Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
School of Chemistry, Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China.
Adv Healthc Mater. 2024 Sep;13(22):e2400797. doi: 10.1002/adhm.202400797. Epub 2024 Jun 3.
The Notch signaling is a key molecular pathway that regulates cell fate and development. Aberrant Notch signaling can lead to carcinogenesis and progression of malignant tumors. However, current therapies targeting Notch pathway lack specificity and induce high toxicity. In this report, a tumor microenvironment-responsive and injectable hydrogel is designed to load plasmid DNA complexes as a cascade gene delivery system to achieve precise Notch-targeted gene therapy of colorectal cancer (CRC). The hydrogels are prepared through cross-linking between phenylboric acid groups containing poly(oligo(ethylene glycol)methacrylate) (POEGMA) and epigallocatechin gallate (EGCG), used to load the complexes between plasmid DNA encoding short hairpin RNAs of Notch1 (shNotch1) and fluorinated polyamidoamine (PAMAM-F) (PAMAM-F/shNotch1). In response to low pH and HO in tumor microenvironment, the hydrogel can be dissociated and release the complexes for precise delivery of shNotch1 into tumor cells and inhibit Notch1 activity to suppress malignant biological behaviors of CRC. In the subcutaneous tumor model of CRC, PAMAM-F/shNotch1-loaded hydrogels can accurately attenuate Notch1 activity and significantly inhibit tumor growth without affecting Notch signal in adjacent normal tissues. Therefore, this therapeutic system can precisely inhibit Notch1 signal in CRC with high responsiveness and low toxicity, providing a promising Notch-targeted gene therapeutic for human malignancy.
Notch 信号通路是调控细胞命运和发育的关键分子途径。异常的 Notch 信号通路可导致肿瘤发生和恶性肿瘤的进展。然而，目前靶向 Notch 通路的治疗方法缺乏特异性，并导致高毒性。在本报告中，设计了一种肿瘤微环境响应型可注射水凝胶，用于负载质粒 DNA 复合物作为级联基因传递系统，以实现结直肠癌（CRC）的精确 Notch 靶向基因治疗。该水凝胶通过含有苯硼酸基团的聚（低聚乙二醇甲基丙烯酸酯）（POEGMA）和表没食子儿茶素没食子酸酯（EGCG）之间的交联制备，用于负载编码 Notch1 的短发夹 RNA（shNotch1）和氟化聚酰胺-胺（PAMAM-F）（PAMAM-F/shNotch1）的质粒 DNA 复合物。响应于肿瘤微环境中的低 pH 和 HO，水凝胶可以解离并释放复合物，以精确递送至肿瘤细胞中的 shNotch1，并抑制 Notch1 活性，从而抑制 CRC 的恶性生物学行为。在 CRC 的皮下肿瘤模型中，负载 PAMAM-F/shNotch1 的水凝胶可以准确地减弱 Notch1 活性并显著抑制肿瘤生长，而不会影响相邻正常组织中的 Notch 信号。因此，这种治疗系统可以精确地抑制 CRC 中的 Notch1 信号，具有高响应性和低毒性，为人类恶性肿瘤提供了一种有前途的 Notch 靶向基因治疗方法。
