Repeated sequential administration of pegylated emulsion of SU5416 and liposomal paclitaxel enhances anti-tumor effect in 4T1 breast cancer-bearing mice

IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Masato Maruyama , Reiya Torii , Hazuki Matsui , Hiroki Hayashi , Ken-ichi Ogawara , Kazutaka Higaki
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引用次数: 0

Abstract

To improve vascular normalization strategy for intractable triple-negative breast cancer 4T1, we examined the anti-tumor effects of repeated sequential administration of polyethylene glycol (PEG)-modified emulsion of SU5416 (PE-SU5416), a vascular endothelial growth factor (VEGF) receptor-2 kinase inhibitor, and PEG-modified liposomal paclitaxel (PL-PTX) in mice bearing 4T1 cells. Three sequential administrations (Seq×3) of PE-SU5416 and PL-PTX exhibited significantly higher anti-tumor activity than a single sequential administration (Seq×1). The tumor vasculatures were structurally normalized until after two PE-SU5416 (PE-SU5416×2) or sequential (Seq×2) administrations, while the improvement in vascular function, such as oxygen supply, blood flow, and PEG-liposomal distribution, was evident until after three administrations of PE-SU5416 (PE-SU5416×3) and Seq×3. Although some discrepancies between the structural and functional improvement in tumor vasculatures were observed after PE-SU5416×3 and Seq×3, cancer-associated fibroblasts (CAFs) and collagen levels were significantly reduced after PE-SU5416×2, PE-SU5416×3, Seq×2, and Seq×3, suggesting that a possible decrease in interstitial fluid pressure due to the reduction in CAFs and collagen would have compensated for vascular function. Furthermore, PE-SU5416×2, PE-SU5416×3, Seq×2, and Seq×3 significantly decreased tumor growth factor-β (TGF-β), an activator of CAFs, in tumor tissues, suggesting that the reduction in TGF-β levels by PE-SU5416 suppresses CAF activation.

Abstract Image

重复序贯给药聚乙二醇乳剂SU5416和脂质体紫杉醇可增强4T1乳腺癌小鼠的抗肿瘤作用。
为了改善顽固性三阴性乳腺癌4 T1的血管正常化策略,我们在携带4 T1细胞的小鼠中,研究了重复顺序给药聚乙二醇(PEG)修饰的SU5416乳剂(PE-SU5416)(血管内皮生长因子(VEGF)受体2激酶抑制剂)和聚乙二醇修饰的脂质体紫杉醇(l - ptx)的抗肿瘤作用。PE-SU5416和PL-PTX三次顺序给药(Seq × 3)比单次顺序给药(Seq × 1)显示出更高的抗肿瘤活性。在两次PE-SU5416 (PE-SU5416 × 2)或连续(Seq × 2)给药后,肿瘤血管结构恢复正常,而在三次PE-SU5416 (PE-SU5416 × 3)和Seq × 3给药后,血管功能(如氧供应、血流量和peg -脂质体分布)的改善是明显的。虽然有些差异肿瘤血管的结构和功能改进后观察PE-SU5416 × 3和Seq × 3,癌症相关的成纤维细胞(保护)和胶原蛋白含量显著降低后PE-SU5416 × 2,PE-SU5416 × 3,Seq × 2,和Seq × 3,表明孔隙流体压力下降可能由于减少战乱国家和胶原蛋白会补偿血管功能。此外,PE-SU5416 × 2、PE-SU5416 × 3、Seq × 2和Seq × 3显著降低肿瘤组织中CAF的激活剂肿瘤生长因子-β (TGF-β),提示PE-SU5416降低TGF-β水平抑制CAF的激活。
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来源期刊
CiteScore
8.80
自引率
4.10%
发文量
211
审稿时长
36 days
期刊介绍: The European Journal of Pharmaceutics and Biopharmaceutics provides a medium for the publication of novel, innovative and hypothesis-driven research from the areas of Pharmaceutics and Biopharmaceutics. Topics covered include for example: Design and development of drug delivery systems for pharmaceuticals and biopharmaceuticals (small molecules, proteins, nucleic acids) Aspects of manufacturing process design Biomedical aspects of drug product design Strategies and formulations for controlled drug transport across biological barriers Physicochemical aspects of drug product development Novel excipients for drug product design Drug delivery and controlled release systems for systemic and local applications Nanomaterials for therapeutic and diagnostic purposes Advanced therapy medicinal products Medical devices supporting a distinct pharmacological effect.
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