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腫瘤靶向遞藥新策略的研究進(jìn)展

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本文關(guān)鍵詞：腫瘤靶向遞藥新策略的研究進(jìn)展，由筆耕文化傳播整理發(fā)布。

高會(huì)樂等:腫瘤靶向遞藥新策略的研究進(jìn)展；?277?；表明,阿霉素在pH5.0時(shí)48h累積釋放達(dá)到88；為了使遞藥系統(tǒng)能夠被特定的細(xì)胞所識(shí)別和攝取,遞藥；腫瘤細(xì)胞是腫瘤的主要組成部分,選擇性殺傷腫瘤細(xì)胞；2.2靶向腫瘤干細(xì)胞；目前,越來(lái)越多的研究表明腫瘤細(xì)胞包含不同的分化階；圖2IL-13p修飾納米粒(ILNPs)與未修飾；Wang等[39]將anti-CD1

高會(huì)樂等: 腫瘤靶向遞藥新策略的研究進(jìn)展

? 277 ?

表明, 阿霉素在pH 5.0時(shí)48 h累積釋放達(dá)到88.3%, 顯著快于pH 7.4 (僅為21.9%), 從而使得該系統(tǒng)在具有良好抗腫瘤效果的同時(shí)具有較低的心臟毒性[30]。 2 主動(dòng)靶向策略

為了使遞藥系統(tǒng)能夠被特定的細(xì)胞所識(shí)別和攝取, 遞藥系統(tǒng)表面可以修飾特定的靶向分子, 如蛋白、抗體、多肽、核酸和化學(xué)小分子等。這些靶向分子能夠與細(xì)胞表面的特定受體、抗原或轉(zhuǎn)運(yùn)體等特異性結(jié)合, 進(jìn)而觸發(fā)細(xì)胞內(nèi)吞, 從而達(dá)到將遞藥系統(tǒng)靶向遞送至特定細(xì)胞的目的。根據(jù)靶向細(xì)胞的不同, 可將主動(dòng)靶向策略分為以下幾類。 2.1 靶向腫瘤細(xì)胞

腫瘤細(xì)胞是腫瘤的主要組成部分, 選擇性殺傷腫瘤細(xì)胞成為腫瘤治療的首要選擇。腫瘤細(xì)胞由于生長(zhǎng)迅速, 其細(xì)胞表面的多種受體表達(dá)顯著高于正常細(xì)胞, 如轉(zhuǎn)鐵蛋白受體、葉酸受體、低密度脂蛋白受體和葡萄糖轉(zhuǎn)運(yùn)體等, 因此相應(yīng)的配體經(jīng)常用作腫瘤細(xì)胞遞藥的靶向分子。如白介素13受體亞型2 (IL-13Rα2) 在腦腫瘤細(xì)胞高表達(dá)[32], 本課題組將IL-13Rα2的特異性配體IL-13p修飾在納米粒表面, 用于多西紫杉醇的靶向遞送[33]。結(jié)果表明, IL-13p修飾納米粒對(duì)腦腫瘤細(xì)胞的選擇性顯著優(yōu)于未修飾納米粒 (圖2); 其在腦腫瘤的蓄積濃度是未修飾納米粒的3.96倍; 經(jīng)過(guò)4次治療后, 其腫瘤體積是生理鹽水組的31.4%, 顯著低于未修飾納米粒組[33]。用于腫瘤細(xì)胞的靶向分子較多, 相對(duì)有效的如pH (low) insertion peptide[34]、angiopep-2[30]、AS1411核酸適配體[35]和葉酸[36]等。

2.2 靶向腫瘤干細(xì)胞

目前, 越來(lái)越多的研究表明腫瘤細(xì)胞包含不同的分化階段, 其中某些未分化的腫瘤細(xì)胞具有很強(qiáng)的成瘤潛力, 并具有很強(qiáng)的分化和增殖能力, 這與其他器官組織中干細(xì)胞的作用類似, 因此稱為腫瘤干細(xì)胞 (cancer stem cells)。一般認(rèn)為, 腫瘤細(xì)胞內(nèi)僅有0.01%～1%的腫瘤干細(xì)胞, 但腫瘤干細(xì)胞對(duì)化療、放

