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Surface functionalization of doxorubicin-loaded liposomes with octa-arginine for enhanced anticancer activity

机译：八辛蛋白加载脂质体的表面官能化与八藻 - 精氨酸加强抗癌活性

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Doxorubicin-loaded PEGylated liposomes (commercially available as DOXIL® or Lipodox®) were surface functionalized with a cell-penetrating peptide, octa-arginine (R8). For this purpose, R8-peptide was conjugated to the polyethylene glycol–dioleoyl phosphatidylethanolamine (PEG–DOPE) amphiphilic co-polymer. The resultant R8–PEG–PE conjugate was introduced into the lipid bilayer of liposomes at 2 mol% of total lipid amount via spontaneous micelle-transfer technique. The liposomal modification did not alter the particle size distribution, as measured by Particle Size Analyzer and transmission electron microscopy (TEM). However, surface-associated cationic peptide increased zeta potential of the modified liposomes. R8-functionalized liposomes (R8-Dox-L) markedly increased the intracellular and intratumoral delivery of doxorubicin as measured by flow cytometry and visualizing by confocal laser scanning microscopy (CLSM) compared to unmodified Doxorubicin-loaded PEGylated liposomes (Dox-L). R8-Dox-L delivered loaded Doxorubicin to the nucleus, being released from the endosomes at higher efficiency compared to unmodified liposomes, which had marked entrapment in the endosomes at tested time point of 1 h. The significantly higher accumulation of loaded drug to its site of action for R8-Dox-L resulted in improved cytotoxic activity in vitro (cell viability of 58.5 ± 7% for R8-Dox-L compared to 90.6 ± 2% for Dox-L at Dox dose of 50 μg/mL for 4 h followed by 24 h incubation) and enhanced suppression of tumor growth (348 ± 53 mm3 for R8-Dox-L, compared to 504 ± 54 mm3 for Dox-L treatment) in vivo compared to Dox-L. R8-modification has the potential for broadening the therapeutic window of pegylated liposomal doxorubicin treatment, which could lead to lower non-specific toxicity.
机译：将载有阿霉素的聚乙二醇化脂质体（可作为DOXIL ®或Lipodox ®商购）用穿透细胞的肽八精氨酸（R8）进行表面功能化。为此，将R8肽与聚乙二醇-二油酰基磷脂酰乙醇胺（PEG-DOPE）两亲共聚物共轭。通过自发胶束转移技术，将所得的R8–PEG–PE共轭物以总脂质量的2 mol％引入脂质体的脂质双层中。脂质体修饰没有改变粒度分布，如通过粒度分析仪和透射电子显微镜（TEM）测量的。然而，表面缔合的阳离子肽增加了修饰脂质体的ζ电势。与未经修饰的载有阿霉素的聚乙二醇化脂质体（Dox-L）相比，通过流式细胞术和共聚焦激光扫描显微镜（CLSM）观察，R8功能化的脂质体（R8-Dox-L）显着增加了阿霉素的细胞内和肿瘤内递送。与未修饰的脂质体相比，R8-Dox-L将负载的阿霉素递送到细胞核，以比未修饰的脂质体更高的效率从内体释放，未修饰的脂质体在1 h的测试时间点已明显地包裹在内体中。 R8-Dox-L的作用位点上载药的积累明显更高，从而改善了体外的细胞毒性活性（R8-Dox-L的细胞生存力为58.5±7％，而Dox-L的细胞活力为90.6±2％ Dox剂量为50μg/ mL，持续4 h，然后孵育24 h），并增强了对肿瘤生长的抑制作用（R8-Dox-L的抑制作用为348±53 mm 3 ），而504±54 mm 3 。 R8修饰具有扩大聚乙二醇化脂质体阿霉素治疗的治疗范围的潜力，这可能导致较低的非特异性毒性。

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