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Significance
The need to boost the number of delivered nucleotides in gene therapy has encouraged the utilization of non-viral vectors as reliable carriers. A brief flashback shows us that until 2012, the Food & Drug Administration had approved only 1843 clinical trials implying DNA and RNA vectorization for gene therapy purposes. Close to two-thirds of those clinical trials were noted to have utilized viral vectors, despite their deficiencies such as low carrying capacity and immunological demerits. Recently, dynamic supermolecular bio-carrier conjugates, alternatively termed as cargo-complexes, emerged as excellent tool to deliver highly large amounts of sophisticated sensitive pharmaco- and bio-active species. The key components of the cargo-complexes are the carrier molecules, which must display selective affinity towards the molecules in transit, and be endowed with molecular segments active towards both the biological targets and the biochemical “assailants and hindrances”. To function in a reproducible manner, carriers must be themselves reproducibly produced. An important number of recently published studies investigate the transfection ability of non-viral vectors produced by the techniques of constitutional dynamic chemistry. Unfortunately, incentive results were obtained in both cases, but the versatility remained conditional.
To this note, a team of researchers led by Professor Mariana Pinteala from the Centre of Advanced Research in Bionano-conjugates and Biopolymers, “Petru Poni” Institute of Macromolecular Chemistry in Romania established a new procedure to construct carriers of cyclodextrin-based polyrotaxane-type. The research team demonstrated their ability to conjunctively cooperate to generate cargo-complexes with plasmid DNA, able to efficiently transfect cells in culture. Their work is currently published in the research journal, Polymer Chemistry.
The research technique employed commenced by obtaining polyrotaxane carriers having an axle of precise length, which allowed the threading of nine functionalized cyclodextrin units, and end capped with silatrane molecules. Next, in order to reduce the carrier cytotoxicity and to increase their physical–chemical versatility in loading nucleic acids, two supplemental ways to functionalize the CD units were investigated: first, with a mixture of polyethylenimines and short linear poly(ethyleneglycol) molecules, and second, by post-decorating polyethylenimines branches with ionizable small molecules: guanidine and arginine. Lastly, the experimental DNA binding capacity of these carriers in relationship with size, morphology and electrical charge was evaluated.
The authors observed that both alternatives numerically diminish the positive charges supported beared by the carrier, the first of them to a greater extent, and thus both reduce the packaging capacity of the carriers, in favor of cytocompatibiliy. The researchers also noted that due to the precise synthesis pathway, highly reproducible carriers were obtained.
Rodinel Ardeleanu and colleagues study has presented an efficient design and synthesis, of a new class of polyrotaxane carriers that were able to collaboratively generate cargo-complexes with nucleic acids. The scholars here demonstrated the cargo-complexes’ ability to transfect HeLa cells with a high efficiency. Altogether, the in vitro tests, showing no cytotoxicity and good transfection efficiency of the investigated carriers, provided new information on gene vector design and prove their excellent attributes and wide applicability. In vivo testing will further corroborate the utility of these new gene vectors for gene therapy.
Acknowledgement
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 667387 WIDESPREAD 2-2014 SupraChem Lab
Reference
Rodinel Ardeleanu, Andrei I. Dascalu, Andrei Neamtu, Dragos Peptanariu, Cristina M. Uritu, Stelian S. Maier, Alina Nicolescu, Bogdan C. Simionescu, Mihail Barboiu and Mariana Pinteala. Multivalent polyrotaxane vectors as adaptive cargo complexes for gene therapy. Polymer Chemistry, 2018, volume 9, page 845
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