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Design and evaluation of thioalkylated mannose-modified dendrimer (G3)/?-cyclodextrin conjugates as antigen-presenting cell-selective siRNA carriers.

ABSTRACT: To design and evaluate the potential use of thioalkylated mannose-modified dendrimer (generation 3; G3) conjugates with ?-cyclodextrin (Man-S-?-CDE (G3)) as novel antigen-presenting cell (APC)-selective siRNA carriers, we investigated the RNAi effects of siRNA complexes with Man-S-?-CDEs (G3). Man-S-?-CDE (G3, average degree of substitution of mannose (DSM) 4)/siRNA complex had the potent RNAi effects in both NR8383 cells, a rat alveolar macrophage cell line, and JAWSII cells, a mouse dendritic cell line, through adequate physicochemical properties, mannose receptor (MR)-mediated cellular uptake, and efficient phagosomal escape of the siRNA complex. In addition, cytotoxic activities of the siRNA complexes with ?-CDE (G3, DS2) and Man-S-?-CDE (G3, DSM4) were almost negligible up to a charge ratio of 100 (carrier/siRNA). Taken together, these results suggest that Man-S-?-CDE (G3, DSM4) has the potential for a novel APC-selective siRNA carrier.

SUBMITTER: Motoyama K

PROVIDER: S-EPMC4389755 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Design and evaluation of thioalkylated mannose-modified dendrimer (G3)/α-cyclodextrin conjugates as antigen-presenting cell-selective siRNA carriers.

Motoyama Keiichi K Mitsuyasu Ryosuke R Akao Chiho C Tanaka Takahiro T Ohyama Ayumu A Sato Nana N Higashi Taishi T Arima Hidetoshi H

The AAPS journal 20140919 6

To design and evaluate the potential use of thioalkylated mannose-modified dendrimer (generation 3; G3) conjugates with α-cyclodextrin (Man-S-α-CDE (G3)) as novel antigen-presenting cell (APC)-selective siRNA carriers, we investigated the RNAi effects of siRNA complexes with Man-S-α-CDEs (G3). Man-S-α-CDE (G3, average degree of substitution of mannose (DSM) 4)/siRNA complex had the potent RNAi effects in both NR8383 cells, a rat alveolar macrophage cell line, and JAWSII cells, a mouse dendritic ...[more]

PMID: 25236864

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Project description:The natural xanthone α-mangostin (αM) exhibits a wide range of pharmacological activities, including antineoplastic and anti-nematode properties, but low water solubility and poor selectivity of the drug prevent its potential clinical use. Therefore, the targeted third-generation poly(amidoamine) dendrimer (PAMAM G3) delivery system was proposed, based on hyperbranched polymer showing good solubility, high biocompatibility and low immunogenicity. A multifunctional nanocarrier was prepared by attaching αM to the surface amine groups of dendrimer via amide bond in the ratio 5 (G32B12gh5M) or 17 (G32B10gh17M) residues per one dendrimer molecule. Twelve or ten remaining amine groups were modified by conjugation with D-glucoheptono-1,4-lactone (gh) to block the amine groups, and two biotin (B) residues as targeting moieties. The biological activity of the obtained conjugates was studied in vitro on glioma U-118 MG and squamous cell carcinoma SCC-15 cancer cells compared to normal fibroblasts (BJ), and in vivo on a model organism Caenorhabditis elegans. Dendrimer vehicle G32B12gh at concentrations up to 20 µM showed no anti-proliferative effect against tested cell lines, with a feeble cytotoxicity of the highest concentration seen only with SCC-15 cells. The attachment of αM to the vehicle significantly increased cytotoxic effect of the drug, even by 4- and 25-fold for G32B12gh5M and G32B10gh17M, respectively. A stronger inhibition of cells viability and influence on other metabolic parameters (proliferation, adhesion, ATP level and Caspase-3/7 activity) was observed for G32B10gh17M than for G32B12gh5M. Both bioconjugates were internalized efficiently into the cells. Similarly, the attachment of αM to the dendrimer vehicle increased its toxicity for C. elegans. Thus, the proposed α-mangostin delivery system allowed the drug to be more effective in the dendrimer-bound as compared to free state against both cultured the cancer cells and model organism, suggesting that this treatment is promising for anticancer as well as anti-nematode chemotherapy.

Dataset Information

Design and evaluation of thioalkylated mannose-modified dendrimer (G3)/?-cyclodextrin conjugates as antigen-presenting cell-selective siRNA carriers.

Publications

Design and evaluation of thioalkylated mannose-modified dendrimer (G3)/α-cyclodextrin conjugates as antigen-presenting cell-selective siRNA carriers.

Similar Datasets

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