Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Tumor-Specific Targeting of Polymer Drug Delivery Systems with Recombinant Proteins Bound via Tris(Nitrilotriacetic Acid)

Michal Pechar
ORCID logo ,
Vlastimil Král
,
Lucie Woldřichová
,
Ladislav Androvič
,
Eliška Hrdá
,
Robert Pola
ORCID logo ,
Sára Pytlíková
,
Martin Studenovský
,
Libor Kostka
ORCID logo ,
Vladimír Šubr
,
Tomáš Etrych
ORCID logo ,
Olga Kočková
,
Jéssica Mariane Ferreira Mendes
,
Milan Fábry
,
Richard Laga
*
Version 1 : Received: 30 June 2023 / Approved: 3 July 2023 / Online: 4 July 2023 (08:01:27 CEST)

A peer-reviewed article of this Preprint also exists.

Pechar, M.; Král, V.; Woldřichová, L.; Androvič, L.; Hrdá, E.; Pola, R.; Pytlíková, S.; Studenovský, M.; Kostka, L.; Šubr, V.; et al. Tumor-Specific Targeting of Polymer Drug Delivery Systems with Recombinant Proteins Bound via Tris(Nitrilotriacetic Acid). International Journal of Pharmaceutics 2023, 123619, doi:10.1016/j.ijpharm.2023.123619. Pechar, M.; Král, V.; Woldřichová, L.; Androvič, L.; Hrdá, E.; Pola, R.; Pytlíková, S.; Studenovský, M.; Kostka, L.; Šubr, V.; et al. Tumor-Specific Targeting of Polymer Drug Delivery Systems with Recombinant Proteins Bound via Tris(Nitrilotriacetic Acid). International Journal of Pharmaceutics 2023, 123619, doi:10.1016/j.ijpharm.2023.123619.

Abstract

Antibody-mediated targeting is an efficient strategy to enhance the specificity and selectivity of polymer nanomedicines towards the target site, typically a tumor. However, direct covalent coupling of an antibody with a polymer usually results in a partial damage of the antibody binding site accompanied with a compromised biological activity. Here, an original solution based on well-defined non-covalent interactions between tris-nitrilotriacetic acid (trisNTA) and hexahistidine (His-tag) groups, purposefully introduced to the structure of each macromolecule, is described. Specifically, trisNTA groups were attached along the chains of a hydrophilic statistical copolymer based on N-(2-hydroxypropyl)methacrylamide (HPMA), and at the end or along the chains of thermo-responsive di-block copolymers based on N-isopropylmethacrylamide (NIPMAM) and HPMA; His-tag was incorporated to the structure of a recombinant single chain fragment of an anti-GD2 monoclonal antibody (scFv-GD2). Static and dynamic light scattering analyses confirmed that mixing of polymer with scFv-GD2 led to the formation of polymer/scFv-GD2 complexes; those prepared from thermo-responsive polymers formed stable micelles at 37 °C. Flow cytometry and fluorescence microscopy clearly demonstrated antigen-specific binding of the prepared complexes to GD2 positive murine T-cell lymphoma cells EL-4 and human neuroblastoma cells UKF-NB3, while no interaction with GD2 negative murine fibroblast cells NIH-3T3 was observed. These non-covalent polymer protein complexes represent a new generation of highly specific actively targeted polymer therapeutics or diagnostics.

Keywords

Hydrophilic polymers; Thermo-responsive polymers; Polymer drug delivery system; Tumor-specific targeting; Recombinant proteins; Non-covalent attachment; Tris(nitrilotriacetic acid) ligation

Subject

Chemistry and Materials Science, Medicinal Chemistry

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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