Drug transport kinetics of intravascular triggered drug delivery systems

Timo L M Ten Hagen,Matthew R Dreher,Mohamadreza Amin,Sara Zalba,Li Li,Dieter Haemmerich,Ann L B Seynhaeve

doi:10.1038/s42003-021-02428-z

Timo L M Ten Hagen, Matthew R Dreher + Show 5 more

Open Access

https://doi.org/10.1038/s42003-021-02428-z

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Abstract

Intravascular triggered drug delivery systems (IV-DDS) for local drug delivery include various stimuli-responsive nanoparticles that release the associated agent in response to internal (e.g., pH, enzymes) or external stimuli (e.g., temperature, light, ultrasound, electromagnetic fields, X-rays). We developed a computational model to simulate IV-DDS drug delivery, for which we quantified all model parameters in vivo in rodent tumors. The model was validated via quantitative intravital microscopy studies with unencapsulated fluorescent dye, and with two formulations of temperature-sensitive liposomes (slow, and fast release) encapsulating a fluorescent dye as example IV-DDS. Tumor intra- and extravascular dye concentration dynamics were extracted from the intravital microscopy data by quantitative image processing, and were compared to computer model results. Via this computer model we explain IV-DDS delivery kinetics and identify parameters of IV-DDS, of drug, and of target tissue for optimal delivery. Two parameter ratios were identified that exclusively dictate how much drug can be delivered with IV-DDS, indicating the importance of IV-DDS with fast drug release (~sec) and choice of a drug with rapid tissue uptake (i.e., high first-pass extraction fraction). The computational model thus enables engineering of improved future IV-DDS based on tissue parameters that can be quantified by imaging.

Highlights

Intravascular triggered drug delivery systems (IV-Drug delivery systems (DDS)) for local drug delivery include various stimuli-responsive nanoparticles that release the associated agent in response to internal or external stimuli
We identified the delivery kinetics of Intravascular triggered drug delivery systems (IV-DDS) based on a computational model integrated with in vivo imaging studies where temperature-sensitive liposomes served as example IV-DDS
Various IV-DDS have been studied for decades without guidance on how to engineer an optimal delivery system, and with limited quantitative data on how the interaction between IV-DDS, drug, and tissue impacts delivery

Summary

Introduction

Intravascular triggered drug delivery systems (IV-DDS) for local drug delivery include various stimuli-responsive nanoparticles that release the associated agent in response to internal (e.g., pH, enzymes) or external stimuli (e.g., temperature, light, ultrasound, electromagnetic fields, X-rays). Tumor intra- and extravascular dye concentration dynamics were extracted from the intravital microscopy data by quantitative image processing, and were compared to computer model results Via this computer model we explain IV-DDS delivery kinetics and identify parameters of IV-DDS, of drug, and of target tissue for optimal delivery. When a solid tumor is subjected to localized hyperthermia, intravascular release of drug from TSL is triggered intratumorally resulting in localized delivery with up to 25 times higher tumor drug uptake than unencapsulated drug[21,33,38,39,40], while TSL circulating in nonheated tissues retain the drug Another prevalent IV-DDS example are microbubbles, which release the associated drug when activated by ultrasound[41,42]. All model parameters were experimentally measured in vivo, and intravital fluorescence microscopy studies were used to validate the computational model

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