加速十克规模合成单组分多功能序列定义可离子化两亲性 Janus 树状大分子 97。

Accelerated Ten-Gram-Scale Synthesis of One-Component Multifunctional Sequence-Defined Ionizable Amphiphilic Janus Dendrimer 97.

机构信息

Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States.

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.

出版信息

Biomacromolecules. 2024 Oct 14;25(10):6871-6882. doi: 10.1021/acs.biomac.4c01107. Epub 2024 Oct 3.

Abstract

One-component multifunctional sequence-defined ionizable amphiphilic Janus dendrimers (IAJDs) were discovered in our laboratories in 2021 to represent a new class of synthetic vectors for the targeted delivery of messenger RNA (mRNA). They coassemble with mRNA by simple injection of their ethanol solution into a pH 4 acetate buffer containing the nucleic acid into monodisperse dendrimersome nanoparticles (DNPs) with predictable dimensions. DNPs are competitive with 4-component lipid nanoparticles (LNPs), which are used in commercial COVID-19 vaccines, except that IAJDs are prepared in fewer reaction steps than each individual component of the LNPs. This simple methodology for the synthesis of IAJDs and their coassembly with mRNA into DNPs, together with the precise placement of their individual components and indefinite stability at room temperature in air, make them attractive candidates for the development of nanomedicine-based targeted mRNA delivery. Access to the large-scale synthesis of IAJDs without the need for sophisticated technologies, instrumentation, and synthetic skills is expected to open numerous new opportunities worldwide in nanomedicine. The goal of this publication is to report an accelerated ten-gram-scale synthesis of IAJD97 from inexpensive food additives obtained from renewable plant phenolic acid starting materials by methodologies accessible to any laboratory. This accelerated synthesis can be accomplished in 4 days. We expect that the work reported here will impact the field of nanomedicine in both developed and less developed countries.

摘要

2021 年,我们实验室发现了一种单一组分多功能序列定义可离子化两亲性 Janus 树状大分子(IAJD),它代表了一类新型的合成载体,可用于靶向递信使 RNA(mRNA)。通过将其乙醇溶液简单注入 pH4 醋酸盐缓冲液中,其中包含核酸,IAJD 与 mRNA 共组装成具有可预测尺寸的单分散树状大分子纳米囊泡(DNP)。DNP 与用于商业 COVID-19 疫苗的 4 组分脂质纳米粒(LNP)具有竞争力,不同之处在于 IAJD 的制备反应步骤少于 LNP 的每个单独组分。这种简单的 IAJD 合成方法及其与 mRNA 共组装成 DNP 的方法,以及其各个组分的精确位置和在室温下空气中的无限稳定性,使它们成为开发基于纳米医学的靶向 mRNA 递药的有吸引力的候选物。无需复杂技术、仪器和合成技能即可获得大规模合成 IAJD 的机会,预计将在全球范围内为纳米医学带来许多新的机会。本出版物的目的是报告一种从可再生植物酚酸起始原料中获得的廉价食品添加剂加速合成 IAJD97 的 10 克规模方法,该方法适用于任何实验室。这种加速合成可以在 4 天内完成。我们预计,这里报道的工作将对发达国家和欠发达国家的纳米医学领域产生影响。

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