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International Journal of Nanomedicine Volume 10, 2015 - Issue
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Original Research

Novel lactoferrin-conjugated amphiphilic poly(aminoethyl ethylene phosphate)/poly(L-lactide) copolymer nanobubbles for tumor-targeting ultrasonic imaging

Binhua Luo1 College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, People’s Republic of China;2 College of Pharmacy, Hubei University of Science and Technology, Xianning, People’s Republic of China
,
Huageng Liang3 Department of Urology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
,
Shengwei Zhang3 Department of Urology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
,
Xiaojuan Qin4 Department of Medical Ultrasound, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
,
Xuhan Liu1 College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
,
Wei Liu1 College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, People’s Republic of China;5 National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence[email protected]
,
Fuqing Zeng3 Department of Urology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
,
Yun Wu6 Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, USA
&
Xiangliang Yang1 College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, People’s Republic of China;5 National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
 show all
Pages 5805-5817 | Published online: 16 Sep 2015

Figures & data

Figure 1 Proton nuclear magnetic resonance spectra (in CDCl3, ppm) of (A) poly(L-lactide), (B) EABoc, (C) 2-N-(t-butoxycarbonyl) ethanolamine-2-oxo-1,3, 2-dioxaphospholane, and (D) poly(aminoethyl ethylene phosphate)/poly(L-lactide) copolymer.

Figure 1 Proton nuclear magnetic resonance spectra (in CDCl3, ppm) of (A) poly(L-lactide), (B) EABoc, (C) 2-N-(t-butoxycarbonyl) ethanolamine-2-oxo-1,3, 2-dioxaphospholane, and (D) poly(aminoethyl ethylene phosphate)/poly(L-lactide) copolymer.

Figure 2 Synthesis procedure of PAEEP-PLLA copolymer.

Abbreviation: PAEEP-PLA, poly(aminoethyl ethylene phosphate)/poly(L-lactide).

Figure 2 Synthesis procedure of PAEEP-PLLA copolymer.Abbreviation: PAEEP-PLA, poly(aminoethyl ethylene phosphate)/poly(L-lactide).

Figure 3 Differential scanning calorimetry (DSC) curve of poly(aminoethyl ethylene phosphate)/poly(L-lactide) copolymer.

Abbreviations: Cp, heat capacity; Tg, glass-transition temperature.

Figure 3 Differential scanning calorimetry (DSC) curve of poly(aminoethyl ethylene phosphate)/poly(L-lactide) copolymer.Abbreviations: Cp, heat capacity; Tg, glass-transition temperature.

Figure 4 Conjugation of lactoferrin onto the nanobubbles through polyethylene glycol spacers.

Figure 4 Conjugation of lactoferrin onto the nanobubbles through polyethylene glycol spacers.

Figure 5 Polyacrylamide gel electrophoresis analysis.

Notes: (A) Poly(aminoethyl ethylene phosphate)/poly(L-lactide) (PAEEP-PLLA) nanobubbles (NBs), (B) free lactoferrin (Lf), (C, D) Lf-conjugated PAEEP-PLLA NBs, and (E) a mixture of free Lf and PAEEP-PLLA NBs.

Figure 5 Polyacrylamide gel electrophoresis analysis.Notes: (A) Poly(aminoethyl ethylene phosphate)/poly(L-lactide) (PAEEP-PLLA) nanobubbles (NBs), (B) free lactoferrin (Lf), (C, D) Lf-conjugated PAEEP-PLLA NBs, and (E) a mixture of free Lf and PAEEP-PLLA NBs.

Figure 6 Fourier transform infrared spectra of lactoferrin-conjugated poly(aminoethyl ethylene phosphate)/poly(L-lactide) (Lf-PAEEP-PLLA) and poly(aminoethyl ethylene phosphate)/poly(L-lactide) (PAEEP-PLLA) copolymer.

Note: The red arrows demonstrate the successful conjugation of Lf to NBs.

Abbreviations: Lf, lactoferrin; NBs, nanobubbles.

