We report a novel quantum dot (QD)-aptamer(Apt)-doxorubicin (Dox) conjugate [QD-Apt(Dox)] as a targeted cancer imaging, therapy, and sensing system. By functionalizing the surface of fluorescent QD with the A10 RNA aptamer, which recognizes the extracellular domain of the prostate specific membrane antigen (PSMA), we developed a targeted QD imaging system (QD-Apt) that is capable of differential uptake and imaging of prostate cancer cells that express the PSMA protein. The intercalation of Dox, a widely used antineoplastic anthracycline drug with fluorescent properties, in the double-stranded stem of the A10 aptamer results in a targeted QD-Apt(Dox) conjugate with reversible self-quenching properties based on a Bi-FRET mechanism. A donor-acceptor model fluorescence resonance energy transfer (FRET) between QD and Dox and a donor-quencher model FRET between Dox and aptamer result when Dox intercalated within the A10 aptamer. This simple multifunctional nanoparticle system can deliver Dox to the targeted prostate cancer cells and sense the delivery of Dox by activating the fluorescence of QD, which concurrently images the cancer cells. We demonstrate the specificity and sensitivity of this nanoparticle conjugate as a cancer imaging, therapy and sensing system in vitro.
The active targeting of drugs in a cell-, tissue-, or diseasespecific manner represents a potentially powerful technology with widespread applications in medicine, including the treatment of cancers. In a typical approach, a drug and a ligand are complementarily functionalized to allow for covalent or noncovalent (for example, biotin-streptavidin) conjugation for targeted delivery. The resulting chemical modifications of the drugs and/or the ligands may adversely affect the safety and efficacy profile of the drugs and the binding characteristics of the ligands, thereby resulting in less efficacious drug-ligand conjugates. It would be desirable to develop simple but effective targeted drug-delivery strategies that do not require chemical modification of the drug or the ligands.Recently our group and other investigators have used nucleic acid ligands or aptamers for therapeutic and diagnostic targeted-delivery applications. [1][2][3][4][5][6] Aptamers are structured single-stranded DNA or RNA molecules that can specifically bind to small molecules, [7] peptides and proteins, [8] and oligosaccharides [9] with high affinity and specificity. Here we report a novel strategy for the targeted delivery of doxorubicin (Dox) to cancer cells through the formation of an aptamer-Dox physical conjugate. Dox is a well-known anticancer drug which has shown efficacy against a range of neoplasms, including acute lymphoblastic and myeloblastic leukemias, malignant lymphomas, soft tissue and bone sarcomas, and breast, ovarian, prostate, bladder, gastric, and bronchogenic carcinomas. This widely used oncology drug is also associated with dose-dependent cardiotoxicities, including dilated cardiomyopathy and congestive heart failure, which make the development of targeted Dox-delivery systems of particular importance.[10] Dox is known to intercalate within the DNA strand due to the presence of flat aromatic rings in this molecule. Other closely associated drugs, such as donarubicin, have also been shown to be intercalated into a double helix of DNA.[11] Since aptamers are known to form tertiary conformations with short doublestranded regions through intramolecular base pairing, [12] we hypothesized that doxorubicin may intercalate into these double-stranded regions and form a physical complex with the aptamers through noncovalent intercalation, a process requiring no modification of the drug or the aptamer (Figure 1). We postulated that the resulting aptamer-Dox physical conjugate may be used for the targeted delivery of Dox by taking advantage of the aptamers binding specificity to its target antigen. In this study, we have examined the feasibility of this concept by using the A10 2'-fluoropyrimidine RNA aptamer [13] that binds to the prostate-specific membrane antigen (PSMA) with high affinity and specificity.The two-dimensional structure of the A10 PSMA [13] aptamer used herein was predicted by the M fold program. [14] It is well known that the anthracycline class of drugs, including Dox, have fluorescence properties that become quen...
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