Tumor Growth Suppression With Novel Intra-arterial Chemotherapy Using Epirubicin-entrapped Water-in-oil-in-water Emulsion In Vivo.

BACKGROUND/AIM: A mixture of anticancer agents and iodized poppy seed oil (IPSO) has been widely used for intra-arterial chemotherapy of hepatocellular carcinoma. However, the anticancer agents can easily separate from IPSO, so the therapeutic potential is limited. We developed epirubicin-entrapped water-in-oil-in-water emulsion (WOW-Epi) using a double-membrane emulsification technique. MATERIALS AND METHODS: We delivered WOW-Epi through a hepatic arterial injection to VX2 hepatic tumor rabbit model (1.2 mg/kg). RESULTS: VX2 tumor growth was selectively suppressed in the WOW-Epi-treated group compared with the control treated groups. The accumulation of WOW in nearby cancer cells was confirmed via electron-microscopy. Endocytosis seemed to be the mechanism underlying the uptake of WOW. CONCLUSION: WOW-Epi led to tumour growth suppression in vivo. WOW does not cause toxicity to arterial vessels. WOW-Epi will be hopefully used for repeated intra-arterial chemotherapy to HCC patients in the near future.

Selective boron delivery by intra-arterial injection of BSH-WOW emulsion in hepatic cancer model for neutron capture therapy.

OBJECTIVE: Boron neutron-capture therapy (BNCT) has been used to inhibit the growth of various types of cancers. In this study, we developed a 10BSH-entrapped water-in-oil-in-water (WOW) emulsion, evaluated it as a selective boron carrier for the possible application of BNCT in hepatocellular carcinoma treatment. METHODS: We prepared the 10BSH-entrapped WOW emulsion using double emulsification technique and then evaluated the delivery efficacy by performing biodistribution experiment on VX-2 rabbit hepatic tumour model with comparison to iodized poppy-seed oil mix conventional emulsion. Neutron irradiation was carried out at Kyoto University Research Reactor with an average thermal neutron fluence of 5 × 1012 n cm-2. Morphological and pathological analyses were performed on Day 14 after neutron irradiation. RESULTS: Biodistribution results have revealed that 10B atoms delivery with WOW emulsion was superior compared with those using iodized poppy-seed oil conventional emulsion. There was no dissemination in abdomen or lung metastasis observed after neutron irradiation in the groups treated with 10BSH-entrapped WOW emulsion, whereas many tumour nodules were recognized in the liver, abdominal cavity, peritoneum and bilateral lobes of the lung in the non-injected group. CONCLUSION: Tumour growth suppression and cancer-cell-killing effect was observed from the morphological and pathological analyses of the 10BSH-entrapped WOW emulsion-injected group, indicating its feasibility to be applied as a novel intra-arterial boron carrier for BNCT. Advances in knowledge: The results of the current study have shown that entrapped 10BSH has the potential to increase the range of therapies available for hepatocellular carcinoma which is considered to be one of the most difficult tumours to cure.

Pilot clinical study of boron neutron capture therapy for recurrent hepatic cancer involving the intra-arterial injection of a (10)BSH-containing WOW emulsion.

A 63-year-old man with multiple HCC in his left liver lobe was enrolled as the first patient in a pilot study of boron neutron capture therapy (BNCT) involving the selective intra-arterial infusion of a (10)BSH-containing water-in-oil-in-water emulsion ((10)BSH-WOW). The size of the tumorous region remained stable during the 3 months after the BNCT. No adverse effects of the BNCT were observed. The present results show that (10)BSH-WOW can be used as novel intra-arterial boron carriers during BNCT for HCC.

Transarterial infusion chemotherapy with epirubicin in water-in-oil-in-water emulsion for recurrent hepatocellular carcinoma in the residual liver after hepatectomy.

PURPOSE: To evaluate the midterm results of transarterial infusion (TAI) with water-in-oil-in-water (W/O/W) emulsion containing an anticancer agent for patients with recurrent hepatocellular carcinoma (HCC) after surgical resection. MATERIALS AND METHODS: We retrospectively analyzed the results of TAI of W/O/W emulsion containing epirubicin for 18 consecutive patients with recurrent HCC after surgical resection. Fourteen patients were males and four were females; their ages ranged from 51 to 86 years (mean 69.8 years). TAI was repeated every 1-6 months based on the response of the tumor. A total of 41 TAI procedures were performed for 18 patients. Angiographically, recurrent HCC appeared a single nodule in nine patients and was multinodular in other nine patients. TAI was performed selectively in 27 procedures and non-selectively in 14 procedures. Maximum response within 3 months was rated as follows: a complete response (CR, complete disappearance of tumor and no evidence of new lesions); partial response (PR, a reduction of <50% in total volume of all tumors calculated from the two longest perpendicular diameters without a new lesion); no response (NC, a reduction of <50% in total volume or an increase of <25% without a new lesion); or progression of disease (PD, an increase of >25% in total volume or evidence of new lesions). Survival time was defined as the time from the date of first TAI to the date of death or last follow-up (median follow-up time: 17 months) and the survival curve was estimated using the Kaplan-Meier method. RESULTS: The CR rate was 33% and the effective response rate (CR rate+PR rate) was 78%. Survival from the time of initial TAI was 94% at 1 year, 76% at 2 years, and 76% at 3 years. CONCLUSIONS: TAI of W/O/W emulsion may be an effective treatment for patients with recurrent HCC after surgical resection.

A human sex hormone-binding globulin isoform accumulates in the acrosome during spermatogenesis.

Human sex hormone-binding globulin (SHBG) binds estradiol and testosterone with high affinity. Plasma SHBG is produced by hepatocytes, but the human SHBG gene is also expressed in the testis. Little is known about SHBG gene expression in the human testis, but human SHBG transcripts accumulate in a spermatogenic stage-dependent manner in the testes of mice containing an 11-kb human SHBG transgene. We have now found that human SHBG transcripts containing an alternative exon 1 sequence are located specifically in the testicular germ cells of these transgenic mice, whereas murine SHBG transcripts are confined to Sertoli cells. In addition, we have detected immunoreactive human SHBG in the acrosome during all stages of spermiogenesis in mice containing an 11-kb human SHBG transgene. Western blots of germ cell extracts from these transgenic mice and from human sperm indicate that the immunoreactive human SHBG in the acrosome composes electrophoretic variants, which are 3-5 kDa smaller than the major electrophoretic isoforms of human SHBG in the blood. This apparent size difference is due in part to differences in glycosylation of plasma and acrosomal SHBG isoforms. The function of the human SHBG isoform in the acrosome is unknown, but it binds steroid ligands with high affinity. This is the first demonstration that human SHBG transcripts encode an SHBG isoform that remains within a cellular compartment.