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We previously reported the utility of 6-O-α-(4-O-α-d-glucuronyl)-d-glucosyl-β-cyclodextrin (GUG-β-CyD) conjugates with polyamidoamine dendrimer [GUG-β-CDE (generation 3; G3)] as siRNA carriers. In this study, to prepare GUG-β-CDE (G3) possessing a targeting ability to tumor cells overexpressing folate receptor-α (FR-α), we newly synthesized folate-...
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In this study, we examined the effect of cationic lipid type in folate (FA)-polyethylene glycol (PEG)-modified cationic liposomes on gene-silencing effects in tumor cells using cationic liposomes/siRNA complexes (siRNA lipoplexes). We used three types of cationic cholesterol derivatives, cholesteryl (3-((2-hydroxyethyl)amino)propyl)carbamate hydroi...
We previously reported that polyamidoamine STARBURST dendrimer (generation 3, G3) (dendrimer) conjugate with alpha-cyclodextrin (alpha-CyD) having an average degree of substitution of 2.4 of alpha-CyD (alpha-CDE) provided remarkable aspects as novel carriers for DNA and siRNA. To develop novel alpha-CDE derivatives with tumor cell specificity, we p...
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... [82]. To further improve the potency of GUG-β-CDEs (G3), Mohamed et al. examined whether Fol-PEG-GUG-β-CDEs (G3, DSC3.7) having DSF of 3.9, 6.7, and 7.3 possess the potential for the utility as tumor-selective siRNA carriers [83]. Of various Fol-PEG-GUG-β-CDEs (G3, DSC3.7, ...
... DSF6.7, DSP6.7) has the potential as a targeted siRNA delivery carrier for FR-α-overexpressing tumor cells [83]. ...
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.
... Prominently, the ternary complex exhibited a higher RNAi effect, compared to the binary analog, after the intravenous injection to mice tumor cells [93]. Moreover, the significant antitumor activity of the PAMAM G3 ternary complexes based on the folate-appended GUG-β-CD conjugates was reported as an effective anti-cancer siRNA carrier specific to pololike kinase 1 (siPLK1) both in vitro and in vivo models [94]. The generated complex revealed the greater cytotoxic activity, compared to the binary analog containing DOX or siPLK1, against the KB cell line [40]. ...
Short interfering RNAs (siRNAs), as small non-coding RNA fragments, are one of the widely studied RNAi inducers for gene modulations. The reasonably designed siRNA probes provide a novel potential therapeutic strategy for cancer therapy via silencing the specific cancer-promoting gene. The optimization of physicochemical properties of delivery vectors, such as stability, the possibility of surface functionalization, size, charge, biocompatibility, biodegradability, and non-immunogenicity with receptor-mediated targeting ligands, is necessary for effective intracellular siRNA delivery. The present review is focused on the recent progress of the non-viral nanocarriers for siRNA cancer treatment based on synthetic approaches associated with cyclodextrin (CD)-based carbohydrate polymers, i.e. CD-cationic polymers, CD-polyrotaxanes, CD-dendrimers, and CD-modified tumor-specific targeting ligands. Besides, the efficiency of nanocarriers-based stimuli-responsive CDs is described for the simultaneous delivery of siRNAs and chemotherapeutic drugs. Further, theranostic CD compounds are introduced for the specific diagnosis and cargo-targeting delivery to the specific disease sites. In the meantime, the development of the inherent fluorescent CD-based supramolecular biomaterials without formal chromophores will open up a new strategy to design an effective theranostic non-viral carrier system.
To achieve a systemic targeted delivery of siRNA using polymeric carriers, there is a dilemma between ligand modification and stabilization of the polyplex. Namely, ligand modification often leads to destabilization of the polyplex in the blood circulation. In fact, we previously developed cyclodextrin (CD)/polyamidoamine dendrimer conjugates (CDE) as siRNA carriers, and the interaction of CDE/siRNA was decreased by the conjugation with folate-polyethylene glycol, leading to the destabilization. To overcome this dilemma, in this study, folate-appended polyrotaxanes (Fol-PRX) were developed. Fol-PRX stabilized CDE/siRNA polyplex by intermolecularly connecting CDE molecules through a host–guest interaction between adamantane at the terminals of Fol-PRX and β-CD in the polyplex. Moreover, the intermolecular connection of the polyplex with Fol-PRX provided movable folate moieties on the surface. As a result, Fol-PRXs enhanced the in vivo antitumor activity of the polyplex after intravenous administration, suggesting their utility as the dual-functional materials for systemic delivery of siRNA polyplexes.
Preassembled Cas9/single-guide RNA complex (Cas9 ribonucleoprotein; Cas9 RNP) induces genome editing efficiently, with small off-target effects compared with the conventional techniques, such as plasmid DNA and mRNA systems. However, penetration of Cas9 RNP through the cell membrane is low. In particular, the incorporation of Cas9 RNP into neurons and the brain is challenging. In the present study, we have reported the use of a dendrimer (generation 3; G3)/glucuronylglucosyl-β-cyclodextrin conjugate (GUG-β-CDE (G3)) as a carrier of Cas9 RNP and evaluate genome editing activity in the neuron and the brain. Cas9 RNP ternary complex with GUG-β-CDE (G3) was prepared by only mixing the components. The resulting complex exhibited higher genome editing activity than the complex with dendrimer (G3), LipofectamineTM 3000 or LipofectamineTM CRISPRMAXTM in SH-SY5Y cells, a human neuroblastoma cell line. In addition, GUG-β-CDE (G3) enhanced the genome editing activity of Cas9 RNP in the whole mouse brain after a single intraventricular administration. Thus, GUG-β-CDE (G3) is a useful Cas9 RNP carrier can induce genome editing in the neuron and brain.
We have previously reported the utility of folate-polyethylene glycol-appended dendrimer conjugate with glucuronylglucosyl-β-cyclodextrin (Fol-PEG-GUG-β-CDE) (generation 3) as a tumor-selective carrier for siRNA against polo-like kinase 1 (siPLK1) in vitro. In the present study, we evaluated the potential of Fol-PEG-GUG-β-CDE as a carrier for the low-molecular antitumor drug doxorubicin (DOX). Further, to fabricate advanced antitumor agents, we have prepared a ternary complex of Fol-PEG-GUG-β-CDE/DOX/siPLK1 and evaluated its antitumor activity both in vitro and in vivo. Fol-PEG-GUG-β-CDE released DOX in an acidic pH and enhanced the cellular accumulation and cytotoxic activity of DOX in folate receptor-α (FR-α)-overexpressing KB cells. Importantly, the Fol-PEG-GUG-β-CDE/DOX/siPLK1 ternary complex exhibited higher cytotoxic activity than a binary complex of Fol-PEG-GUG-β-CDE with DOX or siPLK1 in KB cells. In addition, the cytotoxic activity of the ternary complex was reduced by the addition of folic acid, a competitor against FR-α. Furthermore, the ternary complex showed a significant antitumor activity after intravenous administration to the tumor-bearing mice. These results suggest that Fol-PEG-GUG-β-CDE has the potential of a tumor-selective co-delivery carrier for DOX and siPLK1.
