Development of a Subcellular Semimechanism-Based Pharmacokinetic/Pharmacodynamic Model to Characterize Paclitaxel Effects Delivered by Polymeric Micelles

Abstract

A transit compartment model was widely and successfully applied to characterize the complex time course of cancer chemotherapeutic effects in vivo or in vitro. However, the underlying mechanisms were not quantitatively depicted. This study aimed to develop a semimechanism-based cellular pharmacokinetic/pharmacodynamic (PK/PD) model to characterize paclitaxel (PTX) effect delivered by PLGA-PEG micelles which was based on analysis of drug subcellular distribution, the tubulin assembly level, the cell cycle shift, and the resulting cytotoxicity. Human breast cancer cell line MCF-7 was exposed to PTX at the concentration of 20 and 40 ng/mL. The in vitro pharmacokinetics of micelle-entrapped PTX was described by a 3-compartment model composed of membrane/organelle, nucleus, and cytoskeleton. A hypothetical effect compartment was used to characterize the distribution delay. The time course of tubulin polymerization stimulation was fitted by the indirect response model. The relationship between tubulin polymerization and G2/M cell population was described by a linear model, and the promoting effect of G2/M arrest on the cytotoxicity was characterized by the E max model. The proposed model captured the data successfully and described the cellular mechanism of antimitotic drug nanoparticles quantitatively. The methodology and the resulting model could be a supplement for traditional in vivo studies.

Nanotopography as Artificial Microenvironment for Accurate Visualization of Metastasis Development via Simulation of ECM Dynamics

“…Importantly, cells undergoing AME-induced mesenchymal-like cell transition exhibit morphology similar to cells undergoing transforming growth factor beta (TGF-β) induced EMT, which have been shown to possess enhanced metastatic character compared to epithelial-like cancer cells, − thus indicating that the AME platform induces development of metastasis. Notably, previous studies regarding cell transition and the related mechanisms required analysis of time course treatments of drugs or cytokines. − For example, Haley et al revealed multiple altered transcription and epigenetic pathways associated with mesenchymal trans-differentiation in NSCLC through a time course study of TGF-β treatment . However, the AME platform produced similar stages of metastasis-related transition simultaneously, further supporting the conclusion that the deregulation of ECM over time and resulting development of metastasis can be effectively simulated.…”

Pharmacokinetic behaviors of soft nanoparticulate formulations of chemotherapeutics

“…Pharmacokinetic/pharmacodynamic (PK/PD) models can be used to predict the optimal conditions for a drug carrier to maximize the antitumor effect of the encapsulated drug relative to the free drug (Rodallec et al, 2018). In such PK/PD models, the disposition of the free and encapsulated drugs is often described by compartment models which are linked to the tumor compartment via blood flow rates (Zheng et al, 2019). Using an appropriate cell‐kill kinetic PD model, the number of tumor cells can be expressed quantitatively as a function of the free concentration of drug in the tumor compartment.…”

Evaluating Inhibitory Effects of Paclitaxel and Vitamin D3 Loaded Poly Lactic Glycolic Acid Co-Delivery Nanoparticles on the Breast Cancer Cell Line

“…2 Currently, the co-delivery of anti-cancer drugs has been developed by assistance of biodegradables nanoparticles (NPs) such as polylactic glycolic acid (PLGA) NPs. [3][4][5] PLGA NPs are one group of the commonly used polymers in manufacturing NPs thanks to their high adaptability to biological environments, ability to degrade into natural metabolites, lower toxicity and higher stability than that of liposomes and some other drug delivery systems. PLGA NPs also have the ability to modify their surface to prevent rapid absorption of this polymer by the reticuloendothelial system of the body.…”