Department of Ultrasound, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
College of Chemistry and Materials Science, Shanghai Normal University, Shanghai, People's Republic of China.
Int J Nanomedicine. 2020 Dec 9;15:10007-10028. doi: 10.2147/IJN.S271213. eCollection 2020.
The treatment of breast cancer is often ineffective due to the protection of the tumor microenvironment and the low immunogenicity of tumor cells, leading to a poor therapeutic effect. In this study, we designed a nano-theranostic platform for these obstacles: a photothermal effect mediated by a gold shell could remodel the tumor microenvironment by decreasing cancer-associated fibroblasts (CAFs) and promote the release of doxorubicin (DOX) from nanoparticles. In addition, it could realize photoacoustic (PA)/MRI dual-model imaging for diagnose breast cancer and targeted identification of Her2-positive breast cancer.
Her2-DOX-superparamagnetic iron oxide nanoparticles (SPIOs)@Poly (D, L-lactide-co-glycolide) acid (PLGA)@Au nanoparticles (Her2-DSG NPs) were prepared based on a single emulsion oil-in-water (O/W) solvent evaporation method, gold seed growing method, and carbon diimide method. The size distribution, morphology, PA/MRI imaging, drug loading capacity, and drug release were investigated. Cytotoxicity, antitumor effect, cellular uptake, immunogenic cell death (ICD) effect, and targeted performance on human Her2-positive BT474 cell line were investigated in vitro. BT474/Adr cells were constructed and the antitumor effect of NPs on it was evaluated in vitro. Moreover, chemical-photothermal therapy effect, PA/MRI dual-model imaging, ICD effect induced by NPs, and tumor microenvironment remodeling in human BT474 breast cancer nude mice model were also investigated.
Nanoparticles were spherical, uniform in size and covered with a gold shell. NPs had a photothermal effect, and can realize photothermal-controlled drug release in vitro. Chemical-photothermal therapy had a good antitumor effect on BT474/Adr cells and on BT474 cells in vitro. The targeting evaluation in vitro showed that Her2-DSG NPs could actively target and identify Her2-positive tumor cells. The PA/MRI imaging was successfully validated in vitro/vivo. Similarly, NPs could enhance the ICD effect in vitro/vivo, which could activate an immune response. Immunofluorescence results also proved that photothermal effect could decrease CAFs to remodel the tumor microenvironment and enhance the accessibility of NPs to tumor cells. According to the toxicity results, targeted drug delivery combined with photothermal-responsive drug release proved that NPs had good biosafety in vivo. Chemical-photothermal therapy of Her2-targeted NPs has a good antitumor effect in the BT474 nude mice model.
Our study showed that chemical-photothermal therapy combined with tumor microenvironment remodeling and immune activation based on the Her2-DSG NPs we developed are very promising for Her2-positive breast cancer.
由于肿瘤微环境的保护和肿瘤细胞的低免疫原性，乳腺癌的治疗往往效果不佳，导致治疗效果不佳。在这项研究中，我们设计了一种纳米治疗平台来克服这些障碍：金壳介导的光热效应可以通过减少癌症相关成纤维细胞（CAFs）和促进阿霉素（DOX）从纳米颗粒中的释放来重塑肿瘤微环境。此外，它可以实现用于诊断乳腺癌和靶向识别 Her2 阳性乳腺癌的超声（PA）/磁共振（MRI）双模式成像。
采用单乳液油包水（O/W）溶剂蒸发法、金种子生长法和碳二亚胺法制备了 Her2-DOX-超顺磁性氧化铁纳米粒子（SPIOs）@聚（D，L-乳酸-co- 乙二醇酸）（PLGA）@Au 纳米粒子（Her2-DSG NPs）。考察了其粒径分布、形态、PA/MRI 成像、载药能力和药物释放。体外考察了细胞毒性、抗肿瘤作用、细胞摄取、免疫原性细胞死亡（ICD）效应以及对人 Her2 阳性 BT474 细胞系的靶向性能。构建了 BT474/Adr 细胞，并在体外评价了 NPs 的抗肿瘤作用。此外，还研究了 NPs 在人 BT474 乳腺癌裸鼠模型中的化学-光热治疗效果、PA/MRI 双模式成像、NPs 诱导的 ICD 效应以及肿瘤微环境重塑。
纳米粒子呈球形，粒径均一，表面覆盖金壳。NPs 具有光热效应，可实现体外光热控制药物释放。体外化学-光热治疗对 BT474/Adr 细胞和 BT474 细胞均有较好的抗肿瘤作用。体外靶向评价表明，Her2-DSG NPs 可主动靶向识别 Her2 阳性肿瘤细胞。体外/体内成功验证了 PA/MRI 成像。同样，NPs 可以增强体外/体内的 ICD 效应，从而激活免疫反应。免疫荧光结果也证明光热效应可以减少 CAFs 来重塑肿瘤微环境并增强纳米颗粒对肿瘤细胞的可及性。根据毒性结果，靶向药物递送结合光热响应性药物释放证明 NPs 在体内具有良好的生物安全性。基于我们开发的 Her2-DSG NPs 的化学-光热治疗在 BT474 裸鼠模型中具有良好的抗肿瘤效果。
我们的研究表明，基于我们开发的 Her2-DSG NPs 的化学-光热治疗联合肿瘤微环境重塑和免疫激活对于 Her2 阳性乳腺癌具有广阔的应用前景。
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