Abstract
A polyrotaxane-based nanoconstruct with pliable structure carrying a chemotherapeutic drug was developed for targeting circulating lymphoblastic leukaemia cells in a fluidic environment of blood vessels in vivo. By introducing lymphoblast targeting aptamer DNA through cyclodextrin, threaded in poly(ethylene glycol) as polyrotaxane, target aptamer slides along the long polymeric chain and actively search for target ligand, leading to active targeting in dynamic fluidic system which is enhanced by up to 6–fold compared with that of control carriers with non–sliding targeting ligands. Moreover, the drug carrier was made stimuli-responsive by employing i-motif DNA to selective releases of its payload at intracellular acidic condition. These combined features resulted in the effective remission of lymphoblastic leukaemia both in vitro and in dynamic blood vessels in vivo.
Highlights
A polyrotaxane-based nanoconstruct with pliable structure carrying a chemotherapeutic drug was developed for targeting circulating lymphoblastic leukaemia cells in a fluidic environment of blood vessels in vivo
Lymphoblastic leukaemia is characterized by the uncontrolled production of immature lymphocytes[1,2]
The PR–based stimuli–responsive flexible drug carrier was developed by modifying CD, supramolecule with cyclic structure, and by threading it selectively into polyethylene glycol (PEG)
Summary
A polyrotaxane-based nanoconstruct with pliable structure carrying a chemotherapeutic drug was developed for targeting circulating lymphoblastic leukaemia cells in a fluidic environment of blood vessels in vivo. We hypothesized that the threaded aptamer DNA–CD will slide along the polymeric PEG chain with a high degree of freedom, increasing its probability of binding to target molecules on the surface of circulating cancer cells and maintaining a stronger binding affinity even in the dynamic environment of the bloodstream. We prepared a series of fluorescent Cy5–labelled PRNCs with or without a targeting moiety (T+/−), sliding ability (S+/−), and pH–responsive i–motif DNA sequence (P+/−) (Supplementary Table 2).
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