TMEM16A-inhibitor loaded pH-responsive nanoparticles: A novel dual-targeting antitumor therapy for lung adenocarcinoma

Abstract

To overcome the adverse effects of conventional chemotherapy for cancers, various nanoparticles based drug delivery systems have been developed. However, nanoparticles delivering drugs directly to kill tumor cells still faced with challenges, because tumors possessed adopt complex mechanism to resist damages, which compromised the therapeutic efficacy. TMEM16A/CaCCs (Calcium activates chloride channels) has been identified to be overexpressed in lung adenocarcinoma which can serve as a novel tumor specific drug target in our previous work. Here, we developed a novel dual-targeted antitumor strategy via designing a novel nano-assembled, pH-sensitive drug-delivery system loading with specific inhibitors of TMEM16A against lung adenocarcinoma. For validation, we assayed the novel dual-targeting therapy on xenograft mouse model which exhibited significant antitumor activity and not affect mouse body weight. The dual targeting therapy accomplished in this study will shed light on the development of advanced antitumor strategy.

Introduction

Lung cancer is the most commonly diagnosed malignancy and is associated with the highest mortality rate [1], [2]. Non-small-cell lung cancer (NSCLC) accounts for more than 85% of lung cancer, and 54% of NSCLC is lung adenocarcinoma [3], [4]. Currently, the main method for treating advanced lung adenocarcinoma is chemotherapy [5]. Since chemotherapy drugs are accompanied with serious side effects, it is urgent to identify novel drug targets and develop safe and efficient antitumor strategy [6].

As nanocarriers possess desirable properties of targeting, compatibility and sustained release ability, the nanocarriers delivery systems have been widely explored for tumor therapy exploration. Accurate targeting of tumor tissue are highly desirable to improve based on current nanocarriers because it will greatly reduce the side effects during the cancer targeting process. For enhancing the targeting of anti-tumor drugs, such as doxorubicin, paclitaxel and cisplatin, adopting nanocarriers is an important trend in the development of cancer therapy [7], [8], [9]. However, the current nano-delivery systems can not completely eliminate the high probability of kidney toxicity, neurotoxicity and toxicity to the hematopoietic system and digestive system of the chemotherapy drugs [10], [11]. Therefore, improving the properties of nanocarriers have become urgent issues [12], [13].

The identification of novel and tumor-specific drug targets is another main focus of drug development. Recently, molecular targeted therapy for treating lung adenocarcinoma has shown some promising results, like epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs). However, these TKIs also produce drug resistance, diarrhea, dermatitis, stomatitis and other unwanted side effects [14], [15], [16]. More and more studies have shown that ion channels may be important drug targets for the treatment of lung adenocarcinoma [17], [18]. Our previous studies have shown that TMEM16A, which is highly expressed in lung adenocarcinoma cells, is one of the key targets for treating lung adenocarcinoma [19]. Compared with existing cytotoxic antitumor drugs, the antitumor drugs targeting ion channels have little resistance and toxic side effects. TMEM16A was highly overexpressed in the lung adenocarcinoma cell line LA795 [19]. The Tmem16a gene is located in the human chromosome band 11q13, which is one of the most frequently amplified regions in human cancer [20], [21]. TMEM16A is highly expressed in a variety of cancer cells, therefore TMEM16A is considered as a diagonosis cancer marker and antitumor drug target [22], [23].

In order to improve the anti-cancer efficiency, a targeted nanocarrier system and a TMEM16A inhibitor were combined to develop a novel therapy against lung adenocarcinoma. In this work, we designed a novel pH-sensitive nanocarrier, PEO-b-P(DMAEMA-co-MAEBA), that can specifically deliver drugs to tumor tissues because of the weak acidity microenvironment of lung adenocarcinoma. The nanocarrier can be accumulated in the tumor lesions, thereby increasing the local drug concentration to enhance efficacy. We also tested a previously identified specific inhibitor of TMEM16A, CaCCinh-A01 (A01), and found that it can suppress cancer cell growth by inhibiting TMEM16A. By combining the specific inhibitor of TMEM16A with the pH-sensitive nanocarrier, we developed a dual-targeting anti-cancer system that targets cancer tissue and TMEM16A ion channel, respectively. The results showed this dual-targeting antitumor strategy improved the therapeutic effect to more than two times compared with the therapeutic effect of direct A01 administration, and this new system has no observable side effects.