圖2 IL-13p修飾納米粒 (ILNPs) 與未修飾納米粒 (NPs) 尾靜脈給藥2 h后采用活體成像儀觀察納米粒的腫瘤分布[33]

Wang等[39]將anti-CD133抗體作為靶向分子修飾于碳納米管表面 (anti-CD133-SWNT), 以靶向腦腫瘤干細(xì)胞。結(jié)果表明, 該遞藥系統(tǒng)能被CD133+的腦腫瘤干細(xì)胞選擇性攝取, 濃度顯著高于CD133-的腫瘤細(xì)胞。經(jīng)光熱治療后, 腦腫瘤幾乎消失, 治療效果遠(yuǎn)遠(yuǎn)優(yōu)于普通未修飾碳納米管。透明質(zhì)酸 (HA) 能特異性結(jié)合CD44, 因此也被廣泛應(yīng)用于腫瘤干細(xì)胞的靶向遞送。多種HA修飾的脂質(zhì)體、固體脂質(zhì)納米粒等遞藥系統(tǒng)均能有效靶向至腫瘤干細(xì)胞, 從而提高抗腫瘤效果[40, 41]。 2.3 靶向腫瘤新生血管

腫瘤組織含有大量新生血管, 其是維系腫瘤生長(zhǎng)的重要基礎(chǔ)和特征。通過(guò)藥物阻止新生血管的增生能阻斷腫瘤的營(yíng)養(yǎng)供應(yīng), 從而達(dá)到“餓死”腫瘤的目的。與成熟的血管內(nèi)皮細(xì)胞相比, 腫瘤新生血管內(nèi)皮細(xì)胞高表達(dá)多種蛋白, 包括整合素、跨膜糖蛋白和氨肽酶N等, 能夠識(shí)別這些高表達(dá)蛋白的分子即可用于新生血管靶向藥物遞送[42]。如RGD環(huán)肽能夠選擇性結(jié)合整合素αvβ3, 從而被廣泛應(yīng)用于靶向腫瘤新生血管[43, 44]。本課題組將RGD修飾于熒光碳量子點(diǎn)表面, 結(jié)果表明其對(duì)乳腺癌的診斷效果顯著優(yōu)于未修飾熒光碳量子點(diǎn)[45]。 2.4 靶向腫瘤相關(guān)巨噬細(xì)胞

普通活化的巨噬細(xì)胞 (M1型) 能夠產(chǎn)生促凋亡因子, 并有效清除外來(lái)的病原體和腫瘤細(xì)胞。與此不同的是, 腫瘤相關(guān)巨噬細(xì)胞 (tumor associated macro-phages, TAM) 更接近于M2型, 對(duì)腫瘤細(xì)胞毒性低,

療等抗腫瘤治療的耐受性更大, 且抗腫瘤治療反而導(dǎo)致腫瘤干細(xì)胞的富集, 使其快速增殖或轉(zhuǎn)移, 從而使抗腫瘤治療失敗。因此, 將抗腫瘤藥物靶向遞送至腫瘤干細(xì)胞將有助于提高抗腫瘤效果, 改善預(yù)后效果, 減少腫瘤復(fù)發(fā)和轉(zhuǎn)移。相比普通腫瘤細(xì)胞, 腫瘤干細(xì)胞存在多種高表達(dá)的標(biāo)記物, 如CD44、CD133和EPCAM等, 以這些標(biāo)記物為靶點(diǎn), 能夠?qū)⒓{米遞藥系統(tǒng)靶向輸送至腫瘤干細(xì)胞, 提高對(duì)腫瘤干細(xì)胞的殺傷效果[37, 38]。

? 278 ? 藥學(xué)學(xué)報(bào) Acta Pharmaceutica Sinica 2016, 51 (2): 272?280

具有抗炎癥和組織修復(fù)功能, 且會(huì)促進(jìn)腫瘤的生長(zhǎng)、血管新生乃至轉(zhuǎn)移[46]。因此靶向TAM并選擇性殺傷TAM有助于提高抗腫瘤效果, 其中多種靶向分子被證明具有靶向TAM的效果, 如CD163抗體[42]、Ly6CZhu等[48]研究表明, 甘露糖修抗體[47]和甘露糖[48]等。

