Journal
JOURNAL OF CONTROLLED RELEASE
Volume 224, Issue -, Pages 77-85Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2016.01.009
Keywords
Extracellular vesicles; Drug delivery; Polyethylene glycol; Circulation time; Targeting; Nanobody
Funding
- European Research Council starting grant MINDS in the FP7 ideas program of the European Union [260627]
- VENI Fellowship from The Netherlands Organisation for Scientific Research (NWO) [13667]
- European Union's Horizon research and innovation program under the Marie Sklodowska-Curie grant [660426]
- Marie Curie Actions (MSCA) [660426] Funding Source: Marie Curie Actions (MSCA)
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Extracellular vesicles (EVs) are increasingly being recognized as candidate drug delivery systems due to their ability to functionally transfer biological cargo between cells. However, the therapeutic applicability of EVs may be limited due to a lack of cell-targeting specificity and rapid clearance of exogenous EVs from the circulation. In order to improve EV characteristics for drug delivery to tumor cells, we have developed a novel method for decorating EVs with targeting ligands conjugated to polyethylene glycol (PEG). Nanobodies specific for the epidermal growth factor receptor (EGFR) were conjugated to phospholipid (DMPE)-PEG derivatives to prepare nanobody-PEG-micelles. When micelles were mixed with EVs derived from Neuro2A cells or platelets, a temperature-dependent transfer of nanobody-PEG-lipids to the EV membranes was observed, indicative of a 'post-insertion' mechanism. This process did not affect EV morphology, size distribution, or protein composition. After introduction of PEG-conjugated control nanobodies to EVs, cellular binding was compromised due to the shielding properties of PEG. However, specific binding to EGFR-overexpressing tumor cells was dramatically increased when EGFR-specific nanobodies were employed. Moreover, whereas unmodified EVs were rapidly cleared from the circulation within 10 min after intravenous injection in mice, EVs modified with nanobody-PEG-lipids were still detectable in plasma for longer than 60 min post-injection. In conclusion, we propose post-insertion as a novel technique to confer targeting capacity to isolated EVs, circumventing the requirement to modify EV-secreting cells. Importantly, insertion of ligand-conjugated PEG-derivatized phospholipids in EV membranes equips EVs with improved cell specificity and prolonged circulation times, potentially increasing EV accumulation in targeted tissues and improving cargo delivery. (C) 2015 Elsevier B.V. All rights reserved.
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