Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain; Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada 18071, Spain; Biosanitary Institute of Granada (ibs. GRANADA), Granada 18014, Spain.
Nanobiotechnology for Life Sciences Laboratory, Department of Chemistry in Pharmaceutical Science, Faculty of Pharmacy, Universidad Complutense de Madrid (UCM), Plaza Ramón y Cajal s/n, E-28040 Madrid, Spain.
Eur J Pharm Biopharm. 2023 Dec;193:241-253. doi: 10.1016/j.ejpb.2023.11.011. Epub 2023 Nov 14.
Among the most harmful tumors detected in the human body, such as breast, colon, brain or pancreas, breast (BC) and colorectal cancer (CRC) are the first and third most frequent cancer worldwide, respectively. The current existing chemotherapeutic treatments present serious side effects due to their intravenous administration can induce cytotoxicity in healthy cells. Thus, new treatment methods based on drug-loaded polymeric nanofibers (NFs) have gained significant potential for their use in localized cancer chemotherapy. Here, a deep in vitro comparative analysis between maslinic acid (MA) and a tyramine-maslinic acid (TMA) derivative is initially performed. This analysis includes a proliferation, and a cell cycle assay, and a genotoxicity, antiangiogenic and apoptosis study. Then, the TMA derivative has been incorporated into electrospun polymeric NFs obtaining an implantable dressing material with antitumor activity. Two types of patches containing TMA-loaded polymeric NFs of poly(caprolactone) (PCL), and a mixture of polylactic acid/poly(4-vinylpyridine) (PLA/PVP) were fabricated by the electrospinning technique. The characterization of the drug-loaded NFs showed an encapsulation capacity of 0.027 mg TMA/mg PCL and 0.024 mg TMA/mg PLA/PVP. Then, the cytotoxic activity of both polymeric systems was tested in CRC (T84), BC (MCF-7) and a no tumor (L929) cell lines exposed to TMA-loaded NFs and blank NFs for 48 h. Moreover, cell cycle assay, genotoxicity, angiogenesis and apoptosis tests were carried out to study the mechanism of action of TMA. Blank NFs showed no-toxicity in all cell lines tested and both drug-loaded NFs significantly reduced cell proliferation (relative proliferation of ≈44 % and ≈25 % respectively). Therefore, TMA was less genotoxic than maslinic acid (MA), and reduced VEGFA expression in MCF-7 cells (1.32 and 2.12-fold for MA and TMA respectively). These results showed that TMA-loaded NFs could constitute a promising biocompatible and biodegradable nanoplatform for the local treatment of solid tumors such as CRC or BC.
在人体中检测到的最具危害性的肿瘤中，例如乳腺癌、结肠癌、脑癌或胰腺癌，乳腺癌（BC）和结直肠癌（CRC）分别是全球第一和第三大常见癌症。由于目前现有的化学疗法治疗方法通过静脉给药会在健康细胞中引起细胞毒性，因此，基于载药聚合物纳米纤维（NFs）的新治疗方法因其在局部癌症化疗中的应用而具有显著的潜力。在这里，最初对熊果酸（MA）和酪胺-熊果酸（TMA）衍生物进行了深入的体外比较分析。该分析包括增殖和细胞周期测定，以及遗传毒性、抗血管生成和细胞凋亡研究。然后，将 TMA 衍生物掺入到电纺聚合物 NF 中，获得具有抗肿瘤活性的可植入敷料材料。通过电纺技术制备了含有 TMA 负载聚合物 NF 的两种类型的贴片，聚己内酯（PCL）和聚乳酸/聚（4-乙烯基吡啶）（PLA/PVP）的混合物。药物负载 NF 的表征表明，TMA 的包封能力为 0.027 mg TMA/mg PCL 和 0.024 mg TMA/mg PLA/PVP。然后，在暴露于载有 TMA 的 NF 和空白 NF 的情况下，用 CRC（T84）、BC（MCF-7）和非肿瘤（L929）细胞系测试两种聚合物系统的细胞毒性活性 48 小时。此外，还进行了细胞周期测定、遗传毒性、血管生成和细胞凋亡测试，以研究 TMA 的作用机制。空白 NF 在所有测试的细胞系中均无毒性，两种载药 NF 均显著降低了细胞增殖（相对增殖分别约为 44%和 25%）。因此，TMA 的遗传毒性小于熊果酸（MA），并降低了 MCF-7 细胞中 VEGFA 的表达（MA 和 TMA 分别为 1.32 和 2.12 倍）。这些结果表明，TMA 负载 NF 可构成一种有前途的生物相容性和可生物降解的纳米平台，用于局部治疗 CRC 或 BC 等实体瘤。
