Abstract
Achieving the activation of drugs within cellular systems may provide targeted therapies. Here we construct a tumour-selective cascade activatable self-detained system (TCASS) and incorporate imaging probes and therapeutics. We show in different mouse models that the TCASS system accumulates in solid tumours. The molecules show enhanced accumulation in tumour regions via the effect of recognition induced self-assembly. Analysis of the molecular penetration in tumour tissue shows that in vivo self-assembly increases the penetration capability compared to typical soft or hard nanomaterials. Importantly, the in vivo self-assembled molecules exhibit a comparable clearance pathway to that of small molecules, which are excreted from organs of the reticuloendothelial system (liver and kidney), while are relatively slowly eliminated from tumour tissues. Finally, this system, combined with the NIR probe, shows high specificity and sensitivity for detecting bladder cancer in isolated intact patient bladders.
Highlights
Achieving the activation of drugs within cellular systems may provide targeted therapies
The results indicated that the DEVD motif was hydrolysed in the presence of recombinant human caspase-3 with a substrate-to-enzyme ratio of 1 μM/U in HEPES buffer (Supplementary Fig. 9)
Similar CD signals of β-sheet were observed when molecule 1 was incubated with caspase-3 for 2 h in HEPES buffer (Supplementary Fig. 10), indicating that after removing the responsive motif (Supplementary Fig. 9), the simultaneously released residues would self-assemble into nanofibrils through hydrogen bonding interactions[36]
Summary
Achieving the activation of drugs within cellular systems may provide targeted therapies. By taking advantage of small molecules and nanoscience, we expect in vivo self-assembly to outperform other strategies because (i) in addition to existing active/passive targeting processes, there is a new targeting mechanism which exhibit efficient accumulation and retention at desired sites; (ii) high penetration capability similar to that of small molecules in tumour region; and (iii) pharmacokinetics similar to that of small molecules except for reduced systemic toxicity in vivo. These advantages suggest that supramolecular systems may be promising for multifunctional nanomedicine. By integration of the chemodrug or contrast agent, the TCASS can be successfully employed in the process of drug delivery in mice or image-guided surgery in isolated patient intact bladders
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