Polymeric drug-carriers containing doxorubicin and melanocyte-stimulating hormone: in vitro and in vivo evaluation against murine melanoma.
N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymers containing doxorubicin (DOX, approximately 8% by weight) bound via the lysosomally degradable spacer Gly-Phe-Leu-Gly and, in certain cases, also melanocyte-stimulating hormone (MSH, 5-10% by weight) were synthesized with the aim of developing a drug conjugate for site-specific delivery to malignant melanoma. Polymer-bound MSH, like free MSH, was able to stimulate tyrosinase activity in B16F10 cells in vitro, confirming the ability of conjugated hormone to interact with the MSH receptor. Similarly, a 125I-labelled conjugate containing MSH was captured by B16F10 cells in vitro more rapidly than a similar polymer without the targeting moiety. HPMA copolymers containing DOX bound via the lysosomally degradable Gly-Phe-Leu-Gly linkage were cytotoxic to a mouse melanoma cell line (M3 S91) in vitro, the MSH-containing conjugate being more active than that without (although the difference in the ID50 was not significant). When administered intraperitoneally or intravenously to C57BL/6J mice bearing intraperitoneal B16F10 tumours, HPMA copolymers containing DOX linked via this biodegradable spacer (with or without MSH) significantly increased animal survival, the maximum ratio of the mean survival of the test group (T) to that of the untreated control (C) T/C observed (approximately 200) over the dose range 5-20 mg DOX/kg being similar to that seen for free DOX. In contrast, neither polymer conjugates containing DOX bound via a non-degradable linkage (Gly-Gly) nor free MSH showed antitumour activity. In mice bearing established subcutaneous B16F10 tumours, biodegradable polymer-bound DOX conjugates given intraperitoneally were more effective than free DOX (which was virtually inactive in this system); conjugates containing MSH were significantly more effective than those without, the maximum T/C being approximately 148 and 324 respectively. Preliminary pharmacokinetic experiments showed evidence of selective MSH targeting of polymer conjugates to subcutaneous B16F10.
O'Hare
K B
KB
Cancer Research Campaign's Polymer Controlled Drug Delivery Group, University of Keele, Staffordshire, UK.
Duncan
R
R
Strohalm
J
J
Ulbrich
K
K
Kopeckova
P
P
D000178:Acrylamides; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004337:Drug Carriers; D004354:Drug Screening Assays, Antitumor; D007457:Iodine Radioisotopes; D009074:Melanocyte-Stimulating Hormones / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D014442:Monophenol Monooxygenase / Q000378:metabolism; D011108:Polymers; D011979:Receptors, Pituitary Hormone / Q000378:metabolism
D000178:Acrylamides; D004337:Drug Carriers; D007457:Iodine Radioisotopes; D011108:Polymers; D011979:Receptors, Pituitary Hormone; D004317:Doxorubicin; C029446:MSH receptor; D009074:Melanocyte-Stimulating Hormones; D014442:Monophenol Monooxygenase; C032976:N-(2-hydroxypropyl)methacrylamide