肿瘤靶向递药新策略的研究进展

发布时间：2016-11-17 18:41

本文关键词：肿瘤靶向递药新策略的研究进展，由笔耕文化传播整理发布。

高会乐等:肿瘤靶向递药新策略的研究进展；?277?；表明,阿霉素在pH5.0时48h累积释放达到88；为了使递药系统能够被特定的细胞所识别和摄取,递药；肿瘤细胞是肿瘤的主要组成部分,选择性杀伤肿瘤细胞；2.2靶向肿瘤干细胞；目前,越来越多的研究表明肿瘤细胞包含不同的分化阶；图2IL-13p修饰纳米粒(ILNPs)与未修饰；Wang等[39]将anti-CD1

高会乐等: 肿瘤靶向递药新策略的研究进展

? 277 ?

表明, 阿霉素在pH 5.0时48 h累积释放达到88.3%, 显著快于pH 7.4 (仅为21.9%), 从而使得该系统在具有良好抗肿瘤效果的同时具有较低的心脏毒性[30]。 2 主动靶向策略

为了使递药系统能够被特定的细胞所识别和摄取, 递药系统表面可以修饰特定的靶向分子, 如蛋白、抗体、多肽、核酸和化学小分子等。这些靶向分子能够与细胞表面的特定受体、抗原或转运体等特异性结合, 进而触发细胞内吞, 从而达到将递药系统靶向递送至特定细胞的目的。根据靶向细胞的不同, 可将主动靶向策略分为以下几类。 2.1 靶向肿瘤细胞

肿瘤细胞是肿瘤的主要组成部分, 选择性杀伤肿瘤细胞成为肿瘤治疗的首要选择。肿瘤细胞由于生长迅速, 其细胞表面的多种受体表达显著高于正常细胞, 如转铁蛋白受体、叶酸受体、低密度脂蛋白受体和葡萄糖转运体等, 因此相应的配体经常用作肿瘤细胞递药的靶向分子。如白介素13受体亚型2 (IL-13Rα2) 在脑肿瘤细胞高表达[32], 本课题组将IL-13Rα2的特异性配体IL-13p修饰在纳米粒表面, 用于多西紫杉醇的靶向递送[33]。结果表明, IL-13p修饰纳米粒对脑肿瘤细胞的选择性显著优于未修饰纳米粒 (图2); 其在脑肿瘤的蓄积浓度是未修饰纳米粒的3.96倍; 经过4次治疗后, 其肿瘤体积是生理盐水组的31.4%, 显著低于未修饰纳米粒组[33]。用于肿瘤细胞的靶向分子较多, 相对有效的如pH (low) insertion peptide[34]、angiopep-2[30]、AS1411核酸适配体[35]和叶酸[36]等。

2.2 靶向肿瘤干细胞

目前, 越来越多的研究表明肿瘤细胞包含不同的分化阶段, 其中某些未分化的肿瘤细胞具有很强的成瘤潜力, 并具有很强的分化和增殖能力, 这与其他器官组织中干细胞的作用类似, 因此称为肿瘤干细胞 (cancer stem cells)。一般认为, 肿瘤细胞内仅有0.01%～1%的肿瘤干细胞, 但肿瘤干细胞对化疗、放

图2 IL-13p修饰纳米粒 (ILNPs) 与未修饰纳米粒 (NPs) 尾静脉给药2 h后采用活体成像仪观察纳米粒的肿瘤分布[33]

Wang等[39]将anti-CD133抗体作为靶向分子修饰于碳纳米管表面 (anti-CD133-SWNT), 以靶向脑肿瘤干细胞。结果表明, 该递药系统能被CD133+的脑肿瘤干细胞选择性摄取, 浓度显著高于CD133-的肿瘤细胞。经光热治疗后, 脑肿瘤几乎消失, 治疗效果远远优于普通未修饰碳纳米管。透明质酸 (HA) 能特异性结合CD44, 因此也被广泛应用于肿瘤干细胞的靶向递送。多种HA修饰的脂质体、固体脂质纳米粒等递药系统均能有效靶向至肿瘤干细胞, 从而提高抗肿瘤效果[40, 41]。 2.3 靶向肿瘤新生血管

