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Hyaluronan-based nanocarriers with CD44-overexpressed cancer cell targeting.

Abstract：

PURPOSE:The objective of the work was to evaluate the potential of hyaluronan-based nanoparticles as tumor-targeting nano-systems for CD44-overexpressed cancer therapy. METHODS:The synthesized amphiphilic cholesteryl succinoyl hyaluronan (Chol-Suc-HA) conjugates self-assembled into docetaxel(DTX)-loaded nanoparticles in the aqueous environment. The physiochemical properties of Chol-Suc-HA-DTX NPs were characterized. The in vitro cytotoxicity of Chol-Suc-HA-DTX NPs against MCF-7, 4T1, A549 and L929 cells was evaluated using MTT and LDH assays. Moreover, the cellular uptake mechanism was investigated using the CLSM and flow cytometry. The in vivo animal experiments of Chol-Suc-HA-DTX NPs including pharmacokinetic evaluation, bio-distribution observed by EX vivo NIRF imaging and antitumor efficacy were also carried out in SD rats or 4T1 tumor-bearing BALB/c mice. RESULTS:The self-assembled Chol-Suc-HA-DTX NPs with different degree of substitution (DS) of hydrophobic moiety exhibited high drug loading, uniform particle size distribution and excellent in vitro stability. However, the plasma stability of Chol-Suc-HA-DTX NPs was significantly influenced by the DS of hydrophobic moiety. The higher the DS was, the more stable the NPs were. Cellular uptake demonstrated that Chol-Suc-HA-DTX NPs were internalized into cancer cells via CD44 receptor-mediated endocytosis. Compared with Taxotere®, Chol-Suc-HA-DTX NPs displayed remarkably higher cytotoxicity to CD44-positive cancer cells (MCF-7, 4T1, A549 cells). In vivo animal experiments confirmed that Chol-Suc-HA-DTX NPs with relatively high DS values exhibited prolonged circulation time, excellent tumor-targeting properties and efficient antitumor effects with extremely low systemic toxicity. In addition, blank Chol-Suc-HA NPs also slightly suppressed the tumor growth. CONCLUSIONS:Chol-Suc-HA NPs with a suitable DS value portend to be promising drug vehicles for systemic targeting of CD44-overexpressed cancers.

journal_name

Pharm Res

journal_title

Pharmaceutical research

authors

Song S,Qi H,Xu J,Guo P,Chen F,Li F,Yang X,Sheng N,Wu Y,Pan W

doi

10.1007/s11095-014-1393-4

subject

Has Abstract

pub_date

2014-11-01 00:00:00

pages

2988-3005

issue

11

eissn

0724-8741

issn

1573-904X

journal_volume

31

pub_type

杂志文章

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