乳腺癌靶向纳米药物的可控构建及其荧光/光声可视化代谢分布研究

The rapid development of nanotechnology urged new nanomedicines with high therapeutic efficiency and better safty used for breast cancer therapy. However, some drawbacks lie on the way of breast cancer nanomedicine, including the low tumor targeting efficiency, poor structural stability, and the unclear nanostructure dependent metabolic and biodistributions behaviors. Inspired by these issues, we proposed a versatile nanomedicine for breast cancer therapy by encapsulating CuInS quantum dots (QDs) and DOX into the HA-PCL based polyliposome. The CuInS QDs were proved to be promising candidate used for fluorescence/ photoacoustic imaging agents for the first time. The proposed nanomedicines were eventually endowed with good stability, high tumor targeting efficiency, accurate imaging information derived from fluorescence/ photoacoustic dual-modal imaging, and chemical-photothermal synergistic therapy to breast cancer. Since nanomedicines have physicochemical properties (size and shape) dependent biodistributions and metabolism behaviors, the fluorescence/photoacoustic imaging ability was used for the imaging-guided distributions and metabolism study in vitro and in vivo, respectively. Thus, the correlations between physicochemical properties and distributions behaviors can be uncovered by fabricating nanomedicines with well-defined particle size and shape. This study will contribute to the new breast cancer nanomedicines and also pave the way to clinical translation for nanomedicines.

研发高效、安全的乳腺癌纳米药物是目前乳腺癌治疗领域中的重要研究方向。然而，目前乳腺癌纳米药物通常存在靶向能力弱、结构稳定性差，以及纳米结构所导致的代谢分布不确定性的问题。针对上述问题，本项目拟充分发挥自主研发的CuInS量子点的可荧光/光声双模态成像、结构稳定和成像精准的优势，将其作为成像模块，并以自主合成的乳腺癌靶向能力强、生物安全性好的HA-PCL高分子脂质体为纳米药物系统载体，通过高分子组装技术将阿霉素和双模态量子点进行共载，构建出一种具有结构稳定性好、靶向能力强，并可准确、高效地荧光/光声成像以及化疗/热疗联合治疗等优点的乳腺癌纳米药物。通过调控药物组装技术，制备得到不同粒径和形状的乳腺癌纳米药物，借助荧光和光声成像功能，分别实现该纳米药物在细胞内和动物体内的可视化代谢分布研究。该研究有望在研发新的高效、安全的乳腺癌纳米药物以及推动纳米药物的临床转化研究等方面提供重要的科学依据。

研发高效、安全的乳腺癌纳米药物是乳腺癌治疗领域中的重要研究方向。然而，乳腺癌纳米药物通常存在靶向能力弱、结构稳定性差，以及纳米结构所导致的代谢分布不确定性的问题。针对上述问题，本项目成功制备出了一种集荧光成像、光声成像、光动力治疗和光热治疗等四种功能于一体的新型CuInS/ZnS（ZCIS）量子点；并使用双亲性磷脂分子（DSPE-PEG）对所制备的ZCIS量子点进行生物相容性改性，成功制备得到了粒径可调控的ZCIS@Lip诊疗一体化纳米药物，粒径分别为25nm和80nm。以细胞球为体外模拟肿瘤模型，以乳腺癌（4T1）裸鼠作为动物模型，荧光成像和光声成像结果证明，所制备的两种粒径的ZCIS@Lip纳米药物均可通过EPR效应在肿瘤部位有效富集。粒径为80nm的ZCIS@Lip纳米药物主要富集在肿瘤的外周区域，且24小时后肿瘤区域的信号衰减显著；而粒径为25nm的ZCIS@Lip纳米药物则能够从肿瘤外缘渗透到肿瘤内部区域，呈现出较好的肿瘤渗透能力，同时在肿瘤区域的滞留时间可达36小时。因此，本项目利用荧光和光声成像技术，对于纳米药物在细胞内和动物体内的可视化代谢分布行为开展了比较深入的研究。该研究有望在研发新的高效、安全的乳腺癌纳米药物以及推动纳米药物的临床转化研究等方面提供重要的科学依据。