ZWZ-3, a Fluorescent Probe Targeting Mitochondria for Melanoma Imaging and Therapy.

Zengjin Liu,Hailan Wang,Changzhen Sun,Xia Xiong,Tong Xia,Jianv Wang,Qingbi Zhang,Yuanmin He,Sijin Yang,Li Liu

doi:10.3389/fphar.2022.829684

Abstract

The increased drug resistance and metastasis of melanoma resulted in poor prognosis of patients. Here, we designed and synthesized a novel hemicyanine-based fluorescent probe ZWZ-3, and investigated its application for melanoma imaging and treatment both in vitro and in vivo. ZWZ-3 preferentially accumulated in melanoma cells via a process that depended on the organic anion-transporting polypeptide (OATP), which targeted mitochondria on the hemicyanine cationic nitrogen. In addition, we investigated the effect and molecular mechanism of ZWZ-3 in melanoma. In vitro studies showed that ZWZ-3 promoted the generation of reactive oxygen species and induced mitochondrial-mediated cell apoptosis by upregulating Bax and activating caspase-3, caspase-9, and PARP. Importantly, ZWZ-3 also induced autophagy by upregulating LC-3II and Atg5 and downregulating P62. It significantly suppressed tumor growth of A375 xenograft tumor in mice without notable side effects. Histological and immunohistochemical analyses revealed that ZWZ-3 induced apoptosis and inhibited tumor cell proliferation. Thus, ZWZ-3 represents a novel theranostic agent that can be used to effectively targeting, detecting, and treating melanoma. It could also help monitoring disease progression and response to treatment.

Highlights

Melanoma is one of the most malignant tumors with high metastatic potential
We developed the hemicyanine-based fluorescent probe ZWZ-3, which can be selectively enriched in the mitochondria of melanoma cells, promoting mitochondrial oxidative phosphorylation and inducing apoptosis and autophagy
The structural characterization of ZWZ-3 was determined by 1H-NMR (Supplementary Figure S1), 13CNMR (Supplementary Figure S2) and high resolution mass spectrometry (HRMS) (Supplementary Figure S3)

Summary

Introduction

Melanoma is one of the most malignant tumors with high metastatic potential. It represents only 4% of dermal tumor cases, melanoma is the most dangerous and deadly form of dermal tumor, accounting for 75% of skin cancer-related deaths (Apalla et al, 2017; Hessler et al, 2020). Early-stage melanoma can be treated with surgical intervention, with relatively high 5-year survival rate, yet metastatic melanoma significantly shorten survival rate (Smart et al, 2021). Melanoma patients are often diagnosed at advanced stages with local infiltration or distant metastasis, which cannot be treated with surgery alone (Tse et al, 2017; Zhu et al, 2017). Multifunctional theranostic agents with the potential of simultaneous imaging-guided, tumor targeting and treatment are urgently needed to improve the timely diagnosis and treatment of the disease

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Results

Conclusion