基于大分子骨架的靶向SPECT/PET/MRI多模式分子探针设计新策略

Targeted molecular imaging based personalized medicine is the direction of future medicine. The aim of this study is to design a new strategy for developing multimodal probes for SPECT/PET/MRI imaging. Up to now, most of the reported multimodal probes were sphericized nano-particles with surface modification. The disadvantages of nano-particle approach are in its poor targeting capacity, oversize and risk of safety concerns. In this study, synthetic linear copolymer was selected as backbone for the grafting of coordination groups and targeting molecules. Briefly, the monomers (VNI, VDT and VDP) were obtained by conjugating the chelators (HYNIC, DOTA and DTPA) with styrene structure. The folic acid molecule was introduced into styrene structure to form another monomer for tumor targeting (VFA). Then the copolymers of polystyrene derivatives were prepared by the polymerization of the selected monomers. After labeling with the imaging nuclides (Gd for MRI, 99mTc for SPECT and 68Ga for PET), the copolymers will be evaluated as potential multimodal probes in vitro and in vivo. The benefits of this strategy are in its good biocompatible, safety, controlled molecule weight and adjustable ratios of each special block (monomer). Further more, it is very easy to obtain new probes by assembly the functional monomers like building blocks with different monomers or ratios. The optimized probes were anticipated have improved targeting potential, lower non-targeting organs (such as liver, lung and spleen) uptake, sufficient concentration of nuclide Gd for MRI imaging, and so on. Developing probes for multimodalities imaging is one of the worldwide hot topics in molecular imaging field. This innovative design stratagem has never been reported before; it is expected to overcome the most of shortages of current multimodal probes and/or fulfilling its value as a platform for new probes developing in the future.

基于分子影像的个性化医疗是未来医学的发展方向，本研究目标是设计一类能够同时用于SPECT/PET/MRI显像的多模式分子探针。目前已报道的多模式探针主要是对球形纳米粒子表面进行修饰，存在靶向性差、纳米粒径较大、存在安全风险等不足。本研究选择人工合成共聚物为骨架，嫁接配位基团和靶向分子。简单说：将配位基团HYNIC、DOTA以及DTPA引入苯乙烯结构制得含有乙烯基和配位基团的单体；将叶酸分子引入苯乙烯结构作为靶向单元；最后将各种单体优化组合，通过共聚合反应得到聚苯乙烯衍生物，经核素标记后作为潜在的多模式探针。优势在于：生物相容性好，安全性高；整体分子量和各结构单元的比例易于调控；增强分子靶向性并有效降低肝脾组织的摄取；可调节MRI核素Gd与放射性核素的比例；通过不同组合方式获得新探针等。本课题是一种创新的多模分子探针设计策略，有望解决当前该类探针存在的诸多不足，具有重要的理论与实践意义。

基于分子影像的个性化医疗是精准医学的发展方向之一，本研究设计并制备了基于PS、PE、PEI和PAMAM大分子骨架的多模态和诊疗一体化探针，并用于SPECT/PET、MRI和PAI显像以及光热和放射治疗等研究。研究优化了表面修饰方案，获得了生物相容性好、溶解性好、尺寸可控且具有靶向性的多模态探针。对几种大分子骨架的初步比较后我们认为基于PEI的多模态探针更具优势。据此，我们合成了一个新型的放射性标记的ASGP受体靶向探针。在PEI骨架上同时连接19F基团及靶向基团（PEI-LA-F3）。高密度的19F基团（每分子上连结~333 19F原子）可作为MRI的显像基团。经99mTc标记的PEI-LA-F3 b可特异性靶向肝组织，可检测不同程度的肝纤维化及肝癌；同时PEI-LA-F3b用于19F MRI显像，可获得类似于SPECT的效果，在生物体内提供了一个外源性“热点”；经ICG组装的PEI-LA-F3 b又可用于光声检测。光声在血管成像方面很有优势，如可利用光声对肝癌组织周边血管进行成像，可获得更好的肿瘤监测信息。该探针的合成也为课题提供了一个性能良好的ASGP受体靶向的显像剂，为后期的多核素多受体同时SPECT成像及多模态成像奠定了基础。.本研究还比较了SPECT/MRI/PAI三种成像模式在肝纤维化模型中的成像结果并发现不同成像模式都能反应纤维化程度（纤维化程度越深，FIB/NOR值越小），但是不同成像手段的灵敏度有显著差别，其中PAI最敏感，SPECT最不敏感。另外，由于不同的成像模式所需要的探针剂量差别较大，我们通过不同的给药量及给药顺序得到了SPECT动态曲线。研究发现，提前注射大剂量的PEI-LA-F3 b会对99mTc-PEI-LA-F3 b的成像起到抑制的作用。而注射99mTc-PEI-LA-F3 b 20 min之后再注射大剂量的PEI-LA-F3 b，对SPECT成像不会造成影响，原因可能是99mTc-PEI-LA-F3 b已经结合到相关的受体，后注射的PEI-LA-F3 b不会对此造成影响。由此，设计了多模态成像策略以解决不同成像模态灵敏度差异问题。.本课题提出了一种基于大分子骨架的多模态分子探针设计策略和同步成像策略，具有重要的理论与实践意义。