Pharmacokinetic—Pharmacodynamic Modeling of Tumor Targeted Drug Delivery Using Nano-Engineered Mesenchymal Stem Cells

Abstract

Nano-engineered mesenchymal stem cells (nano-MSCs) are promising targeted drug delivery platforms for treating solid tumors. MSCs engineered with paclitaxel (PTX) loaded poly(lactide-co-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.

Nanotherapeutics Plus Immunotherapy in Oncology: Who Brings What to the Table?

“…A way of predicting such results while avoiding testing infinite in vivo combinations is to develop mathematical models based on drug pharmacokinetics and pharmacodynamics (i.e., PK/PD models) that can simulate and then predict treatment efficacies [15,123]. To this day, only a few models were made available in this field; among them, Cheng et al constructed a PK/PD model of nanoengineered mesenchymal stem cells in a lung cancer mice model and were able to show that dosing interval had little impact, whereas a higher dose could exhibit greater efficacy [124]. Although the design of clinical trials can be guided with PK/PD modeling, we did not find any within the nano-immunotherapy area, notably because of the recent nature of this field which is reflected in the current advancement of clinical studies.…”

Mesenchymal stem cell therapy for neurological disorders: The light or the dark side of the force?

“…Since there exist many methods for encapsulating the biomolecules containing bioactive materials or anti-cancer drugs, recent studies have been centered around the discovery of strategies for optimization of the payload and delivery capacity of MSCs (Hmadcha et al, 2020b). While some utilized nanoparticles to increase the anti-tumor efficacy of MSCs (Layek et al, 2018;Wang et al, 2018;Moku et al, 2019;Cheng et al, 2021;Ebrahimian et al, 2022), others performed microcapsule loading of MSCs for the purpose of testing their ability to serve as a delivery vehicle across a variety of tissue-blood or tumor-blood barriers (Litvinova et al, 2022). For example, a study by Litvinova et al has shown that loading of hMSCs with synthesized microcapsules causes no damage to the cell's structural integrity (Litvinova et al, 2022).…”

Design and Measurement of Drug Tissue Concentration Asymmetry and Tissue Exposure-Effect (Tissue PK-PD) Evaluation

“…Other examples of PK-PD analyses utilizing tumor tissue concentrations in Table primarily focus on differences in the extent of drug entry into tumor compartments. PK-PD analyses of both etoposide and a new mode of delivery for paclitaxel focus on understanding active drugs concentrations at the tumor site. Finally, tumor to plasma ratio differences between erlotinib and gefitinib were included as part of a PK-PD analyses to investigate whether these differences in tumor disposition could explain difference in antitumor efficacy between the two EGFR inhibitors .…”