ABSTRACT
Extracellular vesicles (EVs) represent a next generation drug delivery system that combines nanoparticle size with extraordinary ability to cross biological barriers, reduced immunogenicity, and low offsite toxicity profiles. A successful application of this natural way of delivering biological compounds requires deep understanding EVs intrinsic properties inherited from their parent cells. Herein, we evaluated EVs released by cells of different origin, with respect to drug delivery to the brain for treatment of neurodegenerative disorders. The morphology, size, and zeta potential of EVs secreted by primary macrophages (mEVs), neurons (nEVs), and astrocytes (aEVs) were examined by nanoparticle NTA, DLS, cryoTEM, and AFM. Spherical nanoparticles with average size 110-130 nm and zeta potential around -20 mV were identified for all EVs types. mEVs showed the highest levels of tetraspanins and integrins compared to nEVs and aEVs, suggesting superior adhesion and targeting to the inflamed tissues by mEVs. Strikingly, aEVs were preferentially taken up by neuronal cells in vitro, followed by mEVs and nEVs. Nevertheless, the brain accumulation levels of mEVs in a transgenic mouse model of Parkinson's disease were significantly higher than those of nEVs or aEVs. Therefore, mEVs were suggested as the most promising nanocarrier system for drug delivery to the brain.
ABSTRACT
Drug nanoformulations hold remarkable promise for the efficient delivery of therapeutics to a disease site. Unfortunately, artificial nanocarriers, mostly liposomes and polymeric nanoparticles, show limited applications due to the unfavorable pharmacokinetics and rapid clearance from the blood circulation by the reticuloendothelial system (RES). Besides, many of them have high cytotoxicity, low biodegradability, and the inability to cross biological barriers, including the blood brain barrier. Extracellular vesicles (EVs) are novel candidates for drug delivery systems with high bioavailability, exceptional biocompatibility, and low immunogenicity. They provide a means for intercellular communication and the transmission of bioactive compounds to targeted tissues, cells, and organs. These features have made them increasingly attractive as a therapeutic platform in recent years. However, there are many obstacles to designing EV-based therapeutics. In this review, we will outline the main hurdles and limitations for therapeutic and clinical applications of drug loaded EV formulations and describe various attempts to solve these problems.
ABSTRACT
Efficient targeted delivery of anticancer agents to TNBC cells remains one of the greatest challenges to developing therapies. The lack of tumor-specific markers, aggressive nature of the tumor, and unique propensity to recur and metastasize make TNBC tumors more difficult to treat than other subtypes. We propose to exploit natural ability of macrophages to target cancer cells by means of extracellular vesicles (EVs) as drug delivery vehicles for chemotherapeutic agents, paclitaxel (PTX) and doxorubicin (Dox). We demonstrated earlier that macrophage-derived EVs loaded with PTX (EV-PTX) and Dox (EV-Dox) target cancer cells and exhibited high anticancer efficacy in a mouse model of pulmonary metastases. Herein, we report a manufacture and characterization of novel EV-based drug formulations using different loading procedures that were optimized by varying pH, temperature, and sonication conditions. Selected EV-based formulations showed a high drug loading, efficient accumulation in TNBC cells in vitro, and pronounced anti-proliferation effect. Drug-loaded EVs target TNBC in vivo, including the orthotopic mouse T11 tumors in immune competent BALB/C mice, and human MDA-MB-231 tumors in athymic nu/nu mice, and abolished tumor growth. Overall, EV-based formulations can provide a novel solution to a currently unmet clinical need and reduce the morbidity and mortality of TNBC patients. Graphical Abstract Macrophage-derived extracellular vesicles (EVs) for targeted drug delivery to TNBC tumors. Chemotherapeutics with different water solubility (Dox or PTX, i.e. hydrophilic or hydrophobic drugs, respectively) were loaded into macrophage-derived EVs through parental cells (Dox), or into naïve EVs (Dox or PTX), and their antitumor efficacy was demonstrated in mouse orthotopic TNBC model.
