Folate-targeted therapeutic and imaging agents for cancer

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Cancer therapies that exploit targeting ligands to deliver attached cytotoxic drugs selectively to malignant cells are currently receiving significant attention. While antibody-targeted drugs have been the first to enter the clinic, recent studies demonstrate that the vitamin folic acid can also be used to deliver attached imaging and therapeutic agents selectively to malignant cells in both animal tumor models and human cancer patients. Thus, folate conjugates bind to folate receptors that are overexpressed on ∼40% of human cancers and mediate internalization of their attached drugs by receptor-mediated endocytosis. With the use of proper linkers, folate-targeted drugs can be released inside their target cells where they can perform their desired cytotoxic functions. Based on this strategy, six folate-targeted drugs are currently in human clinical trials.

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.

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