Gamma scintigraphy of the biodistribution of 123I-labelled N-(2-hydroxypropyl)methacrylamide copolymer-doxorubicin conjugates in mice with transplanted melanoma and mammary carcinoma.
An N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin conjugate is currently under clinical evaluation as a new antitumour agent. It has been shown previously that such conjugates exhibit selective tumour accumulation. In this study HPMA copolymer doxorubicin conjugates of low (LMW) or high (HMW) molecular weight were synthesised (which had a weight average molecular weight (Mw) of 25,000 and 94,000 respectively) and additionally contained a small amount (1 mol%) of the comonomer methacryloyltyrosinamide to permit labelling with [123I or 125I]iodide. Gamma camera imaging using the 123I-labelled probes was used to follow time-dependent biodistribution after intraperitoneal (i.p.) or intravenous (i.v.) administration to mice bearing subcutaneously either B16F10 melanoma or a mammary carcinoma. Imaging showed more rapid clearance of LMW conjugate from the peritoneal cavity than HMW conjugate. The images of mice given the LMW conjugate revealed rapid urinary excretion of radioactivity after both i.p. and i.v. injection with an early high concentration of tracer in the bladder, and subsequently a very high concentration in the kidneys, which came to dominate the views. Dissection analysis 2 days after administration of the LMW conjugate revealed a kidney level of radioactivity corresponding to 25-40% dose/g tissue in mice bearing the two tumour models. Following administration of the HMW conjugate kidney accumulation at 2 days was less due to retention of the higher molecular weight polymer molecules in the circulation, and spleen and liver displayed the highest concentrations of radioactivity. The tumour accumulation of LMW and HMW conjugates was; mammary carcinoma 3.18 and 5.29% dose/g respectively; B16F10 melanoma 3.23 and 8.82 %dose/g although these levels of tracer enabled visualisation in the images of the mammary carcinoma with HMW conjugate at later time points. The smaller size of the B16F10 tumour masses did not permit clear visualisation.
Pimm
M V
MV
Cancer Research Laboratories, University of Nottingham, UK.
Perkins
A C
AC
Strohalm
J
J
Ulbrich
K
K
Duncan
R
R
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000648:ultrastructure; D004317:Doxorubicin / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D005260:Female; D005720:Gamma Rays; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D007668:Kidney / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000648:ultrastructure; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000648:ultrastructure; D008689:Methacrylates / Q000378:metabolism* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D009368:Neoplasm Transplantation; D011877:Radionuclide Imaging; D014018:Tissue Distribution
D000903:Antibiotics, Antineoplastic; D007457:Iodine Radioisotopes; D008689:Methacrylates; D004317:Doxorubicin; C032802:hydroxypropyl methacrylate