iRGD‐Liposomes Enhance Tumor Delivery and Therapeutic Efficacy of Antisense Oligonucleotide Drugs against Primary Prostate Cancer and Bone Metastasis

• Published in: Advanced functional materials Vol. 31; no. 24
• Main Authors: Guan, Jibin, Guo, Hong, Tang, Tang, Wang, Yihan, Wei, Yushuang, Seth, Punit, Li, Yingming, Dehm, Scott M., Ruoslahti, Erkki, Pang, Hong‐Bo
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.06.2021
• Subjects: Accumulation; Anticancer properties; antisense oligonucleotides; Biocompatibility; bone metastasis; Bones; cancer therapies; Drugs; Health services; iRGD‐liposomes; Liposomes; Materials science; Metastasis; Nucleotides; Oligonucleotides; Organs; primary prostate cancer; Prostate cancer; Side effects; Toxicity; Tumors; Xenotransplantation
• ISSN: 1616-301X; 1616-3028
• DOI: 10.1002/adfm.202100478

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 in vivo. This problem is particularly evident in solid tumors. Here, liposomes are functionalized 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 exhibit a high loading efficiency of AR‐ASO, and an efficient knockdown of AR gene products is achieved in vitro, including AR splice variants. In vivo, iRGD‐liposomes significantly increase AR‐ASO accumulation in the tumor tissue and decrease AR expression relative to free ASOs in prostate tumors established as subcutaneous xenografts. Similar results are obtained with intra‐tibial xenografts modeling metastasis to bones, the predominant site of metastasis for prostate cancer. In treatment studies, iRGD‐liposomes markedly improve the AR‐ASO efficacy in suppressing the growth of both subcutaneous xenografts and intra‐tibial xenografts. The inhibitory effect on tumor growth is also significantly prolonged by the delivery of the AR‐ASO in the iRGD‐liposomes. Meanwhile, iRGD‐liposomes does not increase ASO accumulation or toxicity in healthy organs. Overall, a delivery system that can significantly increase ASO accumulation and efficacy in solid tumors is provided here. These benefits are achieved without significant side effects, providing a way to increase the antitumor efficacy of ASOs. A peptide (iRGD)‐functionalized liposomal system is generated to improve the delivery of antisense oligonucleotides (ASOs) into solid tumors. This system increases the tumor accumulation and vascular penetration of an ASO against androgen receptor (AR) in castration‐resistant prostate cancer and bone metastases. This results in an increase in short‐ and long‐term antitumor efficacy of AR‐ASO against both primary tumors and metastasis.