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

Nanomedicine. 2018 Feb;14(2):303-315. doi: 10.1016/j.nano.2017.10.012. Epub 2017 Nov 7.

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.

Keywords: Amphiphilic poly(α)glutamate; Anticancer therapy; Cationic polymer; Polyplexes; siRNA systemic delivery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / chemistry
  • Breast Neoplasms / genetics
  • Breast Neoplasms / therapy*
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / genetics
  • Cell Proliferation / drug effects
  • Female
  • Humans
  • Mice
  • Micelles*
  • Polyglutamic Acid / chemistry*
  • Polymers / chemistry*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • RNA, Small Interfering / administration & dosage*
  • RNA, Small Interfering / chemistry
  • RNA, Small Interfering / genetics
  • RNAi Therapeutics*
  • Surface-Active Agents / chemistry
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
  • rac1 GTP-Binding Protein / antagonists & inhibitors
  • rac1 GTP-Binding Protein / genetics

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Micelles
  • Polymers
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Surface-Active Agents
  • Polyglutamic Acid
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1
  • rac1 GTP-Binding Protein