Cohen Oded, Betzer Oshra, Elmaliach-Pnini Noy, Motiei Menachem, Sadan Tamar, Cohen-Berkman Moran, Dagan Or, Popovtzer Aron, Yosepovich Ady, Barhom Hana, Michaeli Shulamit, Popovtzer Rachela
Department of Otolaryngology, Head and Neck Surgery, Kaplan Medical Center, Rehovot, Israel, affiliated to the Hebrew University, Jerusalem, Israel.
Biomater Sci. 2021 Mar 21;9(6):2103-2114. doi: 10.1039/d0bm01735c. Epub 2021 Jan 21.
Exosomes are promising vectors for anti-tumor therapy, due to their biocompatibility, low immunogenicity, and innate ability to interact with target cells. However, promoting clinical application of exosome-based therapeutics requires elucidation of key issues, including exosome biodistribution, tumor targeting and accumulation, and the ability to overcome tumor barriers that limit the penetration of various nano-carriers and drugs. Here, we examined these parameters in exosomes derived from mesenchymal stem cells (MSC-exo) and from the A431 squamous cell carcinoma line (A431-exo), which both have potential use in cancer therapy. Using our novel technique combining gold nanoparticle (GNP) labeling of exosomes and non-invasive computed tomography imaging (CT), we longitudinally and quantitatively tracked the two intravenously-injected exosome types in A431 tumor-bearing mice. CT imaging up to 48 h and subsequent ex vivo analysis revealed tumor homing abilities of both exosome types, yet there was significantly higher tumor accumulation of MSC-exo as compared to A431-exo. Moreover, MSC-exo demonstrated the ability to penetrate the tumor and distribute throughout its bulk, while non-encapsulated GNPs remained concentrated at the tumor periphery. Histological analysis showed penetration of MSC-exo not only into the tumor tissue, but also into tumor cell cytoplasm. While the proportion of biodistribution between organs at 48 h was similar for both exosome types, more rapid clearance was indicated for A431-exo. Thus, our findings demonstrate an effect of exosome type on tumor targeting abilities and biodistribution, and suggest that MSC-exo may have superior abilities for tumor-targeted therapy.
外泌体因其生物相容性、低免疫原性以及与靶细胞相互作用的固有能力，是抗肿瘤治疗中很有前景的载体。然而，要推动基于外泌体的疗法的临床应用，需要阐明一些关键问题，包括外泌体的生物分布、肿瘤靶向与积累，以及克服限制各种纳米载体和药物渗透的肿瘤屏障的能力。在此，我们检测了源自间充质干细胞的外泌体（MSC-exo）和源自A431鳞状细胞癌系的外泌体（A431-exo）的这些参数，这两种外泌体在癌症治疗中都有潜在用途。通过我们将外泌体的金纳米颗粒（GNP）标记与非侵入性计算机断层扫描成像（CT）相结合的新技术，我们纵向且定量地追踪了A431荷瘤小鼠体内静脉注射的这两种外泌体。长达48小时的CT成像及随后的体外分析显示两种外泌体均具有肿瘤归巢能力，但与A431-exo相比，MSC-exo在肿瘤中的积累显著更高。此外，MSC-exo表现出穿透肿瘤并在整个肿瘤块中分布的能力，而未包封的GNPs仍集中在肿瘤周边。组织学分析表明MSC-exo不仅能穿透肿瘤组织，还能进入肿瘤细胞胞质。虽然48小时时两种外泌体在各器官间的生物分布比例相似，但A431-exo的清除速度更快。因此，我们的研究结果证明了外泌体类型对肿瘤靶向能力和生物分布的影响，并表明MSC-exo在肿瘤靶向治疗方面可能具有更优越的能力。
