Compared with intracellular drug delivery, drugs with extracellular targeting sites are rarely considered. As one of these drugs, cyclopamine (CYC) is a promising anticancer drug that functions by targeting the cell membrane receptor. For improving therapeutic effect, an albumin-based nano-system (ABN) with the capacity for extracellular retention was developed. The ABN was formulated by incorporating bovine serum albumin (BSA) into nanoparticles at the denaturing temperature of BSA, with CYC acting as a hydrophobic nucleation site, followed by stabilization upon heat-induced disulfide cross-linking. The resultant ABNs are negatively charged with a nanoparticle size that can be delicately regulated by varying the reaction time. In MDA-MB-231 cells, the size and charge of ABNs significantly affected the extracellular retention capacity, with ABN-300 nm exhibiting an enhanced cytotoxic effect. In vivo fluorescence imaging revealed obvious and persistent tumor accumulation of ABNs. A therapeutic study in an orthotopic mammary fat pad tumor model shows that ABN-300 nm possesses the most remarkable antitumor effect compared with the control groups. These results provide a new strategy for improving the efficacy of drug targeting at extracellular sites.

中文翻译：

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利用更大的尺寸和更多的负电荷来改善乳腺癌治疗的环巴胺纳米制剂的细胞外保留†

与细胞内药物递送相比，很少考虑具有细胞外靶向位点的药物。作为这些药物之一，环巴胺（CYC）是一种有前途的抗癌药物，可通过靶向细胞膜受体发挥作用。为了改善治疗效果，开发了具有细胞外滞留能力的基于白蛋白的纳米系统（ABN）。通过在BSA的变性温度下将牛血清白蛋白（BSA）掺入纳米颗粒中，并以CYC作为疏水性成核位点，然后在热诱导的二硫键交联后稳定下来，制成ABN。所得的ABN带负电荷的纳米颗粒大小可以通过改变反应时间进行精细调节。在MDA-MB-231细胞中，ABN的大小和电荷会显着影响细胞外保留能力，体内荧光成像显示ABNs明显且持续存在肿瘤。在原位乳腺脂肪垫肿瘤模型中进行的治疗研究表明，与对照组相比，ABN-300 nm具有最显着的抗肿瘤作用。这些结果为提高靶向细胞外部位药物的功效提供了新的策略。