靶向调控外泌体分泌功能的杂化脂质体抗胰腺癌效应及机制研究

Tumor-derived exosomes play a crucial role in the cancer development, drug resistance, metastasis and immune suppression. Therefore, blockade of exosome generation becomes a new research approaches in cancer therapy. In order to decrease the production of tumor-derived exosomes, we developed a novel tumor-derived exosomes targeting drug-loaded hybrid liposomes, in which anti-GPC1 was used as the targeting molecule, GW4869 was selected as the inhibitor of exosome secretion, hybrid liposomes by fusing liposomes with exosomes membranes using the freeze-thaw method were developed as the carriers. The GPC1 receptor mediated targeting GW4869-loaded hybrid liposomes can increase the the intracellular uptake of GW4869 by pancreatic cancer cells.The tumor-derived exosomes targeting drug-loaded hybrid liposomes are to be used for blocking the release of tumor-derived exosomes, thus preventing the cancer growth, drug resistance, metastasis and immune suppression arising from tumor-derived exosomes. The present study is promising to provide a start point of an effective strategy for the treatment of pancreatic cancer with potential on improving pancreatic cancer therapy.

肿瘤外泌体在肿瘤的发展、耐药、转移和免疫逃逸中发挥着重要作用。如何有效地抑制甚至是阻断肿瘤外泌体的释放，就成为了治疗肿瘤的新的研究方向。本项目以胰腺癌外泌体为新靶点，针对胰腺癌的表面特异性分子标志glypican-1(GPC1)，选择GPC1抗体为靶向分子，GW4869为抑制外泌体分泌药物，脂质体与外泌体膜融合后重新自组装的杂化脂质体为载体，构建一种新型的靶向调控外泌体分泌功能的载药杂化脂质体来选择性地抑制肿瘤外泌体的分泌。通过主动靶向到胰腺癌细胞，阻断胰腺癌细胞外泌体的释放，克服胰腺癌外泌体导致的胰腺癌增殖、耐药、转移和免疫逃逸等问题，并从分子、细胞、动物水平阐明其抗胰腺癌的作用机制。本课题对于临床上广泛存在的迫切待解决的胰腺癌耐药、转移、免疫抑制等重大科学问题，提供了新的理论与实验基础。

肿瘤外泌体在肿瘤的发展、耐药、转移和免疫逃逸中发挥着重要作用。如何有效地抑制甚至是阻断肿瘤外泌体的释放，就成为了治疗肿瘤的新的研究方向。本项目以胰腺癌外泌体为新靶点，针对胰腺癌的表面特异性分子标志glypican-1(GPC1)，选择GPC1抗体为靶向分子，GW4869为抑制外泌体分泌药物，脂质体与外泌体膜融合后重新自组装的杂化脂质体为载体，构建一种新型的靶向调控外泌体分泌功能的载药杂化脂质体来选择性地抑制肿瘤外泌体的分泌。通过主动靶向到胰腺癌细胞，阻断胰腺癌细胞外泌体的释放，诱导胰腺癌细胞凋亡，显示出良好的体内治疗效果，同时从分子水平阐明了其阻断外泌体合成和分泌的信号通路。本项目对于临床上迫切待解决的胰腺癌治疗问题，提供了新的理论与实验基础。