Reducing Dendrimer Generation and PEG Chain Length Increases Drug Release and Promotes Anticancer Activity of PEGylated Polylysine Dendrimers Conjugated with Doxorubicin via a Cathepsin-Cleavable Peptide Linker,Molecular Pharmaceutics

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Reducing Dendrimer Generation and PEG Chain Length Increases Drug Release and Promotes Anticancer Activity of PEGylated Polylysine Dendrimers Conjugated with Doxorubicin via a Cathepsin-Cleavable Peptide Linker
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-08-14 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00581
Dharmini Mehta _{1,

2} , Nathania Leong ₁ , Victoria M. McLeod ₁ , Brian D. Kelly ₃ , Rashmi Pathak ₃ , David J. Owen ₃ , Christopher J.H. Porter _{1,

2} , Lisa M. Kaminskas _{1,

4}

Affiliation

PEGylation typically improves the systemic exposure and tumor biodistribution of polymeric drug delivery systems, but may also restrict enzyme access to peptide-based drug linkers. The impact of dendrimer generation (G4 vs G5) and PEG length (570 vs 1100 Da) on the pharmacokinetics, tumor biodistribution, drug release kinetics, and anticancer activity of a series of PEGylated polylysine dendrimers conjugated with doxorubicin via a cathepsin-B cleavable valine-citrulline linker was therefore investigated in rodents. Although the smallest G4 PEG570 dendrimer showed the most efficient cathepsin-mediated doxorubicin release, systemic exposure and tumor uptake were limited. The largest G5 PEG1100 dendrimer showed good tumor uptake and retention but restricted drug liberation and therefore limited anticancer activity. Superior anticancer activity was achieved using an intermediate sized dendrimer that showed better drug release kinetics, systemic exposure, tumor uptake, and retention. The data suggest that balancing PEG molecular weight and dendrimer size is critical when designing chemotherapeutic dendrimers.

中文翻译：

减少树状聚合物生成和PEG链长增加药物释放并促进通过组织蛋白酶可裂解的肽接头与阿霉素结合的PEG化多赖氨酸树状聚合物的抗癌活性。

聚乙二醇化通常可改善聚合物药物递送系统的全身暴露和肿瘤生物分布，但也可能限制酶对基于肽的药物接头的访问。树枝状大分子的生成（G4对G5）和PEG长度（570对1100 Da）对一系列通过组织蛋白酶B可裂解的缬氨酸与阿霉素结合的PEG化聚赖氨酸树状大分子的药代动力学，肿瘤生物分布，药物释放动力学和抗癌活性的影响因此，在啮齿动物中研究了-瓜氨酸连接体。尽管最小的G4 PEG570树状聚合物显示出最有效的组织蛋白酶介导的阿霉素释放，但全身暴露和肿瘤吸收受到限制。最大的G5 PEG1100树状聚合物显示出良好的肿瘤吸收和保留能力，但限制了药物的释放，因此抗癌活性有限。使用中等大小的树枝状大分子可获得优异的抗癌活性，该树枝状大分子显示出更好的药物释放动力学，全身暴露，肿瘤吸收和保留。数据表明，在设计化疗树枝状聚合物时，平衡PEG分子量和树枝状聚合物的大小至关重要。

更新日期：2018-08-14

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