A biodegradable amphiphilic and cationic triblock copolymer for the delivery of siRNA targeting the acid ceramidase gene for cancer therapy

Mao, Chengqiong; Du, Jin‐Zhi; Sun, Tianmeng; Yao, Yihong; Zhang, Pei-Zhuo; Song, Erwei; Wang, Jun

doi:10.1016/j.biomaterials.2011.01.006

Cited by 108 publications

(65 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other studies suggest that tumor AC expression may be a predictor of response to neoadjuvant breast cancer therapies [36,37], and a prognostic indicator in melanoma [33]. Inhibition of AC has been shown to induce cell cycle arrest [38,39], and apoptosis [40][41][42], block proliferation [40], and inhibit tumor growth in vivo [19,41], suggesting that AC is a promising target for anti-cancer therapies.…”

Section: Introductionmentioning

confidence: 98%

C6-Ceramide and targeted inhibition of acid ceramidase induce synergistic decreases in breast cancer cell growth

Flowers

Fabriás

Delgado

et al. 2011

Breast Cancer Res Treat

View full text Add to dashboard Cite

The sphingolipid ceramide is known to play a central role in chemo- and radiation-induced cell death. Acid ceramidase (AC) hydrolyzes ceramide, and thus reduces intracellular levels of this proapoptotic lipid. The role of AC as a putative anticancer target is supported by reports of upregulation in prostate cancer and in some breast tumors. In this study, we determined whether the introduction of an AC inhibitor would enhance the apoptosis-inducing effects of C6-ceramide (C6-cer) in breast cancer cells. Cultured breast cancer cells were treated with DM102 [(2R,3Z)-N-(1-hydroxyoctadec-3-en-2-yl)pivalamide, C6-cer, or the combination. Cell viability and cytotoxic synergy were assessed. Activation of apoptotic pathways, generation of reactive oxygen species, and mitochondrial transmembrane potential were determined. DM102 was a more effective AC inhibitor than N-oleoylethanolamine (NOE) and (1R,2R)-2-N-(tetradecanoylamino)-1-(4'-nitrophenyl)-1,3-propandiol (B-13) in MDA-MB-231, MCF-7, and BT-474 cells. As single agents, C6-cer (IC(50) 5-10 μM) and DM102 (IC(50) 20 μM) were only moderately cytotoxic in MDA-MB-231, MCF-7, and SK-BR-3 cells. Co-administration, however, produced synergistic decreases in viability (combination index <0.5) in all cell lines. Apoptosis was confirmed in MDA-MB-231 cells by detection of caspase 3 cleavage and a >3-fold increase in caspase 3/7 activation, PARP cleavage, and a >70% increase in Annexin-V positive cells. C6-cer/DM102 increased ROS levels 4-fold in MDA-MB-231 cells, shifted the ratio of Bax:Bcl-2 to >9-fold that of control cells, and resulted in mitochondrial membrane depolarization. DM102 also increased the synthesis of (3)H-palmitate-labeled long-chain ceramides by 2-fold when C6-cer was present. These data support the effectiveness of targeting AC in combination with exogenous short-chain ceramide as an anticancer strategy, and warrant continued investigation into the utility of the C6-cer/DM102 drug duo in human breast cancer.

show abstract

Section: Introductionmentioning

confidence: 98%

C6-Ceramide and targeted inhibition of acid ceramidase induce synergistic decreases in breast cancer cell growth

Flowers

Fabriás

Delgado

et al. 2011

Breast Cancer Res Treat

View full text Add to dashboard Cite

show abstract

“…[19][20][21] One difficulty that gene therapy strategies encounter is the need for an efficient, easy, and minimally toxic mode of siRNA delivery to cells. [22][23][24] Cationic star-shaped polymers based on cyclodextrins (CDs) have recently attracted considerable attention as nonviral gene carriers due to their dense molecular architecture with moderate flexibility. 25 It is known 26 that CDs have low immunogenicity and toxicity and can enhance the absorption and resistance to nucleases through binding and interacting with oligonucleotides.…”

mentioning

confidence: 99%

Cationic star-shaped polymer as an siRNA carrier for reducing MMP-9 expression in skin fibroblast cells and promoting wound healing in diabetic rats