飾納米粒在腫瘤部位與TAM共定位程度顯著高于未修飾納米粒, 即甘露糖修飾能夠提高遞藥系統(tǒng)對(duì)TAM的靶向性。 2.5 靶向其他基質(zhì)細(xì)胞

除了前述幾種細(xì)胞外, 腫瘤部位還存在腫瘤相關(guān)成纖維細(xì)胞 (tumor-associated fibroblasts)、腫瘤相關(guān)周細(xì)胞 (tumor-associated pericytes)、腫瘤相關(guān)細(xì)胞外基質(zhì) (tumor-associated extracellular matrix) 和腫瘤相關(guān)淋巴細(xì)胞 (tumor-associated lymphocytes) 等。這些細(xì)胞或基質(zhì)均在維持腫瘤微環(huán)境、促進(jìn)腫瘤生長(zhǎng)和轉(zhuǎn)移方面發(fā)揮著重要作用, 因此針對(duì)這些基質(zhì)細(xì)胞的靶向遞藥同樣能夠發(fā)揮抗腫瘤效果[42]。 2.6 靶向多種細(xì)胞

靶向單一細(xì)胞盡管可以選擇性殺死腫瘤相應(yīng)細(xì)胞, 但是由于腫瘤微環(huán)境的復(fù)雜性, 往往會(huì)產(chǎn)生意想的營(yíng)養(yǎng)供應(yīng), 但是同時(shí)也會(huì)阻斷抗腫瘤藥物的進(jìn)入。不僅如此, 腫瘤細(xì)胞在由此導(dǎo)致的氧、營(yíng)養(yǎng)成分匱乏inducible factor-1α, HIF-1α) 蓄積, 而高表達(dá)的HIF-1α

一些問題。

對(duì)于具有環(huán)境響應(yīng)性的納米載體而言, 響應(yīng)的特異性、敏感性是需要關(guān)注的重要問題。內(nèi)源性的環(huán)境, 如pH、酶的差異, 能夠使得納米系統(tǒng)及時(shí)且持續(xù)響應(yīng), 對(duì)于系統(tǒng)給藥而言較為有利。但是這類刺激的特異性往往不夠?qū)�。盡管腫瘤內(nèi)部的pH值較正常組織低, 但是正常組織細(xì)胞內(nèi)的溶酶體仍然具有較低pH值, 從而使得這些納米系統(tǒng)被正常細(xì)胞攝取進(jìn)入溶酶體后同樣會(huì)發(fā)生響應(yīng)性, 導(dǎo)致藥物在正常細(xì)胞內(nèi)的釋放和蓄積。酶的特異性盡管較好, 但一方面某些酶的底物容易被血液和其他組織中的酶在不同位點(diǎn)降解, 從而影響整個(gè)體系響應(yīng)的特異性; 另一方面內(nèi)源性的刺激往往存在濃度不夠高, 使得響應(yīng)速度較慢。如基質(zhì)金屬蛋白酶響應(yīng)性的載體需要24 h才能被充分降解[16]。外源性的環(huán)境刺激, 如紫外線、超聲等強(qiáng)度較大, 且局部刺激, 從而使得納米載體的響應(yīng)速度較快、特異性較好, 但是這種刺激只能選擇特定的時(shí)間間斷性刺激, 持續(xù)時(shí)間短, 從而使得納米載體在非刺激時(shí)段無(wú)法具有響應(yīng)性。

對(duì)于主動(dòng)靶向策略而言, 靶向分子的特異性、有位高表達(dá), 但是其仍然在正常組織中有一定程度的表達(dá), 使得靶向遞藥系統(tǒng)也可能分布于其他組織, 因研究目標(biāo); 另一方面, 靶向分子修飾于納米遞藥系統(tǒng)環(huán)后, 由于血漿蛋白的吸附而在表面形成一層蛋白冠 (protein corona), 而這層蛋白冠會(huì)阻斷靶向分子與受體的特異性結(jié)合從而使得靶向特異性減弱甚至除此之外, 靶向分子的間距也會(huì)影響其與受消失[52]。

