Vitamin-mediated targeting as a potential mechanism to increase drug uptake by tumours.
Targeted chemotherapy for cancer treatment offers a great potential advantage in tumour treatment due to greater specificity of delivery which leads to increased dose of the cytotoxin delivered to the tumour relative to the rest of the body. In order to achieve such selective targeted delivery one needs to identify generic markers that are over-expressed on the surface of tumour cells but are not over-expressed on normal tissue. Work of several authors has shown that some cells, such as those of rapidly dividing, aggressive tumours, over-express surface receptors involved in the uptake of vitamin B(12) [B. Rachmilewitz, M. Rachmilewitz, B. Moshkowitz, J. Gross, J. Lab. Clin. Med. 78 (1971) 275-279; B. Rachmilewitz, A. Sulkes, M. Rachmilewitz, A. Fuks, Israel J. Med. Sci. 17 (1981) 874-879] or folate [P. Garin-Chesa, I. Campbell, P.E. Saigo, J.L. Lewis Jr., L.J. Old, W.J. Rettig, Am. J. Pathol. 142 (1993) 557-567; O.C. Boerman, C.C. van Niekerk, K. Makkink, T.G.J.M. Hanselaar, P. Kenemans, L.G. Poels, Int. J. Gynecol. Pathol. 10 (1991) 15-25; G. Toffoli, C. Cernigoi, A. Russo, A. Gallo, M. Bagnoli, M. Boiocchi, Int. J. Cancer 74 (1997) 193-194; J.A. Reddy, D. Dean, M.D. Kennedy, P.S. Low, J. Pharm. Sci. 88 (1999) 1112-1118; J.A. Reddy, P.S. Low, Crit. Rev. Ther. Drug Carrier Syst. 15 (1998) 587-627; G.J. Russell-Jones, K. McTavish, J.F. McEwan, in: Proceedings of the 2nd International Symposium on Tumor Targeted Delivery Systems, 2002]. Furthermore the degree of over-expression has been found to correlate with the stage of tumour growth, with the highest levels found on stage IV carcinomas. Using fluorescently-labelled polymers to which are linked the targeting agents, vitamin B(12), folate or biotin, the relative uptake of these polymers into various types of tumour cell lines grown both in vitro and in vivo has been examined. These studies have shown that while some tumour types do NOT over-express receptors involved in vitamin uptake, most tumour types over-express receptors for folate, or vitamin B(12). In either case there is also a greatly increased expression of a yet to be identified biotin receptor. In cases of receptor over-expression, binding of the targeted fluorochrome leads to rapid internalization of these molecules within the cells to levels that are two to thirty times higher than with non-targeted polymers. Using a number of cancer models, these studies were extended further and it was found that the increased expression of receptors also leads to increased levels of killing with targeted cytotoxins. Thus the preliminary data described suggests that the use of vitamins as targeting agents has enormous potential for use in cancer diagnosis and chemotherapy.
Access Pharmaceuticals Australia Pty Ltd., Targeted Delivery, Unit 5, 15-17 Gibbes St, Chatswood, NSW, Sydney 2067, Australia. grj@accesspharma.com.au
Gregory
G
Russell-Jones
Kirsten
K
McTavish
John
J
McEwan
John
J
Rice
David
D
Nowotnik
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D000970:Antineoplastic Agents; D008689:Methacrylates; D011108:Polymers; D012235:Rhodamines; D005492:Folic Acid; D014805:Vitamin B 12; C032802:hydroxypropyl methacrylate