年間 6 号発行
ISSN 印刷: 0743-4863
ISSN オンライン: 2162-660X
Indexed in
Folate-Mediated Targeting of Therapeutic and Imaging Agents to Cancers
要約
The vitamin folic acid (FA) enters cells either through a carrier protein, termed the reduced folate carrier, or via receptor-mediated endocytosis facilitated by the folate receptor (FR). Because folate-drug conjugates are not substrates of the former, they penetrate cells exclusively via FR-mediated endocytosis. When FA is covalently linked via its γ-carboxyl to a drug or imaging agent, FR binding affinity (KD ~ 10−10 M) is not measurably compromised, and endocytosis proceeds relatively unhindered, promoting uptake of the attached drug/imaging agent by the FR-expressing cell. Because FRs are significantly overexpressed on a large fraction of human cancer cells (e.g., ovarian, lung, breast, endometrial, renal, colon, and cancers of myeloid hematopoietic cells), this methodology may allow for the selective delivery of a wide range of imaging and therapeutic agents to tumor tissue. Folate-mediated tumor targeting has been exploited to date for delivery of the following molecules and molecular complexes: (i) protein toxins, (ii) low-molecular-weight chemotherapeutic agents, (iii) radioimaging agents, (iv) MRI contrast agents, (v) radiotherapeutic agents, (vi) liposomes with entrapped drugs, (vii) genes, (viii) antisense oligonucleotides, (ix) ribozymes, and (x) immunotherapeutic agents. In virtually all cases, in vitro studies demonstrate a significant improvement in potency and/or cancer-cell specificity over the nontargeted form of the same pharmaceutical agent. Where live animal studies have been conducted, they also reveal significant promise.
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