Gandham Srujan K, Rao Mounika, Shah Aayushi, Trivedi Malav S, Amiji Mansoor M
Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA 02115, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33314, USA.
Mol Ther Oncolytics. 2022 Mar 15;25:57-68. doi: 10.1016/j.omto.2022.03.005. eCollection 2022 Jun 16.
Most advanced-stage ovarian cancer patients, including those with epithelial ovarian cancer (EOC), develop recurrent disease and acquisition of resistance to chemotherapy, leading to limited treatment options. Decrease in Let7b miRNA levels in clinical ovarian cancer has been associated with chemoresistance, increased proliferation, invasion, and relapse in EOC. We have established a murine EOC relapsed model by administering paclitaxel (PTX) and stopping therapy to allow for tumor regrowth. Global microRNA profiling in the relapsed tumor showed significant downregulation of Let7b relative to untreated tumors. Here, we report the use of hyaluronic acid (HA)-based nanoparticle formulation that can deliver Let7b miRNA mimic to tumor cells and achieve cellular programming both and . We demonstrate that a therapeutic combination of Let7b miRNA and PTX leads to significant improvement in anti-tumor efficacy in the relapsed model of EOC. We further demonstrate that the combination therapy is safe for repeated administration. This novel approach of cellular reprogramming of tumor cells using clinically relevant miRNA mimic in combination with chemotherapy could enable more effective therapeutic outcomes for patients with advanced-stage relapsed EOC.
大多数晚期卵巢癌患者，包括上皮性卵巢癌（EOC）患者，都会出现疾病复发并对化疗产生耐药性，导致治疗选择有限。临床卵巢癌中Let7b微小RNA水平的降低与EOC中的化疗耐药、增殖增加、侵袭和复发有关。我们通过给予紫杉醇（PTX）然后停止治疗以允许肿瘤重新生长，建立了一种小鼠EOC复发模型。复发肿瘤中的全局微小RNA谱分析显示，与未治疗的肿瘤相比，Let7b显著下调。在此，我们报告了一种基于透明质酸（HA）的纳米颗粒制剂的应用，该制剂可以将Let7b微小RNA模拟物递送至肿瘤细胞，并在体内和体外实现细胞编程。我们证明，Let7b微小RNA与PTX的联合治疗可使EOC复发模型中的抗肿瘤疗效得到显著改善。我们进一步证明，联合治疗重复给药是安全的。这种使用临床相关微小RNA模拟物与化疗相结合对肿瘤细胞进行细胞重编程的新方法，可为晚期复发EOC患者带来更有效的治疗效果。
