Guan Jibin, Guo Hong, Tang Tang, Wang Yihan, Wei Yushuang, Seth Punit, Li Yingming, Dehm Scott M, Ruoslahti Erkki, Pang Hong-Bo
Department of Pharmaceutics, School of Pharmacy, University of Minnesota, Minneapolis, MN 55455, United States.
Ionis Pharmaceuticals, Inc. Carlsbad, CA 92010, United States.
Adv Funct Mater. 2021 Jun 9;31(24). doi: 10.1002/adfm.202100478. Epub 2021 Apr 10.
Nucleotide-based drugs, such as antisense oligonucleotides (ASOs), have unique advantages in treating human diseases as they provide virtually unlimited ability to target any gene. However, their clinical translation faces many challenges, one of which is poor delivery to the target tissue . This problem is particularly evident in solid tumors. Here, we functionalized liposomes with a tumor-homing and -penetrating peptide, iRGD, as a carrier of an ASO against androgen receptor (AR) for prostate cancer treatment. The iRGD-liposomes exhibited a high loading efficiency of AR-ASO, and an efficient knockdown of AR gene products was achieved , including AR splice variants. , iRGD-liposomes significantly increased AR-ASO accumulation in the tumor tissue and decreased AR expression relative to free ASOs in prostate tumors established as subcutaneous xenografts. Similar results were obtained with intra-tibial xenografts modeling metastasis to bones, the predominant site of metastasis for prostate cancer. In treatment studies, iRGD-liposomes markedly improved the AR-ASO efficacy in suppressing the growth of both subcutaneous xenografts and intra-tibial xenografts. The inhibitory effect on tumor growth was also significantly prolonged by the delivery of the AR-ASO in the iRGD-liposomes. Meanwhile, iRGD-liposomes did not increase ASO accumulation or toxicity in healthy organs. Overall, we provide here a delivery system that can significantly increase ASO accumulation and efficacy in solid tumors. These benefits are achieved without significant side effects, providing a way to increase the antitumor efficacy of ASOs.
基于核苷酸的药物，如反义寡核苷酸（ASO），在治疗人类疾病方面具有独特优势，因为它们几乎具有靶向任何基因的无限能力。然而，它们的临床转化面临许多挑战，其中之一是向靶组织的递送不佳。这个问题在实体瘤中尤为明显。在这里，我们用肿瘤归巢和穿透肽iRGD对脂质体进行功能化，作为一种针对雄激素受体（AR）的ASO载体用于前列腺癌治疗。iRGD脂质体表现出AR-ASO的高负载效率，并实现了AR基因产物的有效敲低，包括AR剪接变体。iRGD脂质体相对于皮下异种移植建立的前列腺肿瘤中的游离ASO，显著增加了肿瘤组织中AR-ASO的积累并降低了AR表达。在模拟骨转移（前列腺癌转移的主要部位）的胫骨内异种移植中也获得了类似结果。在治疗研究中，iRGD脂质体显著提高了AR-ASO在抑制皮下异种移植和胫骨内异种移植生长方面的疗效。通过iRGD脂质体递送AR-ASO，对肿瘤生长的抑制作用也显著延长。同时，iRGD脂质体没有增加健康器官中ASO的积累或毒性。总体而言，我们在此提供了一种递送系统，可显著增加实体瘤中ASO的积累和疗效。这些益处是在没有明显副作用的情况下实现的，为提高ASO的抗肿瘤疗效提供了一种方法。
