BACKGROUND Tamoxifen (Tam) is the most frequent treatment for estrogen receptor (ER) positive breast cancer. We recently showed that fibronectin (FN) leads to Tam resistance and selection of breast cancer stem cells. With the aim of developing a nanoformulation that would simultaneously tackle ER and FN/β1 integrin interactions, we designed polyethylene glycol-polycaprolactone polymersomes polymersomes (PS) that carry Tam and are functionalized with the tumor-penetrating iRGD peptide (iRGD-PS-Tam). RESULTS Polyethylene glycol-polycaprolactone PS were assembled and loaded with Tam using the hydration film method. The loading of encapsulated Tam, measured by UPLC, was 2.4 ± 0.5 mol Tam/mol polymer. Physicochemical characterization of the PS demonstrated that iRGD functionalization had no effect on morphology, and a minimal effect on the PS size and polydispersity (176 nm and Pdi 0.37 for iRGD-TAM-PS and 171 nm and Pdi 0.36 for TAM-PS). iRGD-PS-Tam were taken up by ER+ breast carcinoma cells in 2D-culture and exhibited increased penetration of 3D-spheroids. Treatment with iRGD-PS-Tam inhibited proliferation and sensitized cells cultured on FN to Tam. Mechanistically, treatment with iRGD-PS-Tam resulted in inhibition ER transcriptional activity as evaluated by a luciferase reporter assay. iRGD-PS-Tam reduced the number of cells with self-renewing capacity, a characteristic of breast cancer stem cells. In vivo, systemic iRGD-PS-Tam showed selective accumulation at the tumor site. CONCLUSIONS Our study suggests iRGD-guided delivery of PS-Tam as a potential novel therapeutic strategy for the management of breast tumors that express high levels of FN. Future studies in pre-clinical in vivo models are warranted.

中文翻译：

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iRGD 引导的他莫昔芬聚合物囊泡可抑制雌激素受体转录活性，并减少具有自我更新能力的乳腺癌细胞数量。


背景他莫昔芬（Tam）是雌激素受体（ER）阳性乳腺癌最常用的治疗方法。我们最近表明，纤连蛋白 (FN) 会导致 Tam 耐药性和乳腺癌干细胞的选择。为了开发一种同时解决 ER 和 FN/β1 整合素相互作用的纳米制剂，我们设计了携带 Tam 并用肿瘤穿透 iRGD 肽 (iRGD-PS-Tam) 功能化的聚乙二醇-聚己内酯聚合物囊泡 (PS) 。结果采用水化膜法组装聚乙二醇-聚己内酯PS并负载Tam。通过 UPLC 测量，封装的 Tam 的负载量为 2.4 ± 0.5 mol Tam/mol 聚合物。 PS 的物理化学表征表明，iRGD 官能化对形态没有影响，对 PS 尺寸和多分散性影响极小（iRGD-TAM-PS 为 176 nm 和 Pdi 0.37，TAM-PS 为 171 nm 和 Pdi 0.36）。 iRGD-PS-Tam 被 2D 培养中的 ER+ 乳腺癌细胞吸收，并表现出 3D 球体的渗透增加。 iRGD-PS-Tam 处理可抑制增殖并使 FN 上培养的细胞对 Tam 敏感。从机制上讲，通过荧光素酶报告基因测定评估，iRGD-PS-Tam 治疗会抑制 ER 转录活性。 iRGD-PS-Tam 减少了具有自我更新能力的细胞数量，这是乳腺癌干细胞的一个特征。在体内，全身 iRGD-PS-Tam 在肿瘤部位表现出选择性积累。结论 我们的研究表明，iRGD 引导下的 PS-Tam 递送可作为一种潜在的新型治疗策略，用于治疗表达高水平 FN 的乳腺肿瘤。未来的临床前体内模型研究是有必要的。