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The Targeting Behavior of Folate-Nanohydrogel Evaluated by Near Infrared Imaging System in Tumor-Bearing Mouse Model

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Abstract

Purpose

To synthesize P[(Folate-Allylamine)-co-(N-isopropylacrylamine)- co-Acrylamide] (P(FoAAn-co-NIPA-AAm), folate-NHG) with appropriate diameter and lower critical solution temperature (LCST) for targeting to folate receptor (FR) expressing tumors.

Methods

Folate-NHG was synthesized by free-radical precipitation polymerization method reported in our previous work and other reports. LCST, diameter and morphology of folate-NHG were characterized by UV-vis spectrophotometer, laser particle size analyzer (LPSA) and transmission electron microscope (TEM), respectively. No.12 near infrared dye (NIRD-12) was entrapped into folate-NHG by hydrophobic association to trace the in vivo dynamic behavior of folate-NHG. This process was evaluated by a homemade near infrared (NIR) imaging system.

Results

Spherical folate-NHG with diameter of about 50 nm and LCST of about 40°C was successfully synthesized. The photo stability of NIRD-12 was strengthened after being entrapped into folate-NHG, which enabled NIRD-12 to better trace the in vivo dynamic process of folate-NHG. Folate-NHG showed good targeting capability for all three folate receptor expressing tumor models (SMMC-7721, Bel-7402 and HeLa) with different sizes, and this accumulation could last for more than 96 h. D-folate-NHG, synthesized with double amount of FoAAn, showed better targeting effect for SMMC-7721 tumor model than that of folate-NHG.

Conclusions

Folate-NHG could actively accumulate in three models of folate receptor positive tumors with different sizes and keep retention for more than 96 h, which enables it to be used as a diagnostic reagent or anti-tumor drug carrier for tumor therapy.

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Abbreviations

AAm:

Acrylamide

AAn:

Allylamine

BIS:

N,N-methylene-bis-acrylamide

CCD:

charge-coupled device

CT:

computed tomography

DCC:

N, N’-Dicyclohexylcarbodiimide

DCU:

dicyclohexylurea

D-folate-NHG:

special folate-NHG synthesized with as double amount of FoAAn as that of folate-NHG

DMSO:

dimethyl sulfoxide

FBP:

folate binding protein

FoAAn:

folate-Allylamine

folate-NHG or P(FoAAn-co-NIPA-co-AAm):

P[(Folate-Allylamine)-co-(N-isopropylacrylamide)-co-Acrylamide]

FR:

folate receptor

KPS:

Potassium persulfate

LC:

loading content

LC-MS:

liquid chromatograph-mass spectrum

LCST:

lower critical solution temperature

LPSA:

laser particle size analyzer

MR:

magnetic resonance

MTT:

methyl thiazolyl tetrazolium

NHG:

nanohydrogel

NHS:

N-hydroxysuccinimide

NIPA:

N-isopropylacryl-amide

NIR:

near infrared

NIRD-12:

No.12 near infrared dye

non-NHG:

P[(N-isopropylacrylamide)-co-Acrylamide]

PNIPA:

P(N-isopropylacrylamide)

ROI:

region of interest

RPMI:

Roswell Park Memorial Institute

RT:

room temperature

SBF:

simulated body fluid

SDS:

sodiumdodecyl sulfate

TEA:

triethanolamine

TEM:

transmission electron microscope

US:

ultrasonography

Wt%:

((WAAm/WNIPA) × 100%)

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Acknowledgements

This research was funded by the Natural Science Foundation Committee of China (NSFC30371362, NSFC30672015, NSFC30700779). We thank Dr. Shuaijian Ni for MS resolution.

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Authors and Affiliations

  1. Department of Biomedical Engineering, School of Life Science and Technology, China Pharmaceutical University, Tongjia Lane No. 24, Nanjing, 210009, People’s Republic of China

    Jian Zhang, Dawei Deng, Fei Liu, Xinyang Chen, Lianxiao An & Yueqing Gu

  2. Department of Biomedical Engineering, School of Automation, Nanjing University of Aeronautics and Astronauticss, Nanjing, 210016, People’s Republic of China

    Zhiyu Qian

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  1. Jian Zhang
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  2. Dawei Deng
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  3. Zhiyu Qian
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Correspondence to Yueqing Gu.

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Zhang, J., Deng, D., Qian, Z. et al. The Targeting Behavior of Folate-Nanohydrogel Evaluated by Near Infrared Imaging System in Tumor-Bearing Mouse Model. Pharm Res 27, 46–55 (2010). https://doi.org/10.1007/s11095-009-0005-1

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