Abstract

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-4H-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 BP20-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, BP20-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 BP20-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.

Highlights

  • Accurate tracking of in vivo tumor-speci c behavior with probes is a perfect strategy for targeted sensing and controlled release of prodrugs.[1,2,3] a signi cant limitation of such theranostic nanoprobe design is that multiple components for such a complicated scheme are o en required, inevitably leading to structural heterogeneity, insufficient reproducibility and subsequently huge barriers for clinical translation.[4]

  • Active targeting: shell surface-gra ed biotin directly exposed to receptors on cancer cells for facilitating cellular internalization and visualizing drug release in living cells The in vitro toxicity of our designed molecularly precise prodrugs BPn-DCM-S-CPT (n 1⁄4 0, 5 and 20) was assessed by using the standard MTT assay

  • All the synergistic targeting makes BP20-DCM-S-CPT achieve high carrying efficiency, good targeting properties, and sustained and tumor-speci c release in living mice

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Summary

Introduction

Accurate tracking of in vivo tumor-speci c behavior with probes is a perfect strategy for targeted sensing and controlled release of prodrugs.[1,2,3] a signi cant limitation of such theranostic nanoprobe design is that multiple components for such a complicated scheme are o en required, inevitably leading to structural heterogeneity, insufficient reproducibility and subsequently huge barriers for clinical translation.[4]. We describe the strategy of molecularly precise self-assembly of monodisperse nanotheranostics for BPn-DCM-S-CPT (n 1⁄4 0, 5 and 20) with fixed drug loadings (36%, 23% and 16%) and constant release capacities, permitting in vivo real-time targeted therapy.

Results
Conclusion
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