Teixeira Sofia, Ferreira Débora, Rodrigues Ana Rita O, Rodrigues Ligia R, Castanheira Elisabete M S, Carvalho Maria Alice
Chemistry Centre of University of Minho (CQ-UM), Campus de Gualtar, 4710-057 Braga, Portugal.
Physics Centre of Minho and Porto Universities (CF-UM-UP), LaPMET (Laboratory of Physics for Materials and Emergent Technologies), University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
Pharmaceuticals (Basel). 2025 Aug 15;18(8):1210. doi: 10.3390/ph18081210.
Cancer is one of the deadliest diseases worldwide. Despite the existing treatments, the adverse side effects and the increasing drug resistance to the current therapies lead to a reduced quality of life for patients and poor prognosis. The pyrimido[5,4-]pyrimidine compound () was identified as a promising new anticancer drug due to its potent activity against colorectal and triple-negative breast cancers; however it showed poor aqueous solubility and safety profile. This study aimed the synthesis of compound , its encapsulation in liposomal formulations based on phosphatidylcholines (PC), the characterization of liposomal formulations and its biological evaluation. A new synthesis method for was developed. The compound was incorporated into different liposomal formulations. The hydrodynamic size, polydispersity, and zeta potential of loaded and non-loaded formulations were measured by DLS. The cytotoxic effects of compound , placebo nanoformulations, and -loaded nanoformulations were assessed in colorectal (HCT 116) and triple-negative breast cancer (MDA-MB-231) cell lines, as well as in non-tumor BJ-5ta cells. The compound was efficiently synthesized. The -loaded liposomal formulations exhibit sizes below 150 nm, low polydispersity, and long-time stability upon storage at 4 °C. The antitumor compound was encapsulated with excellent efficiency, and sustained release profiles were obtained. The compound showed high activity against HCT 116 (IC = 2.04 ± 0.45 µM) and MDA-MB-231 (IC = 5.24 ± 0.24 µM) cell lines. DPPC-containing formulations were effective against cancer cells, but showed toxicity comparable to free in BJ-5ta normal cells. Conversely, formulation displayed strong anticancer activity with residual toxicity to normal cells. The -loaded liposomal formulation, composed of 70% PC from egg yolk (EggPC) and 30% cholesterol (Chol), designated as , was the most promising formulation, showing effective anticancer activity in both cancer cell lines and a significant improvement in the safety profile which is of utmost importance to progress to the next phase of drug development.
癌症是全球最致命的疾病之一。尽管现有治疗方法存在，但当前疗法的不良副作用以及对药物耐药性的增加导致患者生活质量下降且预后不佳。嘧啶并[5,4 - ]嘧啶化合物（）因其对结直肠癌和三阴性乳腺癌具有强大活性而被确定为一种有前景的新型抗癌药物；然而，它表现出较差的水溶性和安全性。本研究旨在合成化合物，将其包封在基于磷脂酰胆碱（PC）的脂质体制剂中，对脂质体制剂进行表征并进行生物学评估。开发了一种新的化合物合成方法。该化合物被纳入不同的脂质体制剂中。通过动态光散射（DLS）测量负载和未负载制剂的流体动力学尺寸、多分散性和zeta电位。在结直肠癌（HCT 116）和三阴性乳腺癌（MDA - MB - 231）细胞系以及非肿瘤BJ - 5ta细胞中评估化合物、安慰剂纳米制剂和负载纳米制剂的细胞毒性作用。化合物被高效合成。负载的脂质体制剂尺寸低于150 nm，多分散性低，在4℃储存时具有长期稳定性。抗肿瘤化合物被高效包封，并获得了缓释曲线。化合物对HCT 116（IC = 2.04±0.45 μM）和MDA - MB - 231（IC = 5.24±0.24 μM）细胞系显示出高活性。含二棕榈酰磷脂酰胆碱（DPPC）的制剂对癌细胞有效，但在BJ - 5ta正常细胞中显示出与游离相当的毒性。相反，制剂显示出强大的抗癌活性且对正常细胞有残留毒性。由70％蛋黄来源的PC（蛋黄卵磷脂（EggPC））和30％胆固醇（Chol）组成的负载脂质体制剂，命名为，是最有前景的制剂，在两种癌细胞系中均显示出有效的抗癌活性，并且在安全性方面有显著改善，这对于进入药物开发的下一阶段至关重要。
