Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China.
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences , Beijing 100190, China.
Mol Pharm. 2017 Nov 6;14(11):3739-3749. doi: 10.1021/acs.molpharmaceut.7b00497. Epub 2017 Oct 9.
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 IC values and shown in the range of about 9-11 μM. 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.
为了提高阿霉素（DOX）的肿瘤递送效果，设计并制备了一种肽-DOXO 缀合物，其中由白蛋白结合域（ABD）和肿瘤特异性内化序列（RGDK 或 RPARPAR）组成的肽与 DOX 的（6-马来酰亚胺基己酰基）腙衍生物（DOXO-EMCH）缀合。阿霉素摄取肺癌细胞系 A549 的证据表明，缀合物能够通过肿瘤特异性序列介导的方式被内化，并且 A549 细胞内分布的细胞内成像表明，缀合的阿霉素可以递送到细胞核。肽-DOXO 缀合物对 A549 细胞的细胞毒性表现出 IC 值，范围约为 9-11 μM。药代动力学研究表明，两种缀合物的半衰期均比 DOX 延长近 5.5 倍，比 DOXO-EMCH 延长约 4 倍。两种肽-DOXO 缀合物在荷 A549 肿瘤的 BALB/c 裸鼠体内的生长抑制作用（ABD-RGDK-DOXO 为 47.78%，ABD-RPARPAR-DOXO 为 47.09%）均明显强于阿霉素和 DOXO-EMCH（分别为 24.28%和 25.67%）在阿霉素等效剂量下。此外，体内荧光成像研究证实肽明显增加了载药在肿瘤组织中的积累，并表明白蛋白结合域融合肿瘤特异性序列可有效增强阿霉素的肿瘤递送，从而提高其治疗效果。
