Molecular bottlebrush prodrugs as mono- and triplex combination therapies for multiple myeloma

Detappe, Alexandre; Nguyen, Hung V.-T.; Jiang, Yivan; Agius, Michael P.; Wang, Wencong; Mathieu, Cécile; Su, Nang Kham; Kristufek, Samantha L.; Lundberg, David; Bhagchandani, Sachin; Ghobrial, Irène M.; Ghoroghchian, P. Peter; Johnson, Jeremiah A.

doi:10.1038/s41565-022-01310-1

Cited by 54 publications

(42 citation statements)

References 51 publications

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“…Bottlebrush polymers (BBPs) have attracted considerable interest due to their unique properties originating from chain architecture − and have found a wide range of applications, such as super-soft elastomers, nanomedicine, , electronics, and self-healing materials . Recently, cyclic BBPs have emerged as a very interesting material.…”

Section: Introductionmentioning

confidence: 99%

Cyclic vs Linear Bottlebrush Polymers in Solution: Side-Chain Length Effect

Chen

Dormidontova

2023

Macromolecules

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Bottlebrush polymers (BBPs) of different architecture are of considerable interest for a broad range of applications, including nanomedicine, electronics, and self-healing materials. Using atomistic molecular dynamics simulations, we investigate and compare the structural and hydration properties of cyclic and linear poly(vinyl alcohol)-graft-poly(ethylene oxide) (PVA-g-PEO N sc ) BBPs in aqueous solution as functions of PEO side-chain length, N sc. We find that overall cyclic BBPs are smaller than the corresponding linear BBPs and their shape changes from donutlike to disklike to starlike with increasing side-chain length, while linear BBPs vary in shape from an expanded coil to a rod/cylinder. The radius of gyration of cyclic BBPs increases with an increase of the side-chain length at a somewhat slower rate than the linear BBPs but follows the same scaling R g ∼ N sc 0.58 in the limit of long side chains. For short grafts, we determine that the persistence length, l p, for both cyclic and linear BBPs increases in a similar manner following an l p ∼ N sc 0.54 dependence. In the long side-chain limit, the persistence length (l p) of cyclic BBP saturates, while for linear BBPs l p strongly increases following the expected scaling relation l p ∼ N sc 15/8. We propose a scaling model that shows that the fraction of side-chains located inside the cyclic BBPs depends on the radius of the backbone ring and significantly decreases with an increase of graft length. For both cyclic and linear BBPs, the hydrogen bonding between PEO side chains and water is somewhat reduced near the backbone, where local chain stretching is observed, while reaching full hydration on the periphery. Overall, the hydration shell within 1 nm of the cyclic BBP backbone is found to be more dynamically stable compared to linear BBPs.

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Section: Introductionmentioning

confidence: 99%

Cyclic vs Linear Bottlebrush Polymers in Solution: Side-Chain Length Effect

Chen

Dormidontova

2023

Macromolecules

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“…38) that affords multivalent norbornene imide in extremely high yield, high efficiency, and simplicity, 289 achieving the establishment of a modular, scalable, and well-defined bottlebrush prodrug (BPD) platform. 263–265,290–295…”

Section: Polymers From Bicyclic Alkenesmentioning

confidence: 99%

Design of biomaterials through direct ring-opening metathesis polymerisation of functionalised cyclic alkenes

Kobayashi

Tanaka

2023

Mol. Syst. Des. Eng.

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“…Isolating activation kinetics as a key variable, however, requires a prodrug platform capable of generating multiple physically equivalent TLR agonist prodrugs that only vary by their activation kinetics, which is traditionally very challenging and has, so far, not been explored in the context of immune stimulation. We have created "bottlebrush prodrugs" (BPDs), which are a class of polymers that feature drug molecules covalently linked along their rigid backbones with PEG chains that extend from the backbone to shield the drugs from surface exposure (30)(31)(32). These structures offer unique advantages for controlled delivery, particularly for studying the impact of release kinetics on biological functions, as they can be easily manufactured with a variety of prodrug linkers while maintaining identical sizes, shapes, biodistribution, serum pharmacokinetics (PKs), and other key physical properties.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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Imidazoquinolines (IMDs), such as resiquimod (R848), are of great interest as potential cancer immunotherapies because of their ability to activate Toll-like receptor 7 (TLR7) and/or TLR8 on innate immune cells. Nevertheless, intravenous administration of IMDs causes severe immune-related toxicities, and attempts to improve their tissue-selective exposure while minimizing acute systemic inflammation have proven difficult. Here, using a library of R848 “bottlebrush prodrugs” (BPDs) that differ only by their R848 release kinetics, we explore how the timing of R848 exposure affects immune stimulation in vitro and in vivo. These studies led to the discovery of R848-BPDs that exhibit optimal activation kinetics to achieve potent stimulation of myeloid cells in tumors and substantial reductions in tumor growth following systemic administration in mouse syngeneic tumor models without any observable systemic toxicity. These results suggest that release kinetics can be tuned at the molecular level to provide safe yet effective systemically administered immunostimulant prodrugs for next-generation cancer immunotherapies.

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Molecular bottlebrush prodrugs as mono- and triplex combination therapies for multiple myeloma

Cited by 54 publications

References 51 publications

Cyclic vs Linear Bottlebrush Polymers in Solution: Side-Chain Length Effect

Cyclic vs Linear Bottlebrush Polymers in Solution: Side-Chain Length Effect

Design of biomaterials through direct ring-opening metathesis polymerisation of functionalised cyclic alkenes

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

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