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Tumor extracellular vesicles carrying antitumor (KLAKLAK)2 peptide and tumor-specific antigens for improved tumor therapy

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Abstract

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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Funding

This work was financially supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (grant number: NRF-2021R1A2B5B01001932).

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Authors and Affiliations

  1. Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea

    Eunsol Lee & Eun Seong Lee

  2. Department of Biomedical-Chemical Engineering, The Catholic University of Korea, 43 Jibong-ro, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea

    Eun Seong Lee

Authors
  1. Eunsol Lee
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Correspondence to Eun Seong Lee.

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Conflict of interest

All authors (E. Lee and E.S. Lee) declare no conflict of interest.

Human and Animal Rights

All procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of the Catholic University of Korea (CUK-IACUC-2021-052) for the care and use of animals.

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Lee, E., Lee, E.S. Tumor extracellular vesicles carrying antitumor (KLAKLAK)2 peptide and tumor-specific antigens for improved tumor therapy. J. Pharm. Investig. 53, 505–516 (2023). https://doi.org/10.1007/s40005-023-00617-y

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  • DOI: https://doi.org/10.1007/s40005-023-00617-y

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