ACHMAD Arifudin¹, 山口 藍子², 宮﨑 将也¹, 中島 崇仁³, HUDA Miftakhul⁴, 保坂 純男⁴, 対馬 義人¹

Arifudin ACHMAD¹, Aiko YAMAGUCHI², Masaya MIYAZAKI¹, Takahito NAKAJIMA³, Miftakhul HUDA⁴, Sumio HOSAKA⁴, Yoshito TSUSHIMA¹

¹群馬大学大学院医学系研究科放射線診断核医学, ²群馬大学大学院医学系研究科バイオイメージング情報解析学, ³群馬大学大学院医学系研究科分子画像学, ⁴群馬大学理工学部電子情報理工学科

¹Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, ²Bioimaging Information Analysis, Gunma University Graduate School of Medicine, ³Molecular Imaging, Gunma University Graduate School of Medicine, ⁴Electronics and Informatics, Gunma University School of Science and Technology

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【Purpose】
Direct targeting of solid tumor with microbubble ultrasound（US）contrast agents（UCA）is limited by their size, short half-life and non-targeted properties. Liquid perfluorooctyl bromide（PFOB）has known for its echogenicity. Long-life and stable polymer-based PFOB nanobubbles with targeting moiety might seep immature tumor blood vessel to reach tumor cells.
【Methods】
PEG-PLGA and biotin-PEG-PLGA polymers were synthesized with PFOB to produce PFOB NB. Cetuximab was coupled to PFOB NB to form CTX PFOB NB. Characterization was performed using DLS method, 19F-NMR spectroscopy, electron microscopy and US studies. Tumor specificity was evaluated in cell uptake study with EGFR+ MDA-MB-231 breast cancer cells. Echogenicity of PFOB NB was demonstrated by US phantom study, and in comparison with solid PEG-PLGA nanoparticles（NP）. In vivo echogenicity of PFOB was evaluated by US study on ddY mice i.v. injected with 0.3 mL 50 mg/mL PFOB NB, in comparison with 0.1 mL Sonazoid^®.
【Results】
Mean particle sizes, zeta potentials and polydispersity indexes of PFOB NB and CTX PFOB NB were 156.3±2.0 nm, -6.61 mV, and 0.05; and 241.1±4.7 nm, -47.0 mV and 0.30. PFOB is encapsulated in the final product. Bubble morphology with intact surface was shown with corresponding size, thickness-to-radius ratio was between 0.26 to 0.36. Accumulation of plain PFOB NB provide significantly brighter enhancement compared to NP. CTX PFOB NB was accumulated in cytoplasms of EGFR-expressing cancer cells. Plain PFOB NB enhances inferior vena cava and large vessels of the liver mice at 0.2 MI.
Consideration: In high concentration, PFOB NB showed echogenicity similar to Sonazoid^®. In vivo studies for CTX PFOB NB accumulation and echogenicity in EGFR-expressing tumor are ongoing.
【Conclusion】
The development of CTX PFOB NB as an intratumor-specific UCA is now in progress. Its precursor, PFOB NB showed in vivo potentials for UCA, while CTX PFOB NB itself showed its tumor specificity in EGFR+ cancer cells.