載納米體系能顯著下調(diào)Bcl-2的表達(dá)，使其表達(dá)水平下降80%，同時(shí)誘導(dǎo)腫瘤細(xì)胞凋亡比例高達(dá)92%，具有顯著的抗腫瘤效果。

2 納米共載體負(fù)載的基因類型

由于腫瘤的異質(zhì)性和控制腫瘤生長增殖、遷移信號(hào)通路的復(fù)雜性，使得實(shí)現(xiàn)基因和化療藥物聯(lián)合治療腫瘤最佳效果的關(guān)鍵之一在于選擇合適的外源基因類型，以達(dá)到與化療藥物協(xié)同并增強(qiáng)化療效果的目的。

2.1 逆轉(zhuǎn)耐藥基因

長期化療會(huì)使患者對(duì)化療藥物產(chǎn)生耐藥性，耐藥性是治療腫瘤的一個(gè)主要障礙。隨著對(duì)腫瘤耐藥相關(guān)基因和分子機(jī)制的深入研究，發(fā)現(xiàn)耐藥性與P-gp高度相關(guān)，P-gp在各種惡性腫瘤組織中過度表達(dá)，將化療藥物泵出細(xì)胞，進(jìn)而使腫瘤細(xì)胞對(duì)化療藥物產(chǎn)生耐藥性。因此，逆轉(zhuǎn)腫瘤耐藥基因靶向沉默耐藥相關(guān)蛋白的表達(dá)能顯著逆轉(zhuǎn)耐藥性，其與化療藥物聯(lián)合使用，可增強(qiáng)化療效果[37]。

Xiong和Lavasanifar[38]用聚合物膠束納米粒共遞送P-gp siRNA和DOX進(jìn)行人乳腺癌的靶向治療發(fā)現(xiàn)，與MDA-MB-435細(xì)胞共孵育4 h后，該體系能100%地截留在細(xì)胞質(zhì)內(nèi)，顯著提高了化療藥物在腫瘤細(xì)胞內(nèi)的累積，腫瘤細(xì)胞凋亡率達(dá)80%；動(dòng)物實(shí)驗(yàn)中注射24 h時(shí)通過活體成像發(fā)現(xiàn)，與其他組相比，該體系具有良好的腫瘤靶向性。

2.2 促凋亡基因

腫瘤細(xì)胞的一大特點(diǎn)是其能逃脫程序性細(xì)胞死亡或細(xì)胞凋亡。機(jī)體細(xì)胞的凋亡是一個(gè)復(fù)雜的動(dòng)態(tài)過程，由促凋亡基因和抗凋亡基因共同調(diào)節(jié)。而多種基因突變導(dǎo)致腫瘤細(xì)胞的無限增殖會(huì)使這種平衡發(fā)生紊亂。誘導(dǎo)腫瘤細(xì)胞凋亡基因和促凋亡藥物的聯(lián)合使用有望成為新型的腫瘤療法[39]。

誘導(dǎo)細(xì)胞凋亡依賴于抑癌基因的表達(dá)，如抑癌基因p53；促凋亡則需要某些凋亡因子的表達(dá)，如腫瘤壞死因子α（tumor necrosis factor-α，TNF-α）基因或腫瘤壞死因子相關(guān)凋亡誘導(dǎo)配體（TRAIL）基因，以及一些抗凋亡基因survivin、Bcl-2或BAX的沉默。Xu等[40]用雙層納米粒呈遞p53和DOX，發(fā)現(xiàn)其明顯提高了DOX對(duì)腫瘤細(xì)胞的抑制率。給荷瘤小鼠聯(lián)合使用DOX和TRAIL質(zhì)粒的納米復(fù)合物，結(jié)果表明，與單獨(dú)使用DOX或TRAIL質(zhì)粒相比，其能明顯延長荷瘤小鼠的生存時(shí)間[41-43]。Su等[44]用陽離子脂質(zhì)體復(fù)合物共載TNF-α和DOX用于人神經(jīng)細(xì)胞瘤、肝癌和結(jié)腸癌的治療，研究結(jié)果發(fā)現(xiàn)，TNF-α mRNA在腫瘤細(xì)胞中的表達(dá)水平明顯上升，腫瘤體積與單獨(dú)使用DOX脂質(zhì)體相比亦明顯減少，表明聯(lián)合給藥能顯著增強(qiáng)腫瘤抑制作用。Hu等[37]用β-CD和PEI制備的聚合物膠束共載survivin siRNA和紫杉醇（paclitaxel,PTX）治療卵巢癌，結(jié)果表明，該納米共載體系對(duì)人卵巢癌細(xì)胞SKOV-3促凋亡與抑制腫瘤細(xì)胞生長效果顯著優(yōu)于基因或化療藥物單獨(dú)使用時(shí)的效果。

