A 3D Tumor‐Mimicking In Vitro Drug Release Model of Locoregional Chemoembolization Using Deep Learning‐Based Quantitative Analyses

Abstract

Primary liver cancer, with the predominant form as hepatocellular carcinoma (HCC), remains a worldwide health problem due to its aggressive and lethal nature. Transarterial chemoembolization, the first-line treatment option of unresectable HCC that employs drug-loaded embolic agents to occlude tumor-feeding arteries and concomitantly delivers chemotherapeutic drugs into the tumor, is still under fierce debate in terms of the treatment parameters. The models that can produce in-depth knowledge of the overall intratumoral drug release behavior are lacking. This study engineers a 3D tumor-mimicking drug release model, which successfully overcomes the substantial limitations of conventional in vitro models through utilizing decellularized liver organ as a drug-testing platform that uniquely incorporates three key features, i.e., complex vasculature systems, drug-diffusible electronegative extracellular matrix, and controlled drug depletion. This drug release model combining with deep learning-based computational analyses for the first time permits quantitative evaluation of all important parameters associated with locoregional drug release, including endovascular embolization distribution, intravascular drug retention, and extravascular drug diffusion, and establishes long-term in vitro-in vivo correlations with in-human results up to 80 d. This model offers a versatile platform incorporating both tumor-specific drug diffusion and elimination settings for quantitative evaluation of spatiotemporal drug release kinetics within solid tumors.

Ultrastable Iodinated Oil-Based Pickering Emulsion Enables Locoregional Sustained Codelivery of Hypoxia Inducible Factor-1 Inhibitor and Anticancer Drugs for Tumor Combination Chemotherapy

“…The ex vivo drug release of DOX and ACF in TE and PE was accessed in decellularized liver model (DLM) as a previous study reported . Briefly, fresh livers were harvested from healthy male Sprague–Dawley rats (∼300 g) after euthanasia with carbon dioxide and stored at −80 °C for more than 24 h before decellularization.…”

“…The ex vivo drug release of DOX and ACF in TE and PE was accessed in decellularized liver model (DLM) as a previous study reported. 27 Briefly, fresh livers were harvested from healthy male Sprague−Dawley rats (∼300 g) after euthanasia with carbon dioxide and stored at −80 °C for more than 24 h before decellularization. To prepare DLM, the liver was first thawed to room temperature and then perfused with deionized water for 0.5 h, 4% Triton X-100 containing 0.02% EGTA for 1 h, and 0.5% SDS solution for 5 h through the portal vein to remove cellular components.…”

“…To simulate in vivo local drug release behavior in the tumor tissue, the release of DOX and ACF from emulsions was conducted and monitored in an acellular liver organ model following a modified protocol we previously reported. 27 In the drug release model, drug-loaded emulsion was injected into the portal venous system, and continuous water perfusion throughout the hepatic venous system was applied to replicate the drug depletion process caused by cellular metabolism or blood drainage. For TEs without HSNs, the fluorescent signals of DOX@TE and ACF@TE could be detected for 30 and 5 d, respectively (Figures 3A,B,E and S7A).…”

Radiopaque thermosensitive Pickering emulsion vascular embolist for permanent arterial embolization

“…We designed a simple model of decellularized liver tissue for basic laboratory research. Decellularization involves employing a combination of physical and chemical treatments to effectively eliminate cellular contents from tissue or organs while preserving extracellular matrix (ECM) components and functional proteins [25][26][27][28][29]. The resulting decellularized liver yields a translucent bioscaffold comprising an acellular natural matrix, maintaining both vascular system integrity and mechanical strength [30][31][32][33].…”

Biodegradable Microembolics with Nanografted Polyanions Enable High-Efficiency Drug Loading and Sustained Deep-Tumor Drug Penetration for Locoregional Chemoembolization Treatment

“…The ion-exchange microspheres currently applied in DEB-TACE, which possess high affinity between the fixed anionic groups of the beads with the soluble positively charged chemotherapeutic drugs, present high drug loading capacity that strongly depends on the anionic densities inside the microsphere bulk. , However, for degradable embolic agents, the chemical conjugation of anionic functional groups of extremely high densities can be challenging if considering the restricted selections of biodegradable materials for translation purpose . For instance, gelatin sponge particles, one of the most widely used materials in clinical interventions for tumor vascular embolization, represent an ideal biodegradable material with well-proven excellent biocompatibility and appropriate in vivo degradation rates varying from one to several months. − Nevertheless, the gelatin-based particles are clinically employed as blank embolic agents without drug loading but present inferior drug-carrying properties in previous efforts. − To circumvent this problem, we propose to graft nanosized highly charged low-molecular-weight anionic oligomers, instead of scattered anionic groups, into the main chain of degradable polymer, which can not only efficiently increase the overall anion density but also take advantage of the associated counterion condensation effect , to greatly improve the drug loading performance for the demanding requirements of embolic drug carriers.…”