Gold nanoparticles in tumor sensitize radiotherapy: how to maximize the effect of gold nanorods?

doi:10.3969/j.issn.2095-4344.2014.39.024

Abstract

Abstract:

BACKGROUND: Gold nanorods have unique optical properties, good histocompatibility, easily controlled surface modification, which have a broad application prospect in the field of biology and medicine.

OBJECTIVE: To summarize the optical and thermal properties of gold nanoparticles, and to review the mechanism and research advances of gold nanoparticles, especially gold nanorods in tumor sensitize radiotherapy.

METHODS: A computer-based search of PubMed and CNKI databases was undertaken with the keywords of “gold nanoparticles, radiotherapy sensitivity” in English and Chinese, respectively. The included articles were related to nanoparticles used in vitro and in vivo for clinic study as well as gold nanoparticles-related tumor sensitize radiotherapy.

RESULTS AND CONCLUSION: Gold nanoparticles exhibit unique properties of surface plasmon resonance properties. Compared with the traditional spherical gold nanoparticles, gold nanorods are capsule-like gold nanoparticles containing two absorption peaks that are a transverse surface plasmon resonance absorption peak and a longitudinal surface plasmon resonance absorption peak corresponding to the dimensional characteristics of their horizontal axis and vertical axis, respectively. By regulation of the ratio of horizontal axis and vertical axis, we can realize the manipulation of the longitudinal surface plasmon resonance absorption peak location. Thus, the longitudinal surface plasmon resonance absorption peak can be changed from visible region to the near-infrared region which is the most ideal optical transmission through for all of biological tissues. As a kind of novel radiotherapy sensitization agent, gold nanorods have the properties of low toxicity, high efficiency, high yield. Its sensitization effect is not only related to the exposure dose, own concentration and size, surface modified compounds, but also related to the types of radiation and cell lines. However, for radiotherapy sensitization of gold nanorods how to avoid the limits of radioactive ray species, choose appropriate trim and maximize the use of gold nanorods still need a further research.

中国组织工程研究杂志出版内容重点：生物材料；骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性；组织工程

全文链接：

Key words: nanoparticles, neoplasms, review

CLC Number:

R318

Shen Lei, Gao Bin, He Ke-wu. Gold nanoparticles in tumor sensitize radiotherapy: how to maximize the effect of gold nanorods?[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(39): 6369-6374.

