Heterogeneous distribution of drug inside tumor is ubiquitous, causing regional insufficient chemotherapy, which might be the hotbed for drug resistance, tumor cell repopulation and metastasis. Herein, we verify, for the first time, that heterogeneous drug distribution induced insufficient chemotherapy would accelerate the process of epithelial mesenchymal transition (EMT), consequently resulting in the promotion of tumor metastasis. To eliminate the insufficient chemotherapy promoted metastasis, we conceived a co-delivery strategy by hydroxyethyl starch-polylactide (HES-PLA) nanoparticle, in which DOX and TGF-β receptor inhibitor, LY2157299 (LY), were administered together. In vitro and in vivo studies demonstrate that this co-delivery strategy can simultaneously suppress primary tumor and distant metastasis. Further study on immunofluorescence images of primary tumor verifies that low dose of DOX exasperates the EMT process, whereas the co-delivery nanoparticle can dramatically inhibit the progression of EMT. We reveal the impact of heterogeneous drug distribution on tumor metastasis and develop an effective co-delivery strategy to suppress the metastasis, providing guidance for clinical cancer therapy.

肿瘤内部药物的异质分布无处不在，导致局部化疗不足，这可能是耐药性，肿瘤细胞重新聚集和转移的温床。本文中，我们首次验证了异质药物分布诱导的化疗不足会加速上皮间质转化（EMT）的过程，从而促进肿瘤转移。为了消除化疗不足引起的转移，我们构想了羟乙基淀粉-聚丙交酯（HES-PLA）纳米粒子的共递送策略，其中DOX和TGF-β受体抑制剂LY2157299（LY）一起给药。体外和体内研究表明，这种共同分娩策略可以同时抑制原发肿瘤和远处转移。对原发肿瘤的免疫荧光图像的进一步研究证实，低剂量的DOX会激怒EMT过程，而共输送纳米颗粒可以显着抑制EMT的进程。我们揭示了异质药物分布对肿瘤转移的影响，并制定了有效的共同递送策略来抑制转移，为临床癌症治疗提供了指导。