How Free Cationic Polymer Chains Promote Gene Transfection

verfasst von: Yue Yanan

Verlag: Springer International Publishing

Buchreihe : Springer Theses

Enthalten in: Springer Professional "Wirtschaft+Technik" , Springer Professional "Technik"

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Über dieses Buch

In this PhD thesis, Yue Yanan addresses a long-overlooked and critical question in the development of non-viral vectors for gene delivery. The author determines that those uncomplexed and cationic polymer chains free in the solution mixture of polymer and DNA facilitate and promote gene transfection. Furthermore, by using a combination of synthetic chemistry, polymer physics and molecular biology, Yue confirms that it is those cationic polymer chains free in the solution mixture, rather than those bound to DNA chains, that play a decisive role in intracellular trafficking. Instead of the previously proposed and widely accepted “proton sponge” model, the author's group propose a new hypothesis based on the results of several well-designed and decisive experiments. These results show that free polycationic chains with a length of more than ~10 nm are able to partially block the fusion between different endocytic vesicles, including the endocytic-vesicle-to-endolysosome pathway. This thesis is highly original and its results greatly deepen our understanding of polymer-mediated gene transfection. More importantly, it provides new insights into the rational design of next-generation superior polymeric gene-delivery vectors.

Inhaltsverzeichnis

Frontmatter

Chapter 1. Introduction and Background

Abstract

Gene therapy, considered as treating genetically-caused diseases by transferring exogenous nucleic acids into specific cells of patients, has attracted great interests over the past few decades. Advances in molecular biology and biotechnology as well as the completion of the Human Genome Project have led to the recognition of numerous diseases-relating genes. It has been gradually and generally realized that development of safe, efficient and controllable gene-delivery vectors is now a bottleneck in clinical applications.

Yue Yanan

Chapter 2. Revisiting Complexation Between DNA and Polyethylenimine: The Effect of Uncomplexed Chains Free in the Solution Mixture on Gene Transfection

Abstract

In comparison with viral vectors, more efforts have recently been spent on the development of non-viral vectors because of few fatal accidents in clinical trials of viral carriers [1–3]. It has been well recognized that non-viral vectors have their own advantages, such as low immune toxicity, construction flexibility and facile fabrication, in the gene transfection, especially for clinical applications [4–6]. However, they are still much less efficient than their viral counterparts. Among thousands of experimentally tested non-viral vectors, cationic polyethylenimine (PEI) is still considered as one of the most efficient candidates to deliver genes and often served as a “golden standard” [7–9]. Previously, PEI has been chemically modified in different ways so that additional functions were introduced for a better gene delivery, including the incorporation of intracellular biodegradable linkers, [10, 11] the PEGylation to improve the serum stability during circulation [12, 13] and the attachment of some functional molecules to target specific cells or tissues [12–15]. Less attention, however, has been paid to why PEI remains one of the best non-viral carriers and how it facilitates the intracellular trafficking [16–27].

Yue Yanan

Chapter 3. Revisiting Complexation Between DNA and Polyethylenimine: The Effect of Length of Free Polycationic Chains on Gene Transfection

Abstract

The gene therapy, considered as the treatment of genetically-caused diseases by transferring exogenous nucleic acids into specific cells of patients, has attracted great interests over the past few decades [1]. It has been gradually realized that the development of safe, efficient and controllable gene-delivery vectors has become a bottleneck in clinical applications. The gene transfection vectors can be generally divided as viral and non-viral ones.

Yue Yanan

Chapter 4. Quantitative Comparison of Endocytosis and Intracellular Trafficking of DNA/Polymer Complexes in the Absence/Presence of Free Polycationic Chains

Abstract

The development of smart and multi-functional non-viral polymeric devices (NVPD) for nucleic acid delivery has captured tremendous attention over the past few decades [1–3]. Particularly, cationic polymers are perceived as promising candidates due to their safety profiles and relative ease to incorporate desired functional moieties[4, 5]. Currently, polyethylenimine (PEI) is among the most intensively studied cationic polymeric vehicles and hitherto mediates nearly the highest in vitro transfection efficiency in the absence of any exogenous endosomolytic agent [6–8].

Yue Yanan

Titel: How Free Cationic Polymer Chains Promote Gene Transfection
verfasst von: Yue Yanan
Verlag: Springer International Publishing
Electronic ISBN: 978-3-319-00336-8
Print ISBN: 978-3-319-00335-1
DOI: https://doi.org/10.1007/978-3-319-00336-8

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