Dhandhukia Jugal P, Shi Pu, Peddi Santosh, Li Zhe, Aluri Suhaas, Ju Yaping, Brill Dab, Wang Wan, Janib Siti M, Lin Yi-An, Liu Shuanglong, Cui Honggang, MacKay J Andrew
Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy , Los Angeles, California 90089, United States.
Department of Chemical and Biomolecular Engineering, Johns Hopkins University , Baltimore, Maryland 21218, United States.
Bioconjug Chem. 2017 Nov 15;28(11):2715-2728. doi: 10.1021/acs.bioconjchem.7b00469. Epub 2017 Oct 12.
Recombinant protein-polymer scaffolds such as elastin-like polypeptides (ELPs) offer drug-delivery opportunities including biocompatibility, monodispersity, and multifunctionality. We recently reported that the fusion of FK-506 binding protein 12 (FKBP) to an ELP nanoparticle (FSI) increases rapamycin (Rapa) solubility, suppresses tumor growth in breast cancer xenografts, and reduces side effects observed with free-drug controls. This new report significantly advances this carrier strategy by demonstrating the coassembly of two different ELP diblock copolymers containing drug-loading and tumor-targeting domains. A new ELP nanoparticle (ISR) was synthesized that includes the canonical integrin-targeting ligand (Arg-Gly-Asp, RGD). FSI and ISR mixed in a 1:1 molar ratio coassemble into bifunctional nanoparticles containing both the FKBP domain for Rapa loading and the RGD ligand for integrin binding. Coassembled nanoparticles were evaluated for bifunctionality by performing in vitro cell-binding and drug-retention assays and in vivo MDA-MB-468 breast tumor regression and tumor-accumulation studies. The bifunctional nanoparticle demonstrated superior cell target binding and similar drug retention to FSI; however, it enhanced the formulation potency, such that tumor growth was suppressed at a 3-fold lower dose compared to an untargeted FSI-Rapa control. This data suggests that ELP-mediated scaffolds are useful tools for generating multifunctional nanomedicines with potential activity in cancer.
重组蛋白-聚合物支架，如类弹性蛋白多肽（ELP），为药物递送提供了诸多机会，包括生物相容性、单分散性和多功能性。我们最近报道，将FK-506结合蛋白12（FKBP）与ELP纳米颗粒（FSI）融合可提高雷帕霉素（Rapa）的溶解度，抑制乳腺癌异种移植瘤的生长，并减少游离药物对照组中观察到的副作用。本新报告通过展示含有药物负载和肿瘤靶向结构域的两种不同ELP二嵌段共聚物的共组装，显著推进了这种载体策略。合成了一种新的ELP纳米颗粒（ISR），其包含经典的整合素靶向配体（精氨酸-甘氨酸-天冬氨酸，RGD）。以1:1摩尔比混合的FSI和ISR共组装成具有双功能的纳米颗粒，既含有用于负载Rapa的FKBP结构域，又含有用于整合素结合的RGD配体。通过进行体外细胞结合和药物保留试验以及体内MDA-MB-468乳腺肿瘤消退和肿瘤积累研究，对共组装纳米颗粒的双功能进行了评估。双功能纳米颗粒表现出优于FSI的细胞靶向结合能力和相似的药物保留能力；然而，它增强了制剂效力，与未靶向的FSI-Rapa对照组相比，在低3倍剂量时就能抑制肿瘤生长。这些数据表明，ELP介导的支架是用于生成在癌症中具有潜在活性的多功能纳米药物的有用工具。