2.3 抗腫瘤血管內(nèi)皮基因

腫瘤的生長和增殖需要血管為其提供充足的氧和營養(yǎng)物質(zhì)。抑制血管生成也是目前有望治療腫瘤的方法。血管內(nèi)皮生長因子（vascular endothelial growth factor,VEGF）是公認(rèn)的促進(jìn)血管生成的調(diào)節(jié)因子。將VEGF siRNA或抗VEGF抗體藥物與化療聯(lián)合使用已被證明能有效抑制腫瘤生長和延長生存時(shí)間[45]。Zhu等[46]使用生物可降解陽離子膠束共遞送VEGF siRNA和PTX用于前列腺癌的治療發(fā)現(xiàn)，其能較高地被細(xì)胞內(nèi)吞，既能抑制腫瘤血管的生成，切斷腫瘤營養(yǎng)供應(yīng)，又能抑制腫瘤細(xì)胞的生長，提高化療效果。許多研究亦證明下調(diào)VEGF基因與化療藥物聯(lián)合使用能抑制血管生成，增強(qiáng)抗腫瘤效果[47-49]。

2.4 其他基因類型

化療與免疫療法相結(jié)合是近幾年用于腫瘤治療的新興聯(lián)合療法，即將化療藥物與表達(dá)相應(yīng)細(xì)胞因子（如Bcl-2、白細(xì)胞介素（IL）等）的質(zhì)粒通過共遞送體系作用于腫瘤，達(dá)到治療目的。Kim領(lǐng)導(dǎo)的課題組研究發(fā)現(xiàn)，與單一療法相比，共載IL-12基因和PTX的水溶性脂質(zhì)體能明顯抑制肺部腫瘤的生長[50]。

3 展望

基因和化療藥物納米共載體可克服腫瘤的MDR等障礙，提高腫瘤治療效果。近年的研究表明，基因和化療藥物納米共載體系用于腫瘤的聯(lián)合治療已取得了巨大進(jìn)步，但仍存在完善和發(fā)展的空間。同時(shí)也存在著諸多問題，如納米載體構(gòu)建的安全性，基因和藥物的靶向及其釋放的先后順序問題，基因轉(zhuǎn)染效率低下及溶酶體逃脫，負(fù)載基因和藥物的劑量及其最適比例等。目前，基因和化療藥物納米共載體系的研究仍處于臨床前的研究階段，尚未應(yīng)用于臨床。因此，更為安全、有效、多功能的基因和化療藥物納米共載體仍需深入研究和探索。

利益沖突 無

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Research progress in co-delivery of gene and chemotherapy drugs with nanocarriers for combination cancer therapy

Wei Xiangjuan,Qin Jingwen,Zhang Liuyuan,Chen Guimei,Nan Wenbin,Chen Hongli

School of Life Science and Technology,Xinxiang Medical University;Institute of Nano Biomedical Material,Xinxiang Medical University,Xinxiang 453003,China

Chen Hongli,Email:chenhlhl@126.com

Chemotherapy or gene therapy has many defects when used alone in the treatment of cancers.Codelivery of chemotherapy drugs and gene therapy could achieve synergistic therapeutic effect and overcome the shortcomings of monotherapy.Nanocarrier can package chemotherapy drugs and deliver genes for combination cancer therapy,which will increase the amount of the drug distribution in target organ and reduce the toxic side effects,thus enhancing the treatment efficacy.Meanwhile,the nanocarrier can protect the stability and integrity of genes,and improve the efficiency of gene transfection to a certain extent,to achieve the purpose of reducing side effects and improving the synergetic effects of the therapy.Co-delivery of gene and chemotherapy drugs with nanocarriers for combination cancer therapy is currently the hotspot of tumor treatment.The types of co-delivery carriers for gene and chemotherapy drugs and loading genetic types are summarized as well.On the basis,future research prospect is discussed.

Nanocarier;Gene;Chemotherapy drug;Cancer therapy

陳紅麗，Email:chenhlhl@126.com

10．3760/cma．j．issn．1673-4181．2016．05．011

國家自然科學(xué)基金（U1304819，81401519）；國家級(jí)大學(xué)生創(chuàng)新訓(xùn)練計(jì)劃項(xiàng)目（201410472030）

2016-06-18）