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Hyaluronan-Based Nanocarriers with CD44-Overexpressed Cancer Cell Targeting

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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.

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Abbreviations

4T1:

Mice mammary cancer cells

A549:

Non-small lung cancer cells

C6:

Coumarin-6

CHEMS:

Cholesteryl hemisuccinate

CLSM:

Confocal laser scanning microscope

DCC:

N,N′-dicyclohexylcarbodiimide

DCM:

Dichloromethane

DL:

Drug loading

DLS:

Dynamic light scattering

DMAP:

4-dimethylaminopyridine

DMEM:

Dulbecco’s modified eagle medium

DS:

Degree of substitution

DTX:

Docetaxel

ECM:

Extracellular matrix

EE:

Entrapment efficiency

HA:

Hyaluronan

HAS:

HA synthase

Hyals:

Hyaluronidases

L929:

Mice fibroblasts

LDH:

Lactate dehydrogenase

MCF-7:

Human breast cancer cells

MTT:

3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide

NIRF:

Near infrared fluorescence

RAW 264.7:

Murine macrophage cells

TEM:

Transmission electron microscopy

TIR:

Tumor inhibition rate

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was financially supported by the National Natural Science Foundation of China (NSFC, No.81273447), Hebei Natural Science Foundation of China (HENSF, C2011319007) and special construction projects fund which belongs to “Taishan Scholar——Pharmacy Specially Recruited Experts”.

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Authors and Affiliations

  1. School of Pharmacy, Shenyang Pharmaceutical University, PO Box No. 122, 103 Wenhua Road, Shenyang, 110016, People’s Republic of China

    Shuangshuang Song, Pan Guo, Fen Chen, Fei Li, Xinggang Yang & Weisan Pan

  2. College of Life Science and Biopharmaceutical, Shenyang Pharmaceutical University, PO Box No. 122, 103 Wenhua Road, Shenyang, 110016, People’s Republic of China

    Huan Qi, Jingwen Xu & Yingliang Wu

  3. Institute of Metal Research, University of Chinese Academy of Sciences, 72 Wenhua Road, Shenyang, 110016, China

    Naicheng Sheng

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  1. Shuangshuang Song
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Correspondence to Yingliang Wu or Weisan Pan.

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Song, S., Qi, H., Xu, J. et al. Hyaluronan-Based Nanocarriers with CD44-Overexpressed Cancer Cell Targeting. Pharm Res 31, 2988–3005 (2014). https://doi.org/10.1007/s11095-014-1393-4

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  • DOI: https://doi.org/10.1007/s11095-014-1393-4

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