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Long-circulating and target-specific distributions of cyanine 5.5-labeled hyaluronic acid nanoparticles in mouse organs during 28 days after a single administration

  • Yun, Tae Sik (College of Veterinary Medicine and Veterinary Medical Center, Chungbuk National University) ;
  • Lin, Chunmei (College of Chinese Medicinal Materials, Jilin Agricultural University) ;
  • Yon, Jung-Min (College of Veterinary Medicine and Veterinary Medical Center, Chungbuk National University) ;
  • Park, Seul Gi (College of Veterinary Medicine and Veterinary Medical Center, Chungbuk National University) ;
  • Gwon, Lee Wha (College of Veterinary Medicine and Veterinary Medical Center, Chungbuk National University) ;
  • Lee, Jong-Geol (College of Veterinary Medicine and Veterinary Medical Center, Chungbuk National University) ;
  • Baek, In-Jeoung (Asan Institute for Life Sciences, University of Ulsan College of Medicine) ;
  • Nahm, Sang-Seop (College of Veterinary Medicine, Konkuk University) ;
  • Lee, Beom Jun (College of Veterinary Medicine and Veterinary Medical Center, Chungbuk National University) ;
  • Yun, Young Won (College of Veterinary Medicine and Veterinary Medical Center, Chungbuk National University) ;
  • Nam, Sang-Yoon (College of Veterinary Medicine and Veterinary Medical Center, Chungbuk National University)
  • Received : 2018.10.06
  • Accepted : 2018.12.10
  • Published : 2018.12.31

Abstract

Although hyaluronic acid (HA) has been developed as a nanoparticle (NP; 320-400 nm) for a drug delivery system, the tissue targeting efficacy and the pharmacokinetics of HA-NPs are not yet fully understood. After a dose of 5 mg/kg of cyanine 5.5-labeled HA-NPs or HA-polymers was intravenously administrated into mice, the fluorescence was measured from 0.5 h to 28 days. The HA-NPs fluorescence was generally stronger than that of HA-polymers, which was maintained at a high level over 7 days in vivo, after which it gradually decreased. Upon ex vivo imaging, liver, spleen, kidney, lung, testis and sublingual gland fluorescences were much higher than that of other organs. The fluorescence of HA-NPs in the liver, spleen and kidney was highest at 30 min, where it was generally maintained until 4 h, while it drastically decreased at 1 day. However, the fluorescence in the liver and spleen increased sharply at 7 days relative to 3 days, then decreased drastically at 14 days. Conversely, the fluorescence of HA-polymers in the lymph node was higher than that of HA-NPs. The results presented herein may have important clinical implications regarding the safety of as self-assembled HA-NPs, which can be widely used in biomedical applications.

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Fig. 1. In vivo fluorescence images of Cy5.5-labeled HA-NPs (A) and Cy5.5-labeled HA-polymers (B) in the whole body (n = 6) at 0.5 h, 2 h, 4 h, 1 day (d), 3 d, 7 d, 14 d, and 28 d. Tail vein injection of Cy5.5-labeled HA-NPs or HA-polymers (5 mg/kg) in normal hairless mouse. The fluorescence of HA-NPs was much stronger than that of HA-polymers and was maintained longer within the experimental period relative to HA-polymers. The liver and urinary bladder were the main organs that showed strong fluorescence in both groups. Becoming yellow indicates a higher intensity of fluorescence at 680 nm. Normal, untreated mice.

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Fig. 2. Ex vivo fluorescence images of Cy5.5-labeled HA-NPs (A) and Cy5.5-labeled HA-polymers (B) in different organs (brain, thymus, sublingual gland, heart, lung, liver, spleen, kidney, adrenal gland, testis and epididymis; n = 6) at 0.5 h, 2 h, 4 h, 1 d, 3 d, 7 d, 14 d, and 28 d. Tail vein injection of Cy5.5-labeled HA-NPs or HA-polymers (5 mg/kg) in normal ICR mice. Generally, the overall fluorescence of HA-NPs was stronger than that of HA-polymers and was maintained longer during the experimental period. The liver, spleen, kidney and lung were the main organs that showed strong fluorescence in both groups. Becoming yellow indicates a higher intensity of fluorescence at 680 nm. 1, brain; 2, sublingual glands; 3, thymus; 4, heart; 5, lung; 6, stomach; 7, liver; 8, spleen; 9, adrenal glands; 10, kidneys; 11, testes; 12, epididymes.

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Fig. 3. Fluorescence intensity (106 photons/sec/cm2) of total organs from 0.5 h to 28 d after injection of 0.5 mg/kg of Cy5.5-labeled HA-NPs (A) or Cy5.5-labeled HA-polymers (B). The main organs that showed a high intensity of fluorescence were the liver, lung, spleen, kidney, testis and sublingual gland in both groups. Generally, the intensity of fluorescence peaked within 4 h, then decreased gradually with time. The intensity of Cy5.5-labeled HA-NPs (A) was much stronger than that of Cy5.5-labeled HA-polymers (B). Data are expressed as the means ± SE (n = 6).

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Fig. 4. Fluorescence intensity (106 photons/sec/cm2) in the liver (A), spleen (B), kidney (C), lung (D), testis (E) and lymph node (F) from 0.5 h to 28 d after injection of 0.5 mg/kg of Cy5.5-labeled HA-NPs or Cy5.5-labeled HA-polymers. The intensities of Cy5.5-labeled HA-NPs were much stronger level than those of Cy5.5-labeled HA-polymers. Generally, the intensity of fluorescence peaked within 4 h, then decreased gradually thereafter. However, the lymph node showed more powerful intensities of fluorescence in HApolymers within the experimental period than HA-NPs. ap < 0.05 between HA-NPs and HA-polymers. b,cp < 0.05 compared with the intensity of 0.5 h. Data are expressed as the means ± SE (n = 6).

Acknowledgement

Supported by : National Research Foundation of Korea (NRF)

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