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Evaluation of polyvinylpyrrolidone and block copolymer micelle encapsulation of serine chlorin e6 and chlorin e4 on their reactivity towards albumin and transferrin and their cell uptake.
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2019-11-02 , DOI: 10.1016/j.jconrel.2019.10.010
Ilche Gjuroski 1 , Eleftheria Girousi 1 , Christoph Meyer 1 , Damian Hertig 2 , Darko Stojkov 3 , Michaela Fux 4 , Nicolas Schnidrig 1 , Jan Bucher 1 , Sara Pfister 1 , Luca Sauser 1 , Hans-Uwe Simon 3 , Peter Vermathen 5 , Julien Furrer 1 , Martina Vermathen 1
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2019-11-02 , DOI: 10.1016/j.jconrel.2019.10.010
Ilche Gjuroski 1 , Eleftheria Girousi 1 , Christoph Meyer 1 , Damian Hertig 2 , Darko Stojkov 3 , Michaela Fux 4 , Nicolas Schnidrig 1 , Jan Bucher 1 , Sara Pfister 1 , Luca Sauser 1 , Hans-Uwe Simon 3 , Peter Vermathen 5 , Julien Furrer 1 , Martina Vermathen 1
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Encapsulation of porphyrinic photosensitizers (PSs) into polymeric carriers plays an important role in enhancing their efficiency as drugs in photodynamic therapy (PDT). Porphyrin aggregation and low solubility as well as the preservation of the advantageous photophysical properties pose a challenge on the design of efficient PS-carrier systems. Block copolymer micelles (BCMs) and polyvinylpyrrolidone (PVP) are promising drug delivery vehicles for physical entrapment of PSs. BCMs exhibit enhanced dynamics as compared to the less flexible PVP network. In the current work the question is addressed how these different dynamics affect PS encapsulation, release from the carrier, reaction with serum proteins, and cellular uptake. The porphyrinic compounds serine-amide of chlorin e6 (SerCE) and chlorin e4 (CE4) were used as model PSs with different lipophilicity and aggregation properties. 1H NMR and fluorescence spectroscopy were applied to study their interactions with PVP and BCMs consisting of Kolliphor P188 (KP). Both chlorins were well encapsulated by the carriers and had improved photophysical properties. Compared to SerCE, the more lipophilic CE4 exhibited stronger hydrophobic interactions with the BCM core, stabilizing the system and preventing exchange with the surrounding medium as was shown by NMR NOESY and DOSY experiments. PVP and BCMs protected the encapsulated chlorins against interaction with human transferrin (Tf). However, SerCE and CE4 were released from BCMs in favor of binding to human serum albumin (HSA) while PVP prevented interaction with HSA. Fluorescence spectroscopic studies revealed that HSA binds to the surface of PVP forming a protein corona. PVP and BCMs reduced cellular uptake of the chlorins. However, encapsulation into BCMs resulted in more efficient cell internalization for CE4 than for SerCE. HSA significantly lowered both, free and carrier-mediated cell uptake for CE4 and SerCE. In conclusion, PVP appears as the more universal delivery system covering a broad range of host molecules with respect to polarity, whereas BCMs require a higher drug-carrier compatibility. Poorly soluble hydrophobic PSs benefit stronger from BCM-type carriers due to enhanced bioavailability through disaggregation and solubilization allowing for more efficient cell uptake. In addition, increased PS-carrier hydrophobic interactions have a stabilizing effect. For more hydrophilic PSs, the main advantage of polymeric carriers like PVP or poloxamer micelles lies in their protection during the transport through the bloodstream. HSA binding plays an important role for drug release and cell uptake in carrier-mediated delivery to the target tissue.
