Mitochondria-localized <i>in situ</i> generation of rhodamine photocage with fluorescence turn-on enabling cancer cell-specific drug delivery triggered by green light

Paul, Amrita; Mengji, Rakesh; Bera, Manoranjan; Ojha, Mamata; Jana, Avijit; Singh, N. D. Pradeep

doi:10.1039/d0cc03524f

Cited by 22 publications

(19 citation statements)

References 17 publications

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“…20 And to the best of our knowledge, there exists only a single report on mitochondria-targeted small-molecule photocaged rhodamine dye which allows real-time monitoring of anticancer drug. 21 However, this system too shows phototriggered drug release using green light (546 nm) which does not fall in the phototherapeutic window (650− 850 nm), where the light has maximum penetration and least harmful effects on human tissues. 22 In this paper, we have developed a mitochondria-targeted ohydroxycinnamate-based UV and NIR photoactivatable DDS (MTPDDS) that provides full temporal-control over drug release with real-time monitoring (Figure 1).…”

Section: ■ Introductionmentioning

confidence: 98%

“…In an another report, Dhar and co-workers have developed a drug delivery vehicle based on biodegradable polymer-encapsulated photosensitizer (drug) that initiates apoptosis upon light activation . And to the best of our knowledge, there exists only a single report on mitochondria-targeted small-molecule photocaged rhodamine dye which allows real-time monitoring of anticancer drug . However, this system too shows phototriggered drug release using green light (546 nm) which does not fall in the phototherapeutic window (650–850 nm), where the light has maximum penetration and least harmful effects on human tissues …”

Section: Introductionmentioning

confidence: 99%

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Mitochondria-Targeted Photoactivatable Real-Time Monitoring of a Controlled Drug Delivery Platform

et al. 2021

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The current anticancer therapies are limited by their lack of controlled spatiotemporal release at the target site of action. We report a novel drug delivery platform that provides on-demand, real-time, organelle-specific drug release and monitoring upon photoactivation. The system is comprised of a model anticancer drug doxorubicin, an alkyltriphenylphosphonium moiety to target mitochondria in cancer cells, and a hydroxycinnamate photoactivatable linker that is covalently attached to the drug and mitochondria-targeting moieties such that it can be phototriggered by either UV (one-photon) or NIR (two-photon) light to form a fluorescent coumarin product and facilitate the release of drug payload. The extent of drug release is quantified by the fluorescence intensity of the coumarin formed. Further, the photoactivatable prodrug accumulates in the mitochondria and shows light-triggered temporally controlled cell death. In the future, our platform can be tuned for any biological application of interest, offering immense value in biomedicine.

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Section: ■ Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Mitochondria-Targeted Photoactivatable Real-Time Monitoring of a Controlled Drug Delivery Platform

et al. 2021

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“…Of these, lipophilic cations have been used perhaps most commonly. To date, various lipophilic cations for a mitochondrial-specific ROS generator have been developed, such as triphenylphosphonium, − cyanine, , pyridinium, , isoquinolinium, , Ir(III) complexes, , and rhodamine. , Although mitochondrial-targeting ROS generators have achieved significant progress over the past few decades, some limitations still exist, including easy accumulation and low ROS generation capacity.…”

Section: Introductionmentioning

confidence: 99%

Light-Induced Reactive Oxygen Species (ROS) Generator for Tumor Therapy through an ROS Burst in Mitochondria and AKT-Inactivation-Induced Apoptosis

Zhou

Zhang

et al. 2021

ACS Appl. Bio Mater.

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Mitochondria are identified as a valuable target for cancer therapy owing to their primary function in energy supply and cellular signal regulation. Mitochondria in tumor cells are depicted by excess reactive oxygen species (ROS), which lead to numerous detrimental results. Hence, mitochondria-targeting ROS-associated therapy is an optional therapeutic strategy for cancer. In this contribution, a light-induced ROS generator (TBTP) is developed for evaluation of the efficacy of mitochondria-targeting ROS-associated therapy and investigation of the mechanism underlying mitochondrial-injure-mediated therapy of tumors. TBTP serves as an efficient ROS generator with low cytotoxicity, favorable biocompatibility, excellent photostability, mitochondria-targeted properties, and NIR emission. In vivo and in vitro experiments reveal that TBTP exhibits effective anticancer potential. ROS generated from TBTP could destroy the integrity of mitochondria, downregulate ATP, decrease the mitochondrial membrane potential, secrete Cyt-c into cytoplasm, activate Caspase-3/9, and induce cell apoptosis. Moreover, RNA-seq analysis highlights that an ROS burst in mitochondria can kill tumor cells via inhibition of the AKT pathway. All these results prove that mitochondrialtargeted ROS-associated therapy hold great potential in cancer therapy.

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“…Rhodaminederivatives are thought to exhibit good cellular permeability and rapid cellular accumulation. 44,45 Lipid-rhodamine conjugates were prepared from rhodamine B isothiocyanate (RITC) and aminolipids (Figure 4A). We decided to test a medium-length lipid tail (C10-Rhodamine) and a long lipid tail (C18-Rhodamine) and a derivative without lipid tail for comparison (C2-Rhodamine).…”

Section: Cellular Uptake Of Fluorophore-lipid Conjugatesmentioning

confidence: 99%

Medium-Length Lipids Facilitate Cell-Permeability and Bioactivity

Capecchi

Hinnah²,

Petit-Jacques

et al. 2021

Preprint

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The majority of bioactive molecules act on membrane proteins or intracellular targets and therefore needs to partition into or cross biological membranes. Natural products often exhibit lipid modifications to facilitate critical molecule-membrane interactions and in many cases their bioactivity is markedly reduced upon removal of a lipid group. However, despite its importance in nature, lipid-conjugation of small molecules is not commonly used in chemical biology and medicinal chemistry, and the effect of such conjugation has not been systematically studied. To understand the composition of lipids found in natural products, we carried out a chemoinformatic characterization of the ‘natural product lipidome’. According to this analysis, lipidated natural products predominantly contain saturated linear medium-length lipids, which are significantly shorter than those found in membranes and lipidated proteins. To study the usefulness of such modifications in probe design, we systematically explored the effect of lipid conjugation on five different small molecule chemotypes and find that permeability, cellular retention, subcellular localization, and bioactivity can be significantly modulated depending on the type of lipid tail used. We demonstrate that medium-length lipid tails can render impermeable molecules cell-permeable and switch on their bioactivity. Saturated medium-length lipids (e.g. C10) are found to be ideal for the bioactivity of small molecules in mammalian cells, while saturated long-chain lipids (e.g. C18) often significantly reduce bioavailability and activity. Together, our findings suggest that conjugation of small molecules with medium-length lipids could be a powerful strategy for the design of probes and drugs.

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Mitochondria-localized in situ generation of rhodamine photocage with fluorescence turn-on enabling cancer cell-specific drug delivery triggered by green light

Abstract: We report a new multi-tasking water-soluble photocage based on a well-known rhodamine dye for cancer cell selective anticancer drug delivery triggered by green light.

Cited by 22 publications

References 17 publications

Mitochondria-Targeted Photoactivatable Real-Time Monitoring of a Controlled Drug Delivery Platform

Mitochondria-Targeted Photoactivatable Real-Time Monitoring of a Controlled Drug Delivery Platform

Light-Induced Reactive Oxygen Species (ROS) Generator for Tumor Therapy through an ROS Burst in Mitochondria and AKT-Inactivation-Induced Apoptosis

Medium-Length Lipids Facilitate Cell-Permeability and Bioactivity

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