A pHe sensitive nanodrug for collaborative penetration and inhibition of metastatic tumors

• Published in: Journal of controlled release Vol. 352; pp. 893 - 908
• Main Authors: Huo, Meirong, Zhou, Jiyuan, Wang, Honglan, Zheng, Yuzhao, Tong, Yuqing, Zhou, Jianping, Liu, Jiyong, Yin, Tingjie
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2022
• Subjects: cancer-associated fibroblast inactivation; Cancer-Associated Fibroblasts - metabolism; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Multi-faceted penetration; Multitarget anti-metastasis; Nanoparticles - therapeutic use; pHe sensitive nanodrug; Quercetin; Tumor Microenvironment - physiology; Multitarget anti-metastasis; pHe sensitive nanodrug; Multi-faceted penetration; cancer-associated fibroblast inactivation; Quercetin; pH(e) sensitive nanodrug
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2022.11.012

Current chemotherapies for metastatic tumors are seriously restricted by limited drug infiltration and deficient disturbance of metastasis-associated complex pathways involving tumor cell autocrine as well as paracrine loops in the microenvironment (TME). Of note, cancer-associated fibroblasts (CAFs) play a predominant role in shaping TME favoring drug resistance and metastasis. Herein, we constructed a tumor extracellular pH (pHe) sensitive methotrexate-chitosan conjugate (MTX-GC-DEAP) and co-assembled it with quercetin (QUE) to achieve co-delivered nanodrugs (MTX-GC-DEAP/QUE). The pHe sensitive protonation and disassembly enabled MTX-GC-DEAP/QUE for stroma-specific delivery of QUE and positive-charged MTX-GC-DEAP molecular conjugates, thereby achieving deep tumor penetration via the combination of QUE-mediated CAF inactivation and adsorption-mediated transcytosis. On the basis of significantly promoted drug availability, a strengthened “omnidirectional” inhibition of pre-metastatic initiation was generated both in vitro and in vivo from the CAF inactivation-mediated reversion of metastasis-promoting environments as well as the inhibition of epithelial-mesenchymal transition, local and blood vessel invasion via QUE-mediated direct regulation on tumor cells. Our tailor-designed versatile nanodrug provides a deep insight into potentiating multi-faceted penetration of multi-mechanism-based regulating agents for intensive metastasis inhibition. [Display omitted] •A pHe-sensitive methotrexate-chitosan conjugate co-assembled with quercetin.•Combined penetration via CAFs inactivation and adsorption-mediated transcytosis.•Combined anti-metastasis via regulation both tumor microenvironment and tumor cells.•An avenue for high penetration followed by a multi-mechanism-based anti-metastasis.