卡莫司汀（BCNU）是一种重要的氯乙基亚硝胺（CENU）类药物，通过在鸟嘌呤的O6位诱导DNA损伤，最终形成dG-dC链间交联（ICLs）来抑制肿瘤细胞生长。然而，BCNU的临床应用在一定程度上受到肿瘤选择性缺失、稳定性差以及O6-烷基鸟嘌呤-DNA烷基转移酶（AGT）介导的耐药性的阻碍。近年来，肿瘤微环境已被广泛应用于先进药物传递。鉴于肿瘤微环境的特性，我们构建了一种具有AGT抑制活性的多功能低氧/酯酶可降解纳米胶束，命名为HACB NPs，用于靶向递送BCNU并增强肿瘤敏感性。HACB NPs由透明质酸偶氮苯AGT抑制剂共轭物自组装而成，其中O6-BG类似物作为AGT抑制剂，偶氮苯作为低氧响应连接物，羧酸酯键作为酯酶敏感开关和与透明质酸（HA）连接剂。得到的HACB NPs具有良好的稳定性、有利的生物安全性和低氧/酯酶响应性释药能力。负载BCNU的HACB/BCNU NPs对人宫颈癌细胞HeLa表现出优越的细胞毒性和诱导凋亡能力，相比传统的BCNU加O6-BG联合药物，更加有效。体内研究进一步证明，纳米胶束在选择性积累于肿瘤部位后，可以对低氧肿瘤组织作出快速的药物释放，达到有效治疗剂量。因此，这种多功能刺激响应性纳米载体可能是增强BCNU和其他CENU抗癌疗效、减轻副作用的新有希望的策略。© 2023. BioMed Central Ltd., part of Springer Nature.

Carmustine (BCNU), a vital type of chloroethylnitrosourea (CENU), inhibits tumor cells growth by inducing DNA damage at O6 position of guanine and eventually forming dG-dC interstrand cross-links (ICLs). However, the clinical application of BCNU is hindered to some extent by the absence of tumor selectivity, poor stability and O6-alkylguanine-DNA alkyltransferase (AGT) mediated drug resistance. In recent years, tumor microenvironment has been widely utilized for advanced drug delivery. In the light of the features of tumor microenvironment, we constructed a multifunctional hypoxia/esterase-degradable nanomicelle with AGT inhibitory activity named HACB NPs for tumor-targeting BCNU delivery and tumor sensitization. HACB NPs was self-assembled from hyaluronic acid azobenzene AGT inhibitor conjugates, in which O6-BG analog acted as an AGT inhibitor, azobenzene acted as a hypoxia-responsive linker and carboxylate ester bond acted as both an esterase-sensitive switch and a connector with hyaluronic acid (HA). The obtained HACB NPs possessed good stability, favorable biosafety and hypoxia/esterase-responsive drug-releasing ability. BCNU-loaded HACB/BCNU NPs exhibited superior cytotoxicity and apoptosis-inducing ability toward the human uterine cervix carcinoma HeLa cells compared with traditional combined medication of BCNU plus O6-BG. In vivo studies further demonstrated that after a selective accumulation in the tumor site, the micelles could respond to hypoxic tumor tissue for rapid drug release to an effective therapeutic dosage. Thus, this multifunctional stimulus-responsive nanocarrier could be a new promising strategy to enhance the anticancer efficacy and reduce the side effects of BCNU and other CENUs.© 2023. BioMed Central Ltd., part of Springer Nature.