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Reduction-responsive Crosslinked Micellar Nanoassemblies for Tumor-targeted Drug Delivery

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Abstract

Purpose

The purpose of the study was to devise and evaluate crosslinked nanoassemblies to achieve enhanced drug delivery to tumors.

Methods

A novel copolymer comprised of polyethylene glycol 5000 (PEG114), Vitamin E (VE) and thioctic acid (TA) with a molar ratio of PEG114:VE:TA at 1:4:4 was synthesized. The resulting PEG114-VE4-TA4 copolymer self-assembled into micelles, which formed polydisulfide crosslinks catalyzed by dithiothreitol. Employing paclitaxel as a model drug, the crosslinked PEG114-VE4-TA4 micelles were characterized for the physicochemical and biological properties. The pharmacokinetics and anticancer efficacy of paclitaxel-loaded crosslinked PEG114-VE4-TA4 micelles were assessed in a human ovarian cancer xenograft murine model.

Results

The crosslinked PEG114-VE4-TA4 micelles demonstrated markedly improved thermodynamic and kinetic stability. The disulfide crosslinks were responsive to the intracellular level of glutathione, which caused rapid disassembly of the micelles and accelerated drug release. Intravenous administration of paclitaxel-loaded crosslinked PEG114-VE4-TA4 micelles yielded approximately 3-fold and 5-fold higher plasma concentration than the non-crosslinked micelles and Taxol®, respectively, leading to increased drug accumulation in the tumor. Importantly, paclitaxel-loaded crosslinked micelles exerted superior tumor growth repression compared to the non-crosslinked counterparts and Taxol®.

Conclusions

These results suggest that the crosslinked PEG114-VE4-TA4 nanocarrier system is a promising platform for the delivery of hydrophobic anticancer agents.

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Abbreviations

B-CMs:

Blank crosslinked micelles

B-NCMs:

Blank non-crosslinked micelles

CMC:

Critical micelle concentration

DiD:

1,10-dioctadecyl-3,3,30,30-tetramethylindodicarbocyanine perchlorate

DiI:

1,1’-dioctadecyl-3,3,3’,3’-tetramethylindocarbocyanine perchlorate

DiO:

3,3’-dioctadecyloxacarbocyanine perchlorate

DLS:

Dynamic light scattering

DP-CMs:

DiD/paclitaxel-dual loaded crosslinked micelles

DP-NCMs:

DiD/paclitaxel-dual loaded non-crosslinked micelles

DTT:

Dithiothreitol

EPR:

Enhanced permeability and retention

FRET:

Fluorescence energy transfer

GSH:

Glutathione

H&E:

Hematoxylin and eosin

NIR:

Near Infrared

P-CMs:

Paclitaxel-loaded crosslinked micelles

PCNA:

Proliferating cell nuclear antigen

P-NCMs:

Paclitaxel-loaded non-crosslinked micelles

SDS:

Sodium dodecyl sulfate

TA:

Thioctic acid

TEM:

Transmission electron microscopy

VE:

Vitamin E

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by the National Institutes of Health grant R15 CA152860 to C.T.

Wei Fan and Yingzhe Wang contributed equally to the work.

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Authors and Affiliations

  1. Cancer Nanomedicine Laboratory Department of Pharmaceutical Sciences, Mercer University College of Pharmacy, 3001 Mercer University Drive, Atlanta, Georgia, 30341, USA

    Wei Fan, Yingzhe Wang, Xin Dai, DeAngelo Mckinley & Chalet Tan

  2. School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu, 210093, China

    Lei Shi

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  1. Wei Fan
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  2. Yingzhe Wang
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  3. Xin Dai
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Correspondence to Chalet Tan.

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Fan, W., Wang, Y., Dai, X. et al. Reduction-responsive Crosslinked Micellar Nanoassemblies for Tumor-targeted Drug Delivery. Pharm Res 32, 1325–1340 (2015). https://doi.org/10.1007/s11095-014-1537-6

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  • DOI: https://doi.org/10.1007/s11095-014-1537-6

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