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Encapsulation of polyprodrugs enables an efficient and controlled release of dexamethasone
Nanoscale Horizons ( IF 8.0 ) Pub Date : 2021-07-24 , DOI: 10.1039/d1nh00266j Mengyi Li 1 , Shuai Jiang 1, 2 , Adelina Haller 3 , Sebastian Wirsching 4 , Michael Fichter 4 , Johanna Simon 1, 3 , Manfred Wagner 1 , Volker Mailänder 1, 3 , Stephan Gehring 4 , Daniel Crespy 5 , Katharina Landfester 1
Nanoscale Horizons ( IF 8.0 ) Pub Date : 2021-07-24 , DOI: 10.1039/d1nh00266j Mengyi Li 1 , Shuai Jiang 1, 2 , Adelina Haller 3 , Sebastian Wirsching 4 , Michael Fichter 4 , Johanna Simon 1, 3 , Manfred Wagner 1 , Volker Mailänder 1, 3 , Stephan Gehring 4 , Daniel Crespy 5 , Katharina Landfester 1
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Water-soluble low molecular weight drugs, such as the synthetic glucocorticoid dexamethasone (DXM), can easily leak out of nanocarriers after encapsulation due to their hydrophilic nature and small size. This can lead to a reduced therapeutic efficacy and therefore to unwanted adverse effects on healthy tissue. Targeting DXM to inflammatory cells of the liver like Kupffer cells or macrophages is a promising approach to minimize typical side effects. Therefore, a controlled transport to the cells of interest and selective on-site release is crucial. Aim of this study was the development of a DXM-phosphate-based polyprodrug and the encapsulation in silica nanocontainers (SiO2 NCs) for the reduction of inflammatory responses in liver cells. DXM was copolymerized with a linker molecule introducing pH-cleavable hydrazone bonds in the backbone and obtaining polyprodrugs (PDXM). Encapsulation of PDXMs into SiO2 NCs provided a stable confinement avoiding uncontrolled leakage. PDXMs were degraded under acidic conditions and subsequently released out of SiO2 NCs. Biological studies showed significantly enhanced anti-inflammatory capacity of the polyprodrug nanoformulations over non-encapsulated DXM or soluble polyprodrugs. These results demonstrate the advantage of combining the polyprodrug strategy with nanocarrier-mediated delivery for enhanced control of the delivery of water-soluble low molecular weight drugs.
中文翻译：
多前体药物的封装使地塞米松的有效和受控释放成为可能
水溶性低分子量药物，如合成糖皮质激素地塞米松 (DXM)，由于其亲水性和小尺寸，在封装后很容易从纳米载体中泄漏出来。这会导致治疗功效降低，从而对健康组织产生不利的不利影响。将 DXM 靶向肝脏的炎症细胞，如库普弗细胞或巨噬细胞，是一种有前途的方法，可以最大限度地减少典型的副作用。因此，对感兴趣细胞的受控运输和选择性现场释放至关重要。本研究的目的是开发基于 DXM 磷酸盐的多聚前药，并将其封装在二氧化硅纳米容器 (SiO 2NCs) 用于减少肝细胞的炎症反应。DXM 与接头分子共聚，在主链中引入 pH 可裂解的腙键并获得聚前药 (PDXM)。将 PDXM 封装到 SiO 2 NC 中提供了稳定的限制，避免了不受控制的泄漏。PDXMs 在酸性条件下降解，随后从 SiO 2 NCs 中释放出来。生物学研究表明，与未包封的 DXM 或可溶性聚前药相比，聚前药纳米制剂的抗炎能力显着增强。这些结果证明了将多前药策略与纳米载体介导的递送相结合的优势，以增强对水溶性低分子量药物递送的控制。
更新日期：2021-08-04
中文翻译：
多前体药物的封装使地塞米松的有效和受控释放成为可能
水溶性低分子量药物，如合成糖皮质激素地塞米松 (DXM)，由于其亲水性和小尺寸，在封装后很容易从纳米载体中泄漏出来。这会导致治疗功效降低，从而对健康组织产生不利的不利影响。将 DXM 靶向肝脏的炎症细胞，如库普弗细胞或巨噬细胞，是一种有前途的方法，可以最大限度地减少典型的副作用。因此，对感兴趣细胞的受控运输和选择性现场释放至关重要。本研究的目的是开发基于 DXM 磷酸盐的多聚前药，并将其封装在二氧化硅纳米容器 (SiO 2NCs) 用于减少肝细胞的炎症反应。DXM 与接头分子共聚，在主链中引入 pH 可裂解的腙键并获得聚前药 (PDXM)。将 PDXM 封装到 SiO 2 NC 中提供了稳定的限制，避免了不受控制的泄漏。PDXMs 在酸性条件下降解，随后从 SiO 2 NCs 中释放出来。生物学研究表明，与未包封的 DXM 或可溶性聚前药相比，聚前药纳米制剂的抗炎能力显着增强。这些结果证明了将多前药策略与纳米载体介导的递送相结合的优势，以增强对水溶性低分子量药物递送的控制。
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