Construction of Hierarchical-Targeting pH-Sensitive Liposomes to Reverse Chemotherapeutic Resistance of Cancer Stem-like Cells.

Shuang Ba,Li Jia,Jiulong Zhang,Mingxi Qiao,Dawei Chen,Xiuli Zhao,Haiyang Hu

doi:10.3390/pharmaceutics13081205

Shuang Ba, Li Jia + Show 5 more

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https://doi.org/10.3390/pharmaceutics13081205

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Abstract

Cancer stem-like cells (CSLCs) have been considered to be one of the main problems in tumor treatment owing to high tumorigenicity and chemotherapy resistance. In this study, we synthesized a novel mitochondria-target derivate, triphentlphosphonium-resveratrol (TPP-Res), and simultaneously encapsulated it with doxorubicin (Dox) in pH-sensitive liposomes (PSL (Dox/TPP-Res)), to reverse chemotherapeutic resistance of CSLCs. PSL (Dox/TPP-Res) was approximately 165 nm in size with high encapsulation efficiency for both Dox and TPP-Res. Cytotoxicity assay showed that the optimal synergistic effect was the drug ratio of 1:1 for TPP-Res and Dox. Cellular uptake and intracellular trafficking assay indicated that PSL (Dox/TPP-Res) could release drugs in acidic endosomes, followed by mitochondrial targeting of TPP-Res and nucleus transports for Dox. The mechanisms for reversing the resistance in CSLCs were mainly attributed to a synergistic effect for reduction of mitochondrial membrane potential, activation of caspase cascade reaction, reduction of ATP level and suppression of the Wnt/β-catenin pathway. Further, in vivo assay results demonstrated that the constructed liposomes could efficiently accumulate in the tumor region and possess excellent antineoplastic activity in an orthotopic xenograft tumor model with no evident systemic toxicity. The above experimental results determined that PSL (Dox/TPP-Res) provides a new method for the treatment of heterogenecity tumors.

Highlights

Published: 5 August 2021Tumors are composed of a heterogeneous population of cells [1,2,3]
Dox was degraded in the endosomes due to the drug-resistance effect in cancer stem-like cells (CSLCs). These results suggested that the pH-sensitive liposome delivery system and the synergism of TPP-Res improved the uptake of Dox in the nucleus and reversed the resistance in CSLCs
Dox into the pH-sensitive liposomes to conquer the cancer stem incorporated with Dox into the pH-sensitive liposomes to conquer the cancer stem cellscells-associated therapeutic obstacle

Summary

Introduction

Published: 5 August 2021Tumors are composed of a heterogeneous population of cells [1,2,3]. A small subpopulation of cells, cancer stem-like cells (CSLCs), has self-renewal and tumor formation potential, while the majority of tumors consist of non-tumorigenic cells. CSLCs show a self-renewal capacity, differentiation potential invasiveness and resistance to traditional chemotherapy and radiotherapy, which contribute to tumor progression and therapy resistance [4]. Drug resistance of CSLCs has attracted increasing attention with the development of advanced treatment methods in recent years [5,6,7,8]. DNA repair ability, inhibited apoptosis, self-renewal capacity and multilineage differentiation potential [9,10,11]. Multiple drug resistance (MDR) mechanisms described above are interrelated, leading to CSLCs being able to escape conventional chemotherapy methods

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