Folate-targeted therapeutic and imaging agents for cancer
Introduction
Because most current chemotherapeutic agents distribute indiscriminately into virtually all cells of the body, they can damage both malignant and normal cells alike, often inducing sufficient toxicity to cause the patient to discontinue treatment. The obvious solution to these unwanted toxicities is to somehow focus the therapeutic potency on the cancer cells, preserving the healthy cells to perform their essential functions. While numerous strategies have been proposed to target drugs to tumor cells (for reviews, see [1, 2, 3, 4, 5, 6, 7, 8, 9, 10••]), one approach that has received considerable attention has been the use of folic acid to deliver attached drugs selectively to folate receptor-expressing cancer cells [10••, 11••, 12]. This review will discuss the strengths and weakness of this approach and offer insight into possible clinical applications of the technology.
Section snippets
Folate receptor expression
The vitamin, folic acid, is required in one carbon metabolic reactions, and consequently, is essential for the synthesis of nucleotide bases. Uptake of folates into virtually all cells of the body is mediated by either the reduced folate carrier [13, 14] or the proton coupled folate transporter [15]. Because neither of these membrane-spanning transport proteins displays affinity for folate conjugates, folate-linked drugs show no tendency to bind to most normal cells. Importantly, folic acid can
Folate-targeted drugs in human clinical trials
Because of the overexpression of FR on cancer cells, folate has been exploited to deliver attached drugs to a variety of human malignancies. To illustrate the diverse applications of this targeting technology for tumor-specific drug delivery, the first four folate-targeted drugs to enter human clinical trials will be briefly described below. The initial folate-targeted drug to be tested in humans was 111In-DTPA-folate (Figure 3a), a folate-conjugated chelator of 111In that was demonstrated to
Conclusions
In summary, folic acid displays multiple desirable characteristics for use in the targeting of cytotoxic drugs and imaging agents to cancer tissue. With careful selection of an ideal cytotoxic warhead and releasable hydrophilic spacer, a folate conjugate that not only reduces off-target toxicity but also improves therapeutic efficacy can now be designed. Moreover, because folate receptors are also overexpressed and accessible on activated macrophages (i.e. cells responsible for many
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We wish to thank Endocyte and the Purdue Cancer Center for their support of much of the research described in this review.
References (55)
Translation of the Philadelphia chromosome into therapy for CML
Blood
(2008)- et al.
The neovasculature homing motif NGR: more than meets the eye
Blood
(2008) - et al.
A role for the proton-coupled folate transporter (PCFT-SLC46A1) in folate receptor-mediated endocytosis
J Boil Chem
(2009) - et al.
Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues
Cancer Res
(1992) - et al.
Cellular localization of the folate receptor: potential role in drug toxicity and folate homeostasis
Cancer Res
(1992) - et al.
Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines, physiological and clinical implications
Cancer
(1994) - et al.
The alpha folate receptor is highly activated in malignant pleural mesothelipma
J Thorac Cardiovasc Surg
(2001) - et al.
A functional folate receptor is induced during macrophage activation and can be used to target drugs to activated macrophages
Blood
(2009) - et al.
Folate receptor-mediated drug targeting: from therapeutics to diagnostics
J Pharm Sci
(2005) - et al.
Increased apoptotic neutrophils and macrophages and impaired macrophage phagocytic clearance of apoptotic neutrophils in systemic lupus erythematosus
Arthritis Rheum
(2003)