Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Colloids Surf B Biointerfaces. 2010 Nov 1;81(1):313-20. doi: 10.1016/j.colsurfb.2010.07.025. Epub 2010 Jul 15.
The aim of the study was to develop a polymeric nano-carrier based on methoxy poly(ethylene oxide)-b-poly(epsilon-caprolactone) (MePEO-b-PCL) for the optimum solubilization and delivery of Amphotericin B (AmB). For this purpose, MePEO-b-PCL block co-polymers containing palmitoyl substituent on PCL (at a 100% substitution level) were synthesized through preparation of substituted monomer, that is, alpha-palmitoyl-epsilon-caprolactone, and further ring opening polymerization of this monomer by methoxy PEO (5000 g mol(-1)) using stannous octoate as catalyst. Prepared block co-polymers were characterized for their molecular weight by (1)H NMR and gel permeation chromatography, and assembled to polymeric nano-carriers. The self-assembly of synthesized MePEO-b-PPaCL to spherical particles of nanometer size range was shown by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The efficacy of nano-carriers formed from this structure (abbreviated as MePEO-b-PPaCL) in comparison to unmodified MePEO-b-PCL and those with benzyl and cholesteryl substituent on PCL (abbreviated as MePEO-b-PBCL and MePEO-b-PChCL, respectively) on the solubilization and hemolytic activity of AmB against rat red blood cells was assessed. Under identical conditions, the maximum solubilization of AmB was achieved by nano-carriers prepared from MePEO-b-PPaCL (436 microg/mL), followed by MePEO-b-PChCL (355 microg/mL), MePEO-b-PBCL (296 microg/mL) and MePEO-b-PCL (222 microg/mL). The hemolytic activity of AmB was reduced the most by its encapsulation in MePEO-b-PChCL nano-particles which showed only 7% hemolysis at 30 microg/mL AmB concentration. This was followed by MePEO-b-PCL nano-particles which illustrated 15% hemolysis, MePEO-b-PPaCL with 40% hemolysis and MePEO-b-PBCL with 60% hemolysis at 30 microg/mL AmB concentrations, respectively. In contrast Fungizone showed 90% hemolysis at 30 microg/mL AmB concentration. Based on the improved solubility and reduced hemolytic activity, the MePEO-b-PChCL nano-carriers are considered as optimum structures for AmB delivery.
本研究旨在开发一种基于甲氧基聚（乙二醇）-b-聚（己内酯）（MePEO-b-PCL）的聚合物纳米载体，以实现两性霉素 B（AmB）的最佳溶解和递药。为此，通过制备取代单体，即α-棕榈酰-ε-己内酯，并进一步用辛酸亚锡作为催化剂通过甲氧基 PEO（5000 g/mol）开环聚合，合成了在 PCL 上具有棕榈酰取代基（取代度为 100%）的 MePEO-b-PCL 嵌段共聚物。通过（1）H NMR 和凝胶渗透色谱法对合成的嵌段共聚物的分子量进行了表征，并将其组装成聚合物纳米载体。动态光散射（DLS）和透射电子显微镜（TEM）表明，合成的 MePEO-b-PPaCL 自组装成纳米级球形颗粒。与未改性的 MePEO-b-PCL 以及在 PCL 上具有苄基和胆固醇取代基的 MePEO-b-PBCL 和 MePEO-b-PChCL（分别缩写为 MePEO-b-PPaCL、MePEO-b-PBCL 和 MePEO-b-PChCL）相比，评估了这种结构（缩写为 MePEO-b-PPaCL）形成的纳米载体对 AmB 溶解和对大鼠红细胞溶血活性的影响。在相同条件下，由 MePEO-b-PPaCL 制备的纳米载体实现了最大的 AmB 溶解度（436μg/mL），其次是 MePEO-b-PChCL（355μg/mL）、MePEO-b-PBCL（296μg/mL）和 MePEO-b-PCL（222μg/mL）。AmB 的溶血活性通过其封装在 MePEO-b-PChCL 纳米颗粒中而降低最多，在 30μg/mL AmB 浓度下仅显示 7%溶血。其次是 MePEO-b-PCL 纳米颗粒，在 30μg/mL AmB 浓度下分别显示 15%溶血、MePEO-b-PPaCL 40%溶血和 MePEO-b-PBCL 60%溶血。相比之下，两性霉素 B 浓度为 30μg/mL 时，两性霉素 B 的溶血活性为 90%。基于提高的溶解度和降低的溶血活性，MePEO-b-PChCL 纳米载体被认为是 AmB 递送的最佳结构。
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