title: Evaluation of the potential of doxorubicin loaded microbubbles as a theranostic modality using a murine tumor model.
abstract: In this study, a novel phospholipid-based microbubble formulation containing doxorubicin and perfluoropropane gas (DLMB) was developed. The DLMBs were prepared by mechanical agitation of a phospholipid dispersion in the presence of perfluoropropane (PFP) gas. An anionic phospholipid, distearoyl phosphatidylglycerol (DSPG) was selected to load doxorubicin in the microbubbles by means of electrostatic interaction. The particle size, zeta potential, echogenicity and stability of the DLMBs were measured. Drug loading was ⩾ 92%. The potential of the DLMBs for use as a theranostic modality was evaluated in tumor bearing mice. Gas chromatography analysis of PFP showed significant enhancement of PFP retention when doxorubicin was used at concentrations of 10-82% equivalent to DSPG. The inhibitory effects on the proliferation of B16BL6 melanoma murine cells in vitro were enhanced using a combination of ultrasound (US) irradiation and DLMBs. Moreover, in vivo DLMBs in combination with (US) irradiation significantly inhibited the growth of B16BL6 melanoma tumor in mice. Additionally, US echo imaging showed high contrast enhancement of the DLMBs in the tumor vasculature. These results suggest that DLMBs could serve as US triggered carriers of doxorubicin as well as tumor imaging agents in cancer therapy.
authors: Kyoto University, Graduate School of Pharmaceutical Sciences, Kyoto, Japan.
authors: Rodi
authors: R
authors: Abdalkader
authors: Nagasaki University, Graduate School of Biomedical Sciences, Nagasaki, Japan. Electronic address: skawakam@nagasaki-u.ac.jp.
authors: Shigeru
authors: S
authors: Kawakami
authors: Kyoto University, Graduate School of Pharmaceutical Sciences, Kyoto, Japan.
authors: Johan
authors: J
authors: Unga
authors: Laboratory of Drug and Gene Delivery, Faculty of Pharma-sciences, Teikyo University, Japan.
authors: Ryo
authors: R
authors: Suzuki
authors: Laboratory of Drug and Gene Delivery, Faculty of Pharma-sciences, Teikyo University, Japan.
authors: Kazuo
authors: K
authors: Maruyama
authors: Kyoto University, Graduate School of Pharmaceutical Sciences, Kyoto, Japan.
authors: Fumiyoshi
authors: F
authors: Yamashita
authors: Kyoto University, Graduate School of Pharmaceutical Sciences, Kyoto, Japan; Kyoto University, Institute for Integrated Cell-Material Science (iCeMS), Kyoto, Japan. Electronic address: hashidam@pharm.kyoto-u.ac.jp.
authors: Mitsuru
authors: M
authors: Hashida
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D002214:Capsules / Q000138:chemical synthesis / Q000528:radiation effects; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry*; D004058:Diffusion; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005466:Fluorocarbons / Q000737:chemistry*; D019220:High-Energy Shock Waves; D051379:Mice; D008810:Mice, Inbred C57BL; D045423:Microbubbles; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D016896:Treatment Outcome; D014463:Ultrasonography / Q000379:methods*
chemical_list: D000903:Antibiotics, Antineoplastic; D002214:Capsules; D003287:Contrast Media; D005466:Fluorocarbons; D004317:Doxorubicin; C042852:perflutren
keywords: Cancer therapy; Cavitation; Doxorubicin loaded microbubbles; Theranostics; Ultrasound