Sonodynamic Therapy Using Protoporphyrin IX Conjugated to Gold Nanoparticles: An In Vivo Study on a Colon Tumor Model

Document Type: Original Article


1 Department of Medical Physics and Medical Engineering, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

2 Research Centre and Department of Medical Physics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

3 Skin Research Centre and Department of Pathology, Emam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran

4 Department of Chemistry, School of Science, Ferdowsi University of Mashhad, Mashhad, Iran

5 Pharmaceutical Research Centre, School of Pharmacy, Mashhad University of Medical Sciences, Vakilabad Blvd., School of Pharmacy, Mashhad, Iran

6 Department of Community Medicine &Public Health, School of Health, Mashhad University of Medical Sciences, Mashhad, Iran


Sonodynamic therapy is a physical treatment which utilizes ultrasound waves with an appropriate sensitizer such as protoporphyrin IX (PpIX). The activation of sensitizer depends on cavitation, and therefore, high intensity ultrasound is an important necessity. Beside, high intensity ultrasound can induce side effects on the healthy tissues which have surrounded tumor. The particles in a liquid decrease the ultrasonic intensity threshold needed for onset of cavitation. The non-radiative relaxation time of PpIX in the presence of gold nanoparticles (GNP) is longer than the similar time without GNP.
Materials and Methods
This study was conducted on colon carcinoma tumor in BALB/c mice. The tumors were induced by subcutaneous injection of CT26 cells. Ultrasound irradiation were performed on tumors 24 hr after the injection of PpIX into GNPs. Antitumor effects were estimated by measuring tumor relative volume, doubling time and time being five times of the tumors and by calculating the average survival time of tumor-bearing mice after treatment.
There is no inhibitory effect in control group. Ultrasound irradiation alone showed a slight antitumor effect which was enhanced by ultrasound plus PpIX (SDT). The synergistic inhibitory effect was significant when ultrasound plus PpIX was conjugated to GNPs.
Our experiments suggested a significant synergistic effect of ultrasound combined with Au-PpIX that reduced tumor relative volume and increased average animal survival fraction. This effect was obviously stronger than ultrasound alone and synergistic effect of ultrasound combined with PpIX.


1. Kuroki M, Hachimine K, Abe H, Shibaguchi H., Maekawa S, Yanagisawa J, et al. Sonodynamic therapy of cancer using novel sonosensitizers. Anticancer Res 2005; 27:3673-3677.

2. Tang W, Liu Q, Wang X, Zhang J, Wang P, Mi N. Ultrasound exposure in the presence of hematoporphyrin induced loss of membrane integral proteins and inactivity of cell proliferation associated enzymes in sarcoma 180 cells in vitro. Ultrason Sonochem 2008; 15:747-757.

3. Jin ZH, Miyoshi N,  Ishiguro K, Umemura S, Kawabata K, Yumita N, et al. Combination effect of photodynamic and sonodynamic therapy on experimental skin squamous cell carcinoma in C3H/HeN mice. J Dermatol 2000; 27:294-306.

4. Liu Q, Wang X, Wang P, Xiao L. Sonodynamic antitumor effect of protoporphyrin IX disodium salt on S180 solid tumor. Chemother 2007; 53:429-436.

5. Suzuki N, Okada S, Chida S, Komori C, ShimadaY, Suzuki T. Antitumor effect of acridine orange under ultrasonic irradiation in vitro. Anticancer Res 2007; 27:4179-4184.

6. Liu Q, Wang X, Wang P, Xiao L, Hao Q. Comparison between sonodynamic effect with protoporphyrin IX and hematoporphyrin on sarcoma 180. Cancer Chemother Pharmacol 2007; 60:671-680.

7. Yamashita Y, Kai Y, Shirakusa T. Clinical use of photodynamic therapy for patients with cancer. Int. Cong Ser 2004; 1274:169-174.

8. Clement GT. Perspectives in clinical uses of high intensity focused ultrasound. Ultrasonic 2004; 42:1087-1093.

9. Tuziuti T, Yasui K, Sivakumar M, Iida Y, Miyoshi N. Correlation between cavitation noise and yield enhancement of sonochemical reaction by particle addition. J Phys Chem 2005; 109:4869-4872.

10. Huang X, Jain PK, El-Sayed IH, El-Sayed MA. Plasmonic photothermal therapy (PPTT) using gold nanopaticles. Lasers Med Sci 2008; 23:217-228.

11. Paciotti GF, Myer L, Weinreich D, Goia D, Pavel N, McLaughlin RE. Colloidal gold: a novel nanoparticles vector for tumor directed drug delivery. Drug Deliv 2004; 11:169-183.

12. Perez JLJ, Orea AC, Gallegos ER, Fuentes RG. Photoacoustic Spectroscopy to determine in vitro the non radiative relaxation time of porotoporphyrin IX solution containing gold metallic nanoparticles. Eur Phys J-Spec Top 2008; 152:353-356.

13. Eshghi H, Attaran N, Sazgarnia A, Mirzaie N, Shanei A. Synthesis and Characterization of New Designed Protoporphyrin-Stabillized Gold Nanoparticles for Cancer Cells Nanotechnology-Based Targeting. Int. J. Nanotechnol. 2011; 8: 700-711.

14. Li B, Moriyama H, Li F, Jarvi M, Allen C, Wilson B. Diblock copolymer micelles deliver hydrophobic protoporphyrin IX for photodynamic therapy. Photochem Photobiol 2007; 83:1505-1512.

15. Kim KH, Kim JK, Lee DH. Sonodynamic induced antitumor effect of radachlorin on solid tumor. Current Applied Physics 2010; 9:1-5.

16. Yumita N, Okuyama N, Sasaki K, Umemura S. Sonodynamic therapy on chemically induced mammary tumor: pharmacokinetics, tissue distribution and sonodynamically induced antitumor effect of gallium-porphyrin complex ATX-70. Cancer Chemther Pharmacol 2007; 60:891-897.

17. Milowska K. Ultrasound mechanisms of action and application in sonodynamic therapy. Postepy Hig Med Dosw 2007; 1:338-349.

18. Huang X, Jain PK, El-Sayed IH, El-Sayed MA. Plasmonic photothermal therapy (PPTT) using gold nanopaticles. Lasers Med Sci 2008; 23:217-228.