肿瘤靶向多肽纳米纤维作为疏水性抗肿瘤药物载体的研究

Self-assembled nano-drug carriers have been intensitively applied in controlled drug release and targeting drug delivery. In addition to the chemical composition, size, surface potential and other factors, recent researches have confirmed that the shape of the nanocarriers plays an important role in their in vivo metabolism. For some types of carriers, nanofibers have less uptake by the reticuloendothelial system (RES) and stronger tumor tissue selectivity than nanospheres. Peptide based nanomaterials have been widely used because of their good biocompatibility, easy modification by functional groups and design flexibility according to the needs through a "bottom-up" approach. Self-assembling peptide nanofiber has great application prospects in the field of drug delivery. In this project, we will design a series of peptide molecules with active tumor-targeting motifs. These targeting peptides could assemble with the hydrophobic anticancer drugs such as 10-hydroxycamptothecin to form injectable nanofibers. We will study the impacts of targeting and nontargeting motifs and amino acid configuration on the biodistribution and tumor targeting capacity of the peptide nanofiber carriers by labeling with radionuclide iodine-125. The in vitro and in vivo anti-tumor experiments will also be involved. We expect to develop a tumor-targeting filamentous hydrophobic drug carrier with improved drug solubility, bioavailability and reduced toxicity, and to provide new ideas and methods for tumor targeted therapies and clinical applications of hydrophobic drugs.

自组装纳米药物载体在药物缓控释及靶向传输方面已经发挥了巨大推动作用。研究证实，除化学组成，尺寸大小及表面电位等因素外，形状对于纳米载体体内代谢也具有重要影响。对于某些载体材料，纳米纤维比纳米球表现出更少的网状内皮系统摄取和更强的肿瘤组织选择性。多肽纳米材料因生物相容性好，易连接功能基团，且可以根据需要自下而上地设计序列而被广泛应用。自组装多肽纳米纤维在药物传输领域具有很大的应用前景。因此本项目拟设计多种肿瘤靶向性的多肽分子，与疏水性抗肿瘤药物如10-羟基喜树碱共组装形成可注射的纳米纤维。采用放射性核素碘[125]标记研究靶向与非靶向以及不同氨基酸构型对多肽纤维载体的体内分布及肿瘤组织靶向性的影响。最终通过体内外肿瘤靶向治疗研究来开发一种具有肿瘤靶向性、提高疏水药物溶解度、降低毒副作用和提高生物利用度的多肽纳米纤维药物载体。本研究将为肿瘤的靶向治疗及临床疏水性药物的应用提供新的思路和方法。

自组装纳米药物载体在药物缓控释及靶向传输领域已经发挥了巨大作用。已有研究证实，载体形状对其体内代谢也具有重要的影响，纳米纤维比相同组成的纳米球具有更少的体内网状内皮系统摄取和更强的肿瘤组织选择性。鉴于多肽类自组装材料具有合成简单、毒性小、易于进行功能基团修饰以及可以按需要设计序列等优势，以及其在体内易于被蛋白酶降解的不足，在本项目中我们设计了一组肿瘤靶向多肽分子，并将D构型非天然氨基酸引入到多肽序列中以降低体内蛋白酶的识别和降解作用，从而达到提高多肽体内稳定性的效果。该组分子在体外可以自组装形成纳米纤维，结合多肽纤维荧光标记技术和放射性同位素碘［125］标记技术分别研究了多肽纳米纤维的体内外稳定性和分布代谢以及肿瘤组织选择性。以10-羟基喜树碱和姜黄素为模式药物在细胞水平和动物水平上对多肽纳米纤维的抑瘤效果进行了系统研究。我们首次在体内证明D构型氨基酸的引入能明显提高多肽纤维的体内稳定性，作为载体包载抗肿瘤药物后，发挥了更好的抑瘤效果。本项目开发了具有良好体内稳定性以及高效肿瘤组织选择性和靶向性的自组装多肽分子，为新型高效抗肿瘤药物载体的设计提供了新的思路和方法。