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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 and 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.

SUBMITTER: Xiao K

PROVIDER: S-EPMC5980239 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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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.

Xiao Kai K Liu Qiangqiang Q Al Awwad Nasir N Zhang Hongyong H Lai Li L Luo Yan Y Lee Joyce S JS Li Yuanpei Y Lam Kit S KS

Nanoscale 20180501 17

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 c ...[more]

PMID: 29682647

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Project description:To minimize premature release of drugs from their carriers during circulation in the blood stream, we have recently developed reversible disulfide cross-linked micelles (DCMs) that can be triggered to release drug at the tumor site or in cancer cells. We designed and synthesized thiolated linear-dendritic polymers (telodendrimers) by introducing cysteines to the dendritic oligo-lysine backbone of our previously reported telodendrimers comprised of linear polyethylene glycol (PEG) and a dendritic cluster of cholic acids. Reversibly cross-linked micelles were then prepared by the oxidization of thiol groups to disulfide bond in the core of micelles after the self-assembly of thiolated telodendrimers. The DCMs were spherical with a uniform size of 28 nm, and were able to load paclitaxel (PTX) in the core with superior loading capacity up to 35.5% (w/w, drug/micelle). Cross-linking of the micelles within the core reduced their apparent critical micelle concentration and greatly enhanced their stability in non-reductive physiological conditions as well as severe micelle-disrupting conditions. The release of PTX from the DCMs was significantly slower than that from non-cross-linked micelles (NCMs), but can be gradually facilitated by increasing the concentration of reducing agent (glutathione) to an intracellular reductive level. The DCMs demonstrated a longer in vivo blood circulation time, less hemolytic activities, and superior toxicity profiles in nude mice, when compared to NCMs. DCMs were found to be able to preferentially accumulate at the tumor site in nude mice bearing SKOV-3 ovarian cancer xenograft. We also demonstrated that the disulfide cross-linked micellar formulation of PTX (PTX-DCMs) was more efficacious than both free drug and the non-cross-linked formulation of PTX at equivalent doses of PTX in the ovarian cancer xenograft mouse model. The anti-tumor effect of PTX-DCMs can be further enhanced by triggering the release of PTX on-demand by the administration of the FDA approved reducing agent, N-acetylcysteine, after PTX-DCMs have reached the tumor site.

Dataset Information

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

Publications

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

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