Targeted galectin-7 inhibition with ultrasound microbubble targeted gene therapy as a sole therapy to prevent acute rejection following heart transplantation in a Rodent model

作者：Zhuo Wang, Shuangquan Jiang, Shouqiang Li, Wei‐Dong Yu, Jianfeng Chen, Dandan Yu, Zhao Chen, Yingjie Li, Kai Kang, Ranran Wang, Mengmeng Liang, Mingyuan Xu, Yanmei Ou, Piyu Li, Xiaoping Leng, Jiawei Tian, Thomas R-Porter · 发表于：Biomaterials · 年份：2020 · DOI：10.1016/j.biomaterials.2020.120366 · 被引用次数：37 · 研究领域：RNA Interference and Gene Delivery、Viral gastroenteritis research and epidemiology、Galectins and Cancer Biology

BACKGROUND: Despite significant advances in transplantation, acute cellular rejection (AR) remains a major obstacle that is most prevalent in the first months post heart transplantation (HT). Current treatments require high doses of immunosuppressive drugs followed by maintenance therapies that have systemic side effects including early infection. In this study, we attempted to prevent AR with a myocardial-targeted galectin-7-siRNA delivery method using cationic microbubbles (CMBs) combined with ultrasound targeted microbubble destruction (UTMD) to create local immunosuppression in a rat abdominal heterotopic heart transplantation acute rejection model. METHODS AND RESULTS: Galectin-7-siRNA (siGal-7) bound to CMBs were synthesized and effective ultrasound-targeted delivery of siGal-7 into target cells confirmed in vitro. Based on these observations, three transplant rat models were tested：①isograft (ISO); ② Allograft (ALLO) +UTMD; and ③ALLO + PBS. UTMD treatments were administered at 1, 3, 5, 7 days after HT. Galectin 7 expression was reduced by 50% compared to ALLO + PBS (p < 0.005), and this was associated with significant reductions in both galectin 7 and Interleukin-2 protein levels (p < 0.001). The ALLO + UTMD group had Grade II or less inflammatory infiltration and myocyte damage in 11/12 rats using International Society For Heart and Lung Transplantation grading, compared to 0/12 rats with this grading in the ALLO + PBS group at 10 days post HT (p < 0.001). CONCLUSIONS...