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Pharmaceutical Research

, 36:185 | Cite as

Pharmacokinetic/Pharmacodynamics Modeling of Drug-Loaded PLGA Nanoparticles Targeting Heterogeneously Vascularized Tumor Tissue

  • Hunter A. Miller
  • Hermann B. FrieboesEmail author
Research Paper
  • 185 Downloads

Abstract

Purpose

Nanoparticle-mediated drug delivery and efficacy for cancer applications depends on systemic as well as local microenvironment characteristics. Here, a novel coupling of a nanoparticle (NP) kinetic model with a drug pharmacokinetic/pharmacodynamics model evaluates efficacy of cisplatin-loaded poly lactic-co-glycolic acid (PLGA) NPs in heterogeneously vascularized tumor tissue.

Methods

Tumor lesions are modeled with various levels of vascular heterogeneity, as would be encountered with different types of tumors. The magnitude of the extracellular to cytosolic NP transport is varied to assess tumor-dependent cellular uptake. NP aggregation is simulated to evaluate its effects on drug distribution and tumor response.

Results

Cisplatin-loaded PLGA NPs are most effective in decreasing tumor size in the case of high vascular-induced heterogeneity, a high NP cytosolic transfer coefficient, and no NP aggregation. Depending on the level of tissue heterogeneity, NP cytosolic transfer and drug half-life, NP aggregation yielding only extracellular drug release could be more effective than unaggregated NPs uptaken by cells and releasing drug both extra- and intra-cellularly.

Conclusions

Model-based customization of PLGA NP and drug design parameters, including cellular uptake and aggregation, tailored to patient tumor tissue characteristics such as proportion of viable tissue and vascular heterogeneity, could help optimize the NP-mediated tumor drug response.

KEY WORDS

cancer nanotherapy cancer simulation mathematical modeling PLGA nanoparticles tumor heterogeneity 

ABBREVIATIONS

AUC

Area-under the-curve

ECM

Extracellular matrix

NP

Nanoparticle

NSCLC

Non-small cell lung cancer

PD

Pharmacodynamic

PK

Pharmacokinetic

PLGA

Poly lactic-co-glycolic acid

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

HBF acknowledges partial support by the National Institutes of Health/National Cancer Institute Grant R15CA203605.

Supplementary material

11095_2019_2721_MOESM1_ESM.pdf (1.4 mb)
ESM 1 (PDF 1.35 mb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacology and ToxicologyUniversity of LouisvilleLouisvilleUSA
  2. 2.Department of Bioengineering, Lutz Hall 419University of LouisvilleLouisvilleUSA
  3. 3.James Graham Brown Cancer CenterUniversity of LouisvilleLouisvilleUSA
  4. 4.Center for Predictive MedicineUniversity of LouisvilleLouisvilleUSA

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