Figures/Tables 1

2.1 金纳米颗粒的光学特性 2.1.1 球形金纳米颗粒的光学特性球形金纳米颗粒具有独特光学性质，源于其表面等离子共振效应：当可见光照射到粒径小于光波长的球形金属颗粒表面时，光与金属表面的自由电子相互作用，当光波长与自由电子的振动频率发生共振时就会产生等离子共振效应，在紫外-可见光谱上显示强的吸收峰。等离子共振效应强烈依赖于金属粒子的尺寸，球形金纳米颗粒仅表现为单一的等离子共振效应光谱峰(位于520-530 nm)。 2.1.2 金纳米棒的光学特性金纳米棒是一种胶囊棒状的金纳米颗粒，与金纳米球相似的是都具有强等离子共振效应，不同的是金纳米棒具有2个等离子共振效应光谱峰，即一个横向等离子共振吸收峰(transverse surface plasmon resonance，TSPR)和一个纵向等离子共振吸收峰(longitudinal surface plasmon resonance，LSPR)[7]，分别对应其横轴和纵轴2个特征尺寸，纵轴长度与横轴直径之比为金纳米棒的长径比(aspect ratio，AR)。横向等离子共振吸收峰位于520-530 nm附近，且位置不随金纳米棒长径比的改变而改变。而纵向等离子共振吸收峰的位置取决于金纳米棒的长径比，增加金纳米棒的长径比，使纵向等离子共振吸收峰从可见光区向近红外区偏移，这一红外波长范围正是生物组织所具有的光窗口，金纳米棒为自由进入近红外光区提供了一条有效途径[8-9]。 2.2 金纳米棒的光热特性光热疗法是近年来肿瘤治疗的一种新方法，其原理是通过进入肿瘤细胞内具有光吸收能力的媒介接受激光照射产生过高热，从而杀死肿瘤细胞。大量研究证实肿瘤的光热治疗致使肿瘤细胞内的温度骤增超过20 ℃[10-11]。金纳米棒因其可控的纵向等离子共振吸收峰，通过改变长径比可将最大共振吸收在近红外区域 (600-900 nm)内加以调谐。近红外区域能够穿透进入深部组织达10 cm，并能快速(约1 ps)将光能转化为热能而破坏肿瘤细胞，从而为金纳米棒的光热治疗提供了理论支持[12]。Okuno等[13]构建小鼠MXH10/Mo/lpr模型通过静脉注射将金纳米棒(3.6×1012/mL)注入小鼠体内，利用金纳米棒的光热特性检测肿瘤腋淋巴结的大小，结果显示0，6，9 d下金纳米棒光热疗法的肿瘤肿瘤腋淋巴结较空白对照组和激光照射组明显缩小，且随着时间的增加疗效越显著。最近有学者研究不同尺寸金纳米棒在人类口腔鳞状细胞癌(HSC-3)中的光热疗效，结果表明，与38 nm×11 nm AuNRs和17 nm×5 nm AuNRs相比， 28 nm×8 nm AuNRs的光热疗效最优[14]。不同作用时间及不同尺寸金纳米棒的光热疗效不一，这为临床实施个性化的治疗方案奠定了基础。金纳米棒光热疗法的另一独到之处在于其表面能与一些特定的抗体耦合，形成功能化的金纳米棒探针，而恶性肿瘤细胞表面常过度表达这些抗原，因此能更多地结合这种功能化的金纳米棒探针。高斌等[15]将叶酸通过氨基偶联GNRs@SiO2制备出靶向性金纳米探针，利用ICP-MS法研究证实其短时间内可以与肝癌细胞上大量的叶酸受体结合。当使用相同功率的激光照射后便产生较高的吸光度，只需较低的激光照射量就能达到超过破坏肿瘤细胞阈值的温度，70-80 ℃[16]。基于这个原理，Xia等[17]研究小组采用GNR@SiO2@QDs-FA对宫颈癌Hela细胞进行 3.2 W/cm2激光照射后行锥虫蓝染色，计算细胞死亡率，结果显示GNR@SiO2@QDs-FA联合激光照射组的细胞死亡率明显高于单独行激光照射组，旨在表明GNR@SiO2@QDs-FA能更多选择性进入肿瘤细胞，增加光热治疗的效果。 2.3 金纳米颗粒对肿瘤放疗增敏的机制金纳米颗粒在X射线或γ射线照射后，产生强的光电吸收效应和二次电子[18-19]，加速DNA链断裂，因此可以作为放疗领域中一类新型的放射增敏剂。放射增敏剂是能够增强生物体放射敏感性的一类物质，它可增强射线对肿瘤的杀伤力，尤其是有助于解决实体肿瘤中乏氧细胞对射线抵抗性所致肿瘤放疗治愈率低的问题[20]。Brun等[21-22]指出金纳米颗粒可加速经过放疗的中心小体蛋白质的分解。Brun等[23]研究证实，在相同照射条件下，经金纳米颗粒处理过的实验组DNA双链出现较多圆形、线性及超螺旋等破坏。金纳米颗粒的放射增敏作用还可能作为肿瘤细胞的核目标，诱发细胞胞质分裂阻滞进而引起细胞凋亡[24]，一旦金纳米颗粒有合适的细胞核目标共轭配体，就可作为癌症治疗材料单独使用。