磁响应性经皮递送pH敏感的EPI-SPION治疗恶性黑色素瘤的效果和机制研究

Cutaneous malignant melanoma (CMM) is the most common skin malignant tumor with high mutation rate and malignant degree, early metastasis and poor prognosis. Efficacy of drugs utilized in present clinical treatments is always limited by the their side effects and drug resistance. Novel drug targeting delivery system is an effective means to treat CMM safely and efficiently. The superparamagnetic iron-oxide nanoparticles (SPION) have been enthusiastically investigated in recent decades as a ultrasmall drug vector. Our previous studies have found that SPION can effectively penetrate various biological barriers under the action of external force, significantly improve the antitumor drug Epirubicin (EPI) distribution. After surface functional modification, EPI and other therapeutic molecular such as carnosine can be efficiently grafted onto SPION and achieve tailored release of therapeutic agents. The high concentration of SPION retension has been proved to induce the oxidative stress and immunologic inflamation porcess. Based on our previous breakthrough findings, we are going to optimize the EPI-SPION drug delivery system. We plan to use the magnetic transdermal delivery technique and conbine the pH-sensitive durg release mechanism, avoiding the first-pass effect and other side actions, so as to achieve effective treatment for CMM pharmacotherapy. Our research will explore the effect and mechanism of precise targeting, synergy of carrier materials, to develop a brand-new drug delivery system and provide creative thinking for CMM treatment.

恶性黑色素瘤（CMM）是最常见的皮肤恶性肿瘤，其突变率和恶性程度高、转移早、预后差。现有治疗药物因毒副作用大且易产生耐药，难以实现对其有效治疗。已有研究表明超顺磁性氧化铁纳米粒（SPION）等新型药物递送系统是实现其有效治疗的重要手段。我们前期研究已发现SPION在磁场调控下可有效穿透各类致密生物屏障，显著提高治疗药物表柔比星（EPI）的靶向分布；其表面修饰后可高效嫁接EPI、肌肽等药物，实现药物的可调式释放，且局部滞留的高浓度SPION具有协同诱导细胞发生氧化应激作用。本项目拟在此基础上，开展EPI-SPION递药系统优化研究，通过磁响应性经皮递送并利用CMM组织低pH值微环境精准触发药物释放，避免首过效应及其他毒副作用，实现对CMM高效治疗。本研究将探索CMM病变部位精准靶向的效果与机制、载体材料的协同作用，为拓展新型递药系统和CMM治疗提供创造性研究思路。

恶性黑色素瘤是最常见的皮肤恶性肿瘤，其突变率和恶性程度高、转移早、预后差。现有治疗药物因毒副作用大且易产生耐药，难以实现对其有效治疗。已有研究表明超顺磁性氧化铁纳米粒（EPI-SPION）以及可溶微针介导的光敏剂自组装纳米粒（L-Ce6 MNs）等新型药物递送系统是实现其有效治疗的重要手段。本项目对EPI-SPION和L-Ce6 MNs合成以及相应参数进行了优化，初步阐明了EPI-SPION经皮递药过程机制和靶向调控机制，对EPI-SPION与L-Ce6 MNs开展了体外细胞生物学研究，最后评估了L-Ce6 MNs的体内抗肿瘤效果。我们发现，在毛囊皮脂腺以外的区域都未能检测到纳米颗粒，可以推断EPI-SPION在外加磁场的帮助下透过毛囊皮脂腺结构单位而进入真皮层是本体系中唯一的途径。在体外，EPI-SPION和L-Ce6 MNs分别对WM266和B16F10黑色素瘤细胞表现出显著的细胞杀伤作用。在体内，结合激光照射后，L-Ce6 MNs有效抑制B16F10黑色素瘤细胞的生长速度，并延长双侧荷瘤鼠的生存率。通过磁响应性或者光动力疗法经皮递送能够有效避免首过效应及其他毒副作用，有望实现对CMM的精准高效治疗，为拓展新型递药系统和CMM病变部位精准靶向治疗提供创造性研究思路。