Molecularly precise self-assembly of theranostic nanoprobes within a single-molecular framework for in vivo tracking of tumor-specific chemotherapy† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c8sc01069b

• Published in: Chemical science (Cambridge) 2018-04, Vol.9 (22), p.4959-4969
• Main Authors: Yan, Chenxu, Guo, Zhiqian, Shen, Yanyan, Chen, Yi, Tian, He, Zhu, Wei-Hong
• Format: Article
• Language: English
• Subjects: Chemistry
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/c8sc01069b

The strategy of molecularly precise self-assembly of theranostic nanoprobes within a single-molecular framework is used to avoid batch-to-batch variability, and concurrently achieving real-time tracking of the in vivo behaviour of prodrugs for the first time. Structural heterogeneity and the lack of in vivo real-time tracking of drug release are the utmost barriers for nanocarrier-mediated prodrugs in targeted therapy. Herein, we describe the strategy of molecularly precise self-assembly of monodisperse nanotheranostics for BP n -DCM-S-CPT ( n = 0, 5 and 20) with fixed drug loadings (36%, 23% and 16%) and constant release capacities, permitting in vivo real-time targeted therapy. We focus on regulating the hydrophilic fragment length to construct stable, well-defined nanostructured assemblies. Taking the bis-condensed dicyanomethylene-4 H -pyran (DCM) derivative as the activatable near-infrared (NIR) fluorophore, it makes full use of two terminal conjunctions: the hydrophobic disulfide-bridged anticancer prodrug camptothecin (CPT) and the hydrophilic oligomer-bridged biotin segment serving as an active targeting unit. From the rational design, only BP 20 -DCM-S-CPT forms uniform and highly stable self-assemblies ( ca. 80 nm, critical micelle concentration = 1.52 μM) with several advantages, such as structural homogeneity, fixed drug loading efficiency, real-time drug release tracking and synergistic targeting (passive, active and activatable ability). More importantly, in vitro and in vivo experiments verify that the surface-grafted biotins of nanoassemblies are directly exposed to receptors on cancer cells, thus markedly facilitating cellular internalization. Notably, through synergistic targeting, BP 20 -DCM-S-CPT displays excellent tumor-specific drug release performance in HeLa tumor-bearing nude mice, which has significantly enhanced in vivo antitumor activity and nearly eradicates the tumor (IRT = 99.7%) with few side effects. For the first time, the specific molecularly precise self-assembly of BP 20 -DCM-S-CPT within a single-molecular framework has successfully achieved a single reproducible entity for real-time reporting of drug release and cancer therapeutic efficacy in living animals, providing a new insight into amphiphilic nanotheranostics for clinical translation.