Cross‐Linkable Polyion Complex Micelles from Polypept(o)ide‐Based ABC‐Triblock Copolymers for siRNA Delivery

Macromolecular Rapid Communications, vol. 43, pp. e2100698

Abstract

Abstract ABC‐type triblock copolymers are a rising platform especially for oligonucleotide delivery as they offer an additional functionality besides the anyhow needed functions of shielding and complexation. The authors present a polypept(o)ide‐based triblock copolymer synthesized by amine‐initiated ring‐opening polymerization (ROP) of N‐carboxyanhydrides (NCAs), comprising a shielding block A of polysarcosine (pSar), a poly(S‐ethylsulfonyl‐l‐cystein) (pCys(SO2Et)) block B for bioreversible and chemo‐selective cross‐linking and a poly(l‐lysine) (pLys) block C for complexation to construct polyion complex (PIC) micelles as vehicle for small interfering RNA (siRNA) delivery. The self‐assembly behavior of ABC‐type triblocks is investigated to derive correlations between block lengths of the polymer and PIC micelle structure, showing an enormous effect of the β‐sheet forming pCys(SO2Et) block. Moreover, the block enables the introduction of disulfide cross‐links by reaction with multifunctional thiols to increase stability against dilution. The right content of the additional block leads to well‐defined cross‐linked 50–60 nm PIC micelles purified from production impurities and determinable siRNA loading. These PIC micelles can deliver functional siRNA into Neuro2A and KB cells evaluated by cellular uptake and specific gene knockdown assays.

Authors 8

1. Leon Capelôa Aachen Leiden Academic Centre for Drug Research

   Leiden University · Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

   Affiliation as printed

   Department of Dermatology University Medical Center Johannes Gutenberg‐University Mainz Obere Zahlbacher Straße 63 55131 Mainz Germany

   Leiden Academic Centre for Drug Research (LACDR) Leiden University Einstein weg 55 Leiden 2333CC The Netherlands

   Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einstein weg 55, Leiden, 2333CC The Netherlands

2. Mina Yazdi

   Ludwig-Maximilians-Universität München

   Affiliation as printed

   Pharmaceutical Biotechnology Department of Pharmacy LMU Munich Butenandtstrasse 5‐13 81377 Munich Germany

   Pharmaceutical Biotechnology, Department of Pharmacy, LMU Munich, Butenandtstrasse 5-13, 81377 Munich, Germany

3. Heyang Zhang Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Leiden Academic Center for Drug Research (LACDR) Leiden University Einstein weg 55 Leiden 2333CC The Netherlands

   Leiden Academic Center for Drug Research (LACDR), Leiden University, Einstein weg 55, Leiden, 2333CC The Netherlands

4. Xiaobing Chen

   Sichuan University

   Affiliation as printed

   National Engineering Research Center for Biomaterials Sichuan University Chengdu 610064 P. R. China

   National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064 P. R. China

5. Yu Nie

   Sichuan University

   Affiliation as printed

   National Engineering Research Center for Biomaterials Sichuan University Chengdu 610064 P. R. China

   National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064 P. R. China

6. Ernst Wagner

   Ludwig-Maximilians-Universität München

   Affiliation as printed

   Pharmaceutical Biotechnology Department of Pharmacy LMU Munich Butenandtstrasse 5‐13 81377 Munich Germany

   Pharmaceutical Biotechnology, Department of Pharmacy, LMU Munich, Butenandtstrasse 5-13, 81377 Munich, Germany

7. Ulrich Lächelt

   University of Vienna

   Affiliation as printed

   Division of Pharmaceutical Technology and Biopharmaceutics University of Vienna Althanstrasse 14 Vienna 1090 Austria

   Division of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstrasse 14, Vienna, 1090 Austria

8. Matthias Barz corresponding Aachen Leiden Academic Centre for Drug Research

   Leiden University · Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

   Affiliation as printed

   Department of Dermatology University Medical Center Johannes Gutenberg‐University Mainz Obere Zahlbacher Straße 63 55131 Mainz Germany

   Leiden Academic Centre for Drug Research (LACDR) Leiden University Einstein weg 55 Leiden 2333CC The Netherlands

   Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einstein weg 55, Leiden, 2333CC The Netherlands