Enhancement of the radiation response of EMT-6 tumours by a copper octabromotetracarboranylphenylporphyrin

Abstract

Objective: The carborane-containing porphyrin, copper (II) 2,3,7,8,12,13,17,18-octabromo-5,10,15,20-tetrakis(3-[1,2-dicarba-closo-dodecaboranyl]methoxyphenyl)-porphyrin (CuTCPBr), was investigated as a potential radiation enhancing agent for X-ray radiotherapy (XRT) in a subcutaneously implanted EMT-6 murine carcinoma. Method: The biodistribution and toxicological profile of this porphyrin has been shown to be favourable for another bimodal radiotherapy technique, boron neutroncapture therapy. For the XRT studies, CuTCPBr was formulated in either 9% CremophorH (BASF Corporation, Ludwigschafen, Germany) EL and 18% propylene glycol (9% CRM) or a revised formulation comprising 1% Cremophor ELP, 2% Tween 80H (JT Baker, Mansfield, MA), 5% ethanol and 2.2% PEG 400 (CTEP formulation), which would be more clinically acceptable than the original 9% CRM formulation. Using the 9% CRM formulation of CuTCPBr, doses of 100, 210 or 400 mg kg 21 of body weight were used in combination with single doses of 25-35 Gy 100 kVp X-rays. Results: While doses of 100 mg kg 21 and 210 mg kg 21 did not result in any significant enhancement of tumour response, the 400 mg kg 21 dose did. A dose modification factor of 1.20¡0.10 was obtained based on the comparison of doses that produced a 50% local tumour control probability. With the CTEP formulation of CuTCPBr, doses of 83 and 170 mg kg 21 produced significant radiation enhancement, with dose modification factors based on the TCP 50 of 1.29¡0.15 and 1.84¡0.24, respectively. Conclusion: CuTCPBr significantly enhanced the efficacy of XRT in the treatment of EMT-6 carcinomas in mice. The CTEP formulation showed a marked improvement, with over 9% CRM being associated with higher dose modification factors. Moreover, the radiation response in the skin was not enhanced.

In Vivo Application of Carboranes for Boron Neutron Capture Therapy (BNCT): Structure, Formulation and Analytical Methods for Detection

“…From the beginning of 1990, Miura and colleagues explored the potential of lipophilic porphyrins containing boron for in vivo applications [43,[113][114][115][116][117][118][119][120][121][122][123][124][125][126][127]. Since then, significant progress has been made in the development of a series of porphyrin-based drugs [128,129], also complexed with metals such as Zn and Cu.…”

“…The incorporation of these metal atoms into porphyrins can influence their biological activity and allow the use of radionuclides (i.e., 64 Cu) for tracing and quantifying the boron distribution during in vivo treatment. The functionalization of the porphyrin scaffold led to the synthesis of several compounds tested for in vivo applications in BNCT, including CuTCPH [116][117][118][119]122,124,126,130], ZnTCPH [122], H2TCP [131][132][133][134][135] and BOPP [136,137], whose structures (12-13) are reported in Figure 6. and TPFC (15), containing carborane moieities.…”

“…Formulants such as cremophor EL (CrEL) obtained by the reaction of ethylene oxide and castor oil are non-ionic solubilizers and emulsifiers and have been extensively used for the administration of poorly water-soluble drugs. CrEL has been used from the earliest works of Miura [114][115][116][117][118][119]121,122,124,126,131] as a solubilizer for porphyrin-based carborane drugs, together with propylene glycol. Despite its broad use, CrEl has been reported to be not inert and can potentially induce some clinical reactions [194].…”

Boron Neutron Capture Therapy: Current Status and Challenges

“…Miura et al. synthesized a series of complexed metallic porphyrins ( 60 , 69 – 74 ). Cu(II) and Zn(II) porphyrins complex, also known as CuTCPH and ZnTCPH in Figure 2 , are currently the most deeply studied porphyrin derivatives in vitro and in vivo ( 60 ).…”

Exploiting Blood Transport Proteins as Carborane Supramolecular Vehicles for Boron Neutron Capture Therapy

“…Nowadays, third-generation agents are emerging as potential drugs for BNCT clinical applications, such as boronated natural and non-natural amino acids [8,9], boronated drugs [10], nucleosides [11,12], porphyrines [13][14][15], antibodies [16] and carbohydrates [17].…”