Biodistribution of charged 17.1A photoimmunoconjugates in a murine model of hepatic metastasis of colorectal cancer

Abstract

Optimizing photodynamic therapy involves attempting to increase both the absolute tumour content of photosensitizer and the selectivity between tumour and surrounding normal tissue. One reason why photodynamic therapy has not been considered suitable for treatment of metastatic tumours in the liver, is the poor selectivity of conventional photosensitizers for tumour compared to normal liver. This report details an alternative approach to increasing this selectivity by the use of antibody-targeted photosensitizers (or photoimmunoconjugates) to target intrahepatic tumours caused by human colorectal cancer cells in the nude mouse, and explores the role of molecular charge on the tumour-targeting efficiency of macromolecules. The murine monoclonal antibody 17.1A (which recognizes an antigen expressed on HT 29 cells) was used to prepare site-specific photoimmunoconjugates with the photosensitizer chlorine6. The conjugates had either a predominant cationic or anionic charge and were injected i.v. into tumour-bearing mice. Biodistribution 3 or 24 h later was measured by extraction of tissue samples and quantitation of chlorine6 content by fluorescence spectroscopy. The photoimmunoconjugates were compared to the polylysine conjugates in an attempt to define the effect of molecular charge as well as antibody targeting. The anionic 17.1A conjugate delivered more than twice as much photosensitizer to the tumour at 3 h than other species (5 times more than the cationic 17.1A conjugate) and had a tumour:normal liver ratio of 2.5. Tumour-to-liver ratios were greater than one for most compounds at 3 h but declined at 24 h. Tumour-to-skin ratios were high (> 38) for all conjugates but not for free chlorine6. Cationic species had a high uptake in the lungs compared to anionic species. The photoimmunoconjugates show an advantage over literature reports of other photosensitizers, which can result in tumour:normal liver ratios of less than 1. © 2000 Cancer Research Campaign http://www.bjcancer.com

Interstitial photodynamic laser therapy in interventional oncology

“…As another approach to improve selectivity for tumor tissue in the liver, a US and Italian group tried to use antibody-targeted photosensitizers in a model of hepatic metastasis of colorectal cancer in mice. The photoimmunoconjugates with a tumor-normal liver ratio up to 2.5 shows an advantage over literature reports of other photosensitizers, which results in ratios of less than 1 [45]. Based on these data, a further study was initiated to test the efficacy of selective interstitial treatment of hepatic metastases from colorectal cancer with a 17.1A chlorin e6 immunoconjugate in mice.…”

Photodynamic therapy in colorectal cancer treatment—The state of the art in preclinical research

“…The PIC presented a tumor : normal liver ratio of 2.5. The anionic PIC gave significant reductions in tumor weight and increased survival of the mice not seen with free Ce6 [116].…”

Enhancing Tumor Drug Delivery by Laser-Activated Vascular Barrier Disruption

“…injection had a higher tumor accumulation and tumor-to-normal tissue ratio than the positively charged one in a colorectal cancer-induced hepatic tumor model in nude mice. 81 Using an interstitial fiber, hepatic tumors were treated with light at 3 hours after i.v. injection of either negatively charged conjugates or free chlorin e6, for comparison.…”