Bioconjugates for targeted delivery of therapeutic oligonucleotides

Abstract

Bioconjugates have been used to deliver therapeutic oligonucleotides to their pharmacological targets in diseased cells. Molecular-scale conjugates can be prepared by directly linking targeting ligands with oligonucleotides and the resultant conjugates can selectively bind to cell surface receptors in target cells in diseased tissues. Besides targeted delivery, additional functionality can be incorporated in the conjugates by utilization of carrier molecules, and these larger conjugates are called carrier-associated conjugates. Both molecular and carrier-associated conjugates have achieved initial successes in clinical trials for treating liver diseases; therefore, currently the greater challenge is to deliver oligonucleotides to extrahepatic tissues such as tumors. This review will provide an update on the application of oligonucleotide conjugates for targeted delivery during the last decade. By identifying key elements for successful delivery, it is suggested that oligonucleotide conjugates with intermediate size, cell targeting ability, and endosomal release functionality are superior systems to advance oligonucleotides to achieve their full therapeutic potentials.

Therapeutic Oligonucleotides with Polyethylene Glycol Modifications

“…In contrast, maleimide and triazol linkages (the result of click chemistry based attachment) are much more stable. The main attachment sites are the 3´-and 5´-terminal hydroxyls [47]. For siRNA, the sense strand shows higher tolerance for ligand attachment, but 3´-antisense modification is also an attractive approach.…”

Biological system analysis using a nanopore transduction detector: from miRNA validation, to viral monitoring, to gene circuit feedback studies

“…Preliminary results involving interference tests are provided in the Results section, and a brief background on interference issues is given there. For further details on aptamers in the context of nanopore transduction detection see [17][18][19], and in general see [20][21][22][23][24]. Further details on antibodies pertinent to nanopore detection are placed in the Suppl., including diagrammatic figures and structural details from various references [25][26][27][28][29][30][31][32].…”

“…Reprinted with permission of [18]. A schematic for typical antibody N-glycosylation is shown (drawn from results on the equine IGHD gene [22]), where one possible N-glycosylation site is indicated in region CH2, and three possible N-glycosylation sites are indicated in region CH3. N-glycosylation consists of a covalent bond (glycosidic) between a biantennary N-glycan (in humans) and asparagine (amino acid 'N', thus N-glycan).…”

Systemic Delivery of Small Interfering RNA Therapeutics: Obstacles and Advances

“…Design and development of advanced delivery systems have notably increased the siRNA therapeutics in clinical trials and most of these are targeted via systemic delivery (Ozcan et al, 2015;Chakraborty et al, 2017). Many groups have reported systemic delivery of siRNA with different carrier systems such as bioconjugates (Ming and Laing, 2015;Sivakumar et al, 2018;Srimanee et al, 2018), complexes (Biswas and Torchilin, 2013;Nussbaumer et al, 2016;Takemoto and Nishiyama, 2017) and nanoparticles (Patil and Panyam, 2009;Kozielski et al, 2013;Lin et al, 2014;Tezgel et al, 2018). Recent developments have been the combinatorial formulation of carriers to form complexes on the nanoscale for the systemic delivery of siRNA therapeutics (Garg et al, 2016;Lee and Ahn, 2018;Zheng et al, 2018).…”