Targeting the Hypoxic and Acidic Tumor Microenvironment with pH-Sensitive Peptides.
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ABSTRACT:
SUBMITTER: Dharmaratne NU
PROVIDER: S-EPMC8000199 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In this study, we fabricated tumor-homing pH-sensitive extracellular vesicles for efficient tumor treatment. These vesicles were prepared using extracellular vesicles (EVs; BTEVs extracted from BT-474 tumor cells or SKEVs extracted from SK-N-MC tumor cells), hyaluronic acid grafted with 3-(diethylamino)propylamine (HDEA), and doxorubicin (DOX, as a model antitumor drug). Consequently, HDEA/DOX anchored EVs (HDEA@EVs) can interact with origin tumor cells owing to EVs' homing ability to origin cells. Therefore, EV blends of HDEA@BTEVs and HDEA@SKEVs demonstrate highly increased cellular uptake in both BT-474 and SK-N-MC cells: HDEA@BTEVs for BT-474 tumor cells and HDEA@SKEVs for SK-N-MC tumor cells. Furthermore, the hydrophobic HDEA present in HDEA@EVs at pH 7.4 can switch to hydrophilic HDEA at pH 6.5 as a result of acidic pH-induced protonation of 3-(diethylamino)propylamine (DEAP) moieties, resulting in an acidic pH-activated EVs' disruption, accelerated release of encapsulated DOX molecules, and highly increased cell cytotoxicity. However, EV blends containing pH-insensitive HA grafted with deoxycholic acid (HDOC) (HDOC@BTEVs and HDOC@SKEVs) showed less cell cytotoxicity for both BT-474 and SK-N-MC tumor cells, because they did not act on EVs' disruption and the resulting DOX release. Consequently, the use of these tumor-homing pH-sensitive EV blends may result in effective targeted therapies for various tumor cells.
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Project description:Initially believed to be a disease of deregulated cellular and genetic expression, cancer is now also considered a disease of the tumor microenvironment. Over the past two decades, significant and rapid progress has been made to understand the complexity of the tumor microenvironment and its contribution to shaping the response to various anti-cancer therapies, including immunotherapy. Nevertheless, it has become clear that the tumor microenvironment is one of the main hallmarks of cancer. Therefore, a major challenge is to identify key druggable factors and pathways in the tumor microenvironment that can be manipulated to improve the efficacy of current cancer therapies. Among the different tumor microenvironmental factors, this review will focus on hypoxia as a key process that evolved in the tumor microenvironment. We will briefly describe our current understanding of the molecular mechanisms by which hypoxia negatively affects tumor immunity and shapes the anti-tumor immune response. We believe that such understanding will provide insight into the therapeutic value of targeting hypoxia and assist in the design of innovative combination approaches to improve the efficacy of current cancer therapies, including immunotherapy.
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