Frontiers in Chemistry ( IF 5.5 ) Pub Date : 2020-09-08 , DOI: 10.3389/fchem.2020.584242 Duy-Khiet Ho , Rebekka Christmann , Xabier Murgia , Chiara De Rossi , Sarah Frisch , Marcus Koch , Ulrich F. Schaefer , Brigitta Loretz , Didier Desmaele , Patrick Couvreur , Claus-Michael Lehr
Limited drug loading capacity (LC), mostly below 5% w/w, is a significant drawback of nanoparticulate drug delivery systems (DDS). Squalenoylation technology, which employs bioconjugation of squalenyl moiety and drug, allows self-assemble of nanoparticles (NPs) in aqueous media with significantly high LC (>30% w/w). The synthesis and particle preparation of squalenoylated prodrugs are, however, not facile for molecules with multiple reactive groups. Taking a different approach, we describe the synthesis of amphiphilic squalenyl derivatives (SqDs) as well as the physicochemical and biopharmaceutical characterizations of their self-assembled NPs as DDSs. The SqDs included in this study are (i) cationic squalenyl diethanolamine (ii) PEGylated SqD (PEG 750 Da), (iii) PEGylated SqD (PEG 3,000 Da), and (iv) anionic squalenyl hydrogen sulfate. All four SqDs self-assemble into NPs in a size range from 100 to 200 nm in an aqueous solution. Furthermore, all NP derivatives demonstrate appropriate biocompatibility and adequate colloidal stability in physiological relevant pH environments. The mucoprotein binding of PEGylated NPs is reduced compared to the charged NPs. Most importantly, this technology allows excellent LC (at maximum of 45% w/w) of a wide range of multifunctional compounds, varying in physicochemical properties and molecular weight. Interestingly, the drug release profile can be tuned by different loading methods. In summary, the SqD-based NPs appear as versatile drug delivery platforms.
中文翻译:
基于两亲角鲨烯基衍生物的多功能药物递送平台的合成和生物药物表征
有限的药物负载能力(LC),通常低于5%w / w,是纳米颗粒药物递送系统(DDS)的重大缺陷。角鲨烯酰化技术利用角鲨烯基部分和药物的生物缀合技术,可以使纳米颗粒(NPs)在具有高LC(> 30%w / w)的水性介质中自组装。然而,对于具有多个反应性基团的分子而言,角鲨酰化前药的合成和颗粒制备并不方便。采用不同的方法,我们描述了两亲角鲨烯基衍生物(SqDs)的合成,以及它们作为DDS的自组装NP的理化和生物药物表征。本研究中包括的SqD是(i)阳离子角鲨烯基二乙醇胺(ii)聚乙二醇化SqD(PEG 750 Da),(iii)聚乙二醇化SqD(PEG 3,000 Da)和(iv)阴离子角鲨烯基硫酸氢盐。所有四个SqD在水溶液中自组装成NP的大小范围为100到200 nm。此外,所有NP衍生物在生理相关的pH环境中均表现出适当的生物相容性和足够的胶体稳定性。与带电荷的NP相比,PEG化NP的粘蛋白结合减少。最重要的是,该技术可实现多种理化性质和分子量各不相同的多功能化合物的出色LC(最高45%w / w)。有趣的是,药物释放曲线可以通过不同的加载方法进行调整。总而言之,基于SqD的NP似乎是通用的药物递送平台。所有NP衍生物在生理相关的pH环境中均显示出适当的生物相容性和足够的胶体稳定性。与带电荷的NP相比,PEG化NP的粘蛋白结合减少。最重要的是,该技术可实现多种理化性质和分子量各不相同的多功能化合物的出色LC(最高45%w / w)。有趣的是,药物释放曲线可以通过不同的加载方法进行调整。总而言之,基于SqD的NP似乎是通用的药物递送平台。所有NP衍生物在生理相关的pH环境中均显示出适当的生物相容性和足够的胶体稳定性。与带电荷的NP相比,PEG化NP的粘蛋白结合减少。最重要的是,该技术可实现多种理化性质和分子量各不相同的多功能化合物的出色LC(最高45%w / w)。有趣的是,药物释放曲线可以通过不同的加载方法进行调整。总而言之,基于SqD的NP似乎是通用的药物递送平台。理化性质和分子量各不相同。有趣的是,药物释放曲线可以通过不同的加载方法进行调整。总而言之,基于SqD的NP似乎是通用的药物递送平台。理化性质和分子量各不相同。有趣的是,药物释放曲线可以通过不同的加载方法进行调整。总而言之,基于SqD的NP似乎是通用的药物递送平台。