Enhancing solid tumor therapy with sequential delivery of dexamethasone and docetaxel engineered in a single carrier to overcome stromal resistance to drug delivery
Lu Zhang1 , Haitao Su1 , Yujie Liu, Ning Pang, Ji Li, Xian-Rong Qi* (* corresponding author)
Journal of Controlled Release, 2019, 294 (28):1-16
Nanomedicines are often designed to target and treat solid tumors. Unfortunately, tumor and stroma composed of dense extracellular matrix, abnormal vascular barriers, elevated interstitial fluid pressure, et al., which impede the access and accumulation of nanomedicines into tumors. Strategies to disrupt these deterministic obstacles require a unique combination of promoter drugs and cytotoxic agents to target stroma and tumor simultaneously. Here, we engineered a novel strategy by co-delivery dexamethasone (DEX) and docetaxel (DTX) in the 2-in-1 liposome, namely (DEX + DTX)-Lip, with sequential release property. We proved that the engineered liposomal therapy approach could potentially achieve two objectives in tumor drug delivery: modulate tumor stroma and promote drug penetration and accumulation in tumor. Thus more DTX tenured in intratumoral site to kill tumor cells in a strong way with minimize systemic toxicity. The sequentially released liposomes won excellent antitumor efficacy in multifarious models, including KB, multidrug resistant KBv and metastatic 4 T1 tumor models and low toxicities compared with the combination of free drugs in vivo. Moreover, they demonstrated the potential of prevention tumor cells colonization and anti-metastasis in vivo models. These findings give insights in overcoming the deterministic stroma obstacles and provide a rational strategy to in- crease antitumor efficacy of combination nanomedicines with practical value.
