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Tumor Targeting Synergistic Drug Delivery by Self-Assembled Hybrid Nanovesicles to Overcome Drug Resistance

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Abstract

Purpose

To overcome multi-drug resistance (MDR) in tumor chemotherapy, a polymer/inorganic hybrid drug delivery platform with tumor targeting property and enhanced cell uptake efficiency was developed.

Method

To evaluate the applicability of our delivery platform for the delivery of different drug resistance inhibitors, two kinds of dual-drug pairs (doxorubicin/buthionine sulfoximine and doxorubicin/tariquidar, respectively) were loaded in heparin-biotin/heparin/protamine sulfate/calcium carbonate nanovesicles to realize simultaneous delivery of an anticancer drug and a drug resistance inhibitor into drug-resistant tumor cells.

Results

Prepared by self-assembly, the drug loaded hybrid nanovesicles with a mean size less than 210 nm and a negative zeta potential exhibit good stability in serum contained aqueous media. The in vitro cytotoxicity evaluation indicates that hybrid nanovesicles with tumor targeting biotin moieties have an enhanced tumor cell inhibitory effect. In addition, dual-drug loaded hybrid nanovesicles exhibit significantly stronger cell growth inhibition as compared with doxorubicin (DOX) mono-drug loaded nanovesicles due to the reduced intracellular glutathione (GSH) content by buthionine sulfoximine (BSO) or the P-glycoprotein (P-gp) inhibition by tariquidar (TQR).

Conclusions

The tumor targeting nanovesicles prepared in this study, which can simultaneously deliver multiple drugs and effectively reverse drug resistance, have promising applications in drug delivery for tumor treatments. The polymer/inorganic hybrid drug delivery platform developed in this study has good applicability for the co-delivery of different anti-tumor drug/drug resistance inhibitor pairs to overcome MDR.

A polymer/inorganic hybrid drug delivery platform with enhanced cell uptake was developed for tumor targeting synergistic drug delivery. The heparin-biotin/heparin/protamine sulfate/calcium carbonate nanovesicles prepared in this study can deliver an anticancer drug and a drug resistance inhibitor into drug-resistant tumor cells simultaneously to overcome drug resistance efficiently.

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Abbreviations

BSO:

Buthionine sulfoximine

CLSM:

Confocal laser scanning microscopy

DLS:

Dynamic light scattering

DMEM:

Dulbecco’s modified Eagle’s medium

DOX:

Doxorubicin hydrochloride

EDS:

Energy dispersive spectrometer

EPR:

Enhanced permeability and retention

FBS:

Fetal bovine serum

GSH:

Glutathione

HABA:

2-(4-Hydroxyphenylazo)-benzoic acid/avidin

HP:

Heparin

HPB:

Heparin-biotin

MDR:

Multi-drug resistance

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NV:

Nanovesicles

PDI:

Polydispersity index

P-gp:

P-glycoprotein

PS:

Protamine sulfate

TEM:

Transmission electron microscopy

TGA:

Thermogravimetric analysis

TQR:

Tariquidar

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was supported by National Natural Science Foundation of China (51533006 and 21274113). The grant from Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study (Hengyang, China) is also gratefully acknowledged.

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    Authors and Affiliations

    1. Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, People’s Republic of China

      Meng-Qing Gong, Cong Wu, Xiao-Yan He, Jing-Yi Zong, Jin-Long Wu, Ren-Xi Zhuo & Si-Xue Cheng

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    1. Meng-Qing Gong
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    Correspondence to Si-Xue Cheng.

    Additional information

    Meng-Qing Gong and Cong Wu contributed equally to this work.

    Electronic supplementary material

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    ESM 1

    Experimental details for Western blot analysis of P-gp expression, determination the content of biotin on the surface of nanovesicles and thermogravimetric analysis; bioavailable biotin moieties on the surface of nanovesicles; TGA curves of nanovesicles; size distributions of nanovesicles; cell viability of HeLa cells after being treated by blank biotinylated NV; cell viability of MCF-7/ADR cells after being treated by DOX/BSO@biotinylated NV with different DOX/BSO weight ratios; expressions of P-glycoprotein in different cells. The Supporting Information is available free of charge on the website. (DOC 286 kb)

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    Gong, MQ., Wu, C., He, XY. et al. Tumor Targeting Synergistic Drug Delivery by Self-Assembled Hybrid Nanovesicles to Overcome Drug Resistance. Pharm Res 34, 148–160 (2017). https://doi.org/10.1007/s11095-016-2051-9

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    • DOI: https://doi.org/10.1007/s11095-016-2051-9

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