Cationized gelatin-HVJ envelope with sodium borocaptate improved the BNCT efficacy for liver tumors in vivo.
BACKGROUND
Boron neutron capture therapy (BNCT) is a cell-selective radiation therapy that uses the alpha particles and lithium nuclei produced by the boron neutron capture reaction. BNCT is a relatively safe tool for treating multiple or diffuse malignant tumors with little injury to normal tissue. The success or failure of BNCT depends upon the 10B compound accumulation within tumor cells and the proximity of the tumor cells to the body surface. To extend the therapeutic use of BNCT from surface tumors to visceral tumors will require 10B compounds that accumulate strongly in tumor cells without significant accumulation in normal cells, and an appropriate delivery method for deeper tissues.Hemagglutinating Virus of Japan Envelope (HVJ-E) is used as a vehicle for gene delivery because of its high ability to fuse with cells. However, its strong hemagglutination activity makes HVJ-E unsuitable for systemic administration.In this study, we developed a novel vector for 10B (sodium borocaptate: BSH) delivery using HVJ-E and cationized gelatin for treating multiple liver tumors with BNCT without severe adverse events.


METHODS
We developed cationized gelatin conjugate HVJ-E combined with BSH (CG-HVJ-E-BSH), and evaluated its characteristics (toxicity, affinity for tumor cells, accumulation and retention in tumor cells, boron-carrying capacity to multiple liver tumors in vivo, and bio-distribution) and effectiveness in BNCT therapy in a murine model of multiple liver tumors.


RESULTS
CG-HVJ-E reduced hemagglutination activity by half and was significantly less toxic in mice than HVJ-E. Higher 10B concentrations in murine osteosarcoma cells (LM8G5) were achieved with CG-HVJ-E-BSH than with BSH. When administered into mice bearing multiple LM8G5 liver tumors, the tumor/normal liver ratios of CG-HVJ-E-BSH were significantly higher than those of BSH for the first 48 hours (p < 0.05). In suppressing the spread of tumor cells in mice, BNCT treatment was as effective with CG-HVJ-E-BSH as with BSH containing a 35-fold higher 10B dose. Furthermore, CG-HVJ-E-BSH significantly increased the survival time of tumor-bearing mice compared to BSH at a comparable dosage of 10B.


CONCLUSIONS
CG-HVJ-E-BSH is a promising strategy for the BNCT treatment of visceral tumors without severe adverse events to surrounding normal tissues.
Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Hitoshi
H
Fujii
Akifumi
A
Matsuyama
Hiroshi
H
Komoda
Masao
M
Sasai
Minoru
M
Suzuki
Tomoyuki
T
Asano
Yuichiro
Y
Doki
Mitsunori
M
Kirihata
Koji
K
Ono
Yasuhiko
Y
Tabata
Yasufumi
Y
Kaneda
Yoshiki
Y
Sawa
Chun Man
CM
Lee
D000818:Animals; D001894:Borohydrides / Q000008:administration & dosage*; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D002213:Capsid / Q000737:chemistry; D002277:Carcinoma / Q000473:pathology / Q000532:radiotherapy*; D002412:Cations / Q000494:pharmacology; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D005780:Gelatin / Q000737:chemistry / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D029082:Sendai virus / Q000737:chemistry / Q000648:ultrastructure; D013438:Sulfhydryl Compounds / Q000008:administration & dosage*; D016896:Treatment Outcome
D001894:Borohydrides; D002412:Cations; D004337:Drug Carriers; D013438:Sulfhydryl Compounds; C014651:mercaptoundecahydrododecaborate; D005780:Gelatin
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