中文翻译：
聚乙烯吡咯烷酮和嵌段共聚物胶束封装丝氨酸二氢卟酚e6和二氢卟酚e4对白蛋白和转铁蛋白的反应性及其细胞摄取的评估。
将卟啉光敏剂（PSs）封装到聚合物载体中在提高其作为光动力疗法（PDT）中药物的效率方面起着重要作用。卟啉聚集和低溶解度以及有利的光物理性质的保留对有效PS载体系统的设计提出了挑战。嵌段共聚物胶束（BCM）和聚乙烯吡咯烷酮（PVP）是用于PS物理包裹的有前途的药物输送工具。与不那么灵活的PVP网络相比，BCM表现出增强的动态性。在当前的工作中，需要解决的问题是这些不同的动力学如何影响PS封装，从载体中释放，与血清蛋白反应以及细胞摄取。卟啉e6（SerCE）和卟啉e4（CE4）的卟啉-丝氨酸酰胺被用作具有不同亲脂性和聚集特性的模型PS。1 H NMR和荧光光谱用于研究它们与由Kolliphor P188（KP）组成的PVP和BCM的相互作用。两种二氢卟酚均被载体很好地包裹，并具有改善的光物理性质。与SerCE相比，亲脂性更高的CE4与BCM核之间表现出更强的疏水性相互作用，从而稳定了系统并阻止了与周围介质的交换（如NMR NOESY和DOSY实验所示）。PVP和BCM保护封装的二氢卟酚免受与人类转铁蛋白（Tf）的相互作用。但是，SerCE和CE4从BCM中释放出来，有利于与人血清白蛋白（HSA）结合，而PVP阻止了与HSA的相互作用。荧光光谱研究表明，HSA与PVP的表面结合形成蛋白质电晕。PVP和BCM减少了细胞对二氢卟酚的摄取。但是，封装到BCM中导致CE4的细胞内化比SerCE更为有效。HSA显着降低了CE4和SerCE的游离和载体介导的细胞摄取。总之，PVP似乎是一种更通用的递送系统，涵盖了极性范围广泛的宿主分子，而BCM则需要更高的药物-载体相容性。难溶的疏水性PS通过分解和溶解提高了生物利用度，使BCM型载体更具优势，从而可以更有效地吸收细胞。另外，增加的PS-载体疏水相互作用具有稳定作用。对于更亲水的PS，诸如PVP或泊洛沙姆胶束之类的聚合物载体的主要优势在于它们在通过血液运输过程中的保护作用。HSA结合在载体介导的向靶组织的递送中对于药物释放和细胞摄取起着重要作用。
更新日期：2019-11-02
中文翻译：
聚乙烯吡咯烷酮和嵌段共聚物胶束封装丝氨酸二氢卟酚e6和二氢卟酚e4对白蛋白和转铁蛋白的反应性及其细胞摄取的评估。
将卟啉光敏剂（PSs）封装到聚合物载体中在提高其作为光动力疗法（PDT）中药物的效率方面起着重要作用。卟啉聚集和低溶解度以及有利的光物理性质的保留对有效PS载体系统的设计提出了挑战。嵌段共聚物胶束（BCM）和聚乙烯吡咯烷酮（PVP）是用于PS物理包裹的有前途的药物输送工具。与不那么灵活的PVP网络相比，BCM表现出增强的动态性。在当前的工作中，需要解决的问题是这些不同的动力学如何影响PS封装，从载体中释放，与血清蛋白反应以及细胞摄取。卟啉e6（SerCE）和卟啉e4（CE4）的卟啉-丝氨酸酰胺被用作具有不同亲脂性和聚集特性的模型PS。1 H NMR和荧光光谱用于研究它们与由Kolliphor P188（KP）组成的PVP和BCM的相互作用。两种二氢卟酚均被载体很好地包裹，并具有改善的光物理性质。与SerCE相比，亲脂性更高的CE4与BCM核之间表现出更强的疏水性相互作用，从而稳定了系统并阻止了与周围介质的交换（如NMR NOESY和DOSY实验所示）。PVP和BCM保护封装的二氢卟酚免受与人类转铁蛋白（Tf）的相互作用。但是，SerCE和CE4从BCM中释放出来，有利于与人血清白蛋白（HSA）结合，而PVP阻止了与HSA的相互作用。荧光光谱研究表明，HSA与PVP的表面结合形成蛋白质电晕。PVP和BCM减少了细胞对二氢卟酚的摄取。但是，封装到BCM中导致CE4的细胞内化比SerCE更为有效。HSA显着降低了CE4和SerCE的游离和载体介导的细胞摄取。总之，PVP似乎是一种更通用的递送系统，涵盖了极性范围广泛的宿主分子，而BCM则需要更高的药物-载体相容性。难溶的疏水性PS通过分解和溶解提高了生物利用度，使BCM型载体更具优势，从而可以更有效地吸收细胞。另外，增加的PS-载体疏水相互作用具有稳定作用。对于更亲水的PS，诸如PVP或泊洛沙姆胶束之类的聚合物载体的主要优势在于它们在通过血液运输过程中的保护作用。HSA结合在载体介导的向靶组织的递送中对于药物释放和细胞摄取起着重要作用。
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