RT Journal Article SR Electronic T1 Multi-drug loaded exosomes for combined anti-tumor therapy and drug delivery monitoring via pre-targeting strategy JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 1218 OP 1218 VO 62 IS supplement 1 A1 Ruijie Qian A1 Xiaoli Lan A1 Rui An YR 2021 UL http://jnm.snmjournals.org/content/62/supplement_1/1218.abstract AB 1218Objectives: Exosomes, a type of natural biomaterials with intrinsic tumor-homing capacities, have recently been extensively explored as drug delivery systems. The aim of this study was to develop an integrative strategy based on drug-loaded exosomes for drug delivery monitoring and simultaneous photodynamic tumor suppression. Methods: HCT116 tumor-derived exosomes were mixed with doxorubicin (DOX) and 5-aminoketovaleric acid (ALA) to produce multi-drug loaded materials via simple incubation and hypotonic pre-expansion steps. The obtained TEX@DOX@ALA was characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), and western blot analysis (WB). Its drug release profiles were investigated in vitro by using flow cytometry and confocal microscopy. CCK-8 assay was used to evaluate its anti-tumor effect. Optimal tumor uptake was first examined using TEX@DOX@ALA@Cy5 via fluorescence imaging. For pre-targeting, tumor-bearing mice were first injected with TEX@DOX@ALA@N3 and followed by 68Ga-L-NETA-DBCO for PET/CT imaging via in vivo click chemistry. For photodynamic treatment, seven groups of tumor-bearing mice were monitored for 14 days, and blood samples and major organs (heart, lung, liver, spleen, and kidney) were collected for hematological analysis and H&E staining. Results: TEX@DOX@ALA were cup-shaped membrane vesicles and the hydrodynamic diameters were 113.3 ± 3.7 nm. WB confirmed the expression of three exosome markers: CD9, CD63, and TSG101. Confocal microscopy and flow cytometry showed that DOX could be effectively delivered to tumor cell nucleus and cells treated with TEX@DOX@ALA exhibited excessive ROS production upon laser irradiation. The fluorescence images showed a peak tumor uptake at 24 h after injection. PET/CT imaging with 68Ga-L-NETA-DBCO revealed both subcutaneous and orthotopic colon tumors. Over the treatment course of 14 days, average tumor volumes of the control group exceeded 1000 mm3, while the TEX@DOX@ALA photodynamic group was only 147 mm3, with an overall mouse survival time of 36 days. Conclusions: The research successfully engineered an exosome-based nanoprobe integrating the imaging components and therapeutic drugs in one single system. Our results showed that this drug-loaded exosome system may effectively target tumor and elicit synergistic chemo- and photodynamic anti-tumor effect. Funding: This work was supported by the National Natural Science Foundation of China (No. 81873904).