Polycationic dendrimers interact with RNA molecules: polyamine dendrimers inhibit the catalytic activity of Candida ribozymes

Wu, Jiangyu; Zhou, Jiehua; Qu, Fengli; Bao, Penghui; Zhang, Yi; Peng, Ling

doi:10.1039/b414241a

Cited by 70 publications

(78 citation statements)

References 13 publications

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“…Owing to the ease of synthesis and commercial availability, PAMAM dendrimers are among the most utilized dendrimer-based vectors for gene transfer. [40] Notably, it has been shown recently that PAMAMs possess strong binding affinity for RNA molecules, [41,42] interact tightly with group I intron ribozymes, [41] and, last but not least, can efficiently deliver siRNA and thus induce gene silencing in cell cultures. [43] Notwithstanding these perspectives, relatively few attempts have been made so far along these lines to study in detail the molecular mechanisms underlying the complexa- Figure 12.…”

Section: Resultsmentioning

confidence: 99%

PAMAM Dendrimers for siRNA Delivery: Computational and Experimental Insights

Pavan

Posocco

Tagliabue

et al. 2010

Chemistry A European J

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Short double-stranded RNAs, which are known as short interfering RNA (siRNA), can be used to specifically down-regulate the expression of the targeted gene in a process known as RNA interference (RNAi). However, the success of gene silencing applications based on the use of synthetic siRNA critically depends on efficient intracellular delivery. Polycationic branched macromolecules such as poly(amidoamine) (PAMAM) dendrimers show a strong binding affinity for RNA molecules and, hence, can provide an effective, reproducible, and relatively nontoxic method for transferring siRNAs into animal cells. Notwithstanding these perspectives, relatively few attempts have been made so far along these lines to study in detail the molecular mechanisms underlying the complexation process between PAMAMs and siRNAs. In this work we combine molecular simulation and experimental approaches to study the molecular requirements of the interaction of RNA-based therapeutics and PAMAM dendrimers of different generations. The dendrimers and their siRNA complexes were structurally characterized, and the free energy of binding between each dendrimer and a model siRNA was quantified by using the well-known MM/PBSA approach. DOSY NMR experiments confirmed the structural in silico prediction and yielded further information on both the complex structure and stoichiometry at low N/P ratio values. siRNA/PAMAM complex formation was monitored at different N/P ratios using gel retardation assays, and a simple model was proposed, which related the amount of siRNA complexed to the entropy variation upon complex formation obtained from the computer simulations.

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Section: Resultsmentioning

confidence: 99%

PAMAM Dendrimers for siRNA Delivery: Computational and Experimental Insights

Pavan

Posocco

Tagliabue

et al. 2010

Chemistry A European J

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“…Poly(amidoamine) or PAMAM dendrimers consist of polyamide branches stemming from a central ammine or diaminoalkane core (see Fig. 1 [10][11][12][13][14], whereas the half generation dendrimers have multiple anionic charges which are ideal for cationic drugs or for reversible coordination to platinum complexes [15]. PAMAM dendrimers of generations 1 to 10 are nanometre in diameter, and thus, ideal for targeting tumours through the EPR effect.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of anionic half generation 3.5–6.5 poly(amidoamine) dendrimers as delivery vehicles for the active component of the anticancer drug cisplatin