肿瘤组织含有大量新生血管, 其是维系肿瘤生长的重要基础和特征。通过药物阻止新生血管的增生能阻断肿瘤的营养供应, 从而达到“饿死”肿瘤的目的。与成熟的血管内皮细胞相比, 肿瘤新生血管内皮细胞高表达多种蛋白, 包括整合素、跨膜糖蛋白和氨肽酶N等, 能够识别这些高表达蛋白的分子即可用于新生血管靶向药物递送[42]。如RGD环肽能够选择性结合整合素αvβ3, 从而被广泛应用于靶向肿瘤新生血管[43, 44]。本课题组将RGD修饰于荧光碳量子点表面, 结果表明其对乳腺癌的诊断效果显著优于未修饰荧光碳量子点[45]。 2.4 靶向肿瘤相关巨噬细胞

普通活化的巨噬细胞 (M1型) 能够产生促凋亡因子, 并有效清除外来的病原体和肿瘤细胞。与此不同的是, 肿瘤相关巨噬细胞 (tumor associated macro-phages, TAM) 更接近于M2型, 对肿瘤细胞毒性低,

疗等抗肿瘤治疗的耐受性更大, 且抗肿瘤治疗反而导致肿瘤干细胞的富集, 使其快速增殖或转移, 从而使抗肿瘤治疗失败。因此, 将抗肿瘤药物靶向递送至肿瘤干细胞将有助于提高抗肿瘤效果, 改善预后效果, 减少肿瘤复发和转移。相比普通肿瘤细胞, 肿瘤干细胞存在多种高表达的标记物, 如CD44、CD133和EPCAM等, 以这些标记物为靶点, 能够将纳米递药系统靶向输送至肿瘤干细胞, 提高对肿瘤干细胞的杀伤效果[37, 38]。

? 278 ? 药学学报 Acta Pharmaceutica Sinica 2016, 51 (2): 272?280

具有抗炎症和组织修复功能, 且会促进肿瘤的生长、血管新生乃至转移[46]。因此靶向TAM并选择性杀伤TAM有助于提高抗肿瘤效果, 其中多种靶向分子被证明具有靶向TAM的效果, 如CD163抗体[42]、Ly6CZhu等[48]研究表明, 甘露糖修抗体[47]和甘露糖[48]等。

饰纳米粒在肿瘤部位与TAM共定位程度显著高于未修饰纳米粒, 即甘露糖修饰能够提高递药系统对TAM的靶向性。 2.5 靶向其他基质细胞

除了前述几种细胞外, 肿瘤部位还存在肿瘤相关成纤维细胞 (tumor-associated fibroblasts)、肿瘤相关周细胞 (tumor-associated pericytes)、肿瘤相关细胞外基质 (tumor-associated extracellular matrix) 和肿瘤相关淋巴细胞 (tumor-associated lymphocytes) 等。这些细胞或基质均在维持肿瘤微环境、促进肿瘤生长和转移方面发挥着重要作用, 因此针对这些基质细胞的靶向递药同样能够发挥抗肿瘤效果[42]。 2.6 靶向多种细胞

靶向单一细胞尽管可以选择性杀死肿瘤相应细胞, 但是由于肿瘤微环境的复杂性, 往往会产生意想的营养供应, 但是同时也会阻断抗肿瘤药物的进入。不仅如此, 肿瘤细胞在由此导致的氧、营养成分匮乏inducible factor-1α, HIF-1α) 蓄积, 而高表达的HIF-1α

