Combining reactive triblock copolymers with functional cross-linkers: A versatile pathway to disulfide stabilized-polyplex libraries and their application as pDNA vaccines.

Autor: Heller P; Institute of Organic Chemistry, Johannes Gutenberg University, Duesbergweg 10-14, 55099 Mainz, Germany., Hobernik D; Department of Dermatology, University Medical Center, Johannes Gutenberg University Mainz, Obere Zahlbacher Straße 63, 55131 Mainz, Germany., Lächelt U; Pharmaceutical Biotechnology, Department Pharmacy, LMU Munich, Butenandtstraße 5-13, 81377 Munich, Germany., Schinnerer M; Institute of Physical Chemistry, Johannes Gutenberg University, Duesbergweg 10-14, 55099 Mainz, Germany., Weber B; Institute of Organic Chemistry, Johannes Gutenberg University, Duesbergweg 10-14, 55099 Mainz, Germany., Schmidt M; Institute of Physical Chemistry, Johannes Gutenberg University, Duesbergweg 10-14, 55099 Mainz, Germany., Wagner E; Pharmaceutical Biotechnology, Department Pharmacy, LMU Munich, Butenandtstraße 5-13, 81377 Munich, Germany., Bros M; Department of Dermatology, University Medical Center, Johannes Gutenberg University Mainz, Obere Zahlbacher Straße 63, 55131 Mainz, Germany., Barz M; Institute of Organic Chemistry, Johannes Gutenberg University, Duesbergweg 10-14, 55099 Mainz, Germany. Electronic address: barz@uni-mainz.de.
Jazyk: angličtina
Zdroj: Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2017 Jul 28; Vol. 258, pp. 146-160. Date of Electronic Publication: 2017 May 10.
DOI: 10.1016/j.jconrel.2017.05.012
Abstrakt: Therapeutic nucleic acids such as pDNA hold great promise for the treatment of multiple diseases. These therapeutic interventions are, however, compromised by the lack of efficient and safe non-viral delivery systems, which guarantee stability during blood circulation together with high transfection efficiency. To provide these desired properties within one system, we propose the use of reactive triblock copolypept(o)ides, which include a stealth-like block for efficient shielding, a hydrophobic block based on reactive disulfides for cross-linking and a cationic block for complexation of pDNA. After the complexation step, bifunctional cross-linkers can be employed to bio-reversibly stabilize derived polyplexes by disulfide bond formation and to introduce endosomolytic moieties at the same time. Cross-linked polyplexes show no aggregation in human blood serum. Upon cellular uptake and cleavage of disulfide bonds, the cross-linkers can interact with the endosomal membrane, leading to lysis and efficient endosomal translocation. In principal, the approach allows for the combination of one polymer with various different cross-linkers and thus enables the fast forward creation of a polyplex library. Here, we provide a first insight into the potential of this concept and use a screening strategy to identify a lead candidate, which is able to transfect dendritic cells with a model DNA vaccine.
(Copyright © 2017. Published by Elsevier B.V.)
Databáze: MEDLINE
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