Original ArticleDevelopment of exosome-encapsulated paclitaxel to overcome MDR in cancer cells
Graphical abstract
Exosomes released by autologous macrophages were loaded with paclitaxel (PTX) upon ultrasound treatment. The obtained formulation (exoPTX) showed a high loading capacity, sustained drug release, profound ability to accumulate in resistant cancer cells, and increased cytotoxicity compared to PTX in vitro and in vivo.
Section snippets
Reagents
PTX and doxorubicin (DOX) was purchased from LC Laboratories (Woburn, MA). Lipophilic fluorescent dyes, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindo-carbocyanine perchlorate (DIL), and 2-decanoyl-1-(O-(11-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-propionyl)amino)undecyl)-sn-glycero-3-phosphocholine (BODIPY-PC), were purchased from Invitrogen (Carlsbad, CA) and Molecular Probes (Eugene, OR), respectively. Rhodamine 123 (R123), 4′,6-diamidino-2-phenylindole dihydrochloride (DAPI),
Manufacture and characterization of exosomal formulations of PTX (exoPTX)
Exosomes collected from the conditioned media of RAW 264.7 macrophages were characterized by size, charge, protein content, and morphology (Figure 1, A, B, and D). Exosomes showed elevated expression of exosome-associated proteins (Alix, TSG101, and Flotillin) as compared to cell lysate, which displayed greater levels of β-actin (Figure 1, B). Naive empty exosomes had a narrow size distribution, with an average particle diameter of 110.4 ± 4.2 nm and 70.8 ± 2.8 nm as revealed by NTA and DLS,
Discussion
Exosomal carriers can provide advantages of both cell-based drug delivery and nanotechnology for efficient drug transport capable of overcoming various biological barriers. However, several limitations need to be addressed before their use in the clinic. One of the difficulties is the efficient loading exosomes with a therapeutic agent without significant changes in the structure and content of exosomal membranes. In the present study, we utilized various methods for PTX incorporation into
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This study was supported by the United States National Institutes of Health grants 1RO1 NS057748 and The Carolina Partnership, a strategic partnership between the UNC Eshelman School of Pharmacy and The University Cancer Research Fund through the Lineberger Comprehensive Cancer Center (to EVB), RR021937 (to AVK), and Ministry of Education and Science of Russian Federation grants 11.G34.31.0004, 02.740.11.5232, and RSF-14-13-00731 (both to AVK and NLK).
No competing interests are present.