二重pH响应型SPIO基药物载体的组装及肿瘤诊疗一体化研究

A number of superparamagnetic iron oxide (SPIO)-based theranostic systems have emerged as one of the most versatile and innovative nanocarriers for drug delivery. The major challenge in successful clinical translation of SPIO-based theranostic nanocarriers lies in the low diagnostic sensitivity, poor cellular internalization and insufficient intracellular drug release which always limit the dosages of anticancer drugs to the level below the therapeutic window and hampers the efficacy of cancer chemotherapy. .In this proposal, we present a dual pH-responsive SPIO-based chemotherapeutic agents loaded theranostic nanocarriers, where the SPIO would significantly enhance the diagnostic sensitivity in magnetic resonance imaging (MRI). Moreover, the dual pH-responsive nanocarriers can respond to not only the tumor extracellular (pHe) but also intracellular (pHi) pH gradients for enhanced drug delivery. These responds are expected to simultaneously promote theranostic nanocarriers accumulation at the tumor site via enhanced permeability and retention effect and facilitate the cell internalization as well as intracellular drug release, greatly enhancing the drug delivery efficiency. The research of dual pH-responsive SPIO-based chemotherapeutic agent nanocarriers in this proposal will provide a broad and versatile approach for high efficient tumor theranostics.

超顺磁性氧化铁（SPIO）基药物诊疗体系正在成为新一代多功能抗肿瘤药物传递领域的研究热点。然而，这类载体在传递药物过程中普遍存在肿瘤细胞摄取能力差以及细胞内药物释放不完全等问题。为解决以上问题，本项目拟以SPIO药物载体为研究对象，探索载药聚合物结构中聚酰胺-胺（PAMAM）树状大分子的合成以及双功能化条件、阐明结构中肿瘤细胞间（pHe）以及细胞内（pHi）酸性环境响应化学键构建方式、探讨SPIO基体与载药聚合物的静电组装条件、揭示pHe和pHi两种响应机制对细胞摄入和药物释放两个阶段的影响规律，最终构建二重pH响应型SPIO基药物载体并应用于体内以及体外诊疗一体化研究中。本项目旨在通过二重pH响应体系的构建，实现SPIO基诊疗载体在pHe环境下的高效摄入和pHi环境下的快速释药。本项目研究成果对推动下一代纳米粒子基药物载体的设计和诊疗一体化应用具有重要的借鉴意义和价值。

磁性纳米粒子作为肿瘤等疾病的纳米探针在生物系统中已经得到了广泛的应用。磁性纳米粒子会导致周围溶液产生局部磁场的不均一。当磁性纳米粒子与靶向目标形成聚集体后，周边水分子将会产生明显的T2时间的变化(ΔT2)。基于这个原理，磁性纳米粒子已经作为磁性生物探针在阿尔兹海默以及肿瘤的早期诊断中得到了具体的应用。.当磁性纳米粒子存在水相环境中时，粒子周围的水分子中的质子将受到粒子的影响。在核磁共振体系应用中便体现为弛豫时间的变化。因此，磁性纳米粒子被广泛的用在核磁共振体系下的肿瘤早期诊断中。.在本项目研究中，我们研究了快速检测蛋白的方法。该方法灵敏度较高、检测极限也得到了显著的提高。CRT蛋白的检测灵敏度达到了10 pg/ml，这个浓度已经能够与目前的临床分析手段相当，能够被用作阿尔兹海默以及肿瘤的早期诊断。.