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Multifunctional Tumor-Targeting Nanocarriers Based on Hyaluronic Acid-Mediated and pH-Sensitive Properties for Efficient Delivery of Docetaxel

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ABSTRACT

Purpose

The objective of this work was to develop a multifunctional tumor-targeting nanocarrier based on the mechanism of CD44-mediated endocytosis and pH-induced drug release to improve the therapeutic efficacy of docetaxel (DTX).

Methods

Hyaluronic acid-coated docetaxel-loaded cholesteryl hemisuccinate vesicles (HA-CHEMS vesicles) were prepared. The physiochemical properties and pH-dependent drug release of HA-CHEMS vesicles were evaluated. The HA-CHEMS vesicles were investigated for CD44-mediated internalization and in vitro cell viability using MCF-7,A549 and L929 cells.In addition,tissue distribution as well as antitumor efficacy was also evaluated in MCF-7 tumor-bearing mouse model.

Results

The particle size and zeta potential of HA-CHEMS vesicles were 131.4 ± 6.2 nm and −13.3 ± 0.04 mV,respectively. The in vitro drug release results demonstrated a pH-responsive drug release under different pH conditions. In vitro cell viability tests suggested that the encapsulation of DTX in HA-CHEMS vesicles led to more than 51.6-fold and 46.3-fold improved growth inhibition in MCF-7 and A549 cell lines,respectively compared to Taxotere®. From the cell uptake studies,the coumarin 6-loaded HA-CHEMS vesicles enhanced intracellular fluorescent intensity in the CD44-overexpressing cell line (MCF-7). Biodistribution studies revealed selective accumulation of HA-CHEMS vesicles in the MCF-7 bearing BalB/c nude mice as a result of passive accumulation and active targeting (CD44-mediated endocytosis). Compared to Taxotere®,HA-CHEMS vesicles exhibited higher antitumor activity by reducing tumor volume (P < 0.05) and drug toxicity,demonstrating the success of the multifunctional targeting delivery.

Conclusions

This work corresponds to the preparation of a multifunctional tumor-targeted delivery system. Our investigation shows that hyaluronan-bearing docetaxel-loaded cholesteryl hemisuccinate vesicles (HA-CHEMS vesicles) is a highly promising therapeutic system,leading to tumor regression after intravenous administration without visible toxicity.

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Abbreviations

A549:

Non small-cell lung cancer

C6:

coumarin-6

CHEMS:

cholesteryl hemisuccinate

CLSM:

confocal laser scanning microscopy

DDAB:

dimethyl dioctadecyl ammonium bromide

DL:

drug loading

DLS:

dynamic light scattering

DMEM:

dulbecco’s modified Eagle’s medium

DTX:

docetaxel

EPR:

enhanced permeability and retention

EE:

encapsulation efficiency

HA:

hyaluronic acid hyaluronan

IC50 :

the growth inhibitory concentration for 50% of the cell population

L929:

mice fibroblasts

LYVE-1:

the lymphatic vessel endothelial HA receptor-1

MCF-7:

human breast cancer cells

MTT:

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

MW:

molecular weight

PBS:

phosphate buffered saline

PI:

propidium iodide

RHMM:

receptor for hyaluronate-mediated motility

RPMI:

roswell park memorial institute

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), and Heibei Natural Science Foundation of China (HENSF, C2011139007).

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Authors and Affiliations

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

    Shuangshuang Song, Fen Chen, Fei Li, Tiegang Xin, Tiantian Ye, Xinggang Yang & Weisan Pan

  2. Department of Pharmacology and Toxicology, School of Pharmacy, Shenyang Pharmaceutical University, PO Box No. 122, 103 Wenhua Road, Shenyang, 110016, People’s Republic of China

    Huan Qi & Jingwen Xu

  3. Insitute 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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  2. Fen Chen
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  10. Weisan Pan
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Correspondence to Weisan Pan.

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Song, S., Chen, F., Qi, H. et al. Multifunctional Tumor-Targeting Nanocarriers Based on Hyaluronic Acid-Mediated and pH-Sensitive Properties for Efficient Delivery of Docetaxel. Pharm Res 31, 1032–1045 (2014). https://doi.org/10.1007/s11095-013-1225-y

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  • DOI: https://doi.org/10.1007/s11095-013-1225-y

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