Small extracellular vesicles; doxorubicin; drug delivery systems; melanoma; Polyethylene Glycols; Doxorubicin; Animals; Cell Line, Tumor; Doxorubicin/pharmacology; Doxorubicin/therapeutic use; Humans; Mice; Polyethylene Glycols/therapeutic use; Extracellular Vesicles; Melanoma, Experimental/drug therapy; Melanoma, Experimental/pathology; Melanoma, Experimental; Molecular Medicine; Oncology; Pharmacology; Cancer Research
Abstract :
[en] Tailoring extracellular vesicles (EVs) as targeted drug delivery systems to enhance the therapeutic efficacy showed superior advantage over liposomal therapies. Herein, we developed a novel nanotool for targeting B16.F10 murine melanoma, based on EVs stabilized with Polyethylene glycol (PEG) and loaded with doxorubicin (DOX). Small EVs were efficiently enriched from melanoma cells cultured under metabolic stress by ultrafiltration coupled with size exclusion chromatography (UF-SEC) and characterized by size, morphology, and proteome. To reduce their clearance in vivo, EVs were PEGylated and passively loaded with DOX (PEG-EV-DOX). Our data suggested that the low PEG coverage of EVs might still favor EV surface protein interactions with target proteins from intratumor cells, ensuring their use as "Trojan horses" to deliver DOX to the tumor tissue. Moreover, our results showed a superior antitumor activity of PEG-EV-DOX in B16.F10 murine melanoma models in vivo compared to that exerted by clinically applied liposomal DOX in the same tumor model. The PEG-EV-DOX administration in vivo reduced NF-κB activation and increased BAX expression, suggesting better prognosis of EV-based therapy than liposomal DOX treatment. Collectively, our results highlight the promising potential of EVs as optimal tools for systemic delivery of DOX to solid tumors.
Patras, Laura; Department of Molecular Biology and Biotechnology, Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, "Babes-Bolyai" University, Cluj-Napoca, Romania
Ionescu, Aura Elena; Department of Enzymology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
Munteanu, Cristian; Department of Bioinformatics and Structural Biochemistry, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
Hajdu, Renata; Department of Molecular Biology and Biotechnology, Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, "Babes-Bolyai" University, Cluj-Napoca, Romania
Kosa, Andreea; Department of Molecular Biology and Biotechnology, Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, "Babes-Bolyai" University, Cluj-Napoca, Romania
Porfire, Alina; Department of Pharmaceutical Technology and Biopharmacy, Faculty of Pharmacy, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
Licarete, Emilia; Department of Molecular Biology and Biotechnology, Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, "Babes-Bolyai" University, Cluj-Napoca, Romania ; Molecular Biology Centre, Interdisciplinary Research Institute in Bio-Nano-Sciences, "Babes-Bolyai" University, Cluj-Napoca, Romania
Rauca, Valentin Florian; Department of Molecular Biology and Biotechnology, Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, "Babes-Bolyai" University, Cluj-Napoca, Romania
Sesarman, Alina; Department of Molecular Biology and Biotechnology, Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, "Babes-Bolyai" University, Cluj-Napoca, Romania
Luput, Lavinia ; Department of Molecular Biology and Biotechnology, Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, "Babes-Bolyai" University, Cluj-Napoca, Romania
Bulzu, Paul; Department of Molecular Biology and Biotechnology, Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, "Babes-Bolyai" University, Cluj-Napoca, Romania
Chiroi, Paul; Department of Molecular Biology and Biotechnology, Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, "Babes-Bolyai" University, Cluj-Napoca, Romania
Tranca, Rares Andrei; Department of Molecular Biology and Biotechnology, Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, "Babes-Bolyai" University, Cluj-Napoca, Romania
Meszaros, Marta-Szilvia ; Université de Liège - ULiège > GIGA > GIGA Cancer - Tumors Biology and Development ; Department of Molecular Biology and Biotechnology, Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, "Babes-Bolyai" University, Cluj-Napoca, Romania
Negrea, Giorgiana; Department of Molecular Biology and Biotechnology, Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, "Babes-Bolyai" University, Cluj-Napoca, Romania
Barbu-Tudoran, Lucian; "C.Craciun" Electron Microscopy Center, Faculty of Biology and Geology, "Babes-Bolyai" University, Cluj-Napoca, Romania
Potara, Monica; Nanobiophotonics Center, Interdisciplinary Research Institute in Bio-Nano-Sciences and Faculty of Physics, "Babes-Bolyai" University, Cluj-Napoca, Romania
Szedlacsek, Stefan; Department of Enzymology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
Banciu, Manuela; Department of Molecular Biology and Biotechnology, Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, "Babes-Bolyai" University, Cluj-Napoca, Romania
UEFISCDI - Executive Unit for Financing Higher Education Research Development and Innovation
Funding text :
This work was supported by Romanian grants awarded by CNCS-UEFISCDI under the Ministry of Research and Innovation, project number PN-III-P4-ID-PCE-2016-0342, contract no. 91/2017, within PNCDI III.
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