Targeted drug delivery via the folate receptor

The folate receptor is a highly selective tumor marker overexpressed in gre ater than 90% of ovarian carcinomas. Two general strategies have been devel oped for the targeted delivery of drugs to folate receptor-positive tumor c ells: by coupling to a monoclonal antibody against the receptor and by coup ling to a high affinity ligand, folic acid. First, antibodies against the f olate receptor, including their fragments and derivatives, have been evalua ted for tumor imaging and immunotherapy clinically and have shown significa nt targeting efficacy in ovarian cancer patients. Folic acid, a high affini ty ligand of the folate receptor, retains its receptor binding properties w hen derivatized via its gamma-carboxyl. Folate conjugation therefore, prese nts an alternative method of targeting the folate receptor. This second str ategy has been successfully applied in vitro for the receptor-specific deli very of protein toxins, anti-T-cell receptor antibodies, interleukin-2, che motherapy agents, gamma-emitting radiopharmaceuticals, magnetic resonance i maging contrast agents, liposomal drug carriers, and gene transfer vectors. Low molecular weight radiopharmaceuticals based on folate conjugates showe d much more favorable pharmacokinetic properties than radiolabeled antibodi es and greater tumor selectivity in folate receptor-positive animal tumor m odels. The small size, convenient availability, simple conjugation chemistr y, and presumed lack of immunogenicity of folic acid make it an ideal ligan d for targeted delivery to tumors. (C) 2000 Elsevier Science BN. All rights reserved.