體的結(jié)合。張強(qiáng)課題組[53]證明, 當(dāng)在脂質(zhì)體表面同一個(gè)PEG分子上修飾兩個(gè)RGD, 且兩個(gè)RGD具有特定間距時(shí), 其促進(jìn)細(xì)胞內(nèi)吞的作用更強(qiáng)。

盡管存在上述問題, 但是環(huán)境響應(yīng)性和主動(dòng)靶向性仍然是腫瘤靶向領(lǐng)域的熱點(diǎn)。隨著材料學(xué)的發(fā)展, 研究更為靈敏和特異的響應(yīng)性材料將顯著改善現(xiàn)有納米材料面臨的問題。通過(guò)新技術(shù), 包括噬菌體展示技術(shù)、指數(shù)富集的配基系統(tǒng)進(jìn)化技術(shù) (systematic evolution of ligands by exponential enrichment, SELEX) 和計(jì)算機(jī)輔助設(shè)計(jì)等[54-57], 有助于篩選得到特異性和親和性更好的靶向分子, 從而進(jìn)一步提高腫瘤靶向效果。

不到的不良反應(yīng)。如抗新生血管治療能夠阻斷腫瘤效性是關(guān)注的熱點(diǎn): 一方面, 盡管靶向受體在腫瘤部

環(huán)境下, 使得腫瘤內(nèi)部的缺氧誘導(dǎo)因子1α (hypoxia- 此尋找特異性更好的受體及相關(guān)配體成為本領(lǐng)域的能夠提高腫瘤細(xì)胞的侵襲性和耐藥性[49,50]。因此同表面的有效性仍然有待探索。納米系統(tǒng)進(jìn)入血液循時(shí)靶向腫瘤的多種細(xì)胞, 可以更好地治療腫瘤。如前所述, IL-13p能靶向腦腫瘤細(xì)胞, 而RGD能靶向腫瘤新生血管內(nèi)皮細(xì)胞, 因此本課題組將IL-13p和RGD同時(shí)修飾在納米粒表面, 構(gòu)建得到雙重靶向遞藥系統(tǒng) (IRNP)[51]。體外新生內(nèi)皮細(xì)胞和腦腫瘤細(xì)胞共培養(yǎng)模型中, IRNP在兩種細(xì)胞的攝取濃度均較高, 而單一靶向分子修飾的納米系統(tǒng)僅能選擇性提高相應(yīng)靶細(xì)胞的攝取。體內(nèi)切片共定位結(jié)果同樣發(fā)現(xiàn)IRNP既與腫瘤細(xì)胞共定位, 又與新生血管細(xì)胞共定位。與對(duì)照生理鹽水組相比, 載多西紫杉醇IRNP治療的荷腦腫瘤小鼠的中位生存期延長(zhǎng)106%, 顯著優(yōu)于單一靶向分子修飾的納米遞藥系統(tǒng)[51]。 3 存在的問題及展望

如前所述, 目前的腫瘤靶向策略主要是通過(guò)納米材料結(jié)構(gòu)的設(shè)計(jì)賦予載藥系統(tǒng)以環(huán)境響應(yīng)性調(diào)節(jié)能力, 或通過(guò)表面靶向分子的修飾賦予其主動(dòng)靶向性。盡管這些研究均取得一定的成果, 一定程度提高了藥物遞送和抗腫瘤效果, 但是這些策略仍然存在

References

[1]

Chen W, Zheng R, Zeng H, et al. Annual report on status of

高會(huì)樂等: 腫瘤靶向遞藥新策略的研究進(jìn)展

? 279 ?

cancer in China, 2011 [J]. Chin J Cancer Res, 2015, 27: 2-12. [2]

Barenholz YC. Doxil - the first FDA-approved nano-drug: lessons learned [J]. J Control Release, 2012, 160: 117-134. [3]

Fu Q, Sun J, Zhang WP, et al. Nanoparticle albumin-bound (NAB) technology is a promising method for anti-cancer drug delivery [J]. Recent Pat Anticancer Drug Discov, 2009, 4: 262-272. [4]

Weissig V, Pettinger TK, Murdock N. Nanopharmaceuticals (part 1): products on the market [J]. Int J Nanomedicine, 2014, 9: 4357-4373. [5]

Jain RK. Delivery of molecular and cellular medicine to solid tumors [J]. Adv Drug Deliv Rev, 2001, 46: 149-168. [6]

Fang J, Nakamura H, Maeda H. The EPR effect: unique

tion and pH triggered doxorubicin release [J]. Biomaterials, 2015, 60: 100-110.

