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

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.

Phosphorus and Silicon‐Based Macromolecules as Degradable Biomedical Polymers

“…Selected highlights will be detailed in the following, nevertheless, more extensive literature can be found elsewhere. [9,62a,b,63] [75] Copyright 2023, The Authors, published by Wiley-VCH GmbH. c) top images, reproduced with permission.…”

“…[68][69][70] Especially in respect to polymer therapeutics, PPz enable not only desired water solubility but also accommodate simple and straightforward conjugation of different active pharmaceutical ingredients, ranging from classical cancer drugs such as paclitaxel [71] or camptothecin [72] to platinum pro drugs [73] or specific receptor agonists for immunotherapy. [65] In recent years, also the use of co-polymers of PPz with other well-known and established biomedical polymers such as PEG [74] or polyglutamic acid (PGA) [75] gained more and more interest. In a recent paper from our group, the synthesis of novel PPz-g-PGA bottlebrush polymers was described, in Figure 16a.…”

“…a) Reproduced under the terms of the CC‐BY license. [ 75 ] Copyright 2023, The Authors, published by Wiley‐VCH GmbH. c) top images, reproduced with permission.…”

“…e) Immune response of mice treated with cocaine vaccines containing different adjuvants and their titer after 3 (Bleed 1) and 6 (Bleed 2) weeks. a) Reproduced under the terms of the CC-BY license [75]. Copyright 2023, The Authors, published by Wiley-VCH GmbH.…”

Inorganic Bottlebrush and Comb Polymers as a Platform for Supersoft, Solvent-Free Elastomers

“…Phosphorus-based polymers, including polyphosphazenes, polyphosphoesters and polyphosphoramidates, are also of interest for their easily tunable biodegradation to non-cytotoxic and predictable degradation products. , New, highly controlled synthesis routes have facilitated their use as tools for self-assembly, polymer therapeutics, vaccine delivery agents, tissue engineering, and biomedical coatings . Recently, we have prepared fully water-soluble bottlebrush polyphosphazenes (PPz) as nanomedicines with unique biodistribution profiles . A distinctive feature of PPz is low stiffness; in fact, polydifluorophosphazene has the lowest barrier to rotation ever calculated for skeletal bonding in polymers, significantly lower than C–C bonds.…”