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Targeted Paclitaxel Delivery to Tumors Using Cleavable PEG-Conjugated Solid Lipid Nanoparticles

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Abstract

Purpose

To develop a tumor-targeted drug delivery system based on solid lipid nanoparticles (SLNs) conjugated with the enzymatically cleavable polyethylene glycol (PEG).

Methods

SLNs loaded with paclitaxel (PTX) were prepared using the film ultrasonication method, followed by conjugation with a PEGylated peptide (Pp) that can specifically interact with matrix metalloproteinases (MMPs) that is over-expressed by tumor cells. The physicochemical characteristics of the Pp-PTX-SLNs were studied and the in vitro drug release, cytotoxicity and cell uptake of the formulations were investigated. Furthermore, using an animal model, the pharmacokinetic properties, biodistribution and anti-tumor activity of this system were evaluated.

Results

The resulting Pp-PTX-SLNs penetrated through tumor cells via facilitated uptake mediated by MMPs. The uncleavable Pp’-PTX-SLNs showed a lower cell uptake efficiency, compared with the Pp-PTX-SLNs. In a tumor-bearing mice model, Pp-PTX-SLNs accumulated to a greater extent at the tumor location, persisted longer in blood circulation, and showed lower toxicity than did PTX-SLNs or Taxol®. Most importantly, the mice treated with Pp-PTX-SLNs survived longer than the groups treated with Pp’-PTX-SLNs, PTX-SLNs or Taxol®.

Conclusions

These results suggest that Pp-PTX-SLNs hold promise as a new strategy for paclitaxel chemotherapy, and that Pp-SLNs can be a useful nanocarrier for other chemotherapeutic drugs.

Shielding the SLN with PEG2000-Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln-Cys prolongs its circulation time in blood. Cleavage of the PEG chain by tumor-secreted MMPs leads to paclitaxel uptake by target tumor cells. This SLN modification offers a new strategy for paclitaxel chemotherapy.

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Abbreviations

CE:

Conjugation efficiency

CHO cells:

Chinese hamster ovary cells

DL%:

Drug loading

EE%:

Encapsulation efficiency

EPR:

Enhanced permeability and retention

GMS:

Glyceryl monostearate

HT1080 cells:

Human fibrosarcoma cells

LLC cells:

Lewis lung carcinoma cells

MCT:

Medium-chain triglycerides

MMP:

Matrix metalloproteinase

OA:

Octadecylamine

PEG:

Polyethylene glycol

Pp:

PEG2000-MMP substrate peptide (PEG2000-Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln-Cys)

Pp’:

PEG2000-Ile-Pro-Gly-Gln-Gly-Ala-Leu-Gly-Cys

PTX:

Paclitaxel

RES:

Reticuloendothelial system

SLNs:

Solid lipid nanoparticles

SPC:

Soya phosphatidyl choline

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ACKNOWLEDGMENTS AND DISCLOSURES

Jie Zheng and Yu Wan contributed equally to this work. We are grateful for financial support from the University of Central Lancashire, the National Natural Science Foundation of China (No. 81173011) and the National Science & Technology Major Project of China (No. 2011ZX09401-304(4-3)).

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Authors and Affiliations

  1. Key Laboratory of Drug Targeting and Drug Delivery Systems Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China

    Jie Zheng, Yu Wan, Zhirong Zhang & Xun Sun

  2. Institute of Nanotechnology and Bioengineering School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, PR1 2HE, UK

    Abdelbary Elhissi

  3. West China School of Pharmacy, Sichuan University, Chengdu, 610041, China

    Xun Sun

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  1. Jie Zheng
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  2. Yu Wan
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  4. Zhirong Zhang
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Correspondence to Xun Sun.

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Zheng, J., Wan, Y., Elhissi, A. et al. Targeted Paclitaxel Delivery to Tumors Using Cleavable PEG-Conjugated Solid Lipid Nanoparticles. Pharm Res 31, 2220–2233 (2014). https://doi.org/10.1007/s11095-014-1320-8

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