Nucleic Acid Ligands Aptamers From Discovery To Practice

The feasibility of using antibodies for targeted therapy, particularly for oncologic diseases, has been demonstrated repeatedly in the literature. Rituximab (Rituxan™) was the first therapeutic based on monocloncal antibodies to receive FDA approval in 1997 for treating patients with relapsed or refractory low-grade or follicular, CD20 positive, B-cell non-Hodgkin's lymphoma.27 A wide variety of antibody-based drugs are now under clinical development or are in clinical practice today. For example, denileukin diftitox (Ontak™) is an FDA-approved immunotoxin for the treatment of cutaneous T-cell lymphoma.28 Many other radioimmunoconjugates or chemoimmu-noconjugates directed against cell surface antigens are currently in various stages of clinical and pre-clinical development. Despite the recent success of monoclonal antibodies as targeting moieties, the use of antibodies for drug targeting may have a number of potential disadvantages. First, antibodies are large molecules (~ 20 nm for intact antibodies)29,30 and their use in developing nanoscale therapeutic and diagnostic tools may result in an increase in vehicle size without added advantage. Second, antibodies may be immunogenic. Despite the current engineering approaches to yield improved humanized antibodies, this problem is not universally solved. Third, the biological development of monoclonal antibodies can be difficult and unpredictable. For example, the target antigen may not be well tolerated by the animal used to produce the antibodies, or the target molecules may be inherently less immunogenic, making it difficult to raise antibodies against such targets (although, this problem is overcome with the use of phage display libraries).31,32 Fourth, the production of antibodies involves a biological process that can result in batch-to-batch variability in their performance, particularly when production is scaled up. The ideal targeting molecule for the delivery of nanoscale therapeutic and diagnostic systems should, like monoclonal antibodies, bind with high affinity and specificity to a target antigen but overcome or ameliorate some of the problems associated with the use and production of monoclonal antibodies.

Nucleic acid aptamers are a novel class of ligands25,26 that are small, nonimmunogenic, easy to isolate, characterize and modify, and exhibit high specificity and affinity for their target antigen. Aptamers derive their name from the Latin word aptus, meaning "to fit." In the short time since Jack Szostak and Larry Gold independently described the groundbreaking methodology for in vitro evolution of aptamers, this class of ligands has emerged as an important arsenal in research and clinical medicine.22,33 Considering the many favorable characteristics of aptamers, which have resulted in their rapid progress into clinical practice,33 researchers have begun to exploit this class of molecules for targeted delivery of controlled release polymer drug delivery vehicles. Recently, we described the first proof-of-concept drug delivery vehicles utilizing aptamers for targeted delivery of drug encapsulated nanoparticles23 and have gone on to the show efficacy of similarly designed nanoparticles against prostate cancer tumors in vivo (Farokhzad et al., submitted).14

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