PURPOSE: Exosomes are small membrane vesicles (30-100nm in diameter) secreted by 
cells into extracellular space. The present study evaluated the effect of 
chemotherapeutic agents on exosome production and/or release, and quantified the 
contribution of exosomes to intercellular drug transfer and pharmacodynamics.
METHODS: Human cancer cells (breast MCF7, breast-to-lung metastatic LM2, ovarian 
A2780 and OVCAR4) were treated with paclitaxel (PTX, 2-1000nM) or doxorubicin 
(DOX, 20-1000nM) for 24-48h. Exosomes were isolated from the culture medium of 
drug-treated donor cells (Donor cells) using ultra-centrifugation, and analyzed 
for acetylcholinesterase activity, total proteins, drug concentrations, and 
biological effects (cytotoxicity and anti-migration) on drug-naïve recipient 
cells (Recipient cells). These results were used to develop computational 
predictive quantitative pharmacology models.
RESULTS: Cells in exponential growth phase released ~220 exosomes/cell in 
culture medium. PTX and DOX significantly promoted exosome production and/or 
release in a dose- and time-dependent manner, with greater effects in ovarian 
cancer cells than in breast cancer cells. Exosomes isolated from Donor cells 
contained appreciable drug levels (2-7pmole/106 cells after 24h treatment with 
100-1000nM PTX), and caused cytotoxicity and inhibited migration of Recipient 
cells. Quantitative pharmacology models that integrated cellular PTX 
pharmacokinetics with PTX pharmacodynamics successfully predicted effects of 
exosomes on intercellular drug transfer, cytotoxicity of PTX on Donor cells and 
cytotoxicity of PTX-containing exosomes on Recipient cells. Additional model 
simulations indicate that within clinically achievable PTX concentrations, the 
contribution of exosomes to active drug efflux increased with drug concentration 
and exceeded the p-glycoprotein efflux when the latter was saturated.
CONCLUSIONS: Our results indicate (a) chemotherapeutic agents stimulate exosome 
production or release, and (b) exosome is a mechanism of intercellular drug 
transfer that contributes to pharmacodynamics of neighboring cells.