期刊
MOLECULAR PHARMACEUTICS
卷 20, 期 11, 页码 5543-5553出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.3c00427
关键词
small cell lung cancer; somatostatin receptor 2; astatine-211; octreotide; immune response
Intravenously administered [At-211]SAB-Oct showed significant efficacy against SSTR2-positive SCLC tumors, suppressing tumor growth and enhancing the efficacy of immunotherapy by up-regulating specific proteins on tumor cell membrane surface.
Small cell lung cancer (SCLC) is a neuroendocrine tumor with a high degree of malignancy. Due to limited treatment options, patients with SCLC have a poor prognosis. We have found, however, that intravenously administered octreotide (Oct) armed with astatine-211 ([At-211]SAB-Oct) is effective against a somatostatin receptor 2 (SSTR2)-positive SCLC tumor in SCLC tumor-bearing BALB/c nude mice. In biodistribution analysis, [At-211]SAB-Oct achieved the highest concentration in the SCLC tumors up to 3 h after injection as time proceeded. A single intravenous injection of [At-211]SAB-Oct (370 kBq) was sufficient to suppress SSTR2-positive SCLC tumor growth in treated mice by inducing DNA double-strand breaks. Additionally, a multitreatment course (370 kBq followed by twice doses of 370 kBq for a total of 1110 kBq) inhibited the growth of the tumor compared to the untreated control group without significant off-target toxicity. Surprisingly, we found that [At-211]SAB-Oct could up-regulate the expressions of calreticulin and major histocompatibility complex I (MHC-I) on the tumor cell membrane surface, suggesting that alpha-particle internal irradiation may activate an endogenous antitumor immune response through the regulation of immune cells in the tumor microenvironment, which could synergically enhance the efficacy of immunotherapy. We conclude that [At-211]SAB-Oct is a potential new therapeutic option for SSTR2-positive SCLC.
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