鉴于血管在实体肿瘤中的关键作用，血管破坏疗法在三阴性乳腺癌(triple-negative breast cancer，TNBC)中的应用潜力令人期待。本研究制备负载血管破坏剂康普瑞汀磷酸二钠(combretastatin A4 phosphate disodium，CA4P)和抗血管生成药物雷帕霉素(rapamycin，Rap)的酸敏感脂质体PPD/CA4P/Lip-Rap，探索血管破坏策略在TNBC中的应用潜力。采用1HNMR、动态光散射法及透射电镜对PPD/CA4P/Lip-Rap进行表征，并检测其载药量、酸敏感性。PPD/CA4P/Lip-Rap的粒径为161。53±1。89 nm，zeta电位为-20。03±0。9 mV，具有良好的酸敏感释药能力。通过体外CCK-8实验证明Rap能够增强CA4P的血管破坏能力。Rap能够杀伤边缘残留肿瘤细胞，抑制肿瘤复发。纳米载体能够进一步增强疗效。通过蛋白质免疫印迹(Western blot，WB)实验证明，Rap通过mTOR/p70S6K和mTOR/4E-BP1通路降低缺氧诱导因子-1α(hypoxia-inducible factor-1α，HIF-1α)的表达水平，进而抑制肿瘤缺氧反应激活和血管再生。PPD/CA4P/Lip-Rap能够有效破坏肿瘤血管，抑制肿瘤血管再生和复发，以肿瘤血管破坏作为治疗靶标，为TNBC的治疗提供一种新思路。
Loaded CA4P and rapamycin acid-sensitive liposomes target blood vessels for the treatment of triple-negative breast cancer
Given the vital role of vasculature in solid tumors,the potential of vascular disrupting therapy in the treatment of triple-negative breast cancer(TNBC)is promising.In this study,we prepared the acid-sensitive liposome PPD/CA4P/Lip-Rap loaded with the vascular disrupting agent CA4P and the anti-angiogenic drug rapamycin(Rap)to explore the potential of the vascular disrupting strategy in TNBC.PPD/CA4P/Lip-Rap was characterized by 1H NMR,dynamic light scattering,and transmission electron microscopy.Its drug loading and acid sensitivity were determined.The particle size of PPD/CA4P/Lip-Rap is 161.53±1.89 nm,the zeta potential is-20.03±0.9 mV and it demonstrated good drug release on acidic sensitivity responses.CCK-8 experiments proved that Rap can enhance the ability of CA4P to destroy tumor vascular endothelial cells.Rap can kill marginal residual tumor cells,suppress tumor recurrence.Nanocarriers can further enhance the therapeutic effect.Western blot(WB)showed that Rap decreased the expression of hypoxia-inducible factor-1α(HIF-1α)via the mTOR/p70S6K and mTOR/4E-BP1 pathways.Thus,tumor hypoxia activation and angiogenesis were inhibited.PPD/CA4P/Lip-Rap can effectively destroy tumor vessels,inhibit tumor angiogenesis and recurrence,and provide a new strategy for the treatment of TNBC by targeting disruption of tumor vessels.
combretastatin A4 phosphate disodiumrapamycinpH-sensitive nanocarriervascular disrupting strategytriple negative breast cancer
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