Albumin Binding Domain Fusing R/K-X-X-R/K Sequence for Enhancing Tumor Delivery of Doxorubicin
Albumin Binding Domain Fusing R/K-X-X-R/K Sequence for Enhancing Tumor Delivery of Doxorubicin
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DOI：
10.1021/acs.molpharmaceut.7b00497
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发表时间：
2017-11-01
影响因子：
4.9
通讯作者：
Su, Zhiguo
中科院分区：
文献类型：
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作者：
Liu, Liping;Zhang, Chun;Su, Zhiguo
为了改善阿霉素（DOX）的肿瘤递送，设计并制备了一种肽-DOXO缀合物，其中由白蛋白结合结构域（ABD）和肿瘤特异性内化序列（RGDK或RPARPAR）组成的肽与阿霉素（6-马来酰亚胺己酰基）腙衍生物（DOXO-EMCH）缀合。肺癌细胞系A549对阿霉素的摄取证明了缀合物能够通过肿瘤特异性序列介导的方式内化，并且A549细胞内分布的细胞内成像证明缀合物阿霉素可以被递送至细胞核。肽-DOXO缀合物对A549细胞的细胞毒性以IC50值表示，范围约为9-11μM。药代动力学研究表明，两种缀合物的半衰期比DOX长近5.5倍，比DOXO-EMCH长约4倍。在阿霉素等效剂量下，两种肽-DOXO缀合物对荷瘤BALB/c裸鼠的体内生长抑制作用（ABD-RGDK-DOXO为47.78％，ABD-RPARPAR-DOXO为47.09％）比阿霉素和DOXO-EMCH（分别为24.28％和25.67％）强得多。此外，体内荧光成像研究证实，该肽显着增加了肿瘤组织中的有效负载积累，并表明融合肿瘤特异性序列的白蛋白结合域有效增强了阿霉素的肿瘤递送，从而提高了其治疗效力。
For the purpose of improving the tumor delivery of doxorubicin (DOX), a kind of peptide-DOXO conjugate was designed and prepared, in which the peptide composed of an albumin-binding domain (ABD) and a tumor-specific internalizing sequence (RGDK or RPARPAR) was conjugated to a (6-maleimidocaproyl) hydrazone derivative of doxorubicin (DOXO-EMCH). The doxorubicin uptake by lung cancer cell line of A549 evidenced that the conjugates are capable of being internalized through a tumor-specific sequence mediated manner, and the intracellular imaging of distribution in A549 cell demonstrated that the conjugated doxorubicin can be delivered to the cell nucleus. The A549 cell cytotoxicity of peptide-DOXO conjugates was presented with IC50 values and shown in the range of about 9-11 mu M. Pharmacokinetics study revealed that both conjugates exhibited nearly 5.5 times longer half-time than DOX, and about 4 times than DOXO-EMCH. The in vivo growth inhibitions of the two peptide-DOXO conjugates on BALB/c nude mice bearing A549 tumor (47.78% for ABD-RGDK-DOXO and 47.09% for ABD-RPARPAR-DOXO) were much stronger than that of doxorubicin and DOXO-EMCH (24.28% and 25.67% respectively) at a doxorubicin equivalent dose. Besides, the in vivo fluorescence imaging study confirmed that the peptide markedly increased the payload accumulation in tumor tissues and indicated that albumin binding domain fusing tumor-specific sequence effectively enhanced the tumor delivery of doxorubicin and thus improved its therapeutic potency.