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A Complementary Strategy for Enhancement of Nanoparticle Intracellular Uptake

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Abstract

Purpose

The complementary strategy by combining targeting ligand-mediated selectivity and CPP-mediated transmembrane function could be exploit synergies for enhancing cellular uptake of nanoparticles with negative charge. A heparin-based nanoparticles with negative charge was fabricated by complementary strategy, which was expected to attain efficient uptake and simultaneously exert great anticancer activity.

Methods

We synthesized heparin-based nanoparticles with targeting ligand folate and CPP ligand Tat to deliver paclitaxel (H-F-Tat-P NPs). The NPs were characterized by 1H NMR, DLS and TEM, respectively. The effect of dual ligands on system behavior in aqueous solution was investigated. Moreover, its cellular internalization and anticancer activity were detected by flow cytometry, confocal microscopy and MTT.

Results

Folate played a key role in the formation of heparin-based NPs dependent on the balance of amphiphilic Tat and hydrophobic folate. Although H-F-Tat-P NPs primarily entered FR specific and non-specific cells by similar routes, there were no comparability due to cell-type specific variation. Unlike non-specific cells, the complementary ligands could help negative-charged NPs to enhance cellular uptake facilitating its endosome escape in specific cells thereby exhibiting great anticancer activity.

Conclusions

The complementary strategy for negative-charged NPs was presented a promising delivery system for diverse anticancer agents enable simultaneously targeting and drug delivery.

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Abbreviations

H-F-Tat-P NPs:

Heparin-Folate-Tat-Paclitaxel Nanoparticles

FR:

Folate Receptor

Tat:

Transactivating transcriptional activator peptide

CPP:

Cell-penetrating peptide

MBCD:

Methyl-β-cyclodextrin

CPZ:

Chlorpromazine

DLS:

Dynamic light scattering

TEM:

Transmission electron microscope

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Acknowledgments and Disclosures

Yingjia Li and Ge Wen have equal contribution in this work and are both equally considered as first author. The authors are grateful for financial support by Natural Science Foundation of China (Grant No. 21204036, 81272509, 81371559); Science and Technology Planning Project of Guangdong Province (Grant No. 2011B010400018).

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Authors and Affiliations

  1. Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China

    Yingjia Li, Yaoyong Lu, Jianguo Wang, Lijuan Zhong & Ying Wang

  2. Department of Ultrasonography, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Yingjia Li, Dongxiao Wang & Xia Zhang

  3. Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Ge Wen

  4. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China

    Hongbing Cai

  5. Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China

    Xingmei Zhang

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  1. Yingjia Li
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  2. Ge Wen
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  4. Xia Zhang
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  10. Ying Wang
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Correspondence to Ying Wang.

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Li, Y., Wen, G., Wang, D. et al. A Complementary Strategy for Enhancement of Nanoparticle Intracellular Uptake. Pharm Res 31, 2054–2064 (2014). https://doi.org/10.1007/s11095-014-1307-5

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  • DOI: https://doi.org/10.1007/s11095-014-1307-5

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