Intravenous Administration of Dehydroxymethylepoxyquinomicin With Polymer Enhances the Inhibition of Pancreatic Carcinoma Growth in Mice
Intravenous Administration of Dehydroxymethylepoxyquinomicin With Polymer Enhances the Inhibition of Pancreatic Carcinoma Growth in Mice
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DOI：
10.21873/anticanres.15419
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发表时间：
2021-12-01
影响因子：
2
通讯作者：
Kitagawa, Yuko
中科院分区：
文献类型：
--
作者：
Fujisaki, Hiroto;Nakano, Yutaka;Kitagawa, Yuko
背景/目的：胰腺癌对细胞毒性药物和分子靶向药物具有耐药性，预后极差。核因子κ B （nf - κ B）在许多胰腺癌病例中被组成性激活。尽管NF-kappa B抑制剂dehydroxymethylepoxyquinomicin （DHMEQ）在胰腺癌模型中显示出抗癌作用，但其较差的溶解度限制了其在腹腔内给药的应用。材料与方法：聚（2-甲基丙烯酰氧乙基磷酸胆碱-共甲基丙烯酸正丁酯）（PMB）与DHMEQ形成稳定的聚合物聚集体。采用高效液相色谱-质谱（HPLC-MS）法测定DHMEQ与PMB在人血液中聚集的稳定性。通过体外细胞生长抑制实验和体内肿瘤生长抑制实验评价AsPC-1和MIA PaCa-2胰腺癌细胞的抗胰腺癌作用。结果：与PMB聚集的DHMEQ （PMBDHMEQ）在人血液中培养60 min后仍可检测到，而与羧甲基纤维素聚集的DHMEQ （CMC-DHMEQ）几乎检测不到。与CMC- DHMEQ相比，PMB-DHMEQ可显著抑制AsPC-1和MIA PaCa-2细胞的体外生长。与未治疗或cmc - dhmeq治疗的小鼠相比，静脉注射PMB-DHMEQ减少了肿瘤体积和肝转移。结论：与PMB聚集可提高DHMEQ的溶解度，在体外和体内均能有效抑制胰腺癌细胞的生长。
Background/Aim: Pancreatic cancer, which exhibits resistance to cytotoxic and molecular targeted drugs, has an extremely poor prognosis. Nuclear factor-kappa B (NF-kappa B) is constitutively activated in many pancreatic cancer cases. Although the NF-kappa B inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) has exhibited anti-cancer effects in pancreatic cancer models, its poor solubility limits its use to intraperitoneal administration. Materials and Methods: Poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) (PMB) forms stable polymer aggregates with DHMEQ. The stability of DHMEQ aggregated with PMB in the human blood was measured by high-performance liquid chromatography-mass spectrometry (HPLC-MS) ex vivo. Anti-pancreatic cancer effects in AsPC-1 and MIA PaCa-2 pancreatic cancer cells were evaluated by cell growth inhibition assay in vitro and tumor growth inhibition assay in vivo. Results: DHMEQ aggregated with PMB (PMBDHMEQ) remained detectable after 60 min of incubation in the human blood, whereas DHMEQ aggregated with carboxymethyl cellulose (CMC-DHMEQ) was barely detectable. PMB-DHMEQ significantly inhibited AsPC-1 and MIA PaCa-2 cell growth in vitro compared to CMC- DHMEQ. Intravenous administration of PMB-DHMEQ reduced the tumor volume and liver metastasis compared to untreated or CMC-DHMEQ-treated mice. Conclusion: Aggregation with PMB improved the solubility of DHMEQ, and effectively inhibited pancreatic cancer cell growth both in vitro and in vivo.