Research Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilhã, Portugal.
Int J Pharm. 2023 Jun 10;640:123011. doi: 10.1016/j.ijpharm.2023.123011. Epub 2023 May 3.
Melanoma is the most aggressive form of skin cancer, with increasing incidence and mortality rates. To overcome current treatment limitations, a hybrid molecule (HM) combining a triazene and a sulfur L-tyrosine analogue, was recently synthesized, incorporated in long blood circulating liposomes (LIP HM) and validated in an immunocompetent melanoma model. The present work constitutes a step forward in the therapeutic assessment of HM formulations. Here, human melanoma cells, A375 and MNT-1, were used and dacarbazine (DTIC), a triazene drug clinically available as first-line treatment for melanoma, constituted the positive control. In cell cycle analysis, A375 cells, after 24-h incubation with HM (60 μM) and DTIC (70 μM), resulted in a 1.2 fold increase (related to control) in the percentage of cells in G0/G1 phase. The therapeutic activity was evaluated in a human murine melanoma model (subcutaneously injected with A375 cells) to most closely resemble the human pathology. Animals treated with LIP HM exhibited the highest antimelanoma effect resulting in a 6-, 5- and 4-fold reduction on tumor volume compared to negative control, Free HM and DTIC groups, respectively. No toxic side effects were detected. Overall, these results constitute another step forward in the validation of the antimelanoma activity of LIP HM, using a murine model that more accurately simulates the pathology that occurs in human patients.
黑色素瘤是最具侵袭性的皮肤癌，其发病率和死亡率呈上升趋势。为了克服当前治疗的局限性，最近合成了一种结合三嗪和硫代 L-酪氨酸类似物的混合分子（HM），并将其整合到长循环血的脂质体（LIP HM）中，并在免疫功能正常的黑色素瘤模型中进行了验证。本研究是 HM 制剂治疗评估的一个进步。在此，使用人黑色素瘤细胞 A375 和 MNT-1，并且三嗪药物达卡巴嗪（DTIC）作为黑色素瘤的一线治疗药物构成阳性对照。在细胞周期分析中，A375 细胞在用 HM（60 μM）和 DTIC（70 μM）孵育 24 小时后，G0/G1 期细胞的百分比增加了 1.2 倍（与对照组相比）。在人鼠黑色素瘤模型（皮下注射 A375 细胞）中评估了治疗活性，以最接近人类病理学。用 LIP HM 治疗的动物表现出最高的抗黑色素瘤作用，与阴性对照、游离 HM 和 DTIC 组相比，肿瘤体积分别减少了 6、5 和 4 倍。未检测到毒性副作用。总的来说，这些结果是使用更准确地模拟人类患者发生的病理学的鼠模型验证 LIP HM 的抗黑色素瘤活性的又一步。
