Anticancer siRNA cocktails as a novel tool to treat cancer cells. Part (B). Efficiency of pharmacological action

Dzmitruk, Volha; Szulc, Agata; Shcharbin, Dzmitry; Janaszewska, Anna; Shcharbina, Natallia; Łaźniewska, Joanna; Новопашина, Д. С.; Buyanova, Marina; Йонов, Максим; Klajnert‐Maculewicz, Barbara; Gomez-Ramirez, Rafael; Mignani, Serge; Majoral, Jean‐Pierre; Muñoz‐Fernández, María Ángeles; Bryszewska, Maria

doi:10.1016/j.ijpharm.2015.03.034

Cited by 72 publications

(60 citation statements)

References 51 publications

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“…However, just limited data on their interactions with siRNA and efficiency of delivery are published [17,19,20]. The first example of cationic phosphorus dendrimers contained diethylamine groups on the periphery [13].…”

Section: Discussionmentioning

confidence: 99%

“…An effective application of the cocktail of pro-apoptotic siRNAs (siBCL-2, siBCL-xL, siMCL-1) for inhibition of cancer cells viability was reported in previous studies [17,20]. Here, we report on novel cationic phosphorus containing dendrimers of 3rd and 4th generations grafted with piperidine groups on the periphery that were synthesized and tested as siRNA carriers for RNAi-based cancer gene therapy with a chemotherapeutic combination approach.…”

Section: Introductionmentioning

confidence: 93%

“…With regard to transfection studies, most widely investigated group of CPD is diethylamine-terminated dendrimers with cyclotriphosphazene core. They were successfully implemented as carriers of plasmids [13][14][15], oligodeoxynucleotides [14,16] and siRNAs [17]. Loup et al [13] highlighted better transfection efficiency of dendrimers of this group in the presence of serum than its absence during their plasmid transfection study.…”

Section: Introductionmentioning

confidence: 99%

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Multi-Target Inhibition of Cancer Cell Growth by SiRNA Cocktails and 5-Fluorouracil Using Effective Piperidine-Terminated Phosphorus Dendrimers

Ihnatsyeu-Kachan

Dzmitruk

Apartsin

et al. 2017

Colloids and Interfaces

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Currently, RNAi based approaches for cancer treatment involving short double stranded RNA molecules (siRNA) are under vigorous scrutinization. Due to numerous biological obstacles, siRNA delivery into target cells requires protective escort. On the other hand, combining of siRNA-mediated gene silencing and action of conventional chemotherapeutics can propose additional enhancement of anticancer activity. In the present study, we investigated a siRNA cocktail able to downregulate anti-apoptotic genes (BCL-xL, BCL-2, MCL-1) and the chemotherapeutic agent 5-fluorouracil (5-FU) to evaluate multi-target cytotoxic effect on human cervical carcinoma cells (HeLa cell line). Novel phosphorus containing dendrimers of 3rd and 4th generations (namely AE2G3 and AE2G4) with voluminous piperidine terminal cationic groups were designed and tested as siRNA carriers. Dendrimers of both generations showed remarkable ability to bind pro-apoptotic siRNAs and provided 80-100% siRNA uptake by HeLa cells in the serum containing medium, while the widespread transfection agent Lipofectamine showed only~40% uptake. SiRNA cocktail (in low concentrations 50 and 100 nM) delivered by AE2G3 dendrimer caused almost complete elimination of cancer cells. We have discovered considerable increase of 5-FU cytotoxic effect by addition of AE2G3/siRNA cocktail complexes in low doses. Thus, we demonstrated the effectiveness of combined multi-target siRNA anticancer approach and described new highly effective serum stable nanomaterial vehicle for gene-based drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Multi-Target Inhibition of Cancer Cell Growth by SiRNA Cocktails and 5-Fluorouracil Using Effective Piperidine-Terminated Phosphorus Dendrimers

Ihnatsyeu-Kachan

Dzmitruk

Apartsin

et al. 2017

Colloids and Interfaces

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“…When taking all of these considerations together, our data suggest that silencing any two of the three target genes is better than silencing any one, and that silencing all three genes is better than silencing any two. Similar multi‐component strategies have been successfully employed to treat several other types of cancer, suggesting that LNPs could have broad applicability for cancer treatment.…”

