Transient Lymph Node Immune Activation by Hydrolysable Polycarbonate Nanogels

Advanced Functional Materials, Journal Year: 2022, Volume and Issue: 32(35)

Published: June 26, 2022

Abstract The development of controlled biodegradable materials is fundamental importance in immunodrug delivery to spatiotemporally immune stimulation but avoid systemic inflammatory side effects. Based on this, polycarbonate nanogels are developed as degradable micellar carriers for transient immunoactivation lymph nodes. An imidazoquinoline‐type TLR7/8 agonist covalently conjugated via reactive ester chemistry these nanocarriers. not only provide access complete disintegration by the hydrolysable polymer backbone, also demonstrate a gradual within several days at physiological conditions (PBS, pH 6.4–7.4, 37 °C). These intrinsic properties limit lifetime their payload can still be successfully leveraged immunological studies vitro primary cells well vivo. For latter, spatiotemporal control cell activation draining node found after subcutaneous injection. Overall, features render promising system nodes and may consequently become very attractive further toward vaccination or cancer immunotherapy. Due biodegradability combined with high chemical during manufacturing process, polycarbonate‐based great clinical translation.

Language: Английский

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Efficient Self-Immolative RAFT End Group Modification for Macromolecular Immunodrug Delivery

Biomacromolecules, Journal Year: 2023, Volume and Issue: 24(5), P. 2380 - 2391

Published: April 24, 2023

The reversible addition–fragmentation chain-transfer (RAFT) polymerization provides access to a broad variety of biocompatible and functional macromolecules for diverse polymer–drug conjugates. Due thiocarbonylthio groups at the ends each growing polymer chain, they can straightforwardly be converted into disufilde-containing self-immolative motives drug conjugation by traceless linkers. This may relevant RAFT-polymerized poly(N,N-dimethylacrylamide) (pDMA), which has been demonstrated provide similar properties as poly(ethylene glycol) (PEG) in terms improving drug's poor pharmacokinetic profile or enhancing its bioavailability. For that purpose, we established highly efficient one-pot reaction procedure introducing various functionalities including both primary secondary amines alcohols their release from pDMA's chain end. Next, first conjugate with Toll-like receptor agonist exhibited significantly increased activity vitro compared conventional irreversibly covalently fixed variants. Finally, α-ω-bifunctional dye conjugates could generated cholesterol-modified RAFT agent. It facilitated conjugate's internalization cellular level monitored flow cytometry confocal imaging. approach basis potentially impactful combining versatile small molecular drugs plethora available polymers through reductive-responsive

Language: Английский

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Enantioselective Effect of Chiral Small Molecules in SARS‐CoV‐2 Vaccine‐Induced Immune Response

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(28)

Published: May 11, 2023

Although numerous chiral small molecules have been discovered and synthesized, the investigation on their enantioselective immunological effects remains limited. In this study, we designed synthesized a pair of molecule enantiomers (R/S-ResP) by covalently bonding two immunostimulators (resiquimod/Res) onto planar framework (paracyclophane/P). Notably, found that S-ResP exhibits 4.05-fold higher affinity for toll-like receptor 7 (TLR7) than R-ResP, thereby more effectively enhancing functions dendritic cells macrophages in cytokine secretion antigen internalization. Furthermore, observed significantly enhances RBD antigen-induced cross-neutralization against various SARS-CoV-2 strains compared to R-ResP. These findings demonstrate regulating vaccine-induced immune responses emphasize significance chirality designing molecular adjuvants.

Language: Английский

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Enhancing anti-tumor immunity through intratumoral combination therapy with amphiphilic conjugates of oxaliplatin and imidazoquinoline TLR7/8 agonist

RSC Advances, Journal Year: 2025, Volume and Issue: 15(15), P. 11662 - 11674

Published: Jan. 1, 2025

Combining a cytotoxic drug with an immune-activating eradicates tumors.

Language: Английский

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A reverse vaccinology and immunoinformatics approach for designing a multiepitope vaccine against SARS-CoV-2

Immunogenetics, Journal Year: 2021, Volume and Issue: 73(6), P. 459 - 477

Published: Sept. 20, 2021

Since 2019, the world was involved with SARS-CoV-2 and consequently, announcement by World Health Organization that COVID-19 a pandemic, scientific were an effort to obtain best approach combat this global dilemma. The way prevent pandemic from spreading further is use vaccine against COVID-19. Here, we report design of recombinant multi-epitope four proteins spike or crown (S), membrane (M), nucleocapsid (N), envelope (E) using immunoinformatics tools. We evaluated most antigenic epitopes bind HLA class 1 subtypes, along 2, as well B cell epitopes. Beta-defensin 3 PADRE sequence used adjuvants in structure vaccine. KK, GPGPG, AAY linkers fuse selected nucleotide cloned into pET26b(+) vector restriction enzymes XhoI NdeI, HisTag considered C-terminal construct. results showed proposed candidate 70.87 kDa protein high antigenicity immunogenicity non-allergenic non-toxic. A total 95% have conservancy similar sequences. Molecular docking strong binding between tool-like receptor (TLR) 7/8. docking, molecular dynamics, MM/PBSA analysis established stable interaction both structures TLR7 TLR8. Simulation immune stimulation it evokes responses related humoral cellular immunity.

Language: Английский

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