尺寸可变的智能化金纳米粒前药的制备及其抗肿瘤研究

The size of nanocarriers played an important role in improving the delivery efficiency of each steps for drug delivery, such as long circulation, tumor accumulation and penetration, tumor retention. However, as the rapid blood clearance rate and nonspecific diffused out from tumor tissues of small sized nanocarriers, the large to small strategy and small to aggregates strategy still could not satisfy the demands of all the steps for drug delivery. In this project, the large to small to aggregates strategy was first proposed, which was based on the Au nanoparticle prodrug systems (ANPDS) we constructed. The size of ANPDS was intelligently regulated under the tumor microenvironment through specifically losing hydrophilic layer, charge-switching and electrostatic adsorption in sequence, realizing the size conversion from large to small to aggregates and thereby sustainedly improving the delivery properties of long circulation, tumor accumulation and penetration, tumor retention. The large to small to aggregates strategy of ANPDS was verified by the size change from 69 nm to 33 nm to 280 nm in vitro which was simulated by tumor microenvironment. In this project, the size switched ANPDS will improve the drug delivery ability and achieve in situ tumor chemotherapy, which could finally provide a new thought and strategy for perfecting the drug delivery and anti-tumor efficiency of nanocarriers.

纳米药物载体的尺寸在各个环节的递送效率上扮演着重要的角色，包括体内长循环、肿瘤蓄积和渗透，肿瘤内滞留等。然而基于large to small和small to aggregates策略无法同时满足上述所有环节，这是由于小尺寸粒子会在瘤内非特异性扩散和其体内高清除率导致的。本项目以金纳米粒子为基础构建功能化金纳米粒前药递送系统 (ANPDS)，在肿瘤微环境的调控下依次经历特异性脱壳、响应性电荷反转及静电吸附过程，实现尺寸由large to small to aggregates的智能化转变，从而满足不同递送环节所需的最优尺寸，最终达到提高长循环、肿瘤蓄积和渗透，肿瘤滞留的目的。预试验初步证实了ANPDS在肿瘤微环境下由69 nm-33 nm-280 nm的智能化尺寸转变。通过该项研究，本项目将改善ANPDS的递送性能并实现肿瘤原位化疗，为提高纳米载体的递送效率及抗肿瘤效果提供新的思路和方法。

随着癌症发病率的日益增高及其年轻化，基于纳米药物的各种抗肿瘤策略被广泛应用到癌症治疗。而纳米药物的尺寸在体内各个环节的递送效率上尤为重要。本项目以金纳米粒子为基础构建功能化金纳米粒前药递送系统，在肿瘤微环境的调控下实现尺寸由large to small to aggregates的智能化转变，从而满足不同递送环节所需的最优尺寸。该项目在执行过程中初步的实现了金纳米粒子的智能化尺寸转变。随后我们结合金纳米粒子能够作为放疗增敏剂本身的生物学特性，我们利用了其中的small to aggregates策略，应用到增强放疗的抗肿瘤效率上来。设计合成的金纳米粒子体系（GNPs system）首先具备良好的生物安全性、快速的体内清除速率，这些能够初步满足其作为放疗增敏剂的需求。随后，GNPs system在到达肿瘤组织后通过发生响应性聚集能够使GNPs以聚集体的形式长期的滞留和聚集在肿瘤组织。体外的一系列放疗增敏实验也证实了GNPs system在聚集后显著的提高了由放疗导致的DNA损伤情况，将GNPs的放疗增敏值由1.16提高到1.73。体内的抑瘤实验也进一步证实了GNPs system作为放疗增敏剂提高了放疗的抗肿瘤效率。更重要的是，GNPs system能够进一步降低放疗所使用的剂量以进一步降低对正常组织的副作用。同时，我们进一步开发了GNPs system在响应性聚集后的光热转换效果，实验结果证实其在近红外激光器照射下产生的温度能够足以杀死肿瘤细胞和肿瘤组织。此外，利用GNPs system产生的温和光热治疗能够抑制DNA损伤后的自我修复功能，进而结合放疗能够从DNA水平实现对肿瘤组织的联合治疗，并取得了不错的抗肿瘤效果。综上，基于尺寸转变的金纳米粒子显著的提高了放疗的抗肿瘤效率和光热-放射联合治疗，能够为临床放疗增敏剂的开发和放疗方案的制定提供一定的参考。