For the successful clinical advancement of exosome therapeutics, the biodistribution and pharmacokinetic profile of exogenous exosomes in various animal models must be determined. Compared with fluorescence or bioluminescence imaging, radionuclide imaging confers multiple advantages for the in vivo tracking of biomolecular therapeutics because of its excellent sensitivity for deep tissue imaging and potential for quantitative measurement. Herein, we assessed the quantitative biodistribution and pharmacokinetics of good manufacturing practice-grade therapeutic exosomes labeled with zirconium-89 (⁸⁹Zr) after systemic intravenous administration in mice and rats. Quantitative biodistribution analysis by positron emission tomography/computed tomography and gamma counting in mice and rats revealed that the total ⁸⁹Zr signals in the organs were lower in rats than in mice, suggesting a higher excretion rate of exosomes in rats. A prolonged ⁸⁹Zr signal for up to 7 days in most organs indicated that substantial amounts of exosomes were taken up by the parenchymal cells in those organs, highlighting the therapeutic potential of exosomes for the intracellular delivery of therapeutics. Exosomes were mainly distributed in the liver and to a lesser extent in the spleen, while a moderately distributed in the kidney, lung, stomach, intestine, urinary bladder, brain, and heart. Exosomes were rapidly cleared from the blood circulation, with a rate greater than that of free ⁸⁹Zr, indicating that exosomes might be rapidly taken up by cells and tissues.

Combining standard surgical procedures with personalized chemotherapy and the continuous monitoring of cancer progression is necessary for effective NSCLC treatment. In this study, we developed liposomal nanoparticles as theranostic agents capable of simultaneous therapy for and imaging of target cancer cells. Copper-64 (⁶⁴Cu), with a clinically practical half-life (t_1/2 = 12.7 h) and decay properties, was selected as the radioisotope for molecular PET imaging. An anti-epidermal growth factor receptor (anti-EGFR) antibody was used to achieve target-specific delivery. Simultaneously, the chemotherapeutic agent doxorubicin (Dox) was encapsulated within the liposomes using a pH-gradient method. The conjugates of ⁶⁴Cu-labeled and anti-EGFR antibody-conjugated micelles were inserted into the doxorubicin-encapsulating liposomes via a post-insertion procedure (⁶⁴Cu-Dox-immunoliposomes). We evaluated the size and zeta-potential of the liposomes and analyzed target-specific cell binding and cytotoxicity in EGFR-positive cell lines. Then, we analyzed the specific therapeutic effect and PET imaging of the ⁶⁴Cu-Dox-immunoliposomes with the A549 xenograft mouse model. In vivo therapeutic experiments on the mouse models demonstrated that the doxorubicin-containing ⁶⁴Cu-immunoliposomes effectively inhibited tumor growth. Moreover, the ⁶⁴Cu-immunoliposomes provided superior in vivo PET images of the tumors compared to the untargeted liposomes. We suggest that nanoparticles will be the potential platform for cancer treatment as a widely applicable theranostic system.

Glycosyltransferase-producing Leuconostoc lactis CCK940 produces CCK- oligosaccharides, gluco-oligosaccharide molecules, using sucrose and maltose as donor and acceptor molecules, respectively. In this study, the immunostimulatory activities of CCK-oligosaccharides on RAW264.7 macrophages and BALB/c mice were evaluated. CCK-oligosaccharides induced the expression of phosphorylated-p38, extracellular-signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) and upregulation of phagocytic activity in RAW264.7 macrophages, suggesting their involvement in mitogen-activated protein kinase (MAPK) signaling pathway and phagocytosis. When CCK-oligosaccharides were administered to mice intraperitoneally injected with cyclophosphamide (CY), spleen indices and expressions of interleukin (IL)-6, IL–10, and tumor necrosis factor-α increased, compared with those in only CY-treated group. These findings suggest that CCK-oligosaccharides can be used as an effective immunostimulating agent.

Cell adhesion receptor integrin α_vβ₃ is a promising biomarker for developing tumor-angiogenesis targeted theranostics. In this study, we aimed to examine the therapeutic potential of peptide receptor radionuclide therapy (PRRT) with ¹⁸⁸Re-IDA-D-[c(RGDfK)]₂ (11.1 MBq). The results showed that the tumor volume was significantly decreased by 81% compared with the vehicle-treated group in U87-MG xenografts. The quantitative in vivo anti-angiogenic responses of PRRT were obtained using ^99mTc-IDA-D-[c(RGDfK)]₂ SPECT and corresponded to the measured tumor volume. PRRT combined with temozolomide (TMZ) resulted in a 93% reduction in tumor volume, which was markedly greater than that of each agent used individually. In addition, histopathological characterization showed that PRRT combined with TMZ was superior to PRRT or TMZ alone, even when TMZ was used at half dose. Overall, our results indicated that integrin-targeted PRRT and TMZ combined therapy might be a new medical tool for the effective treatment of glioblastoma.