一些问题。

对于具有环境响应性的纳米载体而言, 响应的特异性、敏感性是需要关注的重要问题。内源性的环境, 如pH、酶的差异, 能够使得纳米系统及时且持续响应, 对于系统给药而言较为有利。但是这类刺激的特异性往往不够专属。尽管肿瘤内部的pH值较正常组织低, 但是正常组织细胞内的溶酶体仍然具有较低pH值, 从而使得这些纳米系统被正常细胞摄取进入溶酶体后同样会发生响应性, 导致药物在正常细胞内的释放和蓄积。酶的特异性尽管较好, 但一方面某些酶的底物容易被血液和其他组织中的酶在不同位点降解, 从而影响整个体系响应的特异性; 另一方面内源性的刺激往往存在浓度不够高, 使得响应速度较慢。如基质金属蛋白酶响应性的载体需要24 h才能被充分降解[16]。外源性的环境刺激, 如紫外线、超声等强度较大, 且局部刺激, 从而使得纳米载体的响应速度较快、特异性较好, 但是这种刺激只能选择特定的时间间断性刺激, 持续时间短, 从而使得纳米载体在非刺激时段无法具有响应性。

对于主动靶向策略而言, 靶向分子的特异性、有位高表达, 但是其仍然在正常组织中有一定程度的表达, 使得靶向递药系统也可能分布于其他组织, 因研究目标; 另一方面, 靶向分子修饰于纳米递药系统环后, 由于血浆蛋白的吸附而在表面形成一层蛋白冠 (protein corona), 而这层蛋白冠会阻断靶向分子与受体的特异性结合从而使得靶向特异性减弱甚至除此之外, 靶向分子的间距也会影响其与受消失[52]。

体的结合。张强课题组[53]证明, 当在脂质体表面同一个PEG分子上修饰两个RGD, 且两个RGD具有特定间距时, 其促进细胞内吞的作用更强。

尽管存在上述问题, 但是环境响应性和主动靶向性仍然是肿瘤靶向领域的热点。随着材料学的发展, 研究更为灵敏和特异的响应性材料将显著改善现有纳米材料面临的问题。通过新技术, 包括噬菌体展示技术、指数富集的配基系统进化技术 (systematic evolution of ligands by exponential enrichment, SELEX) 和计算机辅助设计等[54-57], 有助于筛选得到特异性和亲和性更好的靶向分子, 从而进一步提高肿瘤靶向效果。

不到的不良反应。如抗新生血管治疗能够阻断肿瘤效性是关注的热点: 一方面, 尽管靶向受体在肿瘤部

环境下, 使得肿瘤内部的缺氧诱导因子1α (hypoxia- 此寻找特异性更好的受体及相关配体成为本领域的能够提高肿瘤细胞的侵袭性和耐药性[49,50]。因此同表面的有效性仍然有待探索。纳米系统进入血液循时靶向肿瘤的多种细胞, 可以更好地治疗肿瘤。如前所述, IL-13p能靶向脑肿瘤细胞, 而RGD能靶向肿瘤新生血管内皮细胞, 因此本课题组将IL-13p和RGD同时修饰在纳米粒表面, 构建得到双重靶向递药系统 (IRNP)[51]。体外新生内皮细胞和脑肿瘤细胞共培养模型中, IRNP在两种细胞的摄取浓度均较高, 而单一靶向分子修饰的纳米系统仅能选择性提高相应靶细胞的摄取。体内切片共定位结果同样发现IRNP既与肿瘤细胞共定位, 又与新生血管细胞共定位。与对照生理盐水组相比, 载多西紫杉醇IRNP治疗的荷脑肿瘤小鼠的中位生存期延长106%, 显著优于单一靶向分子修饰的纳米递药系统[51]。 3 存在的问题及展望

如前所述, 目前的肿瘤靶向策略主要是通过纳米材料结构的设计赋予载药系统以环境响应性调节能力, 或通过表面靶向分子的修饰赋予其主动靶向性。尽管这些研究均取得一定的成果, 一定程度提高了药物递送和抗肿瘤效果, 但是这些策略仍然存在

References

[1]

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

高会乐等: 肿瘤靶向递药新策略的研究进展

? 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 ? 药学学报 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 (药学学报), 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 (药学学报), 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 (药学学报), 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 (药学学报), 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 (药学学报), 2012, 47: 850-855.

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