Deep Tissue Penetration of Bottle-Brush Polymers via Cell Capture Evasion and Fast Diffusion

Abstract

Drug nanocarriers (NCs) capable of crossing the vascular endothelium and deeply penetrating into dense tissues of the CNS could potentially transform the management of neurological diseases. In the present study, we investigated the interaction of bottle-brush (BB) polymers with different biological barriers in vitro and in vivo and compared it to nanospheres of similar composition. In vitro internalization and permeability assays revealed that BB polymers are not internalized by brain-associated cell lines and translocate much faster across a blood–brain barrier model compared to nanospheres of similar hydrodynamic diameter. These observations performed under static, no-flow conditions were complemented by dynamic assays performed in microvessel arrays on chip and confirmed that BB polymers can escape the vasculature compartment via a paracellular route. BB polymers injected in mice and zebrafish larvae exhibit higher penetration in brain tissues and faster extravasation of microvessels located in the brain compared to nanospheres of similar sizes. The superior diffusivity of BBs in extracellular matrix-like gels combined with their ability to efficiently cross endothelial barriers via a paracellular route position them as promising drug carriers to translocate across the blood–brain barrier and penetrate dense tissue such as the brain, two unmet challenges and ultimate frontiers in nanomedicine.

Charge, Aspect Ratio, and Plant Species Affect Uptake Efficiency and Translocation of Polymeric Agrochemical Nanocarriers

“…Polymer nanocarriers with different charges and aspect ratios, including low aspect ratio star polymers (L), medium aspect ratio short bottlebrush (M), and high aspect ratio long bottlebrush (H) polymers, were synthesized by a grafting from approach (Figure S1). , The chemical composition of cationic star and bottlebrushes was confirmed by 1 H NMR (Figure S2) and gel permeation chromatography with a multiangle laser light scattering detector (GPC-MALLS), as shown in Figure S3 and Table S1. The theoretical molecular weight ( M n ) of polymer bottlebrushes and star polymers calculated from 1 H NMR and GPC-MALLS ranges from 1.76 × 10 5 to 2.20 × 10 7 g mol –1 , as shown in Table S2.…”

Engineering kinetics of TLR7/8 agonist release from bottlebrush prodrugs enables tumor-focused immune stimulation

“…The concept of using molecular design to tune release and to understand in detail the impact of release kinetics on immune response has not been explored and is uniquely enabled by our BPD platform. Furthermore, the bottlebrush conformation has been shown to improve tissue penetration and cell uptake ( 59 ). These are very small prodrug constructs that are in a size range not accessible to many other systems.…”

All-Atom Molecular Dynamics Simulations of Uncharged Linear Polymer Bottlebrushes: Effect of the Brush Sizes and the Number of Side-Chain Monomers

“…Polymer chains of bottlebrush architecture or bottlebrush polymers (BBPs), also sometimes denoted as comb-type polymer chains, have been widely investigated over the last several decades and have found extensive applications in areas such as lithium-ion batteries, proton-conducting polymers, solar thermal systems, artificial muscles, vectors, drug carriers, , precision medicines, self-healing networks, − flexible sensors, and electronics. , Such BBPs are typically copolymer systems where one type of polymer forms the backbone, while another type forms the side chains that are grafted on the backbone polymer. A vast variety of BBP systems have been designed by varying (a) the nature of the backbone and side chain polymers; (b) the size or number of monomers of the backbone and side chains; (c) the grafting density of the side chains, etc.…”