到目前为止，金纳米颗粒放疗增敏的明确生物学机制仍待进一步的研究。金纳米棒对肿瘤放疗增敏的机制：既往已有文献报道金纳米棒能够增加放疗效果[25-28]。金纳米棒放疗增敏的机制是：第一，辐射敏感材料的光电吸收横截面直接取决于原子半径大小。这个物理性质决定了金原子(原子序数Z=79)比其他对辐射敏感的材料如碳(Z=6)、碘(Z=53)、钆(Z=64)和铂(Z=78)，通过光电效应可以产生更强的辐射增强效果。金纳米棒中的金元素具有高的原子序数，可以在肿瘤组织内产生较周围正常组织强的光电吸收效应，从而可将增强的能量递送给肿瘤组织[29-30]；第二，金纳米棒的尺寸远大于金原子，其光电吸收截面积远超越金原子，所以在肿瘤组织内产生的光电吸收剂量将显著增加[31]；第三，金纳米棒的表面等离子共振特性，即当光入射时在特定波长范围内具有强的光吸收能力，增强的光吸收量也可有效增强肿瘤组织的吸收剂量。另外，金纳米棒具有强光散射能力，也能间接增强肿瘤组织的辐射剂量。Salomeh等[32]通过一种蒙特卡罗方法指出这种现象的原因：纳米材料可以增强局部组织对X射线的吸收；纳米材料能有效释放低能电子，进而产生更多的自由基；通过自由基和电子使能量有效沉积，引起DNA损伤。放疗作为癌症的杀手，其杀灭肿瘤细胞的机制是：当细胞吸收了任何一种形式的放射线后，射线都能与细胞内的结构发生作用，直接或间接的损伤细胞DNA。直接损伤是射线能直接作用于有机分子产生自由基，损伤肿瘤细胞的DNA，DNA双键断裂遭到破坏，诱导肿瘤细胞凋亡；间接损伤是射线对人体组织内水发生电离，激发离子、自由基、自由电子均导致DNA损伤，使肿瘤细胞失去繁殖能力而死亡[33]。 2.4 金纳米颗粒在肿瘤放疗增敏应用中的进展随着金纳米颗粒研究的不断深入，将金纳米颗粒与肿瘤医学相结合的研究备受瞩目，金纳米颗粒的肿瘤放疗增敏作用已成为近年来关注的焦点。Herold等[34]研究小组首次发现金纳米颗粒的放射增敏作用，将金纳米颗粒颗粒混悬至细胞中培养或注射于肿瘤组织中，使用千伏级光子束照射后，金纳米颗粒能够有效增强放疗的疗效。就细胞本身来说，不同品系细胞对放射线敏感程度不同，金纳米颗粒的放射增敏效果受细胞类型影响具有细胞差异性。Wilson等[35]采用实时细胞阻抗传感器评估金纳米颗粒联合2 Gy射线照射MCF-7、DU145、A549和H460细胞的细胞存活分数(SF2)，结果显示这4种细胞的SF2依次为0.32、0.55、0.62、0.66，表明乳腺癌MCF-7细胞对辐射最敏感，而肺癌H460细胞对辐射最抗拒，且辐照时间越长细胞存活率越低，同时细胞辐射敏感性还与每个细胞株的生长速率相关。金纳米颗粒对肿瘤放射的增敏作用取决于其自身尺寸大小和表面修饰物的种类。Liu等[36]研究小组报道尺寸在5 nm范围的金纳米颗粒对于人结肠癌细胞有较强的放射增敏作用。Zhang等[37]研究不同尺寸PEG-金纳米颗粒的放射敏感性，4.6 nm和48.6 nm大小的PEG-金纳米颗粒主要引起细胞快速凋亡，而12.1 nm和 27.3 nm大小的PEG-金纳米颗粒通过细胞凋亡和坏死两种途径来诱导肿瘤细胞的放射敏感性，结果证实 12.1 nm和27.3 nm的大小PEG-金纳米颗粒的辐射敏感性高于粒子尺寸为4.6 nm和48.6 nm的PEG-金纳米颗粒。鉴于此，不同尺寸PEG-金纳米颗粒进行肿瘤的放射治疗及药物靶向运输疗效大相径庭，那么金纳米颗粒的表面修饰物对肿瘤的辐射增敏作用有什么影响呢？Zhang等[38]将人类前列腺癌DU-145细胞给予Glu-金纳米颗粒+放疗、中性金纳米粒子(TGS-GNPs)+放疗、单纯放疗3种不同的处理方式作用后，显示肿瘤细胞生长抑制率分别为45.97%，30.57%，15.88%，表明无论是Glu-金纳米颗粒还是TGS-金纳米颗粒都能明显增强放疗疗效，且Glu-金纳米颗粒+放疗组疗效最佳。Roa等[39]将葡萄糖耦合的金纳米颗粒与人类前列腺癌DU-145细胞共同孵育后，Glu-金纳米颗粒联合照射组(给予2 Gy放射线)对细胞的生长抑制作用是单纯照射组的1.5-2.0倍，然而为何Glu-金纳米颗粒的放射增敏作用最强的具体机制尚不清楚。对于放射线本身来说，金纳米颗粒对肿瘤的放射增敏作用依赖于放射线的种类及能量的高低。大量研究表明金纳米颗粒对X射线有放射增敏作用[40]，而对137Cr及60Co释放的γ射线无增敏作用[41]。