β-Cyclodextrin-Based Polycationic Amphiphilic “Click” Clusters: Effect of Structural Modifications in Their DNA Complexing and Delivery Properties

Abstract

Monodisperse facial amphiphiles consisting of a β-cyclodextrin (βCD) platform exposing a multivalent display of cationic groups at the primary rim and bearing hydrophobic chains at the secondary oxygens have been prepared by implementing two very robust "click" methodologies, namely cuprous cation-catalyzed azide-alkyne cycloaddition (CuAAC) and thiourea-forming reaction. Most interestingly, the use of solid-supported Cu(I) catalysts was found to be very well suited for multiple CuAAC while facilitating purification of the C(7)-symmetric macromolecular triazole adducts. The strategy is compatible with molecular diversity-oriented approaches, which has been exploited to generate a small library of click polycationic amphiphilic CDs (paCDs) for assessing the influence of structural modifications in the ability to complex, compact, and protect pDNA and the efficiency of the resulting paCD:pDNA nanocomplexes (CDplexes) to deliver DNA into cells and promote transfection. The results indicate that fine-tuning the hydrophilic/hydrophobic balance is critical to achieve optimal self-assembling properties and stability of the resulting CDplexes in saline- and serum-containing media. Triazole-type paCDs were, in general, less efficient in promoting gene transfection than thiourea-type derivatives. Nevertheless, the current body of results support that the "dual click" approach implying sequential CuAAC and thiourea-forming reactions represents a versatile strategy to optimize the gene delivery capabilities of cyclodextrin-based facial amphiphiles.

Cyclodextrin-based multivalent glycodisplays: covalent and supramolecular conjugates to assess carbohydrate–protein interactions

“…The increasing awareness of the potential of polycationic CD derivatives in the design of nonviral gene delivery systems has led several groups to explore the suitability of polycationic CD conjugates to impart, simultaneously, stability and targeting capabilities of the corresponding complexes with plasmid DNA (pDNA), for which the term CDplexes has been coined. [148][149][150][151][152][153][154][155][156][157] Uekama, Arima and co-workers conceived a series of multifunctional CD conjugates consisting of a poly(amidoamine) (PAMAM) starburst dendrimer 102 onto which one-to-two aCD units (103) were randomly attached through a single primary (C-6) position by reaction with the corresponding 6 Itosyl derivative 103. Some of the remaining primary amino groups of the dendrimer were subsequently engaged in thiourea forming reactions with isothiocyanate-armed aMan (104) and aGal derivatives to afford the corresponding polycationic aCD-PAMAM glycoconjugates.…”

Recent progress in gene therapy to deliver nucleic acids with multivalent cationic vectors

“…In general, cationic polymers, poly-L-lysines (PLL) and poly-L-arginines (PLA) [126,127]; (c) carbohydrate-based polymers in which the charge is mainly supplied by cationic cyclodextins, glycoamines and so on [128][129][130]; and (d) dendrimers-based polymers as polyamidoaminme (PAMAM) and others [131][132][133]. In addition, electrostatic interaction has been also analyzed in complexes where polycations, based on amphiphilic polycationic cyclodextrins [100,134,135] and calixarenes [136], were used as gene vectors of plasmid DNA or siRNA.…”

“…(ii) multivalent cationic lipids [67,78,139,178,181], derivated oligoamines [182] and tripeptide multivalent lipids [122]; (iii) cationic polymers derivatives from PEI [124,127,183,184], PAMAM [132,140], PDMAEMA [123,133,185], PAA [103,131,186,187], chitosan [188], polyphosphoramidates [189], polyhydroxyalkanoate [92], polyamines [107], polyaminoacids [127,190] or diblock copolymers [191]; (iv) polycations from calixarene [40,136,165,192] or cyclodextrin [134,135,142,164,193] derivatives; (v) lipopolymers from lysine derivatives [170]; (vi) pendant polymercationic cyclodextrins [129,130,163]; and (vii) cationic polymer-cyclodextrin polyrotaxanes [89]. The picture that results from these transfection studies is that many of the polyplexes show efficacies comparable to that reported by the Lipo2000 positive control and also by most of the commercial or synthezised univalent CLs, but its efficacy as transfecting agents of DNA is still below than that reported by most of t...…”

Glycosyl-Nucleolipids as New Bioinspired Amphiphiles

“…R f : 0.46 (methanoldichloromethane 15:85). (11). To a solution of thymidine 10 (5 g, 20.6 mmol, 1.0 equiv) in pyridine (125 mL) was added DMAP (0.126 g, 1.03 mmol, 0.05 equiv.)…”

“…The chemical combination of biological molecules such as nucleic acids [1][2][3], aminoacids [4], peptides [5][6][7][8] or sugar [9][10][11] with lipids, remains an amazing approach to create new hybrid amphiphilic structures. Owning to their biocompatibility properties and biological functions, hybrid amphiphiles hold considerable potential for biomedical and biotechnological applications.…”