Transiently Thermoresponsive Acetal Polymers for Safe and Effective Administration of Amphotericin B as a Vaccine Adjuvant,Bioconjugate Chemistry

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Transiently Thermoresponsive Acetal Polymers for Safe and Effective Administration of Amphotericin B as a Vaccine Adjuvant
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2017-11-26 00:00:00 , DOI: 10.1021/acs.bioconjchem.7b00641
Simon Van Herck _{1,

2} , Lien Van Hoecke _{3,

4} , Benoit Louage _{1,

2} , Lien Lybaert _{1,

2} , Ruben De Coen _{1,

2} , Sabah Kasmi _{1,

2} , Aaron P. Esser-Kahn ₅ , Sunil A. David ₆ , Lutz Nuhn _{1,

2} , Bert Schepens _{3,

4} , Xavier Saelens _{3,

4} , Bruno G. De Geest _{1,

2}

Affiliation

The quest for new potent and safe adjuvants with which to skew and boost the immune response of vaccines against intracellular pathogens and cancer has led to the discovery of a series of small molecules that can activate Toll-like receptors (TLRs). Whereas many small molecule TLR agonists cope with a problematic safety profile, amphotericin B (AmpB), a Food and Drug Administration approved antifungal drug, has recently been discovered to possess TLR-triggering activity. However, its poor aqueous solubility and cytotoxicity at elevated concentrations currently hampers its development as a vaccine adjuvant. We present a new class of transiently thermoresponsive polymers that, in their native state, have a phase-transition temperature below room temperature but gradually transform into fully soluble polymers through acetal hydrolysis at endosomal pH values. RAFT polymerization afforded well-defined block copolymers that self-assemble into micellar nanoparticles and efficiently encapsulate AmpB. Importantly, nanoencapsulation strongly reduced the cytotoxic effect of AmpB but maintained its TLR-triggering capacity. Studies in mice showed that AmpB-loaded nanoparticles can adjuvant an RSV vaccine candidate with almost equal potency as a highly immunogenic oil-in-water benchmark adjuvant.

中文翻译：

瞬态热敏缩醛聚合物，可安全有效地将两性霉素B用作疫苗佐剂

对新的有效且安全的佐剂的追求使得其可以偏斜并增强疫苗针对细胞内病原体和癌症的免疫反应，从而导致发现了一系列可以激活Toll样受体（TLR）的小分子。尽管许多小分子TLR激动剂可解决安全性问题，但是最近发现，经食品和药物管理局批准的两性霉素B（AmpB）具有触发TLR的活性。然而，目前其在较高浓度下不良的水溶性和细胞毒性目前阻碍了其作为疫苗佐剂的发展。我们提出了一类新的瞬态热响应性聚合物，它们在其原始状态下具有低于室温的相变温度，但是在内体pH值下通过缩醛水解逐渐转变为完全可溶的聚合物。RAFT聚合提供了定义明确的嵌段共聚物，它们可以自组装成胶束纳米颗粒并有效地封装AmpB。重要的是，纳米封装强烈降低了AmpB的细胞毒性作用，但保持了其TLR触发能力。小鼠研究表明，载有AmpB的纳米颗粒可以佐剂RSV疫苗候选物，其效力与具有高度免疫原性的水包油基准佐剂几乎相同。纳米封装强烈降低了AmpB的细胞毒性作用，但保持了其TLR触发能力。小鼠研究表明，载有AmpB的纳米颗粒可以佐剂RSV疫苗候选物，其效力与具有高度免疫原性的水包油基准佐剂几乎相同。纳米封装强烈降低了AmpB的细胞毒性作用，但保持了其TLR触发能力。小鼠研究表明，载有AmpB的纳米颗粒可以佐剂RSV疫苗候选物，其效力与具有高度免疫原性的水包油基准佐剂几乎相同。

更新日期：2017-11-26

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