Publicaciones científicas
Compartmentalized drug localization studies in extracellular vesicles for anticancer therapy
Arunkumar Pitchaimani 1 , Miguel Ferreira 1 , Annalisa Palange 1 , Martina Pannuzzo 1 , Claudia De Mei 1 , Raffaele Spano 1 , Roberto Marotta 2 , Beatriz Pelacho 3 , Felipe Prosper 3 4 , Paolo Decuzzi 1
Abstract
In the development of therapeutic extracellular vesicles (EVs), drug encapsulation efficiencies are significantly lower when compared with synthetic nanomedicines.
This is due to the hierarchical structure of the EV membrane and the physicochemical properties of the candidate drug (molecular weight, hydrophilicity, lipophilicity, and so on). As a proof of concept, here we demonstrated the importance of drug compartmentalization in EVs as an additional parameter affecting the therapeutic potential of drug-loaded EVs.
In human adipose mesenchymal stem cell (hADSC) derived EVs, we performed a comparative drug loading analysis using two formulations of the same chemotherapeutic molecule - free doxorubicin (DOX) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) lipid-conjugated doxorubicin (L-DOX) - to enhance the intracellular uptake and therapeutic efficacy. By nano surface energy transfer (NSET) and molecular simulation techniques, along with cryo-TEM analysis, we confirmed the differential compartmentalization of these two molecules in hADSC EVs. L-DOX was preferentially adsorbed onto the surface of the EV, due to its higher lipophilicity, whereas free DOX was mostly encapsulated within the EV core.
Also, the L-DOX loaded EV (LDOX@EV) returned an almost three-fold higher DOX content as compared to the free DOX loaded EV (DOX@EV), for a given input mass of drug. Based on the cellular investigations, L-DOX@EV showed higher cell internalization than DOX@EV.
Also, in comparison with free L-DOX, the magnitude of therapeutic potential enhancement displayed by the surface compartmentalized L-DOX@EV is highly promising and can be exploited to overcome the sensitivity of many potential drugs, which are impermeable in nature. Overall, this study illustrates the significance of drug compartmentalization in EVs and how this could affect intracellular delivery, loading efficiency, and therapeutic effect.
This will further lay the foundation for the future systematic investigation of EV-based biotherapeutic delivery platforms for personalized medicine.
CITA DEL ARTÍCULO Nanoscale Adv. 2023 Nov 8;5(24):6830-6836. doi: 10.1039/d3na00207a. eCollection 2023 Dec 5
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