Polyelectrolyte multilayer capsules modified with antitumor cytokine DR5-B and loaded with doxorubicin for targeted drug delivery to tumor cells
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Shemyakin–Ovchinnikov Institute of bioorganic chemistry RAS, Moscow, Russia
FSRC "Crystallography and Photonics", Russian academy of Sciences, Moscow, Russia
First Moscow State Medical University, Moscow, Russia
Publication date: 2021-09-27
Public Health Toxicol 2021;1(Supplement Supplement 1):A35

The development of targeted drug delivery systems is a challenge in biomedicine. Polyelectrolyte multilayer capsules (PMC) are promising due to their biocompatibility and biodegradability as well as drug encapsulation efficacy1. Cytokine TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) could be used for targeted anticancer therapy due to cell apoptosis induction via death receptors, in particular DR4 and DR5. However, a short half-life and rather low apoptosis-inducing capacity obstruct TRAIL use in clinic. Recently, a DR5-specific TRAIL mutant variant, namely DR5-B with enhanced pro-apoptotic activity has been developed 2. On the other hand, conjugation of TRAIL or its mutants to various nanocarriers is of great importance, since it allows to increase TRAIL stability, half-life and apoptosis-inducing activity. Moreover, loading TRAIL-containing nanocarriers with antitumor drugs could provide an enhanced targeted drug delivery.
The aim of the study was to obtain biodegradable polyelectrolyte capsules, modified by conjugation with DR5-B and loaded with doxorubicin (DOX) and to evaluate their cytotoxicity in both 2D and 3D in vitro models. For this purpose, two types of PMC which differed in mean diameter, namely 500±110 nm and 300±60 (after thermally induced compression) were obtained from poly-L-arginine and dextran sulphate using layer-by-layer technique. The PMC physical-chemical properties (mean diameter, ζ-potential, storage stability, DOX encapsulation efficiency) were studied.
The PMC accumulation and localization in human breast adenocarcinoma MCF-7 cells and human colorectal carcinoma HCT-116 cells in both 2D (monolayer culture) and 3D (tumor spheroids) in vitro models were studied by confocal microscopy and flow cytometry. Thermally compressed PMC with mean diameter of 300 nm were found to accumulate in cells faster than those with mean size of 500 nm. Nevertheless, both types of PMC-DR5-B accumulated in cells faster than free DR5-B. Cytotoxicity of PMC-DR5-B and loaded with DOX was studied by MTT-test for HCT-116 and MCF-7 cells, as well as in human fibroblasts Bj-5ta (normal cells) in both 2D and 3D in vitro models. PMC-DR5-B (300 nm) were shown to be more cytotoxic than PMC-DR5-B (500 nm) in both 2D and 3D models. PMC-DR5-B (300 nm) loaded with DOX were non-toxic to normal Bj-5ta cells.
Thus, PMC-DR5-B could be assumed as promising targeted drug delivery system to cancer cells.
The work was supported by Russian Science Foundation (grant No. 21-14-00224) and the grant of the President of the Russian Federation (МК-1109.2021.1.3).
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Yagolovich AV, Artykov AA, Karmakova TA, et al. Genetically Modified DR5-Specific TRAIL Variant DR5-B Revealed Dual Antitumor and Protumoral Effect in Colon Cancer Xenografts and an Improved Pharmacokinetic Profile. Translational Oncology. 2020;13(4):100762. doi:10.1016/j.tranon.2020.100762
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