Department of Pharmacy, School of Medicine, University of Naples 'Federico II', Napoli, Italy.
Department of Chemical Sciences, University of Napoli "Federico II", Naples, Italy.
Int J Nanomedicine. 2024 Jun 18;19:6057-6084. doi: 10.2147/IJN.S453958. eCollection 2024.
The design of delivery tools that efficiently transport drugs into cells remains a major challenge in drug development for most pathological conditions. Triple-negative breast cancer (TNBC) is a very aggressive subtype of breast cancer with poor prognosis and limited effective therapeutic options.
In TNBC treatment, chemotherapy remains the milestone, and doxorubicin (Dox) represents the first-line systemic treatment; however, its non-selective distribution causes a cascade of side effects. To address these problems, we developed a delivery platform based on the self-assembly of amphiphilic peptides carrying several moieties on their surfaces, aimed at targeting, enhancing penetration, and therapy.
Through a single-step self-assembly process, we used amphiphilic peptides to obtain nanofibers decorated on their surfaces with the selected moieties. The surface of the nanofiber was decorated with a cell-penetrating peptide (gH625), an EGFR-targeting peptide (P22), and Dox bound to the cleavage sequence selectively recognized and cleaved by MMP-9 to obtain on-demand drug release. Detailed physicochemical and cellular analyses were performed.
The obtained nanofiber (NF-Dox) had a length of 250 nm and a diameter of 10 nm, and it was stable under dilution, ionic strength, and different pH environments. The biological results showed that the presence of gH625 favored the complete internalization of NF-Dox after 1h in MDA-MB 231 cells, mainly through a translocation mechanism. Interestingly, we observed the absence of toxicity of the carrier (NF) on both healthy cells such as HaCaT and TNBC cancer lines, while a similar antiproliferative effect was observed on TNBC cells after the treatment with the free-Dox at 50 µM and NF-Dox carrying 7.5 µM of Dox.
We envision that this platform is extremely versatile and can be used to efficiently carry and deliver diverse moieties. The knowledge acquired from this study will provide important guidelines for applications in basic research and biomedicine.
设计能够将药物有效递送至细胞内的输送工具仍然是药物开发的一大挑战，尤其是针对大多数病理情况。三阴性乳腺癌（TNBC）是一种侵袭性很强的乳腺癌亚型，预后较差，有效的治疗选择有限。
在 TNBC 治疗中，化疗仍然是一个里程碑，阿霉素（Dox）代表一线全身治疗；然而，其非选择性分布会引发一系列副作用。为了解决这些问题，我们开发了一种基于在其表面携带多个部分的两亲肽自组装的输送平台，旨在靶向、增强渗透和治疗。
通过一步自组装过程，我们使用两亲肽获得了表面带有所选部分的纳米纤维。纳米纤维的表面用穿膜肽（gH625）、表皮生长因子受体靶向肽（P22）和与 MMP-9 选择性识别和切割的裂解序列结合的 Dox 进行修饰，以获得按需药物释放。对其进行了详细的理化和细胞分析。
得到的纳米纤维（NF-Dox）长度为 250nm，直径为 10nm，在稀释、离子强度和不同 pH 环境下都很稳定。生物学结果表明，gH625 的存在有利于 NF-Dox 在 MDA-MB 231 细胞中 1 小时后完全内化，主要通过转位机制。有趣的是，我们观察到载体（NF）对健康细胞（如 HaCaT）和 TNBC 癌细胞系均无毒性，而在用 50µM 的游离 Dox 和携带 7.5µM Dox 的 NF-Dox 处理后，对 TNBC 细胞观察到类似的增殖抑制作用。
我们设想这个平台具有极高的通用性，可以有效地携带和输送多种部分。从这项研究中获得的知识将为基础研究和生物医学应用提供重要的指导。
