Biodistribution of charged 17.1A photoimmunoconjugates in a murine model of hepatic metastasis of colorectal cancer.
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.
Hamblin
M R
MR
Wellman Laboratories of Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Del Governatore
M
M
Rizvi
I
I
Hasan
T
T
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D000818:Animals; D000838:Anions; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D058846:Antibodies, Monoclonal, Murine-Derived; D002412:Cations; D002735:Chlorophyllides; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D019073:HT29 Cells; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000493:pharmacokinetics*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000556:secondary; D051379:Mice; D011166:Porphyrins / Q000493:pharmacokinetics*; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D000838:Anions; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D002412:Cations; D002735:Chlorophyllides; D018796:Immunoconjugates; D011166:Porphyrins; D011838:Radiation-Sensitizing Agents; C400149:Edrecolomab; C062985:phytochlorin