[17] Ruan SB, He Q, Gao HL. Matrix metalloproteinase triggered

size-shrinkable gelatin-gold fabricated nanoparticles for tumor microenvironment sensitive penetration and diagnosis of glioma [J]. Nanoscale, 2015, 7: 9487-9496.

[18] Yu Y, Zhang XL, Qiu LY. The anti-tumor efficacy of

curcumin when delivered by size/charge-changing multistage polymeric micelles based on amphiphilic poly(β-amino ester) derivates [J]. Biomaterials, 2014, 35: 3467-3479.

[19] Tong R, Hemmati HD, Langer R, et al. Photoswitchable

nanoparticles for triggered tissue penetration and drug delivery [J]. J Am Chem Soc, 2012, 134: 8848-8855.

[20] Tong R, Chiang HH, Kohane DS. Photoswitchable nanopar-features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect [J]. Adv Drug Deliv Rev, 2011, 63: 136-151. [7]

Gao HL, Cao SJ, Yang Z, et al. Preparation, characterization and anti-glioma effects of docetaxel-incorporated albumin-lipid nanoparticles [J]. J Biomed Nanotechnol, 2015, 11: 2137-2147. [8]

Gao HL, Cao SL, Chen C, et al. Incorporation of lapatinib into lipoprotein-like nanoparticles with enhanced water solubility and anti-tumor effect in breast cancer [J]. Nanomedicine, 2013, 8: 1429-1442. [9]

Zhou J, Zhang XM, Li M, et al. Novel lipid hybrid albumin nanoparticle greatly lowered toxicity of pirarubicin [J]. Mol Pharm, 2013, 10: 3832-3841.

[10] Desai NP, Trieu V, Hwang LY, et al. Improved effectiveness of

nanoparticle albumin-bound (nab) paclitaxel versus polysorbate- based docetaxel in multiple xenografts as a function of HER2 and SPARC status [J]. Anticancer Drugs, 2008, 19: 899-909. [11] Pérez-Herrero E, Fernández-Medarde A. Advanced targeted

therapies in cancer: drug nanocarriers, the future of chemo-therapy [J]. Eur J Pharm Biopharm, 2015, 93: 52-79. [12] Cabral H, Matsumoto Y, Mizuno K, et al. Accumulation of

sub-100 nm polymeric micelles in poorly permeable tumours depends on size [J]. Nat Nanotechnol, 2011, 6: 815-823. [13] Popovi? Z, Liu WH, Chauhan VP, et al. A nanoparticle size

series for in vivo fluorescence imaging [J]. Angew Chem Int Ed Engl, 2010, 49: 8649-8652.

[14] Perrault SD, Walkey C, Jennings T, et al. Mediating tumor

targeting efficiency of nanoparticles through design [J]. Nano Lett, 2009, 9: 1909-1915.

[15] Wong C, Stylianopoulos T, Cui J, et al. Multistage nanoparticle

delivery system for deep penetration into tumor tissue [J]. Proc Natl Acad Sci U S A, 2011, 108: 2426-2431.

[16] Ruan SB, Cao X, Cun XL, et al. Matrix metalloproteinase-

sensitive size-shrinkable nanoparticles for deep tumor penetra-ticles for in vivo cancer chemotherapy [J]. Proc Natl Acad Sci U S A, 2013, 110: 19048-19053.

[21] Blum AP, Kammeyer JK, Rush AM, et al. Stimuli-responsive

nanomaterials for biomedical applications [J]. J Am Chem Soc, 2015, 137: 2140-2154.

