Photoactivatable prodrug for simultaneous release of mertansine and CO along with a BODIPY derivative as a luminescent marker in mitochondria: a proof of concept for NIR image-guided cancer therapy. Issue 7 (12th January 2021)

• Record Type: Journal Article
• Authors: Tiwari, Rajeshwari; Shinde, Prashant S.; Sreedharan, Sreejesh; Dey, Anik Kumar; Vallis, Katherine A.; Mhaske, Santosh B.; Pramanik, Sumit Kumar; Das, Amitava
• Is Part Of: Chemical science. Volume 12:Issue 7(2021)
• Page Start: 2667
• Page End: 2673
• Publication Date: 2021-01-12
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d0sc06270g
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : Simultaneous release of two therapeutic reagents, mertansine and CO through photo-induced cleavage of a mitochondria-specific prodrug with improved drug efficacy. Abstract : Controlled and efficient activation is the crucial aspect of designing an effective prodrug. Herein we demonstrate a proof of concept for a light activatable prodrug with desired organelle specificity. Mertansine, a benzoansamacrolide, is an efficient microtubule-targeting compound that binds at or near the vinblastine-binding site in the mitochondrial region to induce mitotic arrest and cell death through apoptosis. Despite its efficacy even in the nanomolar level, this has failed in stage 2 of human clinical trials owing to the lack of drug specificity and the deleterious systemic toxicity. To get around this problem, a recent trend is to develop an antibody-conjugatable maytansinoid with improved tumor/organelle-specificity and lesser systematic toxicity. Endogenous CO is recognized as a regulator of cellular function and for its obligatory role in cell apoptosis. CO blocks the proliferation of cancer cells and effector T cells, and the primary target is reported to be the mitochondria. We report herein a new mitochondria-specific prodrug conjugate (Pro-DC ) that undergoes a photocleavage reaction on irradiation with a 400 nm source (1.0 mW cm −2 ) to induce a simultaneous release of the therapeutic components mertansine and CO along with a BODIPY derivative (BODIPY(PPH3 )2 ) as a luminescent marker in the mitochondrial matrix. The efficacy of the process is demonstrated using MCF-7 cells and could effectively be visualized by probing the intracellular luminescence of BODIPY(PPH3 )2 . This provides a proof-of-concept for designing a prodrug for image-guided combination therapy for mainstream treatment of cancer.