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Penetration Efficiency of Antitumor Agents in Ovarian Cancer Spheroids: The Case of Recombinant Targeted Toxin DARPin-LoPE and the Chemotherapy Drug, Doxorubicin

1
Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin ave., Nizhny Novgorod 603950, Russia
2
Laboratory of molecular immunology, Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 16/10 Miklukho-Maklay St., Moscow 117997, Russia
3
Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, 8-2 Trubetskaya str., Moscow 119991, Russia
4
Research Nuclear Reactor Center, National Research Tomsk Polytechnic University, 30 Lenin ave., Tomsk 634050, Russia
5
Institute of Engineering Physics for Biomedicine (PhysBio), National Research Nuclear University “MEPhI”, 31 Kashirskoe shosse, Moscow 115409, Russia
*
Author to whom correspondence should be addressed.
Pharmaceutics 2019, 11(5), 219; https://doi.org/10.3390/pharmaceutics11050219
Received: 28 March 2019 / Revised: 26 April 2019 / Accepted: 5 May 2019 / Published: 7 May 2019
The efficiency of delivering a therapeutic agent into a tumor is among the crucial factors determining the prospects for its clinical use. This problem is particularly acute in the case of targeted antitumor agents since many of them are high-molecular-weight compounds. In this work, the penetration of therapeutic agents of two distinct molecular weights into the spheroids of ovarian adenocarcinoma overexpressing human epidermal growth factor receptor 2 (HER2) was studied. It was shown that the low-molecular-weight chemotherapy drug, doxorubicin (~0.5 kDa), effectively penetrates through almost the entire depth of a 300 to 400 μm spheroid, while the penetration depth of the HER2-specific recombinant targeted toxin, DARPin-LoPE (~42 kDa), is only a few surface layers of cells and does not exceed 70 μm. The low penetration of the targeted toxin into spheroid was shown along with a significant decrease in its efficiency against the three-dimensional tumor spheroid as compared with the two-dimensional monolayer culture. The approaches to increasing the accumulation of agents in the tumor are presented and prospects of their use in order to improve the effectiveness of therapy are discussed. View Full-Text
Keywords: drug penetration into tumor; HER2; spheroid; targeted therapy; targeted toxin; DARPin; Pseudomonas exotoxin A drug penetration into tumor; HER2; spheroid; targeted therapy; targeted toxin; DARPin; Pseudomonas exotoxin A
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Sokolova, E.; Kutova, O.; Grishina, A.; Pospelov, A.; Guryev, E.; Schulga, A.; Deyev, S.; Balalaeva, I. Penetration Efficiency of Antitumor Agents in Ovarian Cancer Spheroids: The Case of Recombinant Targeted Toxin DARPin-LoPE and the Chemotherapy Drug, Doxorubicin. Pharmaceutics 2019, 11, 219.

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