[22] Nam J, Won N, Jin H, et al. pH-Induced aggregation of gold

nanoparticles for photothermal cancer therapy [J]. J Am Chem Soc, 2009, 131: 13639-13645.

[23] Lee DJ, Oh YT, Lee ES. Surface charge switching nanopar-ticles for magnetic resonance imaging [J]. Int J Pharm, 2014, 471: 127-134.

[24] Heldin CH, Rubin K, Pietras K, et al. High interstitial fluid

pressure - an obstacle in cancer therapy [J]. Nat Rev Cancer, 2004, 4: 806-813.

[25] Fan YC, Du WW, He B, et al. The reduction of tumor

interstitial fluid pressure by liposomal imatinib and its effect on combination therapy with liposomal doxorubicin [J]. Bi-omaterials, 2013, 34: 2277-2288.

[26] Zhang L, Wang Y, Yang YT, et al. High tumor penetration

of paclitaxel loaded pH sensitive cleavable liposomes by depletion of tumor collagen I in breast cancer [J]. ACS Appl Mater Interfaces, 2015, 7: 9691-9701.

[27] Kohli AG, Kivim?e S, Tiffany MR, et al. Improving the

distribution of Doxil in the tumor matrix by depletion of tumor hyaluronan [J]. J Control Release, 2014, 191: 105-114. [28] Chauhan VP, Stylianopoulos T, Martin JD, et al. Normalization

of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner [J]. Nat Nanotechnol, 2012, 7: 383-388.

[29] Maes H, Kuchnio A, Peric A, et al. Tumor vessel normalize-tion by chloroquine independent of autophagy [J]. Cancer Cell, 2014, 26: 190-206.

[30] Ruan SB, Yuan MQ, Zhang L, et al. Tumor microenvironment

? 280 ? 藥學(xué)學(xué)報(bào) Acta Pharmaceutica Sinica 2016, 51 (2): 272?280

sensitive doxorubicin delivery and release to glioma using angiopep-2 decorated gold nanoparticles [J]. Biomaterials, 2015, 37: 425-435.

[31] Li L, Sun W, Zhong JJ, et al. Multistage nanovehicle delivery

system based on stepwise size reduction and charge reversal for programmed nuclear targeting of systemically administered anticancer drugs [J]. Adv Funct Mater, 2015, 25: 4101-4113. [32] Mintz A, Gibo DM, Slagle-Webb B, et al. IL-13Rα2 is a

glioma-restricted receptor for interleukin-13 [J]. Neoplasia, 2002, 4: 388-399.

[33] Gao HL, Yang Z, Zhang S, et al. Glioma-homing peptide

with a cell-penetrating effect for targeting delivery with enhanced glioma localization, penetration and suppression of glioma growth [J]. J Control Release, 2013, 172: 921-928. [34] Weerakkody D, Moshnikova A, Thakur MS, et al. Family of

pH (low) insertion peptides for tumor targeting [J]. Proc Natl Acad Sci U S A, 2013, 110: 5834-5839.

[35] Guo JW, Gao XL, Su LN, et al. Aptamer-functionalized

PEG-PLGA nanoparticles for enhanced anti-glioma drug delivery [J]. Biomaterials, 2011, 32: 8010-8020.

[36] Li JJ, Guo MM, Han SP, et al. Preparation and in vitro eval-uation of borneol and folic acid co-modified doxorubicin loaded PAMAM drug delivery system [J]. Acta Pharm Sin (藥學(xué)學(xué)報(bào)), 2015, 50: 899-905.

[37] Krishnamurthy S, Ke XY, Yang YY. Delivery of therapeutics

using nanocarriers for targeting cancer cells and cancer stem cells [J]. Nanomedicine, 2015, 10: 143-160.

[38] Qiao MX, Zhang XJ, Shuang BA, et al. Progress in the study

of targeted drug delivery systems for cancer stem cells [J]. Acta Pharm Sin (藥學(xué)學(xué)報(bào)), 2013, 48: 477-483.

[39] Wang CH, Chiou SH, Chou CP, et al. Photothermolysis of

glioblastoma stem-like cells targeted by carbon nanotubes conjugated with CD133 monoclonal antibody [J]. Nanomedi-cine, 2011, 7: 69-79.

