TY - JOUR
T1 - iRGD-Liposomes Enhance Tumor Delivery and Therapeutic Efficacy of Antisense Oligonucleotide Drugs against Primary Prostate Cancer and Bone Metastasis
AU - Guan, Jibin
AU - Guo, Hong
AU - Tang, Tang
AU - Wang, Yihan
AU - Wei, Yushuang
AU - Seth, Punit
AU - Li, Yingming
AU - Dehm, Scott M.
AU - Ruoslahti, Erkki
AU - Pang, Hong Bo
N1 - Publisher Copyright:
© 2021 Wiley-VCH GmbH
PY - 2021/6/9
Y1 - 2021/6/9
N2 - 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.
AB - 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.
KW - antisense oligonucleotides
KW - bone metastasis
KW - cancer therapies
KW - iRGD-liposomes
KW - primary prostate cancer
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U2 - 10.1002/adfm.202100478
DO - 10.1002/adfm.202100478
M3 - Article
C2 - 34211360
AN - SCOPUS:85104157940
SN - 1616-301X
VL - 31
JO - Advanced Functional Materials
JF - Advanced Functional Materials
IS - 24
M1 - 2100478
ER -