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

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

doi:10.1016/j.nano.2017.10.012

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

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

Research output: Contribution to journal › Article › Academic › peer-review

15 Citations (Scopus)

Abstract

RNAi therapeutics carried a great promise to the area of personalized medicine: the ability to target “undruggable” oncogenic pathways. Nevertheless, their efficient tumor targeting via systemic administration had not been resolved yet. Amphiphilic alkylated poly(α)glutamate amine (APA) can serve as a cationic carrier to the negatively-charged oligonucleotides. APA polymers complexed with siRNA to form round-shaped, homogenous and reproducible nano-sized polyplexes bearing ~50 nm size and slightly negative charge. In addition, APA:siRNA polyplexes were shown to be potent gene regulators in vitro. In light of these preferred physico-chemical characteristics, their performance as systemically-administered siRNA nanocarriers was investigated. Intravenously-injected APA:siRNA polyplexes accumulated selectively in tumors and did not accumulate in the lungs, heart, liver or spleen. Nevertheless, the polyplexes failed to induce specific mRNA degradation, hence neither reduction in tumor volume nor prolonged mice survival was seen.

Original language	English
Pages (from-to)	303-315
Number of pages	13
Journal	Nanomedicine: Nanotechnology, Biology, and Medicine
Volume	14
Issue number	2
DOIs	https://doi.org/10.1016/j.nano.2017.10.012
Publication status	Published - 1 Feb 2018
Externally published	Yes

Keywords

Amphiphilic poly(α)glutamate
Anticancer therapy
Cationic polymer
Polyplexes
siRNA systemic delivery
RNA, Small Interfering/administration & dosage
Antineoplastic Agents/administration & dosage
Cell Cycle Proteins/antagonists & inhibitors
Humans
Proto-Oncogene Proteins/antagonists & inhibitors
Protein-Serine-Threonine Kinases/antagonists & inhibitors
Polymers/chemistry
Xenograft Model Antitumor Assays
Animals
Micelles
Female
Breast Neoplasms/genetics
Mice
RNAi Therapeutics
Cell Proliferation/drug effects
Polyglutamic Acid/chemistry
Tumor Cells, Cultured
rac1 GTP-Binding Protein/antagonists & inhibitors
Surface-Active Agents/chemistry
Amphiphilic poly(alpha)glutamate

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10.1016/j.nano.2017.10.012

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Krivitsky, A., Polyak, D., Scomparin, A., Eliyahu, S., Ofek, P., Tiram, G., Kalinski, H., Avkin-Nachum, S., Feiner Gracia, N., Albertazzi, L., & Satchi-Fainaro, R. (2018). Amphiphilic poly(α)glutamate polymeric micelles for systemic administration of siRNA to tumors. Nanomedicine: Nanotechnology, Biology, and Medicine, 14(2), 303-315. https://doi.org/10.1016/j.nano.2017.10.012

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title = "Amphiphilic poly(α)glutamate polymeric micelles for systemic administration of siRNA to tumors",

abstract = "RNAi therapeutics carried a great promise to the area of personalized medicine: the ability to target “undruggable” oncogenic pathways. Nevertheless, their efficient tumor targeting via systemic administration had not been resolved yet. Amphiphilic alkylated poly(α)glutamate amine (APA) can serve as a cationic carrier to the negatively-charged oligonucleotides. APA polymers complexed with siRNA to form round-shaped, homogenous and reproducible nano-sized polyplexes bearing ~50 nm size and slightly negative charge. In addition, APA:siRNA polyplexes were shown to be potent gene regulators in vitro. In light of these preferred physico-chemical characteristics, their performance as systemically-administered siRNA nanocarriers was investigated. Intravenously-injected APA:siRNA polyplexes accumulated selectively in tumors and did not accumulate in the lungs, heart, liver or spleen. Nevertheless, the polyplexes failed to induce specific mRNA degradation, hence neither reduction in tumor volume nor prolonged mice survival was seen.",

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author = "Adva Krivitsky and Dina Polyak and Anna Scomparin and Shay Eliyahu and Paula Ofek and Galia Tiram and Hagar Kalinski and Sharon Avkin-Nachum and {Feiner Gracia}, Nat{\`a}lia and Lorenzo Albertazzi and Ronit Satchi-Fainaro",

