Journal of Controlled Release, 28 ( 1994) 45- 58 0 1994 Elsevier Science B.V. All rights reserved 0168-3659/94/$07.00 45 COREL 00937 XW10168-3659(93)E0122-V Targeted delivery of diagnostic agents by surface-modified liposomes Vladimir P. Torchilin”, Vladimir S. Trubetskoy”, Alexander M. Milshteyn”, John Canillo”, Gerald L. Wolf”, M&hail I. Papisovb, Alexei A. Bogdanovb, Jagat Narulac, Ban An KhawC and Vladimir G. Omelyanenkod “Center for Imaging and Pharmaceutical Research and bMGH-NMR Center, Department ofRadiology, Massachusetts General Hospital-East, Charlestown.MA, USA 'Center for Drug Targeting and Analysis, Northeastern University, Boston, MA, USA and ‘Department of Pharmaceutics, Universityof Utah, Salt Lake City, UT, USA (Received 26 February 1993; accepted in revised form 29 July 1993) Surface-modified LS have been used for the specific delivery of heavy metal-based imaging agents. The liposome surface was modified with PEG, AMmAb, Dext-SA, chelating agent DTPA-PE, and with NGPE-modified chelating polymer: DTPA-NPLGNGPE. The hypothesis is suggested attempting to explain the phenomenon of long circulation of PEG-coated LS from the point of view of statistical properties of flexible polymer molecule in solution. Direct experiments using fluorescent labels were performed to prove the hypothesis. The calculations performed on the basis of the hypothesis were designed to find the optimal concentration of PEG on the LS surface, and suggested that it not only provides a protective effect but also does not create steric hindrances for the surface-immobilized mAb. As a result, long circulating targeted ILS have been prepared. Intravenously administered ” ‘In-la- belled PEG-AMmAb-LS were targeted to the area of experimental myocardial infarction in rabbits under y-scintigraphic control. Infarct-to-normal ratios of “‘In radioactivity of about 20 were achieved. PEG-and Dext-modified liposomes with surface-incorporated Gd-labelled DTPA-PE or DTPA-NPLL- NGPE were used for the subcutaneous administration and subsequent NMR-imaging of lymph nodes in rabbits. Two mechanisms of MR-signal enhancement were found for the surface-modified Gd-con- taining LS: the increase in signal intensity due to the increase in water quantity in the vicinity of Gd atoms because of PEG-associated water; and better lymph node accumulation of Dext-LS via receptor- mediated endocytosis. Surface modification of LS opens the possibilitiy for targeted delivery of heavy metal-based imaging agents. Key words: Long-circulating immunoliposome; Polyethylene glycol; Heavy metal chelator; Myocardial infarction y-scintigraphy; Lymph node NMR-imaging Correspondence to: V.P.Torchilin, Center for Imaging and Pharmaceutical Research, Department of Radiology, Massachusetts General Hospital-East, 149, 13th Street, Charlestown, MA 02 129, USA.