Photoactivatable Prodrug of Doxazolidine Targeting Exosomes.

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 IC50 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.