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Krivitsky, A, Polyak, D, Scomparin, A, Eliyahu, S, Ofek, P, Tiram, G, Kalinski, H, Avkin-Nachum, S, Feiner Gracia, N, Albertazzi, L & Satchi-Fainaro, R 2018, 'Amphiphilic poly(α)glutamate polymeric micelles for systemic administration of siRNA to tumors', Nanomedicine: Nanotechnology, Biology, and Medicine, vol. 14, no. 2, pp. 303-315. https://doi.org/10.1016/j.nano.2017.10.012

TY - JOUR

T1 - Amphiphilic poly(α)glutamate polymeric micelles for systemic administration of siRNA to tumors

AU - Krivitsky, Adva

AU - Polyak, Dina

AU - Scomparin, Anna

AU - Eliyahu, Shay

AU - Ofek, Paula

AU - Tiram, Galia

AU - Kalinski, Hagar

AU - Avkin-Nachum, Sharon

AU - Feiner Gracia, Natàlia

AU - Albertazzi, Lorenzo

AU - Satchi-Fainaro, Ronit

PY - 2018/2/1

Y1 - 2018/2/1

N2 - RNAi therapeutics carried a great promise to the area of personalized medicine: the ability to target “undruggable” oncogenic pathways. Nevertheless, their efficient tumor targeting via systemic administration had not been resolved yet. Amphiphilic alkylated poly(α)glutamate amine (APA) can serve as a cationic carrier to the negatively-charged oligonucleotides. APA polymers complexed with siRNA to form round-shaped, homogenous and reproducible nano-sized polyplexes bearing ~50 nm size and slightly negative charge. In addition, APA:siRNA polyplexes were shown to be potent gene regulators in vitro. In light of these preferred physico-chemical characteristics, their performance as systemically-administered siRNA nanocarriers was investigated. Intravenously-injected APA:siRNA polyplexes accumulated selectively in tumors and did not accumulate in the lungs, heart, liver or spleen. Nevertheless, the polyplexes failed to induce specific mRNA degradation, hence neither reduction in tumor volume nor prolonged mice survival was seen.

AB - RNAi therapeutics carried a great promise to the area of personalized medicine: the ability to target “undruggable” oncogenic pathways. Nevertheless, their efficient tumor targeting via systemic administration had not been resolved yet. Amphiphilic alkylated poly(α)glutamate amine (APA) can serve as a cationic carrier to the negatively-charged oligonucleotides. APA polymers complexed with siRNA to form round-shaped, homogenous and reproducible nano-sized polyplexes bearing ~50 nm size and slightly negative charge. In addition, APA:siRNA polyplexes were shown to be potent gene regulators in vitro. In light of these preferred physico-chemical characteristics, their performance as systemically-administered siRNA nanocarriers was investigated. Intravenously-injected APA:siRNA polyplexes accumulated selectively in tumors and did not accumulate in the lungs, heart, liver or spleen. Nevertheless, the polyplexes failed to induce specific mRNA degradation, hence neither reduction in tumor volume nor prolonged mice survival was seen.

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KW - Cell Cycle Proteins/antagonists & inhibitors

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KW - Protein-Serine-Threonine Kinases/antagonists & inhibitors

KW - Polymers/chemistry

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KW - Animals

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KW - Breast Neoplasms/genetics

KW - Mice

KW - RNAi Therapeutics

KW - Cell Proliferation/drug effects

KW - Polyglutamic Acid/chemistry

KW - Tumor Cells, Cultured

KW - rac1 GTP-Binding Protein/antagonists & inhibitors

KW - Surface-Active Agents/chemistry

KW - Amphiphilic poly(alpha)glutamate

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U2 - 10.1016/j.nano.2017.10.012

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SN - 1549-9634

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JO - Nanomedicine: Nanotechnology, Biology, and Medicine

JF - Nanomedicine: Nanotechnology, Biology, and Medicine

IS - 2

ER -

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

Abstract

Keywords

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