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Reversibly disulfide cross-linked micelles improve the pharmacokinetics and facilitate the targeted, on-demand delivery of doxorubicin in the treatment of B-cell lymphoma

Abstract

Doxorubicin (DOX) is commonly used to treat human malignancies, and its efficacy can be maximized by limiting the cardiac toxicity when combined with nanoparticles. Here, we reported a unique type of reversibly disulfide cross-linked micellar formulation of DOX (DOX-DCMs) for the targeted therapy of B-cell lymphoma. DOX-DCMs exhibited high drug loading capacity, optimal particle sizes (15-20 nm), outstanding stability in human plasma, and stimuli-responsive drug release profile under reductive conditions. DOX-DCMs significantly improved the pharmacokinetics of DOX, and its elimination half-life (t1/2) and area under curve (AUC) were 5.5 and 12.4 times of that of free DOX, respectively. Biodistribution studies showed that DOX-DCMs were able to preferentially accumulate in the tumor site and significantly reduce the cardiac uptake of DOX. In a xenograft model of human B-cell lymphoma, compared with the equivalent dose of free DOX and non-crosslinked counterpart, DOX-DCMs not only significantly inhibited the tumor growth, prolonged the survival rate, but also remarkably reduced DOX-associated cardiotoxicity. Furthermore, the exogenous administration of N-acetylcysteine (NAC) at 24 h further improved the therapeutic efficacy of DOX-DCMs, which provides a “proof-of-concept” for precise drug delivery on-demand, and may have great translational potential as future cancer nano-therapeutics.

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Publication details

The article was received on 24 Jan 2018, accepted on 23 Mar 2018 and first published on 27 Mar 2018


Article type: Paper
DOI: 10.1039/C8NR00680F
Citation: Nanoscale, 2018, Accepted Manuscript
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    Reversibly disulfide cross-linked micelles improve the pharmacokinetics and facilitate the targeted, on-demand delivery of doxorubicin in the treatment of B-cell lymphoma

    K. Xiao, Q. Liu, N. A. Awwad, H. Zhang, L. Lai, Y. Luo, J. Lee, Y. Li and K. Lam, Nanoscale, 2018, Accepted Manuscript , DOI: 10.1039/C8NR00680F

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