Hybrid peptides as platform for synchronized combination therapy.
Hybrid peptides as platform for synchronized combination therapy.
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DOI：
10.1016/j.colsurfb.2023.113326
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发表时间：
2023-06
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联合治疗，其中两种或更多种治疗剂组合以靶向不同的细胞途径，是癌症治疗中的有效工具，但通常难以执行。在这里，我们提出了基于胶原蛋白肽的平台，该平台允许三种不同药剂的同步和共定位细胞递送。该肽是胶原蛋白和细胞穿透肽（CPP）之间的杂合物，其组装成异源三聚体螺旋并形成完全有机的高纵横比纳米颗粒。该方法的有效性用缀合至肽的N-末端的三种化学上不同的试剂（紫杉醇、阿霉素和5-氟尿嘧啶;用于临床治疗（ER）阳性和（PR）阳性乳腺癌的组合）进行测试。这种基于肽的药物递送系统的设计提供了几个优点：它避免了药物装载问题;消除了对正交合成的需要;并且允许多达三种药物的共定位递送（这导致每种药物具有相同的生物分布）。此外，已知杂合胶原/CPP肽增强细胞摄取并改善药物的溶解度。还计算了紫杉醇-多柔比星-5-氟尿嘧啶组合在增强功效方面的协同效应。我们设想自组装肽作为药物共递送的平台，其可以扩展成个性化组合的库，其还可以包括其他功能，如靶向或成像。
Combination therapy, where two or more therapeutic agents are combined to target different cellular pathways, is an effective tool in cancer treatment but often difficult to execute. Here we present the collagen peptide-based platform that allows for synchronous and colocalized cellular delivery of three different agents. The peptide is a hybrid between collagen and cell penetrating peptide (CPP) that assembles into a heterotrimer helix and forms fully organic, high aspect ratio nanoparticles. The validity of the approach was tested with three chemically different agents (Paclitaxel, Doxorubicin, and 5-Fluorouracil; a combination used in clinical treatment of (ER)-positive and (PR)-positive breast cancer) conjugated to N-terminus of the peptide. The design of this peptide-based drug delivery system provides several advantages: it avoids drug loading problems; removes the need for orthogonal synthesis; and allows for colocalized delivery of up to three drugs (which leads to the same biodistribution for each drug). In addition, hybrid collagen/CPP peptides are known to enhance cellular uptake and improve solubility of drugs. The synergistic effect, in terms of enhanced efficacy, of the Paclitaxel-Doxorubicin-5-Fluorouracil combination was also calculated. We envision self-assembling peptides as a platform for drug codelivery that can be expanded into a library of personalized combinations that may also include other functionalities like targeting or imaging.
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