1. Amphiphilic poly(α)glutamate polymeric micelles for systemic administration of siRNA to tumors.
- Author
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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, and Satchi-Fainaro R
- Subjects
- Animals, Antineoplastic Agents chemistry, Breast Neoplasms genetics, Cell Cycle Proteins antagonists & inhibitors, Cell Cycle Proteins genetics, Cell Proliferation drug effects, Female, Humans, Mice, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases genetics, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins genetics, RNA, Small Interfering chemistry, RNA, Small Interfering genetics, Surface-Active Agents chemistry, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, rac1 GTP-Binding Protein antagonists & inhibitors, rac1 GTP-Binding Protein genetics, Polo-Like Kinase 1, Antineoplastic Agents administration & dosage, Breast Neoplasms therapy, Micelles, Polyglutamic Acid chemistry, Polymers chemistry, RNA, Small Interfering administration & dosage, RNAi Therapeutics
- 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., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
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