期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 8, 页码 3401-3409出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm5000722
关键词
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资金
- National Institute of General Medical Sciences of the National Institutes of Health [P20 GM103639]
- DoD [Breast Cancer Research Program] [W81XWH-09-1-0071]
We recently developed photo-unclick chemistry, a novel chemical tool involving the cleavage of aminoacrylate by singlet oxygen, and demonstrated its application to visible light-activatable prodrugs. In this study, we prepared an advanced multifunctional prodrug, Pc-(L-CA4)(2), composed of the fluorescent photosensitizer phthalocyanine (Pc), an SO-labile aminoacrylate linker (L), and a cytotoxic drug combretastatin A-4 (CA4). Pc-(L-CA4)(2) had reduced dark toxicity compared with CA4. However, once illuminated, it showed improved toxicity similar to CA4 and displayed bystander effects in vitro. We monitored the time-dependent distribution of Pc-(L-CA4)(2) using optical imaging with live mice. We also effectively ablated tumors by the illumination with far-red light to the mice, presumably through the combined effects of photodynamic therapy (PDT) and released chemotherapy drug, without any sign of acute systemic toxicity.
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