由于低能射线存在易散射、剂量分布差等缺点导致对肿瘤治疗疗效不佳，一些学者采用高能放射线评估放射增敏的疗效，Chang 等[42]构建种植B16F10恶性黑色素瘤细胞的小鼠模型，采用金纳米颗粒联合6 MeV高能电子线照射，结果表明金纳米颗粒+放疗组的细胞凋亡率约为单纯放疗组的2倍，使肿瘤鼠的生存期明显延长。概括的说，选择适宜尺寸的金纳米颗粒并采用高能X射线才能在提高放射增敏效果、加强肿瘤细胞杀伤作用的同时，降低对人体正常细胞的放射损伤。此外，肿瘤细胞处于G2/M期对放射线的敏感性最高[43]，有学者认为金纳米颗粒作为一种放射增敏剂能将细胞周期阻滞于G2/M期有关，有研究研究认为Glu-金纳米颗粒能激活细胞周期蛋白依赖性激酶，降低细胞周期蛋白A和P53的表达，提高细胞周期蛋白B1、E的表达，从而促使细胞快速通过G0/G1期而滞于G2/M期。 2.4.1 金纳米棒对肿瘤放疗的增敏进展目前文献报道多聚焦于金纳米颗粒且位于细胞水平上的研究，而关于金纳米棒对肿瘤放射敏感性的报道尚不多见。徐文才等[44]研究小组利用金纳米棒联合6MeV放射线照射人黑色素瘤A375细胞，研究证实金纳米棒联合放疗组的细胞凋亡率为9.1%，明显高于单纯放疗组和单纯金纳米棒组，其机制可能是金纳米棒在肿瘤细胞中集聚，使能量有效地沉降于肿瘤细胞。Xu等[45]研究发现RGD-金纳米棒通过整合素avβ3内吞作用进入细胞，给予人黑色素瘤细胞4种不同的治疗：金纳米棒、RGD-金纳米棒、单纯放疗、RGD-金纳米棒+放疗，细胞周期处于G2/M期的比率分别为35%，36.14%，40.9%，46.5%，结果表明RGD-金纳米棒联合放疗组肿瘤细胞明显滞于G2/M期，其可能的机制是RGD-金纳米棒能抑制整合素avβ3表达。Rizwan等[46]制备出一种纳米复合材料—金纳米棒偶联鞘氨醇激酶SiRNA(GNR-SphK1 siRNA)，用作头颈部肿瘤的辐射增敏剂，研究证实金纳米棒能有效靶送促凋亡基因siRNA进入肿瘤组织，接受低的辐射剂量足以增强肿瘤细胞的感光性，达到对肿瘤细胞的最大杀伤力。对接种移植瘤的小鼠模型给予GNR-SphK1 siRNA和辐射治疗IRRA使肿瘤体积缩小60%，采用IHC法得出GNR-SphK1 siRNA+IRRA组中肿瘤组织Ki67和caspase-3的阳性率分别为38%和9.5%，而GNR-SphK1 siRNA组中肿瘤组织Ki67和caspase-3的阳性率分别为63%和5.2%，其可能是GNR-SphK1 siRNA能够敲击肿瘤细胞高表达的SphK1，诱导凋亡途径来增加辐射的敏感性。 2.4.2 金纳米颗粒联合放射性核素治疗肿瘤的研究进展值得补充说明的是，随着放射性核素内治疗的发展，一些新核素相继出现，如99Tcm、111In、64Cu、90Y、177Lu、188Re等。这些新核素在体内的代谢、半衰期、能量、药物标记等方面更具优势，这些优势促使人们对核素内照射治疗肿瘤的研究越来越广泛，各种放射性核素同样能标记到金纳米颗粒上，Vilchis-Juarez等[47]成功构建了小鼠神经胶质瘤模型，将生物多肽c[RGDfK(C)]共轭包覆的金纳米颗粒用177Lu标记，对肿瘤鼠行靶向性放射治疗，证实177Lu-AuNP-c[RGDfK(C)]治疗组能够明显提高肿瘤组织的辐射吸收剂量，约67 Gy，还能抑制肿瘤内血管的生成和表皮生长因子的表达，显著延缓肿瘤生长。一般来说，金纳米颗粒通过瘤内注射或有选择的动脉输入肿瘤组织内，要尽量避免其被组织网状内皮系统所吞噬，采用SPECT/NIR、SPECT/MIR、PET/MIR及PET/NIR等多种成像方法来标识肿瘤，有效将纳米材料高摄入肿瘤组织中，进而实现对肿瘤组织的杀伤[48]。Xie等[49]用64Cu-DOTA标记金纳米棒运用热疗辅助内放疗治疗小鼠头颈部鳞状细胞癌，PET/CT扫描显示肿瘤组织对金纳米棒摄取持续长达 20 h，与对照组相比联合治疗组肿瘤内出现大量出血和大面积坏死其疗效显著。Buckway等[50]采用金纳米棒联合90Y标记的HPMA聚合物治疗小鼠前列腺肿瘤，CT扫描显示金纳米棒与90Y-HPMA聚合物主要聚集在肿瘤组织内，再对其行激光照射局部形成高热(43±1) ℃，40 d后对肿瘤鼠心肝肾脾肺及肿瘤组织进行苏木精-伊红染色，肿瘤组织内出现大量纤维化、液泡化及凋亡小体，肿瘤生长明显抑制。"

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