Gomes Isabela Pereira, Silva Juliana de Oliveira, Cassali Geovanni Dantas, De Barros André Luís Branco, Leite Elaine Amaral
Department of Pharmaceutical Products, Faculty of Pharmacy, Federal University of Minas Gerais, Av. Antônio Carlos, 6627, Belo Horizonte 31270-901, MG, Brazil.
Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Av. Antônio Carlos, 6627, Belo Horizonte 31270-901, MG, Brazil.
Pharmaceutics. 2023 Feb 9;15(2):583. doi: 10.3390/pharmaceutics15020583.
Cisplatin (CDDP) is a potent antitumor drug used in first-line chemotherapy against several solid tumors, including breast cancer. However, toxicities and drug resistance limit its clinical application. Thermosensitive liposome (TSL) functionalized with hyaluronic acid (HA) containing cisplatin (TSL-CDDP-HA) was developed by our research group aiming to promote the release of CDDP in the tumor region under hyperthermia conditions, as well as to decrease toxicity. Thus, this study aimed to evaluate this new formulation (HA-coated TSL-CDDP) concerning in vitro behavior and in vivo toxicity compared to non-coated TSL-CDDP and free CDDP. Cytotoxicity assays and nuclear morphology were carried out against triple-negative breast cancer cells (MDA-MB-231), while an in vivo toxicity study was performed using healthy Swiss mice. The results showed an increase (around 3-fold) in cytotoxicity of the cationic formulation (non-coated TSL-CDDP) compared to free CDDP. On the other hand, TSL-CDDP treatment induced the appearance of 2.5-fold more senescent cells with alteration of nuclear morphology than the free drug after hyperthermia condition. Furthermore, the association of liposomal formulations treatment with hyperthermia increased the percentage of apoptotic cells compared to those without heating. The percentage of apoptotic cells was 1.7-fold higher for TSL-CDDP-HA than for TSL-CDDP. For the in vivo toxicity data, the TSL-CDDP treatment was also toxic to healthy cells, inducing nephrotoxicity with a significant increase in urea levels compared to the saline control group (73.1 ± 2.4 vs. 49.2 ± 2.8 mg/mL). On the other hand, the HA-coated TSL-CDDP eliminated the damages related to the use of CDDP since the animals did not show changes in hematological and biochemical examinations and histological analyses. Thus, data suggest that this new formulation is a potential candidate for the intravenous therapy of solid tumors.
顺铂（CDDP）是一种强效抗肿瘤药物，用于包括乳腺癌在内的多种实体瘤的一线化疗。然而，毒性和耐药性限制了其临床应用。我们的研究小组开发了用含顺铂的透明质酸（HA）功能化的热敏脂质体（TSL）（TSL-CDDP-HA），旨在促进顺铂在热疗条件下于肿瘤区域释放，并降低毒性。因此，本研究旨在评估这种新制剂（HA包被的TSL-CDDP）与未包被的TSL-CDDP和游离CDDP相比的体外行为和体内毒性。针对三阴性乳腺癌细胞（MDA-MB-231）进行了细胞毒性测定和核形态分析，同时使用健康的瑞士小鼠进行了体内毒性研究。结果显示，与游离CDDP相比，阳离子制剂（未包被的TSL-CDDP）的细胞毒性增加（约3倍）。另一方面，热疗后，TSL-CDDP处理诱导出现的衰老细胞比游离药物多2.5倍，且核形态发生改变。此外，与未加热的情况相比，脂质体制剂处理与热疗相结合增加了凋亡细胞的百分比。TSL-CDDP-HA的凋亡细胞百分比比TSL-CDDP高1.7倍。对于体内毒性数据，TSL-CDDP处理对健康细胞也有毒性，与生理盐水对照组相比，诱导肾毒性，尿素水平显著升高（73.1±2.4 vs. 49.2±2.8 mg/mL）。另一方面，HA包被的TSL-CDDP消除了与使用CDDP相关的损害，因为动物在血液学、生化检查和组织学分析中未显示变化。因此，数据表明这种新制剂是实体瘤静脉治疗的潜在候选药物。
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