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Biodegradable Polymer-Curcumin Conjugate Micelles Enhance the Loading and Delivery of Low-Potency Curcumin

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ABSTRACT

Purpose

To utilize a novel type of polymer-drug conjugate micelle to enhance the delivery of low-potency curcumin.

Methods

Multiple curcumin molecules were conjugated to poly(lactic acid) (PLA) via tris(hydroxymethyl)aminomethane (Tris) linker producing the hydrophobic drug-binding block; methoxy-poly(ethylene glycol) (mPEG) was employed as the hydrophilic block. Micelles were characterized by size, loading capacity, stability, and critical micelle concentration (CMC). Human hepatocellular carcinoma (HepG2) cells were employed to assess cytotoxicity and intracellular targeting ability of micelles.

Results

mPEG-PLA-Tris-Cur micelles were within nanorange (<100 nm). CMC of such micelles (2.3 ± 0.4 μg/mL) was 10 times lower than mPEG-PLA micelles (27.4 ± 0.8 μg/mL). Curcumin loading in mPEG-PLA-Tris-Cur micelles reached 18.5 ± 1.3% (w/w), compared to traditional mPEG-PLA micelles at 3.6 ± 0.4% (w/w). IC50 of mPEG-PLA-Tris-Cur micelles (~22 μg/mL at curcumin-equivalent dose) was similar to unmodified curcumin. Placebo and drug-encapsulated conjugate micelles could be efficiently internalized to cytoplasmic compartment of HepG2 cells.

Conclusions

Micelle-forming polymer-drug conjugates containing multiple drug molecules were an efficient means to increase loading and intracellular delivery of low-potency curcumin.

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Abbreviations

CLSM:

confocal laser scanning microscope

CMC:

critical micelle concentration

Cur:

curcumin

Cur-GA:

mono-carboxyl-terminated curcumin

DCC:

dicyclohexylcarbodiimide

DMAP:

4-dimethylamino pyridine

DMEM:

Dulbecco’s modification of eagle’s medium

DMF:

N,N-dimethylformamide

EPR:

enhanced permeability and retention effect

GA:

gluraric anhydride

GRAS:

generally regarded as safe

HepG2:

human hepatocellular carcinoma cells

HPLC:

high performance liquid chromatography

mPEG:

methoxy-poly(ethylene glycol)

MPS:

mononuclear phagocyte system

MWCO:

molecular weight cut-off

NHS:

N-hydroxy succinimide

NMR:

nuclear magnetic resonance

PCL:

polycaprolactone

PLA:

poly(lactic acid)

RBC:

red blood cells

THF:

tetrahydrofuran

Tris:

tris(hydroxymethyl)aminomethane

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Acknowledgments and Disclosures

This work was supported by Tianjin Research Program of Application Foundation and Advanced Technology (11JCZDJC20600; 11JCYBJC10300), National Natural Science Foundation of China (81171478; 31100699), and the Research Fund for the Doctoral Program of Higher Education of China (20110032120077).

The authors of this article have no conflicts of interest to declare.

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Authors and Affiliations

  1. Tianjin Key Laboratory for Modern Drug Delivery & High Efficiency School of Pharmaceutical Science & Technology, Tianjin University, 92 Weijin Rd., Nankai District,, Tianjin, 300072, China

    Rulei Yang, Xuli Gao, Yanjun Zhao & Zheng Wang

  2. Institute of Biomedical Engineering, Chinese Academy of Medical Sciences Peking Union Medical College, Tianjin, 300192, China

    Suai Zhang & Deling Kong

  3. Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Science, Nankai University, Tianjin, 300071, China

    Deling Kong

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  1. Rulei Yang
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  2. Suai Zhang
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  3. Deling Kong
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  4. Xuli Gao
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  5. Yanjun Zhao
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  6. Zheng Wang
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Corresponding authors

Correspondence to Yanjun Zhao or Zheng Wang.

Electronic supplementary material

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Esm 1

1H NMR spectra of mPEG-PLA, mPEG-PLA-COOH, and mPEG-PLA-Tris. (TIFF 4019 kb)

Esm 2

1H NMR spectra of Cur-GA, 821. (TIFF 183 kb)

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Yang, R., Zhang, S., Kong, D. et al. Biodegradable Polymer-Curcumin Conjugate Micelles Enhance the Loading and Delivery of Low-Potency Curcumin. Pharm Res 29, 3512–3525 (2012). https://doi.org/10.1007/s11095-012-0848-8

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  • DOI: https://doi.org/10.1007/s11095-012-0848-8

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