Twenty Years of Research on Cyclodextrin Conjugates with PAMAM Dendrimers

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.

Exploring the Influence of Spacers in EDTA–β-Cyclodextrin Dendrimers: Physicochemical Properties and In Vitro Biological Behavior

“…Rf = 0.3 (CH 2 Cl 2 /MeOH (9:1 v:v)). 1 (13)(14)(15) According to the previously reported procedures [29,56], EDTA dianhydride 1 eq and DIPEA 2.2 eq were suspended in 5 mL of DMF anh. at 0 • C and the reaction mixture was stirred for 20 min.…”

“…1 The di alkyne 14 was obtained as a white solid (99% yield). 1 Disubstituted EDTA Alkyne (15) The di alkyne 15 was obtained as a white solid (99% yield). 1 3.2.7.…”

“…Specifically, the conjugation with carbohydrates to the periphery of dendrimers offers improved properties in their biological behavior, such as lower hemolytic toxicity, reduced immunogenicity, and targeted delivery [13,14]. In this way, modifying the surface of the dendrimers, for example, with β-cyclodextrin (βCD) molecules, allows the creation of a synergy in the properties of both components, such as biocompatibility and solubility [15]. βCD is hydrophilic entity possessing a hydrophobic conical cavity.…”

“…For the obtention of the disubstituted alkyne intermediates bearing an EDTA core (13)(14)(15), EDTA dianhydride was used as starting material and reacted through nucleophilic addition with the selected amine under basic conditions. For this reaction, 2.2 eq of amines 10-12 was required and a subsequent recrystallization from MeOH was necessary for obtaining a 99% yield in all cases, as shown in Scheme 2.…”

CRISPR-Cas9-Based Technology and Its Relevance to Gene Editing in Parkinson’s Disease

“…The development of cyclodextrin conjugates with the starburst polyamidoamine (PAMAM) dendrimer (CDEs) for passive and active targeting genes have been progressing. Importantly, CDE has been demonstrated to be a useful Cas9-RNA ribonucleoprotein (Cas9 RNP) carrier for gene editing in the neuron and brain [294].…”