Murugesan Kalaimathi, Srinivasan Padmapriya, Mahadeva Raghunandan, Gupta Chhitar M, Haq Wahajul
Institute of Bioinformatics and Applied Biotechnology (IBAB), Bangalore, India.
Central Drug Research Institute (CDRI), Medicinal and Process Chemistry Division, Lucknow, India.
Int J Nanomedicine. 2020 Dec 31;15:10547-10559. doi: 10.2147/IJN.S276336. eCollection 2020.
Targeted multidrug-loaded delivery systems have emerged as an advanced strategy for cancer treatment. In this context, antibodies, hormones, and small peptides have been coupled to the surface of drug carriers, such as liposomes, polymeric and metallic nanoparticles loaded with drugs, as tumor-specific ligands. In the present study, we have grafted a natural macrophage stimulating peptide, tuftsin, on the surface of the liposomes (LPs) that were loaded with doxorubicin (DOX) and/or curcumin (CUR), by attaching to its C-terminus a palmitoyl residue (Thr-Lys-Pro-Arg-CO-NH-(CH)-NH-COCH, P.Tuft) to enable its grafting within the liposome's bilayer.
The prepared drug-loaded liposomes (DOX LPs, CUR LPs, DOX-CUR LPs, P.Tuft-LPs, P.Tuft-DOX LPs, P.Tuft-CUR LPs, P.Tuft-DOX-CUR LPs) were thoroughly characterised in terms of particle size, drug content, encapsulation efficiency and structural properties using UV-visible spectroscopy, dynamic light scattering (DLS) and Fourier transform infrared spectroscopy (FTIR). The anti-cancer activity and drug toxicity of the liposomal formulations were examined on Ehrlich ascites carcinoma (EAC) tumor-induced mice model.
A significant reduction in the tumor weight and volume was observed upon treating the tumor-bearing mice with palmitoyl tuftsin-grafted dual drug-loaded liposomes (P.Tuft-DOX-CUR LPs), as compared to the single drug/peptide-loaded formulation (DOX LPs, CUR LPs, DOX-CUR LPs, P.Tuft- LPs, P.Tuft-DOX LPs, P.Tuft-CUR LPs). Western blot analysis revealed that the tumor inhibition was associated with p53-mediated apoptotic pathway. Further, the biochemical and histological analysis revealed that the various liposomal preparation used in this study were non-toxic to the animals at the specified dose (10mg/kg).
In conclusion, we have developed a targeted liposomal formulation of P.Tuftsin-bearing liposomes co-encapsulated with effective anti-cancer drugs such as doxorubicin and curcumin. In experimental animals, tumor inhibition by P.Tuft-DOX-CUR LPs indicates the synergistic therapeutic effect of the peptide and the dual drug.
靶向多药递送系统已成为癌症治疗的一种先进策略。在此背景下，抗体、激素和小肽已作为肿瘤特异性配体与药物载体表面偶联，如负载药物的脂质体、聚合物纳米颗粒和金属纳米颗粒。在本研究中，我们通过在天然巨噬细胞刺激肽（促吞噬素）的C端连接一个棕榈酰残基（苏氨酸 - 赖氨酸 - 脯氨酸 - 精氨酸 - 羰基 - 氨基 - (CH) - 氨基 - 羰基 - 甲基，P.Tuft），使其能够接枝到脂质体双层内，从而将促吞噬素接枝到负载阿霉素（DOX）和/或姜黄素（CUR）的脂质体（LPs）表面。
使用紫外可见光谱、动态光散射（DLS）和傅里叶变换红外光谱（FTIR），对制备的载药脂质体（DOX LPs、CUR LPs、DOX - CUR LPs、P.Tuft - LPs、P.Tuft - DOX LPs、P.Tuft - CUR LPs、P.Tuft - DOX - CUR LPs）的粒径、药物含量、包封率和结构性质进行了全面表征。在艾氏腹水癌（EAC）诱导的肿瘤小鼠模型上检测了脂质体制剂的抗癌活性和药物毒性。
与单药/肽负载制剂（DOX LPs、CUR LPs、DOX - CUR LPs、P.Tuft - LPs、P.Tuft - DOX LPs、P.Tuft - CUR LPs）相比，用棕榈酰促吞噬素接枝的双药负载脂质体（P.Tuft - DOX - CUR LPs）治疗荷瘤小鼠后，肿瘤重量和体积显著降低。蛋白质印迹分析表明，肿瘤抑制与p53介导的凋亡途径有关。此外，生化和组织学分析表明，本研究中使用的各种脂质体制剂在指定剂量（10mg/kg）下对动物无毒。
总之，我们开发了一种靶向脂质体制剂，即负载促吞噬素的脂质体与阿霉素和姜黄素等有效的抗癌药物共包封。在实验动物中，P.Tuft - DOX - CUR LPs对肿瘤的抑制表明了该肽和双药的协同治疗效果。
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