In order to avoid the toxicities associated with prescription drug use today, we have explored novel methods for delivering drugs selectively to pathologic cells, thereby avoiding the collateral damage that accompanies their uptake by healthy cells. In this Account, we describe our quest for the ideal targeted therapeutic agent. This effort began with a search for ligands that would bind selectively to pathologic cells, displaying no affinity for healthy cells. After identification of an optimal targeting ligand, effort was focused on construction of linkers that would carry the attached drug to pathologic cells with receptors for the selected ligand. In the case of cancer, we exploited the well-characterized up-regulation of folate receptors on malignant cells to target folate-linked pharmaceuticals to cancer tissues in vivo. Drugs that have been linked to folic acid for tumor-selective drug delivery to date include (i) protein toxins, (ii) chemotherapeutic agents, (iii) gene therapy vectors, (iv) oligonucleotides (including small interfering RNA (siRNA)), (v) radioimaging agents, (vi) magnetic resonance imaging (MRI) contrast agents, (vii) liposomes with entrapped drugs, (viii) radiotherapeutic agents, (ix) immunotherapeutic agents, and (x) enzyme constructs for prodrug therapy. Current clinical trials of four folate-linked drugs demonstrate that folate receptor-targeting holds great promise for increasing the potency while reducing toxicity of many cancer therapies. In the course of developing folate-conjugated drugs for cancer, we discovered that folate receptors are also overexpressed on activated (but not resting or quiescent) macrophages. Recognizing that activated macrophages either cause or contribute to such diseases as rheumatoid arthritis, Crohn's disease, atherosclerosis, lupus, inflammatory osteoarthritis, diabetes, ischemia reperfusion injury, glomerulonephritis, sarcoidosis, psoriasis, Sjogren's disease, and vasculitis, we initiated studies aimed at developing folate-conjugated imaging and therapeutic agents for the diagnosis and treatment of such diseases. In very brief time, significant progress has been made towards identification of clinical candidates for targeted treatment of several inflammatory and autoimmune diseases. This Account summarizes the discovery and development of a variety of folate-targeted drugs for the diagnosis and therapy of cancers and inflammatory/autoimmune diseases.

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Ligand-targeted therapeutics have increased in prominence because of their potential for improved potency and reduced toxicity. However, with the advent of personalized medicine, a need for greater versatility in ligand-targeted drug design has emerged, where each tumor-targeting ligand should be capable of delivering a variety of therapeutic agents to the same tumor, each therapeutic agent being selected for its activity on a specific patient's cancer. In this report, we describe the use of a prostate-specific membrane antigen (PSMA)-targeting ligand to deliver multiple unrelated cytotoxic drugs to human prostate cancer (LNCaP) cells. We demonstrate that the PSMA-specific ligand, 2-[3-(1, 3-dicarboxy propyl)ureido] pentanedioic acid, is capable of mediating the targeted killing of LNCaP cells with many different therapeutic warheads. These results suggest that flexibility can be designed into ligand-targeted therapeutics, enabling adaptation of a single targeting ligand for the treatment of patients with different sensitivities to different chemotherapies.

Rapid identification of infectious pathogens constitutes an important step toward limiting the spread of contagious diseases. Whereas antibody-based detection strategies are often selected because of their speed, mutation of the pathogen can render such tests obsolete. In an effort to develop a rapid yet mutation-proof method for pathogen identification, we have explored the use of "immutable ligands" to capture the desired microbe on a detection device. In this "proof-of-principle" study, we immobilize pyoverdine, a siderophore that Pseudomonas aeruginosa must bind to obtain iron, onto gold-plated glass chips and then examine the siderophore's ability to capture P. aeruginosa for its subsequent identification. We demonstrate that exposure of pyoverdine-coated chips to increasing dilutions of P. aeruginosa allows detection of the bacterium down to concentrations as low as 10(2)/mL. We further demonstrate that printing of the siderophore in a periodic pattern on the detection chip enables a sensitive method of detecting the bound pathogen by a Fourier transform analysis of light scattered by the patterned chip. Because unrelated bacteria are not captured on the pyoverdine chip, we conclude that pyoverdine can be exploited for the specific binding and identification of P. aeruginosa. It follows that the utilization of other microbe-specific "immutable ligands" may allow the specific identification of their cognate pathogens.