Synlett 2021; 32(11): 1098-1103
DOI: 10.1055/a-1503-6425
letter

Axially Substituted Silicon Phthalocyanine Payloads for Antibody–Drug Conjugates

Kazuki Takahashi
a  Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
,
Akira Sugiyama
b  Isotope Science Center, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
,
Kei Ohkubo
c  Institute for Advanced Co-Creation Studies, Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan
d  Institute for Open and Transdisciplinary Research Initiatives, Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan
,
Toshifumi Tatsumi
a  Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
,
Tatsuhiko Kodama
e  Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan
,
a  Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
,
a  Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
› Author Affiliations
This work was supported by JSPS KAKENHI Grants JP18H04536 (K.Y.), JP20H04819 (K.O.), JP20H02779 (K.O.), JP20H00489 (M.K.) and JP20K21472 (M.K.).


Abstract

IR700, a silicon phthalocyanine (SiPc) photosensitizer, is an antibody–drug conjugate payload used clinically. It is, however, the sole SiPc payload to date, possibly due to the difficulty of its synthesis, resulting from its asymmetric phthalocyanine skeleton. Here, we report a new axially substituted SiPc payload that is more easily synthesized. Trastuzumab conjugated with the SiPc showed light- and antigen-dependent cytotoxicity in HER2-overexpressing cancer cell lines.

Supporting Information



Publication History

Received: 19 April 2021

Accepted after revision: 08 May 2021

Publication Date:
08 May 2021 (online)

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
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  • 14 Conjugation of NHS-SiPcs with Antibodies; General Procedure Trastuzumab (8.0 mg; Roche) was purified by using a PD Minitrap G-25 column with pH 8.0 phosphate buffer to afford a 7.7 mg/mL trastuzumab solution. To 100 μL of this solution was added a solution of NHS-SiPc (50 nmol) in DMSO (20 μL), and the mixture was stirred at rt in darkness for 12 h. The mixture was then purified twice on a PD Minitrap G-25 column with phosphate-buffered saline (PBS) to afford an Ab-SiPc stock solution.
  • 15 In Vitro Phototoxicity Studies The phototoxicities of Ab-NuSiPc, Ab-CyaSiPc, and Ab-IR700 were quantified by using Cell Counting Kit-8 (Dojindo Molecular Technologies, Inc.) according to the method described in the manufacturer’s manual. Briefly, ten thousand cells per well with 50 μL of medium were seeded into 96-well plates and cultured overnight. Subsequently, the cells were separately incubated for 24 h at 37 °C with the addition of 50 μL of various concentrations of Ab-NuSiPc, Ab-CyaSiPc, or Ab-IR700, prepared by three-times sequential dilution from 20 μg mL–1. The drug-containing medium was then removed and the cells were washed with PBS once, and fresh medium was added. The cells were irradiated from the bottom of the 96-wells plate with a 690 nm LED lamp (Yamato Scientific Co., Ltd.) at 100 J cm–2 at rt. After 24 h, Cell Counting Kit-8 reagent was added at 10 μL per well and the cells were incubated for 1.5 h. The absorbance of the samples was then measured on an iMark™ Microplate Absorbance Reader (BIO-RAD) with a 450 nm-wavelength filter.