Kirkpatrick

Plumb

Sutcliffe

et al. 2011

Journal of Inorganic Biochemistry

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Title: Evaluation of anionic half generation 3.5-6.5 poly(amidoamine) dendrimers as delivery vehicles for the active component of the anticancer drug cisplatin Article Type: Regular Paper Keywords: cancer; platinum; PAMAM dendrimer; cisplatin; guanosine; cytotoxicity; diffusion NMR. Abstract: Aquated cisplatin was added to half-generation PAMAM dendrimers and the resultant complexes were purified by centrifuge. The drug-dendrimer complexes were then characterised by 1-D and diffusion 1H NMR y and ICP-AES. The amount of drug bound was found to increase in proportion with dendrimer size: G3.5, 22 cis-{Pt(NH3)2}molecules per dendrimer; G4.5, 37; G5.5, 54; and G6.5, 94, which represent only a fraction of the available binding sites on each dendrimer (68, 58, 42 and 37%, respectively). Drug release studies showed that some drug remains bound to the dendrimer even after prolonged incubation with 5'GMP at temperatures of 60 oC for over a week (percentage of drug released 18, 30, 35 and 63%, respectively). Attachment of the drug was found to decrease the radius of the dendrimers. Finally, the effect of the dendrimer on drug cytotoxicity was determined using in vitro assays with the A2780, A2780cis and A2780cp ovarian cancer cell lines. The free dendrimers display no cytotoxicity whilst the drug-dendrimer complexes showed moderate activity. In vivo activity was examined using an A2780 tumour xenograft. Cisplatin, at its maximum tolerated dose of 6 mg/kg, reduced tumour size by 33% compared to an untreated control group. The G6.5 cisplatin-dendrimer complex was administered at two doses (6 and 8 mg/kg equivalent of cisplatin). Both were well tolerated by the mice. The lower dose displayed comparable activity to cisplatin with a tumour volume reduction of 32%, but the higher dose was significantly more active than free cisplatin with a tumour reduction of 45%. We have revised the manuscript taking into account all your listed corrections and stylistic requirements.As siDNA and PBS were used only once in the manuscript we have now written these in full and not used them as abbreviations.For simplicity, we have made figure 5 just black and white and have changed the figure caption to reflect this. G4.5, 37; G5.5, 54; and G6.5, 94, which represent only a fraction of the available binding sites on each dendrimer (68, 58, 42 and 37%, respectively). Drug release studies showed that some drug remains bound to the dendrimer even after prolonged incubation with 5'GMP at temperatures of 60 o C for over a week (percentage of drug released 18, 30, 35 and 63%, respectively). Attachment of the drug was found to decrease the radius of the dendrimers. Finally, the effect of the dendrimer on drug cytotoxicity was determined using in vitro assays with the A2780, A2780cis and A2780cp ovarian cancer cell lines. The free dendrimers display no cytotoxicity whilst the drug-dendrimer complexes showed moderate activity. In vivo activity was examined using an A2780 tumour xenograft. Cisplatin, at its maximum tolerated dose of 6 mg/kg, reduced tu...

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“…Dendrimers (Scheme 1) are also unique synthetic macromolecules of nanometer dimensions with a highly branched structure and globular shape with strong affinity towards DNA and RNA complexation [4][5][6][7][8][9][10]. It has been shown that synthetic polymers induce significant changes in DNA and RNA solubility and structure under given conditions [8][9][10][11][12][13][14][15][16][17][18][19][20]. Synthetic polymers are also used to transport miRNA and siRNA in vitro [11][12][13][14][15][16][17][18][19][20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

“…It has been shown that synthetic polymers induce significant changes in DNA and RNA solubility and structure under given conditions [8][9][10][11][12][13][14][15][16][17][18][19][20]. Synthetic polymers are also used to transport miRNA and siRNA in vitro [11][12][13][14][15][16][17][18][19][20][21][22][23][24]. PEGylation of synthetic polymers such as dendrimers is shown to reduce toxicity and increase biocompatibility and DNA Transfection [6,7,9].…”

Section: Introductionmentioning

confidence: 99%

Effect of Synthetic Polymers on tRNA Nanoparticle Formation

HA¹

2015

JNMR

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In this review, we have examined the effects of several synthetic nanoparticles such as poly (ethylene glycol) PEG-(PEG-3350, PEG-6000), methoxypoly (ethylene glycol) anthracene (mPEG-anthracene), methoxypoly (ethylene glycol) poly (amidoamine) (mPEG-PAMAM-G3), (mPEG-PAMAM-G4) and poly (amidoamine) (PAMAM-G4) on tRNA structure and dynamics. Atomic force microscopic (AFM) images and spectroscopic data were analysed and the effects of synthetic polymer complexation on tRNA stability, aggregation and particle formation are discussed. Hydrophilic and hydrophobic contacts were dominated in the polymer-tRNA complexation and the overall binding constants showed that the order of binding is PEG-6000>PAMAM-G4>PEG-3350>mPEG-PAMAM-G4>mPEG-PAMAM-G3>mPEG-anthracene. The morphology of polymer-tRNA complexes showed major aggregation and nanoparticle formation of tRNA, in the presence of synthetic nanoparticles.

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Polycationic dendrimers interact with RNA molecules: polyamine dendrimers inhibit the catalytic activity of Candida ribozymes

Abstract: Various polyamine dendrimers with a triethanolamine core inhibit the activity of the Candida ribozyme by forming RNA-dendrimer complexes via electrostatic interactions.

Cited by 70 publications

References 13 publications

PAMAM Dendrimers for siRNA Delivery: Computational and Experimental Insights

PAMAM Dendrimers for siRNA Delivery: Computational and Experimental Insights

Evaluation of anionic half generation 3.5–6.5 poly(amidoamine) dendrimers as delivery vehicles for the active component of the anticancer drug cisplatin

Effect of Synthetic Polymers on tRNA Nanoparticle Formation

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