Mitochondrial Induced and Self-Monitored Intrinsic Apoptosis by Antitumor Theranostic Prodrug: In Vivo Imaging and Precise Cancer Treatment

Abstract

Activation of apoptosis, the cell death machinery, in tumor cells by organelle-specific delivery of antitumor theranostic agent is the utmost challenge in cancer therapy. Herein, we developed a highly efficient mitochondria-targeting antitumor theranostic prodrug 7 that contained two molecules of drug 5'-deoxy-5-fluorouridine and an apoptotic marker ethidium for self-monitoring intrinsic (mitochondrial) apoptosis after its activation in tumor cells. Theranostic 7 was activated by endogenously produced mitochondrial-overexpressed H2O2 and released drug 5'-deoxy-5-fluorouridine and apoptotic marker ethidium to the tumor cells. The in vitro and in vivo drug release was monitored by observing the fluorescence changes of ethidium. Theranostic 7 exhibited an enhanced cytotoxicity over commercial 5-fluorouracil (an active drug of 5'-deoxy-5-fluorouridine) leading to intrinsic apoptosis monitored by in situ generated ethidium. Enhanced expression of mitochondria-mediated apoptotic genes (NOXA, PUMA, BID, BAX, and BAK), Cyt C, Caspase-3 and -9, and cell surface death receptors was observed after theranostic 7 activation in tumor cells. In vivo and ex vivo xenografts revealed that theranostic 7 significantly inhibited tumor progression and cured the tumor-bearing mice. Such organelle-specific theranostic strategies have great potential for the early diagnosis and precise treatment of cancer.

Visualization of drug delivery processes using AIEgens

“…ethidium) into prodrugs or nanoparticles, in situ monitoring of the drug therapeutic effects has also been realized. 11,12 In addition, some of the theranostic DDSs based on AIEgens have also been developed for real-time monitoring of the therapeutic responses which are discussed in this section. 54–56 …”

“…8–10 Recently, real-time monitoring of the therapeutic responses has been realized by imaging the drug induced cancer cell apoptosis, a pathway commonly involved in cell death. 11,12 The majority of theranostic DDSs relies on fluorescent dyes with aggregation-caused quenching (ACQ) to report the signal, which limits the detection sensitivity. In addition, the intrinsic fluorescence of most dyes requires careful selection of energy acceptors or quencher moieties to realize fluorescence change, which complicates the design of self-reporting DDSs, especially the ones for reporting multiple processes.…”

Reactive Oxygen, Nitrogen, and Sulfur Species (RONSS)‐Responsive Polymersomes for Triggered Drug Release

“…Notably, recent progresses have demonstrated that other ROS and RNS, such as HOCl and ONOOˉ, can also oxidize arylboronate moieties . These highly efficient reactions have been extensively used to develop luminescent ROS imaging probes and ROS‐activatable proinhibitors and prodrugs . In addition, ROS‐sensitive polymers and polymeric nanoparticles originating from arylboronate oxidation have been explored to achieve ultrasensitive detection and vaccines or drugs delivery …”

Mitochondrion‐Targeting Identification of a Fluorescent Apoptosis‐Triggering Molecule by Mass Spectrometry Elucidates Drug Tracking

“…Direct delivery of chemotherapeutic agents to subcellular mitochondria for organelle‐targeting therapy has attracted increasing attention . Most currently used mitochondrion‐targeting therapeutic agents are fluorescent molecules, because compounds containing fluorophores can be traced in the cells through fluorescence imaging. For compounds that do not contain fluorophores, conjugation with additional fluorescent tags is required; however, such modifications change the structures of compounds and have been known to alter their metabolism pathways .…”