Nano-Oncology and Translational Therapeutics Group, Health Research Institute of Santiago de Compostela (IDIS), SERGAS, 15706 Santiago de Compostela, Spain; Paul Papin ICO Cancer Center, INSERM 1232, Angers University, 49100 Angers, France.
Nano-Oncology and Translational Therapeutics Group, Health Research Institute of Santiago de Compostela (IDIS), SERGAS, 15706 Santiago de Compostela, Spain; Biomedical Research Networking Center on Oncology (CIBERONC), 28029 Madrid, Spain; CPIRN-IPG- Center of Potential and Innovation of Natural Resources, Polytechnic Institute of Guarda, Av. Dr. Francisco de Sá Carneiro, No. 50, 6300-559 Guarda, Portugal.
Int J Pharm. 2022 Apr 5;617:121618. doi: 10.1016/j.ijpharm.2022.121618. Epub 2022 Feb 24.
Senescent cells accumulation can contribute to the development of several age-related diseases, including cancer. Targeting and eliminating senescence cells, would allow the development of new therapeutic approaches for the treatment of different diseases. The 4N1Ks peptide, a 10 amino acid peptide derived from TSP1 protein, combines both features by targeting the CD47 receptor present in the surface of senescent cells and demonstrating senolytic activity, thereby representing a new strategy to take into account. Nonetheless, peptide drugs are known for their biopharmaceutical issues, such as low short half-life and tendency to aggregate, which reduces their bioavailability and limits their therapeutic potential. In order to overcome this problem, herein we propose the use of biodegradable and biocompatible sphingomyelin nanosystems (SNs), decorated with this peptide for the targeting of senescent cells. In order to efficiently associate the 4N1Ks peptide to the nanosystems while exposing it on their surface for an effective targeting of senescent cells, the 4N1Ks peptide was chemically conjugated to a PEGylated hydrophobic chain. The resulting SNs-4N1Ks (SNs-Ks), were extensively characterized for their physicochemical properties, by dynamic light scattering, multiple-angle dynamic light scattering, nanoparticle tracking analysis and atomic force microscopy. The SNs-Ks demonstrated suitable features in terms of size (∼100 nm), association efficiency (87.2 ± 6.9%) and stability in different biorelevant media. Cell toxicity experiments in MCF7 cancer cells indicated an improved cytotoxic effect of SNs-Ks, decreasing cancer cells capacity to form colonies, with respect to free peptide, and an improved hemocompatibility. Lastly, senescence escape preliminary experiments demonstrated the improvement of SNs-Ks senolytic activity of in chemotherapy-induced senescence model of breast cancer cells. Therefore, these results demonstrate for the first time the potential of the combination of SNs with 4N1Ks peptide for the development of innovative senolytic therapies to battle cancer.
衰老细胞的积累可能导致多种与年龄相关的疾病的发生，包括癌症。靶向和消除衰老细胞将为治疗不同疾病开发新的治疗方法。4N1Ks 肽是一种源自 TSP1 蛋白的 10 个氨基酸肽，通过靶向存在于衰老细胞表面的 CD47 受体并表现出溶衰老细胞活性，从而兼具这两种特性，代表了一种新的考虑策略。尽管如此，肽类药物因其生物制药问题而众所周知，例如半衰期短和倾向于聚集，这降低了它们的生物利用度并限制了它们的治疗潜力。为了克服这个问题，我们在这里提出使用可生物降解和生物相容的神经鞘磷脂纳米系统 (SNs)，并用这种肽对衰老细胞进行靶向修饰。为了有效地将 4N1Ks 肽与纳米系统结合，同时将其暴露在表面上以有效靶向衰老细胞，将 4N1Ks 肽化学偶联到聚乙二醇化的疏水链上。所得的 SNs-4N1Ks (SNs-Ks) 通过动态光散射、多角度动态光散射、纳米颗粒跟踪分析和原子力显微镜对其理化性质进行了广泛的表征。SNs-Ks 在尺寸（约 100nm）、结合效率（87.2±6.9%）和在不同生物相关介质中的稳定性方面表现出合适的特性。MCF7 癌细胞的细胞毒性实验表明，SNs-Ks 具有改善的细胞毒性作用，降低了癌细胞形成集落的能力，与游离肽相比，具有更好的血液相容性。最后，衰老逃逸初步实验表明，SNs-Ks 在化疗诱导的乳腺癌细胞衰老模型中的溶衰老细胞活性得到了改善。因此，这些结果首次证明了将 SNs 与 4N1Ks 肽结合用于开发创新的溶衰老细胞疗法来对抗癌症的潜力。
