Jang, Hochung Choi, Jiwoong Park, Daeho Han, Geonhee Kim, Eun Hye Kim, Kwangmeyung Kim, Sun Hwa Shim, Man Kyu Yang, Yoosoo 2024-10-10T08:00:40Z 2024-10-10T08:00:40Z 2024-10-10 2024-08 1838-7640 https://pubs.kist.re.kr/handle/201004/150786 Rationale: Oral chemotherapy has been emerging as a hopeful therapeutic regimen for the treatment of various cancers because of its high safety and convenience, lower costs, and high patient compliance. Despite the current advancements in nanoparticle-mediated drug delivery, numerous anticancer drugs susceptible to the hostile gastrointestinal (GI) environment exhibit poor permeability across the intestinal epithelium, rendering them ineffective in providing therapeutic benefits. In this paper, we focus on harnessing milk-derived extracellular vesicles (mEVs) for gut-to-tumor oral drug delivery by leveraging their high bioavailability. Methods: The tumor-activated prodrug (a cathepsin B-specific cleavable FRRG peptide and doxorubicin, FDX) is used as a model drug and is complexed with mEVs, resulting in FDX@mEVs. To verify stability in the GI tract, prolonged intestinal retention, and enhanced trans-epithelial transport via neonatal Fc receptor (FcRn)-mediated transcytosis, intestinal transport evaluation is conducted using in vitro intestinal barrier model and mouse model. Results: : FDX@mEVs form a stable nanostructure with an average diameter of 131.1 +/- 70.5 nm and complexation processes do not affect the inherent properties of FDX. Orally administered FDX@mEVs show significantly improved bioavailability compared to uncomplexed FDX via FcRn-mediated transcytosis of mEVs resulting in increased tumor accumulation of FDX in tumor-bearing mouse model. Conclusions: After oral administration of FDX@mEVs, it is observed that remarkable antitumor efficacy in colon tumor-bearing mice without adverse effects, such as body weight loss, liver/kidney dysfunction, and cardiotoxicity. English Ivyspring International Publisher Milk-derived extracellular vesicles enable gut-to-tumor oral delivery of tumor-activated doxorubicin prodrugs Article 10.7150/thno.97269 1 Theranostics, v.14, no.14, pp.5413 - 5428 Theranostics 14 14 5413 5428 Y scie scopus 001312857600004 2-s2.0-85203454387 Medicine, Research & Experimental Research & Experimental Medicine Article NEONATAL FC-RECEPTOR DRUG-DELIVERY IMMUNOGLOBULIN-G EXOSOMES TECHNOLOGIES CHALLENGES BINDING SYSTEM cancer therapy extracellular vesicles oral drug delivery prodrug chemotherapy