Photoactivatable Prodrug of Doxazolidine Targeting Exosomes

Abstract

Natural lipid nanocarriers, exosomes, carry cell-signaling materials such as DNA and RNA for intercellular communications. Exosomes derived from cancer cells contribute to the progression and metastasis of cancer cells by transferring oncogenic signaling molecules to neighboring and remote premetastatic sites. Therefore, applying the unique properties of exosomes for cancer therapy has been expected in science, medicine, and drug discovery fields. Herein, we report that an exosome-targeting prodrug system, designated MARCKS−ED−photodoxaz, could spatiotemporally control the activation of an exquisitely cytotoxic agent, doxazolidine (doxaz), with UV light. The MARCKS−ED peptide enters a cell by forming a complex with the exosomes in situ at its plasma membrane and in the media. MARCKS−ED− photodoxaz releases doxaz under near-UV irradiation to inhibit cell growth with low nanomolar IC 50 values. The MARCKS−ED−photodoxaz system targeting exosomes and utilizing photochemistry will potentially provide a new approach for the treatment of cancer, especially for highly progressive and invasive metastatic cancers.

A Photocleavable Contrast Agent for Light-Responsive MRI

“…The process was monitored by UV–vis spectrometry and the photocleavage rate determined by UPLC (see Supporting Figure S1 ). Based on this analysis, the photocleavage quantum yield was calculated as 4.4%, indicating that the photocleavage efficiency of our photoactive scaffold lies in the same range as the one of comparable examples of NVOC-photocaged carboxylic acids, including methyl-substituted ones [ 47 , 48 , 49 ]. Still, it has to be noted that the quantum yield in aqueous medium possibly differs from the one in aprotic organic solvent, since—at least for photocaged alcohols—the cleavage mechanism is based on proton transfer and is known to be affected by changes in pH and solvent.…”

Computational Study on the Mechanism of the Photouncaging Reaction of Vemurafenib: Toward an Enhanced Photoprotection Approach for Photosensitive Drugs

“…The phototoxicity of numerous pharmaceutical materials is a major therapeutic concern that can conspicuously constrain their clinical applications [14][15][16][17][18]. Several approaches have been recently developed toward reducing the impact of such undesired side effects, including photocaging [19][20][21][22][23][24]. Recently, the importance of the incorporation of photocaging groups into photoactive pharmaceutical materials has been increasingly recognized as an effectual approach toward reducing the phototoxicity of a wide spectrum of photoactive drugs [20][21][22][23][24].…”

“…As such, several studies have been recently reported concerning the photocaging of materials of biological and pharmaceutical importance, such as the antimelanoma agent vemurafenib [20], anticancer drug doxazolidine [21], anticancer kinase inhibitor imatinib [22], small-molecule tubulin inhibitor [23], and photocaged materials for homeostasis [24]. Various types of photolabile-protecting groups (PPGs) have been developed and utilized in these works to afford the photocaged prodrugs of interest.…”

“…However, although VFB is considered as a first-line anticancer drug, several studies have reported the severe phototoxicity associated with the administration of the drug [28][29][30][31][32][33]. On the other hand, investigating the physicochemical properties of materials of biological and medicinal applications at the molecular level is essential for a better understanding of their activities and functionalities [21][22][23][24][25][26][27][28][29][30][31]. As such, investigating the photochemical properties of photosensitive biological materials, such as the first-line anticancer drug VFB, at the molecular level is necessary to enhance the efficacy of the photocaging process and, consequently, reduce the potential phototoxicity.…”

Overview of Recent Strategic Advances in Medicinal Chemistry

“…off-target effects of systemically administered anticancer drugs heavily constrained their efficacy and tolerability. The photocaging concept has been used in the delivery of drugs across membranes; it reduces off-target effects, as exemplified by photoactivatable prodrug (97) of the anti-melanoma agent vemurafenib (96), caged RET kinase inhibitor 99, 113 photoactivatable caged prodrugs (101 and 102) of imatinib (100), 114 photocontrolled HDAC inhibitors 103,104 115,116 and 106, a photoactivatable prodrug of doxazolidine (105) targeting exosomes (Figure 14) 117. Meanwhile, a number of PPGs have been exploited for this purpose, including p-nitrobenzyl, 4,5-dimethoxy-2-nitrobenzyl, 7-diethylaminocoumarin-4-ylmethyl, and 6-bromo-7-hydroxycoumarine-4-ylmethyl.…”