Abstract
Inefficient extravasation and penetration in solid tissues hinder the clinical outcome of nanoparticles (NPs). Recent studies have shown the extravasation and penetration of NPs in solid tumor are mostly achieved via an active transcellular route. Numerous efforts are devoted to elucidate the endocytosis and subcellular trafficking of NPs. However, how they exit from one cell and re-enter into neighboring ones (termed intercellular exchange) remains poorly understood. The previous study showed that a significant portion of NPs are transferred inside extracellular vesicles (EVs). Inhibition of EV biogenesis significantly reduces tumor accumulation and vascular penetration of various NPs in vivo. Here, a manual chemical screen is performed with this assay, which identifies that LDN-214117 (an inhibitor for activin receptor-like kinase-2, ALK-2) as an agonist of NP intercellular exchange. LDN-214117 is showed to regulate the intercellular exchange by increasing the EV biogenesis via bone morphogenetic protein–mitogen-activated protein kinase (BMP–MAPK) signaling pathway. LDN-214117 treatment further enhances tumor accumulation and vascular penetration of a variety of NPs in multiple tumor models, which improves their antitumor efficacy. Overall, the identification of a novel chemical compound with intercellular exchange assay is showcase to modulate EV-mediated transport, thus boosting the delivery and therapeutic efficacy of nanomaterials.
Original language | English (US) |
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Article number | 2200173 |
Journal | Advanced Therapeutics |
Volume | 6 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2023 |
Bibliographical note
Funding Information:Research reported in this publication was supported by grants from the National Institute of Health (Grant Nos. R01CA214550, R01GM133885) and the State of Minnesota (Grant No. MNP#19.08). The content was solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A portion of this work was carried out in the Minnesota Nano Center, which receives partial support from the National Science Foundation through the NNCI program.
Publisher Copyright:
© 2022 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH.
Keywords
- LDN-214117
- compound screening
- extracellular vesicles
- intercellular exchange
- nanoparticle penetration
PubMed: MeSH publication types
- Journal Article