Tumour tropism and anti-cancer efficacy of polymer-based doxorubicin prodrugs in the treatment of subcutaneous murine B16F10 melanoma.
Doxorubicin (5 mg kg-1) was administered intravenously to C57 mice bearing subcutaneous B16F10 melanomas, distributing into the tumour with an area under the concentration-time curve (0-48 h; AUC) of 8.7 micrograms h g-1. Injection of doxorubicin-N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugate, containing 5 mg of doxorubicin equivalent per kg, mediated an AUC for free doxorubicin (i.e. doxorubicin released from the conjugate) of 15.2 micrograms h g-1 and for total doxorubicin (i.e. free plus conjugated) of 149.1 micrograms h g-1. An increased dose of doxorubicin-HPMA copolymer conjugate (18 mg of doxorubicin equivalent per kg) produced AUC values of 40.1 micrograms h g-1 and 671.7 micrograms h g-1 for free and total doxorubicin respectively. Hence administration of doxorubicin-HPMA copolymer conjugate achieved rises of 1.7- to 4.6-fold in tumour AUC (free doxorubicin) and 17.19 to 77.0-fold in tumour AUC (total doxorubicin). HPMA copolymers bearing fluorescein isothiocyanate accumulated in vascularised stromal regions, particularly in new growth sites at the tumour periphery. Treatment of mice with doxorubicin-HPMA copolymer conjugate achieved treated/control lifespans up to 320% (three doses of 27 mg of doxorubicin equivalent per kg) compared with only 133% using aggressive regimens of free doxorubicin (3 x 5 mg kg-1).
Seymour
L W
LW
Institute for Cancer Studies, University of Birmingham School of Medicine, UK.
Ulbrich
K
K
Steyger
P S
PS
Brereton
M
M
Subr
V
V
Strohalm
J
J
Duncan
R
R
D000818:Animals; D002199:Capillary Permeability; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016650:Fluorescein-5-isothiocyanate / Q000493:pharmacokinetics; D007279:Injections, Subcutaneous; D046911:Macromolecular Substances; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D008689:Methacrylates / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014018:Tissue Distribution
D046911:Macromolecular Substances; D008689:Methacrylates; D011355:Prodrugs; D004317:Doxorubicin; D016650:Fluorescein-5-isothiocyanate; C032802:hydroxypropyl methacrylate