Transformative Nanomedicine of an Amphiphilic Camptothecin Prodrug for Long Circulation and High Tumor Uptake in Cancer Therapy

We report a camptothecin (CPT) prodrug that was well formulated in solution and rapidly transformed into long-circulating nanocomplexes in vivo for highly efficient drug delivery and effective cancer therapy. Specifically, using a redox-responsive disulfide linker, CPT was conjugated with an albumin...

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Bibliographic Details
Published in:ACS nano 2017-09, Vol.11 (9), p.8838-8848
Main Authors: Zhang, Fuwu, Zhu, Guizhi, Jacobson, Orit, Liu, Yi, Chen, Kai, Yu, Guocan, Ni, Qianqian, Fan, Jing, Yang, Zhen, Xu, Frederick, Fu, Xiao, Wang, Zhe, Ma, Ying, Niu, Gang, Zhao, Xiaobin, Chen, Xiaoyuan
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents, Phytogenic - administration & dosage
Antineoplastic Agents, Phytogenic - blood
Antineoplastic Agents, Phytogenic - chemistry
Antineoplastic Agents, Phytogenic - pharmacokinetics
Camptothecin - administration & dosage
Camptothecin - blood
Camptothecin - chemistry
Camptothecin - pharmacokinetics
Drug Delivery Systems
Female
HCT116 Cells
Humans
Mice
Mice, Nude
Nanoconjugates - administration & dosage
Nanoconjugates - chemistry
Nanoparticles - chemistry
Neoplasms - drug therapy
Oxidation-Reduction
Prodrugs - administration & dosage
Prodrugs - chemistry
Prodrugs - pharmacokinetics
Solubility
Surface-Active Agents - chemistry
Surface-Active Agents - pharmacokinetics
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Summary:We report a camptothecin (CPT) prodrug that was well formulated in solution and rapidly transformed into long-circulating nanocomplexes in vivo for highly efficient drug delivery and effective cancer therapy. Specifically, using a redox-responsive disulfide linker, CPT was conjugated with an albumin-binding Evans blue (EB) derivative; the resulting amphiphilic CPT-ss-EB prodrug self-assembled into nanostructures in aqueous solution, thus conferring high solubility and stability. By binding CPT-ss-EB to endogenous albumin, the 80 nm CPT-ss-EB nanoparticles rapidly transformed into 7 nm albumin/prodrug nanocomplexes. CPT-ss-EB was efficient at intracellular delivery into cancer cells, released intact CPT in a redox-responsive manner, and exhibited cytotoxicity as potent as CPT. In mice, the albumin/CPT-ss-EB nanocomplex exhibited remarkably long blood circulation (130-fold greater than CPT) and efficient tumor accumulation (30-fold of CPT), which consequently contributed to excellent therapeutic efficacy. Overall, this strategy of transformative nanomedicine is promising for efficient drug delivery.
ISSN:1936-0851
1936-086X
DOI:10.1021/acsnano.7b03003