Figure 6 Fourier transform infrared spectra of lactoferrin-conjugated poly(aminoethyl ethylene phosphate)/poly(L-lactide) (Lf-PAEEP-PLLA) and poly(aminoethyl ethylene phosphate)/poly(L-lactide) (PAEEP-PLLA) copolymer.Note: The red arrows demonstrate the successful conjugation of Lf to NBs.Abbreviations: Lf, lactoferrin; NBs, nanobubbles.

Figure 7 Characterization of lactoferrin-conjugated poly(aminoethyl ethylene phosphate)/poly(L-lactide) nanobubbles: (A) appearance, (B) size distribution, and (C) transmission electron microscopy images.

Figure 7 Characterization of lactoferrin-conjugated poly(aminoethyl ethylene phosphate)/poly(L-lactide) nanobubbles: (A) appearance, (B) size distribution, and (C) transmission electron microscopy images.

Figure 8 Effect of lactoferrin on the cellular uptake: (A) uptake curves of rat C6 glioma cells, (B) uptake curves of human umbilical vein endothelial cells.

Note: Data are reported as mean ± standard deviation (n=3).

Abbreviations: Lf-PAEEP-PLA, lactoferrin-conjugated poly(aminoethyl ethylene phosphate)/poly(L-lactide); PAEEP-PLA, poly(aminoethyl ethylene phosphate)/poly(L-lactide); MFI, mean fluorescence intensity.

Figure 8 Effect of lactoferrin on the cellular uptake: (A) uptake curves of rat C6 glioma cells, (B) uptake curves of human umbilical vein endothelial cells.Note: Data are reported as mean ± standard deviation (n=3).Abbreviations: Lf-PAEEP-PLA, lactoferrin-conjugated poly(aminoethyl ethylene phosphate)/poly(L-lactide); PAEEP-PLA, poly(aminoethyl ethylene phosphate)/poly(L-lactide); MFI, mean fluorescence intensity.

Figure 9 In vitro ultrasonic images of lactoferrin-conjugated poly(aminoethyl ethylene phosphate)/poly(L-lactide) nanobubbles in agarose mold.

Note: The temperature was increased from 20°C to 38°C in 2°C intervals.

Figure 9 In vitro ultrasonic images of lactoferrin-conjugated poly(aminoethyl ethylene phosphate)/poly(L-lactide) nanobubbles in agarose mold.Note: The temperature was increased from 20°C to 38°C in 2°C intervals.

Figure 10 Representative in vitro ultrasonic images.

Notes: (A) The nanobubbles under high-frequency diagnostic ultrasound in agarose mold. (B) Pre-destroyed and (C) post-destroyed of the nanobubbles upon high frequency ultrasound exposure.

Figure 10 Representative in vitro ultrasonic images.Notes: (A) The nanobubbles under high-frequency diagnostic ultrasound in agarose mold. (B) Pre-destroyed and (C) post-destroyed of the nanobubbles upon high frequency ultrasound exposure.

Figure 11 Ultrasound images of subcutaneous tumors (red circles) in BALB/c nude mice.

Notes: (A) 0 second, (B) 30 seconds, (C) 10 minutes, and (D) 120 minutes after injection of lactoferrin-conjugated poly(aminoethyl ethylene phosphate)/poly(L-lactide) nanobubbles.

Figure 11 Ultrasound images of subcutaneous tumors (red circles) in BALB/c nude mice.Notes: (A) 0 second, (B) 30 seconds, (C) 10 minutes, and (D) 120 minutes after injection of lactoferrin-conjugated poly(aminoethyl ethylene phosphate)/poly(L-lactide) nanobubbles.

Figure 12 Ultrasound images of subcutaneous tumors (red circles) in BALB/c nude mice after injection of (A) SonoVue® and (B) lactoferrin-conjugated poly(aminoethyl ethylene phosphate)/poly(L-lactide) nanobubbles.

Figure 12 Ultrasound images of subcutaneous tumors (red circles) in BALB/c nude mice after injection of (A) SonoVue® and (B) lactoferrin-conjugated poly(aminoethyl ethylene phosphate)/poly(L-lactide) nanobubbles.

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