Mitochondrial Targeting and pH-Responsive Nanogels for Co-Delivery of Lonidamine and Paclitaxel to Conquer Drug Resistance.

Enping Chen,Fu Liu,Dechun Huang,Junmei Zhang,Wei Chen,Ting Wang,Yafan Niu,Xiang Zhou,Yinan Zhong

doi:10.3389/fbioe.2021.787320

Enping Chen, Fu Liu + Show 7 more

Open Access

https://doi.org/10.3389/fbioe.2021.787320

Copy DOI

Abstract

Multidrug resistance (MDR) is one of the leading causes of the failure of cancer chemotherapy and mainly attributed to the overexpression of drug efflux transporters in cancer cells, which is dependent on adenosine triphosphate (ATP). To overcome this phenomenon, herein, a mitochondrial-directed pH-sensitive polyvinyl alcohol (PVA) nanogel incorporating the hexokinase inhibitor lonidamine (LND) and the chemotherapeutic drug paclitaxel (PTX) was developed to restore the activity of PTX and synergistically treat drug-resistant tumors. The introduction of 2-dimethylaminoethanethiol (DMA) moiety into the nanogels not only promoted the drug loading capacity but also enabled the lysosomal escape of the nanogels. The subsequent mitochondrial targeting facilitated the accumulation and acid-triggered payload release in the mitochondria. The released LND can destroy the mitochondria by exhausting the mitochondrial membrane potential (MMP), generating reactive oxygen species (ROS) and restraining the energy supply, resulting in apoptosis and susceptibility of the MCF-7/MDR cells to PTX. Hence, the nanogel-enabled combination regimen of LND and PTX showed a boosted anti-tumor efficacy in MCF-7/MDR cells. These mitochondrial-directed pH-sensitive PVA nanogels incorporating both PTX and LND represent a new nanoplatform for MDR reversal and enhanced therapeutic efficacy.

Highlights

Chemotherapy remains one of the major means for treating tumors; the therapeutic efficacy is perplexed by many reasons including the multidrug resistance (MDR) (Lage 2008; Holohan et al, 2013; Rebucci and Michiels, 2013)
We started with the synthesis of polyvinyl alcohol (PVA)-g-Vinyl ether acrylate (VEA)/VEA-DMA/TPP polymer, in which the pendent VEA, positively charged DMA, and mitochondria-recognizable TPP were successively conjugated onto the water-soluble PVA backbone (Scheme 1)
T-D-NGs were obtained by dissolving the polymer of PVA-g-VEA/VEA-DMA/TPP in water, adjusting pH to 7.8, crosslinking acrylate in the presence of I2959 under UV light

Summary

INTRODUCTION

Chemotherapy remains one of the major means for treating tumors; the therapeutic efficacy is perplexed by many reasons including the multidrug resistance (MDR) (Lage 2008; Holohan et al, 2013; Rebucci and Michiels, 2013). We have constructed a triphenylphosphine (TPP)installed pH-sensitive biocompatible polyvinyl alcohol (PVA) nanogel containing 2-dimethylaminoethanethiol (DMA) moiety for mitochondrial-directed co-delivery of LND and the chemotherapeutic drug paclitaxel (PTX) in drug-resistant tumors. After the internalization in the drug-resistant tumor cells, T-DNGs@LND and PTX escaped from the lysosome due to the proton sponge effect of DMA moiety, effectively accumulated in the mitochondria with the orientation of TPP module, and rapidly released the payload resulting from the acid-triggered cleavage of the acetal linker within the network of nanogels (Scheme 1). Through adjusting the solution pH to 6.8 and in situ crosslinking of acrylate in the polymers under UV light for 10 min, PTX and LND co-loaded nanogels were obtained. The level of significance was set at probabilities of *p < 0.05, **p < 0.01, and ***p < 0.001

RESULTS AND DISCUSSION

CONCLUSION

DATA AVAILABILITY STATEMENT