Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, 52242, USA.
Department of Pharmaceutics, Minia University, Minia, 61519, Egypt.
Small. 2024 Oct;20(41):e2302931. doi: 10.1002/smll.202302931. Epub 2023 Jul 31.
Combinations of chemotherapeutic agents comprise a clinically feasible approach to combat cancers that possess resistance to treatment. Type II endometrial cancer is typically associated with poor outcomes and the emergence of chemoresistance. To overcome this challenge, a combination therapy is developed comprising a novel ciprofloxacin derivative-loaded PEGylated polymeric nanoparticles (CIP2b-NPs) and paclitaxel (PTX) against human type-II endometrial cancer (Hec50co with loss of function p53). Cytotoxicity studies reveal strong synergy between CIP2b and PTX against Hec50co, and this is associated with a significant reduction in the IC of PTX and increased G2/M arrest. Upon formulation of CIP2b into PEGylated polymeric nanoparticles, tumor accumulation of CIP2b is significantly improved compared to its soluble counterpart; thus, enhancing the overall antitumor activity of CIP2b when co-administered with PTX. In addition, the co-delivery of CIP2b-NPs with paclitaxel results in a significant reduction in tumor progression. Histological examination of vital organs and blood chemistry was normal, confirming the absence of any apparent off-target toxicity. Thus, in a mouse model of human endometrial cancer, the combination of CIP2b-NPs and PTX exhibits superior therapeutic activity in targeting human type-II endometrial cancer.
化疗药物联合应用是一种临床可行的方法，可用于治疗对治疗有抗药性的癌症。Ⅱ型子宫内膜癌通常与不良预后和化疗耐药的出现有关。为了克服这一挑战，开发了一种联合治疗方法，包括一种新型环丙沙星衍生物负载的聚乙二醇化聚合物纳米粒（CIP2b-NPs）和紫杉醇（PTX），用于治疗人类Ⅱ型子宫内膜癌（Hec50co，p53 功能丧失）。细胞毒性研究表明，CIP2b 与 PTX 对 Hec50co 具有强烈的协同作用，这与 PTX 的 IC 显著降低和 G2/M 期阻滞增加有关。将 CIP2b 制成聚乙二醇化聚合物纳米粒后，与游离的 CIP2b 相比，CIP2b 在肿瘤中的积累显著增加；因此，当与 PTX 联合使用时，CIP2b 的整体抗肿瘤活性增强。此外，CIP2b-NPs 与紫杉醇的共同递送导致肿瘤进展显著减少。重要器官的组织学检查和血液化学检查均正常，证实无明显的脱靶毒性。因此，在人子宫内膜癌的小鼠模型中，CIP2b-NPs 和 PTX 的联合应用在靶向人Ⅱ型子宫内膜癌方面表现出优越的治疗活性。
