Li Min, Chu Kaile, Zhou Qin, Wang Hongliang, Zhang Wenjun, Zhang Yaqiong, Lv Junping, Zhou Haitao, An Jie, Wu Zhifang, Li Sijin
Department of Nuclear Medicine, The First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan 030001, Shanxi Province, PR China; Molecular Imaging Precision Medical Collaborative Innovation Center, Shanxi Medical University, Taiyuan 030001, Shanxi Province, PR China.
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, Liaoning Province, PR China; School of Chemical Engineering, Dalian University of Technology, Panjin 124221, Liaoning Province, PR China.
Int J Biol Macromol. 2025 May;308(Pt 2):142559. doi: 10.1016/j.ijbiomac.2025.142559. Epub 2025 Mar 26.
Although combination of chemotherapy and photothermal therapy (PTT) holds significant promise for treating triple-negative breast cancer, the existing delivery systems for achieving synergistic antitumor activity remains unsatisfactory. Herein, we developed of dual-drug loaded hyaluronic acid (HA) nanodrugs, which exhibited pH, glutathione (GSH), and thermal triple-responsiveness and CD44-targeting capabilities for chemo-PTT synergistic therapy in breast cancer. Gemcitabine (GCB) and metformin (MET) were conjugated to HA via amide and disulfide bonds to form dual-drug loaded prodrugs (HSGM), which were then coated onto the surface of polydopamine nanoparticles (PDA NPs) to self-assemble into HSGM/PDA NPs. These NPs selectively accumulated at the tumor site through HA receptors and released GCB and MET in response to low pH and high GSH concentrations. The NPs demonstrated excellent photothermal performance, with heat generated from near-infrared (NIR)-laser irradiation accelerating drug release within tumor. Additionally, MET inhibited the production of heat shock protein 70 (HSP 70), mitigating thermotolerance induced by PTT, thereby enhancing the PTT effect. The combination of chemotherapy and PTT synergistically improved anti-tumor efficacy (tumor inhibition ratio: 99.11 %) while showing negligible systemic toxicity, effectively preventing tumor metastasis and recurrence. This integrated approach offers valuable insights for the clinical treatment of breast cancer and other malignant tumors.
尽管化疗与光热疗法（PTT）联合应用在治疗三阴性乳腺癌方面具有巨大潜力，但现有的用于实现协同抗肿瘤活性的递送系统仍不尽人意。在此，我们开发了负载双药的透明质酸（HA）纳米药物，其具有pH、谷胱甘肽（GSH）和热三重响应性以及CD44靶向能力，用于乳腺癌的化疗 - PTT协同治疗。吉西他滨（GCB）和二甲双胍（MET）通过酰胺键和二硫键与HA偶联形成负载双药的前药（HSGM），然后将其包覆在聚多巴胺纳米颗粒（PDA NPs）表面自组装成HSGM/PDA NPs。这些纳米颗粒通过HA受体选择性地在肿瘤部位积聚，并在低pH和高GSH浓度下释放GCB和MET。纳米颗粒表现出优异的光热性能，近红外（NIR）激光照射产生的热量加速了肿瘤内药物的释放。此外，MET抑制热休克蛋白70（HSP 70）的产生，减轻PTT诱导的热耐受性，从而增强PTT效果。化疗与PTT联合应用协同提高了抗肿瘤疗效（肿瘤抑制率：99.11%），同时显示出可忽略不计的全身毒性，有效预防了肿瘤转移和复发。这种综合方法为乳腺癌和其他恶性肿瘤的临床治疗提供了有价值的见解。