Section: Discussionmentioning

confidence: 95%

Lipid nanoparticle siRNA cocktails for the treatment of mantle cell lymphoma

Knapp¹,

Lister

et al. 2018

Bioengineering & Transla Med

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Mantle cell lymphoma is an aggressive and incurable subtype of non‐Hodgkin B cell lymphoma. Patients typically present with advanced disease, and most patients succumb within a decade of diagnosis. There is a clear and urgent need for novel therapeutic approaches that will affect mantle cell lymphoma through a unique mechanism compared to current therapies. This study examined the use of RNA interference (RNAi) therapy to attack mantle cell lymphoma at the mRNA level, silencing genes associated with cancer cell proliferation. We identified a lipid nanoparticle formulated with the lipidoid 306O13 that delivered siRNA to JeKo‐1 and MAVER‐1 mantle cell lymphoma cell lines. Three therapeutic gene targets were examined for their effect on lymphoma growth. These included Cyclin D1, which is a cell cycle regulator, as well as Bcl‐2 and Mcl‐1, which prevent apoptosis. Gene knockdown with siRNA doses as low at 10 nM increased lymphoma cell apoptosis without carrier‐mediated toxicity. Silencing of Cyclin D1 induced apoptosis despite a twofold “compensation” upregulation of Cyclin D2. Upon simultaneous silencing of all three genes, nearly 75% of JeKo‐1 cells were apoptosing 3 days post‐transfection. Furthermore, cells proliferated at only 15% of their pretreatment rate. These data suggest that lipid nanoparticles‐formulated, multiplexed siRNA “cocktails” may serve as a beneficial addition to the treatment regimens for mantle cell lymphoma and other aggressive cancers.

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“…The cocktail mixture contained siBcl‐xl, siBcl‐2, siMcl‐1 siRNAs, known to suppress the synthesis of anti‐apoptotic proteins. The in vitro cell line studies using HeLa and HL‐60 cells suggested the CPD as most effective among the three classes of dendrimer for the delivery of cocktail siRNA (Dzmitruk et al, ; Ionov et al, ). The outcomes unlocked the possibility for delivery of combination of siRNA through different classes of dendrimers in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Dendrimer mediated targeting of siRNA against polo‐like kinase for the treatment of triple negative breast cancer

Jain

Mahira

Majoral

et al. 2019

J Biomedical Materials Res

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Irresponsiveness of triple negative breast cancer (TNBC) toward conventional therapies has drawn attention toward siRNA therapeutics. In gene delivery, dendrimers are gaining significant attention due to their characteristic features and polo‐like kinase (PLK1) is reported as a potential target for TNBC. In this work, phosphorus and polyamidoamine dendrimer (generation 3 and 4 of each type) are explored to address delivery challenges of PLK1 siRNA (siPLK1). Dendriplexes were formed and complexation was found at 3:1 N/P ratio for all dendrimers by gel electrophoresis. Complexation was also supported by zeta potential, circular dichroism and intercalation assay. Dendriplexes were found to be stable in presence of ribonuclease and serum. Dendriplexes resulted in enhanced cell uptake of siPLK1 compared to siPLK1 solution in MDA‐MB‐231 and MCF‐7 cells. Dendriplexes caused increased cell arrest in sub‐G1 phase compared to solution. These observations suggested phosphorus and polyamidoamine dendrimers as potential carriers for siPLK1 delivery to treat TNBC.

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Anticancer siRNA cocktails as a novel tool to treat cancer cells. Part (B). Efficiency of pharmacological action

Cited by 72 publications

References 51 publications

Multi-Target Inhibition of Cancer Cell Growth by SiRNA Cocktails and 5-Fluorouracil Using Effective Piperidine-Terminated Phosphorus Dendrimers

Multi-Target Inhibition of Cancer Cell Growth by SiRNA Cocktails and 5-Fluorouracil Using Effective Piperidine-Terminated Phosphorus Dendrimers

Lipid nanoparticle siRNA cocktails for the treatment of mantle cell lymphoma

Dendrimer mediated targeting of siRNA against polo‐like kinase for the treatment of triple negative breast cancer

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