Degradable Bottlebrush Polypeptides and the Impact of their Architecture on Cell Uptake, Pharmacokinetics, and Biodistribution In Vivo

Author(s)
Paul Strasser, Bianca Montsch, Silvia Weiss, Haider Sami, Christoph Kugler, Sonja Hager, Hemma Schueffl, Robert Mader, Oliver Brüggemann, Christian R. Kowol, Manfred Ogris, Petra Heffeter, Ian Teasdale
Abstract

Bottlebrush polymers are highly promising as unimolecular nanomedicines due to their unique control over the critical parameters of size, shape and chemical function. However, since they are prepared from biopersistent carbon backbones, most known bottlebrush polymers are non-degradable and thus unsuitable for systemic therapeutic administration. Herein, we report the design and synthesis of novel poly(organo)phosphazene-g-poly(α-glutamate) (PPz-g-PGA) bottlebrush polymers with exceptional control over their structure and molecular dimensions (Dh ≈ 15–50 nm). These single macromolecules show outstanding aqueous solubility, ultra-high multivalency and biodegradability, making them ideal as nanomedicines. While well-established in polymer therapeutics, it has hitherto not been possible to prepare defined single macromolecules of PGA in these nanosized dimensions. A direct correlation was observed between the macromolecular dimensions of the bottlebrush polymers and their intracellular uptake in CT26 colon cancer cells. Furthermore, the bottlebrush macromolecular structure visibly enhanced the pharmacokinetics by reducing renal clearance and extending plasma half-lives. Real-time analysis of the biodistribution dynamics showed architecture-driven organ distribution and enhanced tumor accumulation. This work, therefore, introduces a robust, controlled synthesis route to bottlebrush polypeptides, overcoming limitations of current polymer-based nanomedicines and, in doing so, offers valuable insights into the influence of architecture on the in vivo performance of nanomedicines.

Organisation(s)
Department of Food Chemistry and Toxicology, Department of Pharmaceutical Sciences, Department of Inorganic Chemistry
External organisation(s)
Johannes Kepler Universität Linz, Medizinische Universität Wien, Research Cluster Translational Cancer Therapy Research
Journal
Small
Volume
19
ISSN
1613-6810
DOI
https://doi.org/10.1002/smll.202300767
Publication date
06-2023
Peer reviewed
Yes
Austrian Fields of Science 2012
301205 Pharmacokinetics, 106002 Biochemistry, 106006 Biophysics
Keywords
ASJC Scopus subject areas
Biotechnology, General Chemistry, Biomaterials, General Materials Science
Sustainable Development Goals
SDG 3 - Good Health and Well-being
Portal url
https://ucrisportal.univie.ac.at/en/publications/c350a40c-a758-4584-bb33-ec88e6f7cfc4