Gadolinium-loaded chitosan nanoparticles for neutron-capture therapy: Influence of micrometric properties of the nanoparticles on tumor-killing effect.
As a nanoparticulate device for controlled delivery of Gd in NCT, the authors have developed gadolinium-loaded chitosan nanoparticles (Gd-nanoCPs). In the present study, influence of micrometric properties such as particle size, particle-surface charge and Gd content of Gd-nanoCPs on tumor-killing effect by Gd-NCT was investigated with Gd-nanoCPs. Two types of Gd-nanoCPs with different mean particle size, zeta potential and Gd-content (Gd-nanoCP-400; 391nm, 28mV, 9wt% and Gd-nanoCP-200; 214nm, 19mV, 24wt%) could be prepared by using chitosans with different molecular weights. Gd-nanoCPs incorporating 1.2mg of natural Gd were injected intratumorally once or twice to mice subcutaneously-bearing B16F10 melanoma. Eight hours after the last administration, thermal neutron was irradiated to tumor region of the mice. Remarkable tumor-growth was observed in both hot and cold control groups. In contrast, Gd-NCT groups showed significant tumor-growth suppression effect, though their efficacy was found to depend on the micrometric properties of Gd-nanoCPs. In particular, the Gd-nanoCP-200 exhibited stronger tumor-killing effect than the Gd-nanoCP-400 at the same Gd dose and it was still similar to Gd-nanoCP-400 in tumor-growth suppressing effect even at the half of Gd dose of Gd-nanoCP-400. This significance in tumor-killing effect would be ascribed from a higher Gd retention in the tumor tissue and an improved distribution of Gd with intratumorally administered Gd-nanoCP-200. Indeed, the Gd concentration in tumor tissue at the time corresponding to the onset of thermal neutron irradiation was determined to be significantly higher in Gd-nanoCP-200, compared with Gd-nanoCP-400. These results demonstrated that appropriate modification of Gd-nanoCPs in micrometric properties would be an effective way to improve the retention of Gd in the tumor tissue after intratumoral injection, leading to the enhanced tumor-killing effect in Gd-NCT.
Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe 650-8586, Japan; Cooperative Research Center of Life Sciences, Kobe Gakuin University, Kobe 650-8586, Japan. Electronic address: ichikawa@pharm.kobegakuin.ac.jp.
Hideki
H
Ichikawa
Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe 650-8586, Japan.
Takeshi
T
Uneme
Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe 650-8586, Japan.
Tooru
T
Andoh
Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe 650-8586, Japan.
Yuya
Y
Arita
Department of Orthopaedic Surgery, Hyogo Cancer Center, Akashi 673-8558, Japan.
Takuya
T
Fujimoto
Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, Sennan-gun 590-0494, Japan.
Minoru
M
Suzuki
Division of Radiation Life Science, Research Reactor Institute, Kyoto University, Sennan-gun 590-0494, Japan.
Yoshinori
Y
Sakurai
Department of Chemical Engineering, Kyoto University, Kyoto 615-8510, Japan.
Hiroyuki
H
Shinto
Department of Chemical Engineering, Kyoto University, Kyoto 615-8510, Japan.
Tomonori
T
Fukasawa
Sector of Science Communication and Production, JT Biohistory Research Hall, Osaka 569-1125, Japan.
Fumihiko
F
Fujii
Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe 650-8586, Japan; Cooperative Research Center of Life Sciences, Kobe Gakuin University, Kobe 650-8586, Japan.
Yoshinobu
Y
Fukumori
D000818:Animals; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D045744:Cell Line, Tumor; D048271:Chitosan / Q000737:chemistry*; D005682:Gadolinium / Q000008:administration & dosage* / Q000737:chemistry; D015552:Injections, Intralesional; D008297:Male; D008545:Melanoma / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure*; D010316:Particle Size; D011879:Radiotherapy Dosage; D016896:Treatment Outcome
D053769:Nanocapsules; D048271:Chitosan; D005682:Gadolinium
Cancer; Chitosan; Gadolinium; Gd-DTPA; Nanoparticle; Neutron capture therapy