Luo

Yang

et al. 2014

IJN

View full text Add to dashboard Cite

Background Excessive expression of matrix metalloproteinase-9 (MMP-9) is deleterious to the cutaneous wound-healing process in the context of diabetes. The aim of the present study was to explore whether a cationic star-shaped polymer consisting of β-cyclodextrin (β-CD) core and poly(amidoamine) dendron arms (β-CD-[D 3 ] 7 ) could be used as the gene carrier of small interfering RNA (siRNA) to reduce MMP-9 expression for enhanced diabetic wound healing. Methods The cytotoxicity of β-CD-(D 3 ) 7 was investigated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MMT) method in the rat CRL1213 skin fibroblast cell line. The transfection efficiency of β-CD-(D 3 ) 7 /MMP-9-small interfering RNA (siRNA) complexes was determined by confocal microscopy and flow cytometry. Quantitative real time (RT) polymerase chain reaction was performed to measure the gene expression of MMP-9 after the transfection by β-CD-(D 3 ) 7 /MMP-9-siRNA complexes. The β-CD-(D 3 ) 7 /MMP-9-siRNA complexes were injected on the wounds of streptozocin-induced diabetic rats. Wound closure was measured on days 4 and 7 post-wounding. Results β-CD-(D 3 ) 7 exhibited low cytotoxicity in fibroblast cells, and easily formed the complexes with MMP-9-siRNA. The β-CD-(D 3 ) 7 /MMP-9-siRNA complexes were readily taken up by fibroblast cells, resulting in the downregulation of MMP-9 gene expression ( P <0.01). Animal experiments revealed that the treatment by β-CD-(D 3 ) 7 /MMP-9-siRNA complexes enhanced wound closure in diabetic rats on day 7 post-wounding ( P <0.05). Conclusion β-CD-(D 3 ) 7 may be used as an efficient carrier for the delivery of MMP-9-siRNA to reduce MMP-9 expression in skin fibroblast cells and promote wound healing in diabetic rats.

show abstract

“…Recently, Mao et al reported a triblock copolymer consisting of monomethoxy poly(ethylene glycol), poly(e-caprolactone), and poly(2-aminoethyl ethylene phosphate). Th ese nanoparticles, in aqueous solution, are self-assembled into micellar nanoparticles (MNPs) with an average diameter of 60 nm and a zeta potential of 48 mV (Mao et al 2011). Effi cient gene knockdown eff ect was observed in BT474 breast cancer cells once the micelleplex formed by the interaction of MNPs and siRNA and was internalized by cells followed by siRNA release.…”

Section: Advantages and Limitations Of Nanoparticlesmentioning

confidence: 99%

RNA interference technology with emphasis on delivery vehicles—prospects and limitations

Prabha

Vyas

Gupta

et al. 2015

Artificial Cells, Nanomedicine, and Biotechnology

View full text Add to dashboard Cite

show abstract

A biodegradable amphiphilic and cationic triblock copolymer for the delivery of siRNA targeting the acid ceramidase gene for cancer therapy

Cited by 108 publications

References 57 publications

C6-Ceramide and targeted inhibition of acid ceramidase induce synergistic decreases in breast cancer cell growth

C6-Ceramide and targeted inhibition of acid ceramidase induce synergistic decreases in breast cancer cell growth

Cationic star-shaped polymer as an siRNA carrier for reducing MMP-9 expression in skin fibroblast cells and promoting wound healing in diabetic rats

RNA interference technology with emphasis on delivery vehicles—prospects and limitations

Contact Info

Product

Resources

About