In vivo rendezvous of small nucleic acid drugs with charge-matched block catiomers to target cancers

Abstract

Stabilisation of fragile oligonucleotides, typically small interfering RNA (siRNA), is one of the most critical issues for oligonucleotide therapeutics. Many previous studies encapsulated oligonucleotides into ~100-nm nanoparticles. However, such nanoparticles inevitably accumulate in liver and spleen. Further, some intractable cancers, e.g., tumours in pancreas and brain, have inherent barrier characteristics preventing the penetration of such nanoparticles into tumour microenvironments. Herein, we report an alternative approach to cancer-targeted oligonucleotide delivery using a Y-shaped block catiomer (YBC) with precisely regulated chain length. Notably, the number of positive charges in YBC is adjusted to match that of negative charges in each oligonucleotide strand (i.e., 20). The YBC rendezvouses with a single oligonucleotide in the bloodstream to generate a dynamic ion-pair, termed unit polyion complex (uPIC). Owing to both significant longevity in the bloodstream and appreciably small size (~18 nm), the uPIC efficiently delivers oligonucleotides into pancreatic tumour and brain tumour models, exerting significant antitumour activity.

Effect of Mixing Ratio of Oppositely Charged Block Copolymers on Polyion Complex Micelles for In Vivo Application

“…The Cy5-PIC/m prepared with a C/A of 0.90, 1.00 and 1.10 were evaluated in vivo, as follows: The Cy5-PIC/m were intravenously (i.v.) injected into mice, and the fluorescent intensity in the vein was continuously monitored by intravital real-time confocal laser scanning microscopy (IVRT-CLSM) [25]. The results showed that PIC/m with a C/A of 0.90 and 1.00 disappeared from the bloodstream almost immediately after the administration, and only 10% of the injected dose was detecTable 60 min after administration (Figure 3a).…”

Synthetic MIR143-3p Suppresses Cell Growth in Rhabdomyosarcoma Cells by Interrupting RAS Pathways Including PAX3–FOXO1

“…Recently, MIRNA delivery via LNP successfully suppressed xenografted tumors [ 49 ]. In the current study, we also efficiently inhibited tumor growth by using uPIC, the diameter of which is approximately 20 nm and which was selectively prepared as a charge-matched polyionic complex ( Figure S4A ) [ 36 , 37 , 50 ].…”

Poly(α-l-lysine)-based nanomaterials for versatile biomedical applications: Current advances and perspectives

“…The spontaneous ion-pair interactions between the PLL chain and the oligonucleotide generated a uPIC that conferred dynamic stability to oligonucleotide drugs in the bloodstream. The uPIC was able to efficiently deliver oligonucleotides into mice, bearing pancreatic and brain tumors, due to the significant longevity in the bloodstream and appreciably small size (~18 nm) [ 337 ]. In another pancreatic cancer mouse model, the Y-shaped block catiomer was utilized for delivering DNA-chimeric siRNAs, allowing for high transfection efficiency and protection from kidney filtration [ 338 ].…”