基于NMR的4T1荷瘤小鼠脾脏受不同给药方式影响的代谢组学研究

联合阿霉素和紫杉醇治疗肿瘤的策略在临床上已有广泛应用，为了进一步借助纳米载体对肿瘤组织的靶向优势，以良好生物相容性纳米载体包埋阿霉素和紫杉醇的新型给药方式得以发展.虽然前期研究结果显示纳米给药方式相对传统给药治疗有更好的抑制肿瘤生长的效果，但是它们在分子代谢水平对机体的影响并没有被确切研究.本文采用4T1荷瘤乳腺癌模型小鼠，通过比较荷瘤小鼠分别在不处理、传统给药方式和通过纳米载体给药处理的条件下与健康小鼠脾脏代谢组的差异，发现传统给药处理对小鼠肠道微生物相关的代谢紊乱有较好的恢复效果，而通过纳米载体的给药处理可以更好的调节荷瘤小鼠的葡萄糖和延胡索酸等与能量供应相关的代谢途径.此外，这两种给药方式都不能有效改善荷瘤小鼠显著的脾脏肿大症状，也不能改善脾脏免疫调节功能和供应肿瘤生长而导致的氨基酸、有机酸、核酸和胆碱等一系列代谢物变化.这可能与脾脏对外来肿瘤的免疫反应较为激烈而有效药物治疗时间较短有关.该研究为更全面认识荷瘤小鼠脾脏代谢表型变化和不同给药方式对脾脏代谢组的影响提供了基础数据.

NMR-Based Metabonomic Analyses on Spleen Tissues of 4T1 Tumor-Bearing Mice Subjected to Chemotherapies with Different Drug Delivery Strategies

The combination of doxorubicin and paclitaxel is widely used in clinical cancer therapy.Due to enhanced permeation and retention effects of nanomaterials in tumor tissues,nanoearriers with good biocompatibility have been designed to encapsulate doxorubicin/paclitaxel,and used to facilitate delivery of the drugs to achieve better therapeutic outcome.In this study,NMR-based metabonomic analyses were used to study the metabolic profiles in spleen tissues of normal healthy mice and of 4T1 tumor-bearing mice,which were treated with either saline,or doxorubicin/paclitaxel in their free forms,or doxorubicin/paclitaxel encapsulated in nanocarriers.The results demonstrated that treatment with the free forms of doxorubicin/paclitaxel remitted tumor-induced disturbances in gut mierobiota,while treatment with nanoearrier-encapsulated doxorubicir/paclitaxel alleviated increased glucose and fumarate metabolism associated with tumor bearing.In contrast,tumor-related splenomegaly and metabolic alterations in amino acids,organic acids,nucleic acids and choline,both attributable to immune responses of the spleen,were not ameliorated by drug treatment.This could also be due to the fact that the treatment period was too short to have any significant effects.This work provided metabolic phenotypical information of the spleen tissues in 4T 1 tumor-bearing mice,and helped to understand the metabolic impacts of drug delivery systems on the spleen.