Amphiphilic poly(α)glutamate polymeric micelles for systemic administration of siRNA to tumors

Krivitsky, Adva; Polyak, Dina; Scomparin, Anna; Eliyahu, Shay; Ofek, Paula; Tiram, Galia; Kalinski, Hagar; Avkin-Nachum, Sharon; Gracia, Natàlia Feiner; Albertazzi, Lorenzo; Satchi‐Fainaro, Ronit

doi:10.1016/j.nano.2017.10.012

Cited by 13 publications

(16 citation statements)

References 56 publications

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“…Next, in order to determine the ability of the polyplex to be administered systemically, stability of the polyplex was evaluated in vitro in 100% fetal bovine serum (FBS). There was no release of miRNA from the polyplexes prepared at N/P ratio of 2 up to 12 h of incubation, while polyplexes of APA and siRNA prepared at 1.5 N/P ratio demonstrated much lower stability 30 . Moreover, APA polymer stabilized miR-34a and prevented its degradation for a longer time (12 h) compared to naked miR-34a (Fig.…”

Section: Resultsmentioning

confidence: 89%

“…APA nanocarrier was synthesized by subsequently conjugating ethylenediamine and alkylamine moieties to the pending carboxylic groups of the PGA backbone 30 . The resulting polymer (12,513 gmol −1 , polydispersity index (PDI) 1.145, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The final Cy5-APA conjugate was purified by dialysis in DDW using a 3.5 kDa a dialysis membrane (GeBaFlex, Gene Bio-Application). Chemical analysis and characterization was published elsewhere 30 .…”

Section: Methodsmentioning

confidence: 99%

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Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer

et al. 2018

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The heterogeneity of pancreatic ductal adenocarcinoma (PDAC) suggests that successful treatment might rely on simultaneous targeting of multiple genes, which can be achieved by RNA interference-based therapeutic strategies. Here we show a potent combination of microRNA and siRNA delivered by an efficient nanocarrier to PDAC tumors. Using proteomic-microRNA profiles and survival data of PDAC patients from TCGA, we found a novel signature for prolonged survival. Accordingly, we used a microRNA-mimic to increase miR-34a together with siRNA to silence PLK1 oncogene. For in vivo dual-targeting of this combination, we developed a biodegradable amphiphilic polyglutamate amine polymeric nanocarrier (APA). APA-miRNA–siRNA polyplexes systemically administered to orthotopically inoculated PDAC-bearing mice showed no toxicity and accumulated at the tumor, resulting in an enhanced antitumor effect due to inhibition of MYC oncogene, a common target of both miR-34a and PLK1. Taken together, our findings warrant this unique combined polyplex’s potential as a novel nanotherapeutic for PDAC.

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Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

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Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer

et al. 2018

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“…These data were compared with those obtained after incubation in HeLa cells and helped to distinguish intact functional quatsome from fragments of degraded particles. The destabilization of polymeric micelles upon incubation with serum was also studied using STORM that showed a lower degree of colocalization and smaller sizes structures compared to the freshly prepared micelles 134 .…”

Section: [H2] Cellular Trafficking and Localizationmentioning

confidence: 99%

Super-resolution microscopy as a powerful tool to study complex synthetic materials

et al. 2019

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“…As a matter of cardinal importance to the field of polymer therapeutics, we set to illustrate the consequences of polymer’s length on its activity. Aminated poly(α)glutamate (PGA) was previously shown to be a potent delivery vehicle for siRNA [24,25,26,27]. In addition, it is a synthetic biodegradable polymer that is water-soluble, non-toxic, and non-immunogenic at concentrations required for activity.…”

Section: Introductionmentioning

confidence: 99%

Molecular Weight-Dependent Activity of Aminated Poly(α)glutamates as siRNA Nanocarriers

Krivitsky

Polyak

et al. 2018

Polymers

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RNA interference (RNAi) can contribute immensely to the area of personalized medicine by its ability to target any gene of interest. Nevertheless, its clinical use is limited by lack of efficient delivery systems. Polymer therapeutics can address many of the challenges encountered by the systemic delivery of RNAi, but suffer from inherent drawbacks such as polydispersity and batch to batch heterogeneity. These characteristics may have far-reaching consequences when dealing with therapeutic applications, as both the activity and the toxicity may be dependent on the length of the polymer chain. To investigate the consequences of polymers' heterogeneity, we have synthesized two batches of aminated poly(α)glutamate polymers (PGAamine), differing in their degree of polymerization, but not in the monomer units or their conjugation. Isothermal titration calorimetry study was conducted to define the binding affinity of these polymers with siRNA. Molecular dynamics simulation revealed that Short PGAamine:siRNA polyplexes exposed a higher amount of amine moieties to the surroundings compared to Long PGAamine. This resulted in a higher zeta potential, leading to faster degradation and diminished gene silencing. Altogether, our study highlights the importance of an adequate physico-chemical characterization to elucidate the structure-function-activity relationship, for further development of tailor-designed RNAi delivery vehicles.

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Amphiphilic poly(α)glutamate polymeric micelles for systemic administration of siRNA to tumors

Cited by 13 publications

References 56 publications

Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer

Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer

Super-resolution microscopy as a powerful tool to study complex synthetic materials

Molecular Weight-Dependent Activity of Aminated Poly(α)glutamates as siRNA Nanocarriers

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