Neurotensin receptor-based targeted delivery of thymoquinone for non-small cell lung cancer

Abstract Non-small cell lung cancer (NSCLC) is a very recalcitrant cancer, accounting for 80% to 85% of all lung cancer diagnoses. About 40% of NSCLC are adenocarcinomas. Thus, there is an urgent need to identify targeted therapies, specifically for NSCLC. Although, multiple signaling molecules have now been identified within the last decade, among them Neurotensin receptor 1 (NTSR1) have afforded an improved understanding of the underlying pathology and significant heterogeneity of NSCLC. NTSR1 belongs to the G-protein coupled receptors (GPCR) superfamily that has been shown numerous oncogenic effects in tumor initiation, progression, proliferation, apoptosis, and metastasis. In the present study, we used a novel method for targeted delivery of Thymoquinone (TQ), a constituent of Nigella sativa at the desired location. We described a proprietary planetary ball milling (PBM) approach that uses a natural polysaccharide (starch; FDA approved) to create a drug-polysaccharide nanoparticle as a core that is subsequently coated with poly (ϵ-caprolactone) / poly (ethylene glycol) copolymer and conjugated with anti-NTSR1-mAb, which allows binding to high-affinity NTSR1 receptors presents on NSCLC. Our tissue microarray data show higher expression of NTSR1 in lung cancer patients, which were negligible in normal cells. These studies were further confirmed by targeting NTSR1 in lung cancer cell lines NCI-H1563, NCI-H1975 and MRC-5 using our novel anti-NTSR1 conjugated, and TQ encapsulated PBM nanoparticle and further, validated using flow cytometry, immunofluorescence, qRT-PCR and western blot techniques. Our result showed the PBM nanoparticles encapsulated with TQ rapidly internalized and depolymerized the microtubule network by inducing apoptosis. The up-regulation of pro-apoptotic (BAX, BID) and down-regulation of anti-apoptotic (BCL-2, MCL-1) makers to confirm the targeted delivery of PBM-NPs to the tumor cells. This study strongly suggests anti-NTSR1-mAb conjugated PBM-NPs has its application to drugs targeting for the treatment of NSCLC. In summary, this study combines innovative ideas with an innovative technology to create new therapeutics and a new strategy to improve the treatment of NSCLC and has the potential to create a new class of targeted treatments for advanced lung cancer. Citation Format: Santosh Kumar Singh, James W. Lillard, Rajesh Singh. Neurotensin receptor-based targeted delivery of thymoquinone for non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4665.