Targeted Delivery of Chlorin e6 via Redox Sensitive Diselenide-Containing Micelles for Improved Photodynamic Therapy in Cluster of Differentiation 44-Overexpressing Breast Cancer.

Chan Feng,Yun Lin,Shujing Liang,Xia Zhang,Yabin Ma,Na Yoon Kim,Donglei Zhu,Chunyan Dong,Lv Chen,Yonglin Lu,Jie Liu

doi:10.3389/fphar.2019.00369

Chan Feng, Yun Lin + Show 9 more

Open Access

https://doi.org/10.3389/fphar.2019.00369

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Abstract

The off-target activation of photosensitizers is one of the most well-known obstacles to effective photodynamic therapy (PDT). The selected activation of photosensitizers in cancer cells is highly desired to overcome this problem. We developed a strategy that enabled diselenide bonds to link hyaluronic acid (HA) and photosensitizer chlorin e6 (Ce6) to assemble the micelles (HA-sese-Ce6 NPs) that can target cancer and achieve a redox responsive release of drugs to enhance the PDT efficiency in breast cancer. The HA was used to form a hydrophilic shell that can target cluster of differentiation 44 (CD44) on the cancer cells. The selenium-containing core is easily dissembled in a redox environment to release Ce6. The triggered release of Ce6 in a redox condition and the positive feedback release by activated Ce6 were observed in vitro. In cytotoxicity assays and in vitro cellular uptake assays, the increased PDT efficiency and targeted internalization of HA-sese-Ce6 NPs in the cells were verified, compared to a free Ce6 treated group. Similar results were showed in the therapeutic study and in vivo fluorescence imaging in an orthotopic mammary fat pad tumor model. In addition, a significant inhibition of metastasis was found after the HA-sese-Ce6 NPs treatment. In general, this study promises an ingenious and easy strategy for improved PDT efficiency.

Highlights

Photodynamic therapy (PDT) is a promising noninvasive, localized therapeutic method that has a variety of advantages for cancer treatment, especially for tumors located close to the skin such as breast cancer (Agostinis et al, 2011; Wang et al, 2018)
The chemical structure and synthetic process of hyaluronic acid (HA)-sese-NH2 and HA-sese-chlorin e6 (Ce6) were shown in Scheme 2
As shown in Scheme 1, HA acts as a hydrophilic coat, and Ce6 acts as a hydrophobic core of the micelle

Summary

INTRODUCTION

Photodynamic therapy (PDT) is a promising noninvasive, localized therapeutic method that has a variety of advantages for cancer treatment, especially for tumors located close to the skin such as breast cancer (Agostinis et al, 2011; Wang et al, 2018). The relatively low electronegativity and large atomic radius give selenium unique chemical properties, such as high reactivity and sensitivity (Xia et al, 2016, 2018b; Sun et al, 2017) Due to their high sensitivity to both oxidation and reduction, diselenide-containing polymers have been gaining attention as attractive drug delivery candidates that can perform controlled drug release in tumor microenvironment with rich redox stimuli (Ma et al, 2010; Gong et al, 2017; Zhou et al, 2017, 2018). The PDT efficacy was investigated in a breast cancer cell line and orthotopic mammary fat pad tumor model

MATERIALS AND METHODS

Methods

RESULTS AND DISCUSSION

ETHICS STATEMENT

CONCLUSIONS