Abstract
Recently, the number of gene and oligonucleotide drugs are increasing. Of various drug delivery systems (DDSs) for gene and oligonucleotide drugs, few examples of the clinical application of polymer as drug carriers are known, despite development of the novel polymers has been progressing. Cyclodextrin (CD) conjugates with starburst polyamidoamine (PAMAM) dendrimer (CDEs), as a new type of polymer-based carriers, were first published in 2001. After that, galactose-, lactose-, mannose-, fucose-, folate-, and polyethyleneglycol (PEG)-appended CDEs have been prepared for passive and active targeting for gene, oligonucleotide, and low-molecular-weight drugs. PEG-appended CDE formed polypsuedorotaxanes with α-CD and γ-CD, which are useful for a sustained release system of gene and oligonucleotide drugs. Interestingly, CDEs were found to have anti-inflammatory effects and anti-amyloid effects themselves, which have potential as active pharmaceutical ingredients. Most recently, CDE is reported to be a useful Cas9-RNA ribonucleoproteins (Cas9 RNP) carrier that induces genome editing in the neuron and brain. In this review, the history and progression of CDEs are overviewed.
Highlights
The modalities of pharmaceuticals are diversifying, and genes, oligonucleotides, cells, and digital medicines have been developed recently [1]
RNA interference (RNAi) effects of the shRNA expressing pDNA (shpDNA) complex with α-CDE (G3, DSC2.4) could be ascribed to the stabilizing effect of α-CDE (G3, DS2.4) on enzymatic degradation of shpDNA and negligible cytotoxicity. These results suggest that α-CDE (G3, DSC2.4) possesses the potential to be a novel carrier for shpDNA and siRNA [41]
Lacα-CDE (G2, DSL2.6) provided gene transfer activity higher than jetPEI® -Hepatocyte to hepatocytes with much less changes in blood chemistry values 12 h after intravenous administration in mice. These results suggest the potential use of Lac-α-CDE (G2, DSC1, DSL2.6) as a nonviral vector for gene delivery toward hepatocytes [52]
Summary
The modalities of pharmaceuticals are diversifying, and genes, oligonucleotides, cells, and digital medicines have been developed recently [1]. The interesting point regarding DDS is that the LNP itself does not have the ability to target the liver, but it is an active targeting agent that acquires the ability to target liver parenchymal cells by adsorbing endogenous ApoE after intravenous administration [5] Another DDS technology used in Givlaari® (givosiran) is a chemically modified siRNA drug conjugation with three. N-acetylgalactosamine (GalNAc) molecules for targeting to asialoglycoprotein receptor (ASGP-R), which is highly expressed on liver parenchymal cell membranes [6] As described above, both Onpattro® and Givlaari® are siRNA products using DDS technology that targets liver parenchymal cells. Ionis Pharmaceuticals, a pioneer in the development of antisense oligonucleotide drugs, has introduced GalNAc’s DDS technology, and mutual collaboration on active targeting of antisense oligonucleotides is being implemented. Examples of the use of unit polyion complexes and exosomes as oligonucleotide drug carriers, in addition to aptamers and siRNA conjugates with antibodies, are being investigated, and we look forward to good results in future research and clinical trials
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