Globular Protein-Coated Paclitaxel Nanosuspensions: Interaction Mechanism, Direct Cytosolic Delivery, and Significant Improvement in Pharmacokinetics
Globular Protein-Coated Paclitaxel Nanosuspensions: Interaction Mechanism, Direct Cytosolic Delivery, and Significant Improvement in Pharmacokinetics
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DOI：
10.1021/mp5008037
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发表时间：
2015-05-01
影响因子：
4.9
通讯作者：
Yin, Lifang
中科院分区：
文献类型：
--
作者：
Li, Yongji;Wu, Zhannan;Yin, Lifang
大约40%的上市药物和70%-90%的新药候选药物不溶于水，因此生物利用度很低，这严重影响了它们的治疗效果。通过将纯药物颗粒尺寸减小到SEB-微米范围来实现纳米混悬液的配方是克服这种不溶性的最有前途的方法之一。然而，由于成核和颗粒生长，纳米悬浮剂配方容易发生不稳定。因此，在制备过程中需要在纳米混悬剂配方中加入稳定剂来抑制药物颗粒的聚集。β-LG是一种球状蛋白，通过热诱导变性而破碎，其疏水性区域暴露，使其能够与有机颗粒结合。PTX是一种不溶性药物，广泛用于人类癌症的临床治疗。然而，该药物的临床应用受到溶解性差、副作用大、肿瘤穿透性差等固有缺陷的极大限制。在本研究中，我们通过将蛋白质包覆在纳米级药物颗粒上，制备了β-LG稳定的PTX纳米混悬液，考察了β-LG对PTX-NS的稳定作用，并对其体内外性能进行了评价。很容易制备出直径约200 nm的PTX-NS。β-LG通过蛋白质疏水区域与药物颗粒疏水表面的相互作用对PTX-NS产生显著的稳定作用，导致蛋白质构象发生变化，二级结构和三级结构均丧失，色氨酸残基向疏水性较弱的状态转变。重要的是，与其他传统纳米粒子不同，PTX-NS可以以不依赖于能量的方式直接跨膜转移到胞浆中，而不会被包裹在内体溶酶体系统中。此外，与紫杉醇相比，PTX-NS使AUC和C-max分别增加26倍和16倍，使T-1/2延长314倍。不出所料，PTX-NS在体内外的抗肿瘤活性均好于PTX单独使用。此外，β-LG是细胞和生物相容的，PTX-NS对健康组织没有毒性。综上所述，目前的研究表明，球状蛋白，如β-LG，可作为新型生物材料用于纳米悬浮平台，以改善疾病治疗的药物输送。
About 40% of the marketed drugs and 70-90% of new drug candidates are insoluble in water and therefore poorly bioavailable, which significantly compromises their therapeutic effects. A formulation of nanosuspensions achieved by reducing the pure drug particle size down to seb-micron range is one of the most promising approaches to overcome the insolubility. However, the nanosuspension formulations are subject to instability because of nucleation and particle growth. Therefore, a stabilizer is needed to be incorporated into the nanosuspension formulation during the preparation process to suppress the aggregation of drug particles. beta-LG, a globular protein, is broken by heat-induced denaturation, and its hydrophobic area is exposed, which allows it to associate with organic particles. PTX, an insoluble drug, is widely used for the clinical treatment of human cancer. However, this drug's clinical application is greatly limited by intrinsic defects including poor solubility, adverse side effects, and poor tumor penetration. In this study, we prepared,beta-LG-stabilized PTX nanosuspensions (PTX-NS) by coating the protein onto nanoscaled drug particles, investigating the stabilization effect of beta-LG on PTX-NS, and evaluating its in vitro and in vivo performance. PTX-NS with a diameter of approximately 200 nm was easily prepared. beta-LG produced significantly stabilized effect on PTX-NS via the interaction between the hydrophobic area of the protein and the hydrophobic surface of the drug particles, which resulted in a conformational change of the protein, the loss of both secondary and tertiary structures, and the transition of Trp residues to a less hydrophobic condition. Importantly, unlike other conventional nanoparticles, PTX-NS could directly translocated across the membrane into the cytosol in an energy-independent manner, without entrapment within the endosomal lysosomal system. Moreover, compared with Taxol, PTX-NS increased AUC and C-max by 26- and 16-fold, respectively, and prolonged T-1/2 by 314-fold. As expected, PTX-NS had better in vitro and in vivo antitumor activity compared to PTX alone. Additionally, beta-LG is cyto- and bio-compatible, and PTX-NS is not toxic to healthy tissues. In conclusion, the present study has suggested the high potency of globular proteins, such as beta-LG, as novel biomaterials for nanosuspension platform to improve the drug delivery for disease treatment.