Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Shanghai Key Laboratory of Functional Materials Chemistry, Collaborative Innovation Centre for Coal Based Energy (i-CCE), School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China.
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Shanghai Key Laboratory of Functional Materials Chemistry, Collaborative Innovation Centre for Coal Based Energy (i-CCE), School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China.
Biomaterials. 2017 Mar;120:1-10. doi: 10.1016/j.biomaterials.2016.11.011. Epub 2016 Dec 2.
Efficient and site-specific delivery of anticancer drugs to tumors is important in the development of effective cancer chemotherapy. As an undecapeptide of the tachykinin neuropeptide family, the substance P (SP)/neurokinin-1 receptor (NK1R) system has been identified as a promising ligand-receptor pair in tumor-specific drug delivery. However, the rational design of suitable theranostic agents with high drug loading capacity and tumor targeting for cancer patients remains a great challenge. Herein, we report a dendritic strategy that utilizes the two amine functionalities of lysine to create branch points that allow conjugation of the anticancer drug 5-fluorouracil (5-FU) to the tumor-targeting ligand substance P, along with an additional near-infrared (NIR) squaraine dye, to construct a theranostic dendritic agent, P-FU 4. This cytotoxic theranostic agent, containing four carboxyl-modified 5-FU molecules, has several desirable advantages: i) the ability to self-assemble into nanoparticles; ii) enhanced cytotoxicity with high drug loading capacity (16%) and a specific receptor-targeted interaction with NK1R through the SP moiety; and iii) a high NIR squaraine fluorescence efficiency due to the specific dendron isolation, avoiding aggregation-mediated quenching. As demonstrated in this report, the cytotoxic activity of P-FU 4 is dose-dependent against the tested cancer cells. The improved drug loading capacity with dendritic branching distinctly enhanced cytotoxicity to tumor cells but had little effect on the viability of normal cells. P-FU 4 was preferentially taken up by tumor cells through a receptor-mediated interaction, which was monitored by effective NIR fluorescence with high tissue penetration. Studies using a mouse model revealed that P-FU 4 can significantly inhibit tumor progression, with a tumor-inhibition rate of 60.2%. The receptor-targeted cytotoxic dendritic theranostic agent is highly preferable to standard chemotherapeutic treatments and decreases the negative side effects of medications on healthy cells, which establishes its utility in drug delivery and cancer chemotherapy.
高效且靶向特定部位向肿瘤递送抗癌药物对于开发有效的癌症化学疗法至关重要。作为速激肽神经肽家族的一种十一肽，P 物质（SP）/神经激肽-1 受体（NK1R）系统已被确定为肿瘤特异性药物递送中很有前途的配体-受体对。然而，为癌症患者设计具有高载药量和肿瘤靶向性的合适的治疗诊断试剂仍然是一个巨大的挑战。在这里，我们报告了一种基于树枝状大分子的策略，该策略利用赖氨酸的两个氨基官能团创建支化点，使抗癌药物 5-氟尿嘧啶（5-FU）与肿瘤靶向配体 P 物质连接，并结合额外的近红外（NIR）方酸染料，构建治疗诊断树枝状大分子，即 P-FU4。这种细胞毒性治疗诊断试剂含有四个羧基修饰的 5-FU 分子，具有几个理想的优点：i）能够自组装成纳米颗粒；ii）通过 SP 部分与 NK1R 具有高载药量（16%）和特异性受体靶向相互作用，增强了细胞毒性；iii）由于特定的树枝状大分子隔离，避免了聚集诱导的淬灭，具有高的 NIR 方酸荧光效率。正如本报告所证明的，P-FU4 的细胞毒性活性对测试的癌细胞呈剂量依赖性。通过树枝状大分子支化提高的载药能力明显增强了对肿瘤细胞的细胞毒性，但对正常细胞的活力影响很小。P-FU4 通过受体介导的相互作用被肿瘤细胞优先摄取，这可以通过有效的具有高组织穿透性的近红外荧光来监测。使用小鼠模型的研究表明，P-FU4 可以显著抑制肿瘤进展，肿瘤抑制率为 60.2%。这种受体靶向的细胞毒性树枝状大分子治疗诊断试剂优于标准化学疗法，并且减少了药物对健康细胞的负面副作用，这使其在药物递送和癌症化学疗法中具有实用性。
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