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.
Highlights
Stabilisation of fragile oligonucleotides, typically small interfering RNA, is one of the most critical issues for oligonucleotide therapeutics
To overcome the above issue, the present study establishes an alternative approach to SNA stabilisation in vivo by engineering a Y-shaped block catiomer (YBC) with precisely regulated chain length, which abrogates the need for large nanoparticles
We first demonstrated the spontaneous formation of unit polyion complex (uPIC) in an aqueous solution using small interfering RNA (siRNA) and YBC, a block catiomer comprising poly(Llysine) (PLL) and two-armed poly(ethylene glycol) (PEG) (molecular weight (MW) of PEG = 2 × 37 kDa)[10,11]
Summary
Stabilisation of fragile oligonucleotides, typically small interfering RNA (siRNA), is one of the most critical issues for oligonucleotide therapeutics. 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. The number of positive charges in the YBC is adjusted to match the number of negative charges in each SNA strand (i.e. 20) This charge-matching enables dynamic and selective ion-pairing of a single molecule of siRNA or ASO with a dyad or single molecule (s) of YBC in the bloodstream, generating a dynamically equilibrated unit polyion complex (uPIC). The uPICs exert significant antitumour activity for a spontaneous pancreatic tumour model and an orthotopic brain tumour model by transporting an apoptosis-inducing siRNA coding polo-like kinase 1 (PLK1) and an ASO coding turine upregulated gene 1 (TUG1), respectively
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