Engineered Perfluorochemical Cancer-Derived Exosomes Loaded with Indocyanine Green and Camptothecin Provide Targeted Photochemotherapy for Effective Cancer Treatment

Yu-Hsiang Lee,1– 3 Cheng-You Huang1 1Department of Biomedical Sciences and Engineering, National Central University, Taoyuan City, Taiwan, Republic of China; 2Department of Chemical and Materials Engineering, National Central University, Taoyuan City, Taiwan, Republic of China; 3Department of Medical Research, Cathay General Hospital, Taipei City, Taiwan, Republic of ChinaCorrespondence: Yu-Hsiang Lee, Department of Biomedical Sciences and Engineering, National Central University, No. 300, Jhongda Road, Taoyuan City, 320317, Taiwan, Republic of China, Tel +886-3-422-7151 Ext# 27755, Fax +886-3-280-4627, Email [email protected]: Cancer treatments are still limited by various challenges, such as off-target drug delivery, posttreatment inflammation, and the hypoxic conditions in the tumor microenvironment; thus, the development of effective therapeutics remains highly desirable. Exosomes are extracellular vesicles with a size of 30– 200 nm that have been widely applied as drug carriers over the last decade. In this study, melanoma-derived exosomes were used to develop a perfluorocarbon (PFC) drug nanocarriers loaded with indocyanine green (ICG) and camptothecin (CPT) (ICFESs) for targeted cancer photochemotherapy.Methods: The ICFESs were fabricated by emulsification approach and characterized through instrumental detection. The capabilities of the ICFESs on tumor targeting, intratumoral retention, and cancer photochemotherapy were evaluated using melanoma tumor-bearing mice in association with histological studies and serum marker analyses.Results: ICFESs can be rapidly internalized by homologous melanoma cells, induce hyperthermia and increase the yield of singlet oxygen upon exposure to near-infrared (NIR) irradiation. After 5 min of NIR exposure and 24 h of in vitro culture, ICFESs encapsulating ≥ 10/10 μM [ICG]/[CPT] effectively killed more than 70% of the cancer cells, inducing greater mortality than that caused by a 4-fold higher dose of CPT alone. In a murine melanoma model, we demonstrated that ICFESs indeed targeted homologous tumors with prolonged intratumoral retention compared with free ICG in vivo. Moreover, tumor growth was significantly arrested by ICFESs containing 40/40 μM [ICG]/[CPT] in combination with 30 sec of NIR exposure without systemic toxicity, and the resulting tumors were approximately 15-fold smaller than those treated for 14 days with 40 μM free CPT alone.Conclusion: We suggest that the aforementioned anticancer efficacy was achieved via a dual-stage mechanism, phototherapy followed by chemotherapy. Taken together, the developed ICFESs are anticipated to be highly applicable for clinical cancer treatment. Keywords: exosome, photochemotherapy, perfluorocarbon, hypoxia, homologous targeting, NIR irradiation