高分子复合材料靶向超声造影剂用于产前诊断

Ultrasound imaging (sonography) is a safe, rapid and effective method for detecting fetal morphological, and has become one of the most important technologies of the prenatal diagnosis. But in many cases, the ultrasonic imaging resolution is poor due to maternal obesity, less amniotic fluid. So far, there is not any ultrasonic contrast agent (UVA) that had been used in the amniotic fluid, although the UVA can improve ultrasound imaging resolution. The UVA will be evenly dispersed in the amniotic fluid due to molecular diffusivity and the relatively closed environment of the amniotic cavity, that is to say, if the UVA cannot be concentrated on the fetal specific tissues or organs, it is useless for improving ultrasound imaging clarity. .Therefore, we plan to synthetize the functionalized amphiphilic block copolymer with targeting ligands, which will further be made into the targeted micron polymer vesicles as the amniotic cavity UVA with special affinity to the fetal skin and gastrointestinal mucous membrane. The special UVA will improve ultrasound imaging resolution for diagnosis of fetal deformity through the implementation of adsorbing to the fetal skin surface or gastrointestinal mucous membrane. In the experiment, we can determine the dispersion, stability, long time retention capacity and safety of targeted micron polymer vesicles by using precise regulation of the microcapsule composition, micro structure and morphology..We will establish the ultrasonic pregnant rat model and cultivate skin epidermis cells of the rat for detecting the characterization and property including the aggregation behavior of polymers, the binding capacity of functional material. We will try our best to ensure obtain all data of micro polymer functional system in ultrasonic pregnant rat model and conclude a new prenatal diagnosis method to improve the ultrasonic image for human fetal ultrasonic screening in the near futrher.

超声成像是孕期胎儿形态结构检查的安全、有效方法，已成为产前诊断的最重要方法之一。但由于子宫羊膜腔相对封闭环境会造成造影剂的均匀分散，使得目前现有超声造影剂尚不能在产前诊断中得到应用，严重影响对胎儿疾病的诊断效果。本项目提出合成配体官能化的生物相容性两亲嵌段聚合物，用以制备对胎儿皮肤和消化道内皮具特异性作用的微米高分子靶向囊泡，通过微囊在胎儿特定部位的聚集行为实现对胎儿器官的清晰成像，提高对胎儿畸形诊断效果。同时，通过对微囊组成、微结构、形貌等的精确调控，保证其在羊膜腔内分散性、稳定性、长时间的保留能力及安全性，尽可能长期增强超声诊断的清晰度。本项目针对产科临床工作的紧迫需求，利用高分子聚集行为的可控性和功能物质结合能力，在建立超声孕鼠模型和大鼠胎儿皮肤细胞培养技术基础上，力求获得适用于特定组织和生理环境的羊膜腔高分子造影功能体系，并以此为基础建立新的产前诊断方法，为今后临床应用打下基础。

项目的背景.超声成像因其无放射性、操作简单方便、实时成像等优点，广泛应用于产前胎儿畸形筛查。由于部分孕妇腹壁肥厚、胃肠气体干扰或疾病等原因，会严重影响超声成像清晰度，造成一定比例的漏诊和误诊。如何大幅度提升早孕期羊膜腔胎儿超声成像质量、提高畸胎诊断率，成为临床上亟待解决的难点问题。.目前尚无可用于羊膜腔内的超声造影剂，研发羊膜腔专用超声造影剂是增强超声成像质量、解决上述难题的有效方法之一。.主要研究内容.本课题拟制备一种对胎儿皮肤具有靶向吸附作用的、对母胎绝对安全的高分子两亲纳米囊泡颗粒，对其体外性能进行表征；建立孕鼠、孕兔的体内、体外超声造影模型，并对上述造影剂进行体内超声成像效果评价；并对上述造影剂进行母胎安全性评价。.重要结果.制备了6种高分子纳米微囊颗粒，确定PLGA5050-Janus颗粒为最佳选择。.确定PLGA5050-Janus靶向超声造影剂对大鼠胎儿皮肤具有特异吸附作用。.建成体外、实验动物体内超声造影试验模型，并获得PLGA5050-Janus相应超声显影效果评价数据.通过实验动物急性毒性试验、生殖毒性试验，初步确定PLGA5050-Janus对实验动物母胎具有较好的使用安全性。.关键数据.Wistar大鼠胎儿皮肤表皮吸附实验电镜下检查胚胎表皮组织及羊水数据（见图17、18）。.利用医用橡胶手套（8#）建立、模拟体外羊膜腔超声成像试验模型后，体外羊膜腔模型的超声观察试验超声数据见表2..建立日本大耳白兔体内超声显影实验动物模型后，动物体内超声图像试验数据，见图15-图23。.日本大耳白孕兔母体各脏器病理切片数据，见图26-图29，以及脾脏脾脏器官指数表。.科学意义.本课题试图确定两亲高分子纳米囊泡颗粒在羊膜腔增强超声造影的可能性和安全性，提高超声对胎儿体表及消化道形态与结构的分辨率，增加超声在胎儿早、中期筛畸中的重要作用。.此外，通过将上述高分子囊泡装载缓释药物，从而实现羊膜腔内对胎儿早期干预性治疗。