[40] Yao HJ, Zhang YG, Sun L, et al. The effect of hyaluronic

acid functionalized carbon nanotubes loaded with salinomycin on gastric cancer stem cells [J]. Biomaterials, 2014, 35: 9208-9223.

[41] Shen HX, Shi SJ, Zhang ZR, et al. Coating solid lipid nano-particles with hyaluronic acid enhances antitumor activity against melanoma stem-like cells [J]. Theranostics, 2015, 5: 755-771.

[42] Zhao G, Rodriguez BL. Molecular targeting of liposomal

nanoparticles to tumor microenvironment [J]. Int J Nanome-dicine, 2013, 8: 61-71.

[43] Zhao B, Fan YC, Wang XQ, et al. Cellular toxicity and an-ti-tumor efficacy of iRGD modified doxorubixin loaded steri-cally stabilized liposomes [J]. Acta Pharm Sin (藥學(xué)學(xué)報(bào)), 2013, 48: 417-422.

[44] Tu LX, Xu YH, Tang CY, et al. In vivo imaging in tumor-

bearing animals and pharmacokinetics of PEGylated liposomes modified with RGD cyclopeptide [J]. Acta Pharm Sin (藥學(xué)學(xué)報(bào)), 2012, 47: 646-651.

[45] Ruan SB, Qian JB, Shen S, et al. Non-invasive imaging of

breast cancer using RGDyK functionalized fluorescent carbo-naceous nanospheres [J]. RSC Adv, 2015, 5: 25428-25436. [46] Raggi C, Mousa HS, Correnti M, et al. Cancer stem cells and

tumor-associated macrophages: a roadmap for multitargeting strategies [J]. Oncogene, 2015. DOI: 10.1038/onc.2015.132.

[47] Yokoi K, Godin B, Oborn CJ, et al. Porous silicon nanocarriers

for dual targeting tumor associated endothelial cells and mac-rophages in stroma of orthotopic human pancreatic cancers [J]. Cancer Lett, 2013, 334: 319-327.

[48] Zhu SJ, Niu MM, O’Mary H, et al. Targeting of tumor-

associated macrophages made possible by PEG-sheddable, mannose-modified nanoparticles [J]. Mol Pharm, 2013, 10: 3525-3530.

[49] Blagosklonny MV. Antiangiogenic therapy and tumor

progression [J]. Cancer Cell, 2004, 5: 13-17.

[50] Yu JL, Rak JW, Coomber BL, et al. Effect of p53 status on

tumor response to antiangiogenic therapy [J]. Science, 2002, 295: 1526-1528.

[51] Gao HL, Yang Z, Cao SJ, et al. Tumor cells and neovascula-ture dual targeting delivery for glioblastoma treatment [J]. Biomaterials, 2014, 35: 2374-2382.

[52] Gao HL, He Q. The interaction of nanoparticles with plasma

proteins and the consequent influence on nanoparticles behavior [J]. Expert Opin Drug Deliv, 2014, 11: 409-420. [53] Guo Z, He B, Jin H, et al. Targeting efficiency of RGD-

modified nanocarriers with different ligand intervals in response to integrin αvβ3 clustering [J]. Biomaterials, 2014, 35: 6106-6117.

[54] Yang Y, Yang DL, Schluesener HJ, et al. Advances in

SELEX and application of aptamers in the central nervous system [J]. Biomol Eng, 2007, 24: 583-592.

[55] Zhan CY, Li B, Hu LJ, et al. Micelle-based brain-targeted

drug delivery enabled by a nicotine acetylcholine receptor lig-and [J]. Angew Chem Int Ed Engl, 2011, 50: 5482-5485. [56] Li JW, Feng L, Fan L, et al. Targeting the brain with PEG-

PLGA nanoparticles modified with phage-displayed peptides [J]. Biomaterials, 2011, 32: 4943-4950.

[57] Wang XL, Wang QQ, Song HF. Advance in the study of

targeting delivery system for siRNA mediated by aptamers [J]. Acta Pharm Sin (藥學(xué)學(xué)報(bào)), 2012, 47: 850-855.

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