Invading target cells: multifunctional polymer conjugates as therapeutic nucleic acid carriers

doi:10.1007/s11705-011-1203-z

Front Chem Sci Eng

2011, Vol. 5

Issue (3) : 275-286 https://doi.org/10.1007/s11705-011-1203-z

REVIEW ARTICLE

Invading target cells: multifunctional polymer conjugates as therapeutic nucleic acid carriers

Ulrich L?CHELT(

), Ernst WAGNER

Pharmaceutical Biotechnology, Center for System-based Drug Research, and Center for NanoScience, Ludwig-Maximilians-Universit?t Munich, Butenandtstrasse 5-13, D-81377 Munich, Germany

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Abstract

Polymer-based conjugates are an interesting option and challenge for the design of nano-sized drug-delivery systems, as they require advanced conjugation chemistry and precise engineering. In the case of nucleic acid therapy, non-viral carriers face several biological barriers during the delivery process, namely 1) protection of the cargo from extracellular degradation, 2) avoidance of non-specific interactions with non-targeted tissues, 3) efficient entry into the target cells, 4) intracellular trafficking to the site of action and 5) cargo release. To take on these obstacles, multifunctional conjugates can act as “smart polymers” with microenvironment-sensing dynamics to facilitate the separate delivery steps. Synthesis of defined polymer architectures with precise functionalization enables structure-activity relationships to be investigated and the integration of key functions for efficient delivery. Thus bioresponsive polymer conjugates, which are equipped with molecular devices responding to the certain microenvironments within the delivery pathway (e.g. pH, redox potential, enzymes) can be assembled. This review focuses on the modular engineering and conjugation of multifunctional polymeric structures for the utilization as “tailor-made” nucleic acid carriers.

Keywords conjugate DNA gene transfer polymer RNA targeting

Corresponding Author(s): L?CHELT Ulrich,Email:ulrich.laechelt@cup.uni-muenchen.de

Issue Date: 05 September 2011

Cite this article:

Ulrich L?CHELT,Ernst WAGNER. Invading target cells: multifunctional polymer conjugates as therapeutic nucleic acid carriers[J]. Front Chem Sci Eng, 2011, 5(3): 275-286.

URL:

https://academic.hep.com.cn/fcse/EN/10.1007/s11705-011-1203-z
https://academic.hep.com.cn/fcse/EN/Y2011/V5/I3/275

Fig.1 Frequently used cationic polymers for nucleic acid complexation and delivery

Fig.2 Selectivity of targeted nucleic acid carriers

Fig.3 Synergy of dual-targeting approach mimicking the biphasic cell entry of natural viruses. Attachment of the dual-targeted polyplexes is primarily achieved by RGD peptide targeting integrins on the cell surface, whereas TfR binding B6 mediates internalization and uptake []

Fig.4 Multifunctional nucleic acid carrier. A polymeric backbone encapsulating (complexing) nucleic acids is equipped with diverse functionalities addressing the separate delivery steps: 1) PEGylation for surface-shielding, prevention of non-specific interactions with non-target cells and long systemic circulation. 2) Targeting ligands for the homing to target cells, specific interactions and cellular uptake. Use of different ligands can cause dual- (plural-) targeting effects. 3) Endosomolytic domains facilitating endosomal escape and delivery to the cytosol.

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