TY - JOUR

T1 - Novel doxorubicin derivatives: Synthesis and cytotoxicity study in 2D and 3D in vitro models

AU - Akasov, Roman

AU - Drozdova, Maria

AU - Zaytseva-Zotova, Daria

AU - Leko, Maria

AU - Chelushkin, Pavel

AU - Marc, Annie

AU - Chevalot, Isabelle

AU - Burov, Sergey

AU - Klyachko, Natalia

AU - Vandamme, Thierry

AU - Markvicheva, Elena

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Purpose: Multidrug resistance (MDR) of tumors to chemotherapeutics often leads to failure of cancer treatment. The aim of the study was to prepare novel MDR-overcoming chemotherapeutics based on doxorubicin (DOX) derivatives and to evaluate their efficacy in 2D and 3D in vitro models. Methods: To overcome MDR, we synthesized five DOX derivatives, and then obtained non-covalent complexes with human serum albumin (HSA). Drug efficacy was evaluated for two tumor cell lines, namely human breast adenocarcinoma MCF-7 cells and DOX resistant MCF-7/ADR cells. Additionally, MCF-7 cells were entrapped in alginateoligochitosan microcapsules, and generated tumor spheroids were used as a 3D in vitro model to study cytotoxicity of the DOX derivatives. Results: Due to 3D structure, the tumor spheroids were more resistant to chemotherapy compared to monolayer culture. DOX covalently attached to palmitic acid through hydrazone linkage (DOX-N2H-Palm conjugate) was found to be the most promising derivative. Its accumulation levels within MCF-7/ADR cells was 4- and 10-fold higher than those of native DOX when the conjugate was added to cultivation medium without serum and to medium supplemented with 10% fetal bovine serum, respectively. Non-covalent complex of the conjugate with HSA was found to reduce the IC50 value from 32.9 μM (for free DOX-N2H-Palm) to 16.8 μM (for HSA-DOX-N2H-Palm) after 72 h incubation with MCF-7/ADR cells. Conclusion: Palm-N2H-DOX conjugate was found to be the most promising DOX derivative in this research. The formation of non-covalent complex of Palm-N2H-DOX conjugate with HSA allowed improving its anti-proliferative activity against both MCF-7 and MCF-7/ADR cells.

AB - Purpose: Multidrug resistance (MDR) of tumors to chemotherapeutics often leads to failure of cancer treatment. The aim of the study was to prepare novel MDR-overcoming chemotherapeutics based on doxorubicin (DOX) derivatives and to evaluate their efficacy in 2D and 3D in vitro models. Methods: To overcome MDR, we synthesized five DOX derivatives, and then obtained non-covalent complexes with human serum albumin (HSA). Drug efficacy was evaluated for two tumor cell lines, namely human breast adenocarcinoma MCF-7 cells and DOX resistant MCF-7/ADR cells. Additionally, MCF-7 cells were entrapped in alginateoligochitosan microcapsules, and generated tumor spheroids were used as a 3D in vitro model to study cytotoxicity of the DOX derivatives. Results: Due to 3D structure, the tumor spheroids were more resistant to chemotherapy compared to monolayer culture. DOX covalently attached to palmitic acid through hydrazone linkage (DOX-N2H-Palm conjugate) was found to be the most promising derivative. Its accumulation levels within MCF-7/ADR cells was 4- and 10-fold higher than those of native DOX when the conjugate was added to cultivation medium without serum and to medium supplemented with 10% fetal bovine serum, respectively. Non-covalent complex of the conjugate with HSA was found to reduce the IC50 value from 32.9 μM (for free DOX-N2H-Palm) to 16.8 μM (for HSA-DOX-N2H-Palm) after 72 h incubation with MCF-7/ADR cells. Conclusion: Palm-N2H-DOX conjugate was found to be the most promising DOX derivative in this research. The formation of non-covalent complex of Palm-N2H-DOX conjugate with HSA allowed improving its anti-proliferative activity against both MCF-7 and MCF-7/ADR cells.

KW - Aantitumor drug screening assays

KW - Microencapsulation

KW - Multicellular spheroids

KW - Multiple drug resistance

KW - Serum albumin

UR - http://www.scopus.com/inward/record.url?scp=85043398199&partnerID=8YFLogxK

U2 - 10.15171/apb.2017.071

DO - 10.15171/apb.2017.071

M3 - Article

AN - SCOPUS:85043398199

VL - 7

SP - 593

EP - 601

JO - Advanced Pharmaceutical Bulletin

JF - Advanced Pharmaceutical Bulletin

SN - 2228-5881

IS - 4

ER -