基于预定位技术和超小纳米颗粒的乳腺癌精准诊疗研究

Tumor-targeting nanoprobes is the frontiers of research of precision diagnosis and treatment of breast cancer. However, the conversional nanoprobes have several disadvantages, such as high non-specific accumulation in liver and spleen as well as long-term risk of toxic injury, which greatly limited their clinical translation potential. Ultrasmall nanoparticles (USNP) can be quickly excreted from the kidneys and hence have low hepatic and splenic accumulation. However, the size of USNP is so small that the surface modification of tumor-targeting components is technically challenging, which makes the construction of breast cancer-targeting ultrasmall nanoprobes difficult. Therefore, a method of constructing breast cancer-targeting nanoprobes with low hepatic and splenic accumulation is urgently needed for the precision diagnosis and treatment of breast cancer. Inspired by the separation of targeting components and probes in pretargeting approach, this project proposes a new strategy to construct ultrasmall nanoprobes for HER2-targeting imaging and treatment by adapting pretargeting approach to ultrasmall nanoparticles. We hypothesize that by injecting monoclonal antibody against HER2 and ultrasmall nanoparticles successively, the USNP can target HER2-overexpressing breast cancer cell with no increase in size and thus no increase in hepatic and splenic accumulation. Then the HER2-overexpressing breast cancer will be imaged by CT, fluorescence and photoacoustic imaging and treated by photothermal therapy. We expect that these pretargeting ultrasmall nanoprobes, featuring high tumor specificity, low hepatic and splenic accumulation, and high biosafety, will provide new strategies and tools for precision imaging and treatment of breast cancer.

靶向型纳米诊疗探针是乳腺癌精准诊疗研究的前沿。传统靶向型纳米诊疗探针存在肝脾非特异摄取高、长期毒性伤害风险大的缺点，临床转化阻力大。超小纳米颗粒可从肾脏快速排出体外，肝脾摄取量低，但其超小尺寸限制了靶向组件的修饰，用于构建乳腺癌靶向型诊疗探针技术难度大。因此寻找构建肝脾摄取低的靶向型诊疗探针的新方法是乳腺癌精准诊疗的关键科学问题。本项目参考预定位技术将靶向组件和诊疗探针分开应用的技术特点，提出将预定位技术和超小纳米颗粒联合以实现乳腺癌HER2靶向成像和治疗的新设想。通过先后注射HER2单抗和超小纳米颗粒，在不增加超小纳米颗粒尺寸的前提下，实现超小纳米颗粒的高特异靶向和低肝脾摄取。并通过CT、荧光和光声成像/光热治疗对HER2过表达型乳腺癌进行精准成像和治疗。预期这类预定位型超小纳米诊疗探针可提高乳腺癌靶向性、成像信噪比和治疗疗效，降低肝脾摄取和远期毒性，为精准诊疗提供新策略和新工具。

靶向型纳米诊疗探针是乳腺癌精准诊疗研究的前沿。传统靶向型纳米诊疗探针存在肝脾非特异摄取高、长期毒性伤害风险大的缺点，临床转化阻力大。小尺寸纳米颗粒和小分子药物可从肾脏快速排出体外，肝脾摄取量低，但用于构建乳腺癌靶向型诊疗探针技术难度大。因此寻找构建肝脾摄取低的靶向型诊疗探针的新方法是乳腺癌精准诊疗的关键科学问题。本项目设计了多种靶向乳腺癌等肿瘤的诊疗纳米探针和小分子药物，可通过CT、MRI、荧光和超声成像/光热治疗对肿瘤进行精准成像和治疗。预期这类纳米诊疗探针和小分子药物拥有高肿瘤特异性、低肝脾摄取和高生物安全性的特点，可为肿瘤精准成像和治疗提供新策略和新工具。