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KMID : 1146920230530040505
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Journal of Pharmaceutical Investigation
2023 Volume.53 No. 4 p.505 ~ p.516
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Tumor extracellular vesicles carrying antitumor (KLAKLAK)2 peptide and tumor-specific antigens for improved tumor therapy
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Lee Eun-Sol
Lee Eun-Seong
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Abstract
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Purpose : This study aimed to fabricate tumor-originated extracellular vesicles (EVs) targeting tumors for use in combination with immunotherapy and chemotherapy.
Methods : The antitumor immune EVs (iEVs) consisted of EVs anchored to hyaluronic acid conjugated with 3-(diethylamino)propylamine (HDEA, as a pH-sensitive segment), monophosphoryl lipid A [MPLA, as a Toll-like receptor 4 (TLR4) targeted moiety], and mucin 1 antigen (MUC1, as a tumor-associated antigen) using the sonication method to carry tumor-associated antigens, and were referred to as (HDEA/MPLA/MUC1)@EVs. The chemotherapeutic EVs (cEVs) consisted of EVs anchored to HDEA (as a pH-sensitive segment) and (KLAKLAK)2 peptide (KLAK, as an antitumor model peptide drug) to carry a tumor-killing peptide, and were referred to as (HDEA/KLAK)@EVs. The blended EVs (bEVs) were prepared by physically mixing iEVs and cEVs for combined antitumor immunotherapy and chemotherapy.
Results : The bEVs were efficiently internalized by the dendritic cells (DCs) via MPLA-TLR4 receptor mediated endocytosis and by the MDA-MB-231 tumor cells via HA-CD44 receptor mediated endocytosis. In particular, the internalized EVs were physically destabilized owing to the protonation of DEAP (pKb ~6.8) in the endosomal compartments, thereby accelerating the release of MUC1 antigen (promoting the antitumor immune response) and KLAK peptide (promoting the tumor-killing activity), and resulting in improved antitumor activity compared with that achieved by single EV administration
Conclusion : We demonstrated the antitumor effect of the bEVs in vitro/in vivo tumor model studies. These results indicate that the bEVs can provide a synergistic effect compared to single EV administration.
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KEYWORD
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Combined therapy, Extracellular vesicles, pH-responsive, KLAK peptide, MUC1 antigen, Antitumor therapy
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