Nano-engineered mesenchymal stem cells (nano-MSCs) are promising targeted drug delivery platforms for treating solid tumors. MSCs engineered with paclitaxel (PTX) loaded poly(lactideco-glycolide) (PLGA) nanoparticles (NPs) are efficacious in treating lung and ovarian tumors in mouse models. The quantitative description of pharmacokinetics (PK) and pharmacodynamics (PD) of nano-MSCs is crucial for optimizing their therapeutic efficacy and clinical translatability. However, successful translation of nano-MSCs is challenging due to their complex composition and physiological mechanisms regulating their pharmacokinetic-pharmacodynamic relationship (PK–PD). Therefore, in this study, a mechanism-based preclinical PK–PD model was developed to characterize the PK–PD relationship of nano-MSCs in orthotopic A549 human lung tumors in SCID Beige mice. The developed model leveraged literature information on diffusivity and permeability of PTX and PLGA NPs, PTX release from PLGA NPs, exocytosis of NPs from MSCs as well as PK and PD profiles of nano-MSCs from previous in vitro and in vivo studies. The developed PK–PD model closely captured the reported tumor growth in animals receiving no treatment, PTX solution, PTX-PLGA NPs and nano-MSCs. Model simulations suggest that increasing the dosage of nano-MSCs and/or reducing the rate of PTX-PLGA NPs exocytosis from MSCs could result in improved anti-tumor efficacy in preclinical settings.
|Original language||English (US)|
|Number of pages||22|
|State||Published - Jan 2021|
Bibliographical noteFunding Information:
This research was funded by Minnesota Ovarian Cancer Alliance Research Grant and National Institute of Health, grant number EB022558. The APC was funded by EB022558 and M.A.-K.?s funds from University of Minnesota.
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
- Mesenchymal stem cells
- Modeling and simulation
- Pharmacokinetics and pharmacodynamics
- Targeted therapy
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Mark A Sanders (Program Director) & Guillermo Marques (Scientific Director)University Imaging Centers