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

Abstract

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.

Artificial exosomes for translational nanomedicine

“…However, the yield of NVs by this method was not reported. In another study, Guo et al enhanced the extruding method for NVs generation by magnetism [ 62 ]. They incubated cells with 10 nm iron oxide NPs (IONPs) for endosome encapsulation.…”

DR5-Selective TRAIL Variant DR5-B Functionalized with Tumor-Penetrating iRGD Peptide for Enhanced Antitumor Activity against Glioblastoma

“…Peptide iRGD (CRGDKGPDC) enhances tissue penetration by different molecules upon binding to integrins αVβ3 and αVβ5 followed by proteolytical cleavage and obtain specificity to the NRP-1 receptor [ 4 ]. This unique ability has been widely exploited to enhance the penetration of various compounds, from small molecules [ 5 ] to nanoparticles [ 6 , 7 , 8 ], liposomes [ 9 ], and exosomes [ 10 , 11 ]. The construction of chimeric proteins with the iRGD peptide was used to enhance the tumor permeability of the variable domain from the heavy chain of the anti-epidermal growth factor receptor antibody (anti-EGFR VHH) [ 12 ], recombinant analogue of lactaptin (RL2) [ 13 ], proapoptotic peptide KLA [ 14 ], interleukin-24 (IL-24) [ 15 ], and DNA fragmenting factor (DFF40) [ 16 ].…”

Extracellular Vesicles Mediate the Intercellular Exchange of Nanoparticles

“…[ 63 ] We recently showed that our liposomes remain largely intact in the tumor tissue up to a few hours after intravenous injection. [ 64 ] Further studies are needed to accurately quantify the ratio of intact organic NPs that can be exocytosed inside EVs.…”