2. Academic Validation
  3. Design, synthesis and pharmacological evaluation of a novel PEG-cRGD-conjugated irinotecan derivative as potential antitumor agent

Design, synthesis and pharmacological evaluation of a novel PEG-cRGD-conjugated irinotecan derivative as potential antitumor agent

  • Eur J Med Chem. 2018 Oct 5:158:82-90. doi: 10.1016/j.ejmech.2018.08.091.
Yang-Qing Huang 1,  Jian-Dong Yuan 2,  Hai-Feng Ding 2,  Yun-Song Song 2,  Gang Qian 2,  Jia-Li Wang 3,  Min Ji 4,  Ye Zhang 5
Affiliations

Affiliations

  • 1 Pharmaceutical Research Center, School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, China; BrightGene Bio-Medical Technology Co., Ltd., Suzhou, 215123, China.
  • 2 BrightGene Bio-Medical Technology Co., Ltd., Suzhou, 215123, China.
  • 3 Suzhou Vocational Health College, Suzhou, 215009, China.
  • 4 School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China. Electronic address: jimin@seu.edu.cn.
  • 5 School of Pharmacy, Guilin Medical University, Guilin, 541004, China; Department of Chemistry & Pharmaceutical Science, Guilin Normal College, Guangxi, 541001, China; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin, 541004, China. Electronic address: zhangye81@126.com.
PMID: 30199708 DOI: 10.1016/j.ejmech.2018.08.091
Abstract

A novel PEG-cRGD-conjugated irinotecan derivative BGC0222 was designed and synthesized as antitumor agent. Antitumor activity screening assay indicated that BGC0222 exhibited better in vitro antiproliferation activity than irinotecan and NKTR-102 against HT29, MIA PaCa-2 and MCF-7 tumor cell lines, with IC50 of 1.83 ± 0.09 μM, 3.95 ± 0.16 μM and 0.68 ± 0.04 μM, respectively, while it displayed better in vivo antiproliferation activity than irinotecan and NKTR-102 in HT-29, MIA PaCa-2, NCI-H446, U-87 MG and MDA-MB-231 xenograft models. The action mechanism of BGC0222 was then investigated by integrin-binding competition (IBC) and chick chorioallantoic membrane (CAM) angiogenesis assays, which indicated that BGC0222 may exert antitumor activity by binding to αvβ3 target and consequently inducing neovascularization effect. Pharmacokinetic analysis showed that BGC0222 could slowly and steadily release irinotecan, which was subsequently metabolized into 7-ethyl-10-hydroxycamptothecin (SN-38) in the whole blood.

Keywords

Antitumor activity; Derivative; Length of blood vessels; PEG-cRGD-conjugated irinotecan; Synthesis; αvβ3.

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