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lüll Quantum dot-A10 RNA aptamer-doxorubicin conjugate Zhang HMolecular Imaging and Contrast Agent Database (MICAD)-/-ä 2004[]; ä (ä): äProstate-specific membrane antigen (PSMA) is a type II membrane glycoprotein with a molecular weight of ~100 kDa (1). PSMA is composed of several domains, including a potential phosphorylation site in the cytoplasmic tail (amino acids 1-18), a highly hydrophobic alpha-helix in the transmembrane region (amino acids 19-43), and catalytic sites in the extensive extracellular domain (amino acids 44-750). Two unique enzymatic functions are found in PSMA: N-acetylated, alpha-linked, dipeptidase (NAALADase) activity and folate hydrolase activity. As a prostate cancer cell marker, PSMA expression is primarily prostate-specific, with very low levels (~1,000-fold less) in the brain, salivary glands, and small intestine. PSMA has become an excellent target for imaging and therapy prostate cancer. Aptamers (from the Latin aptus, to fit, and the Greek meros, part or region) are single-stranded or double-stranded oligonucleotides (RNA or DNA, respectively) that are modified to bind a variety of targets with high binding affinity and specificity (2). Aptamers range in size from 20 to 80 base pairs (~6-26 kDa) with dissociation constants in the range of 10 pM to 10 nM (3). Unlike linear oligonucleotides, which contain genetic information or antisense oligonucleotides that interrupt the transcription of genetic information, aptamers are globular molecules with a shape similar to tRNA and bind to target proteins specifically (4). A10 RNA aptamer (Apt) is a nuclease-stabilized 2'-fluoropyrimidine RNA molecule of 57 base pairs with a molecular weight of 18.5 kDa (5). Its 2'-fluoro-modified ribose on all pyrimidines and 3'-inverted deoxythymidine cap provide significant resistance to nuclease in blood (6). Apt has a single 5'-CG-3' sequence in its predicted double-stranded stem region, which is a preferred binding site for the anthracycline class of anticancer drugs such as doxorubicin (Dox) (7). Dox intercalates within the GC pair in Apt to form physical conjugate Apt(Dox) at molar ratio of 1.11:1 (dissociation constant = 600 nM) and emit fluorescence simultaneously. Because Dox possesses high 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 (8), this complex can be used as a PSMA-specific drug carrier to deliver Dox to prostate cancer cells. Quantum dots (QDs) are semiconductor nanocrystals 2 to 10 nm in diameter (200-10,000 atoms) that possess a quantum confinement effect (hence the name "quantum dots") caused by the restriction of electrons and holes in all three dimensions (9, 10). Like classic semiconductors that are composed of two types of atoms from the II/VI or III/V group elements in the periodic table, these nanocrystals have a valence band and a conduction band separated by an energy gap (band gap). Upon excitation, an electron is promoted from the filled valence band to the largely empty conduction band, which creates a positive vacancy "hole" in the valence band. The spatial separation (Bohr radius) of this electron-hole pair ("exciton") is typically 1-10 nm for most semiconductors (10). The quantum confinement arises when one of the dimensions in the nanocrystals becomes comparable to its Bohr radius, at which time these valence/conduction bands are quantized with an energy value that is directly related to the nanocrystal size. Thus, the excitons are confined in a manner similar to a particle-in-the-box problem, leading to a finite band gap and discretization of energy levels. When the electron fills the vacancy in the valence band, light of a certain wavelength is emitted, which corresponds to the respective band gap energy that is a function of nanocrystal size. For instance, the emission wavelength is 550 nm for 3-nm CdSe QDs and 650 nm for 7-nm CdSe QDs (11, 12). For biological applications, QDs are generally encapsulated with biocompatible polymers, functionalized for various bioconjugations, and widely used to label molecules for optical imaging. The QD-Apt(Dox) conjugate is an PSMA-specific agent used for optical imaging of the delivery of the anticancer drug Dox (13). QD-Apt(Dox) consists of three components: PSMA-specific Apt covalently attached to the core surface as targeting molecule and drug carrier, an anthracycline class of anticancer drug Dox as a therapeutic agent and optical sensor, and a carboxyl core-CdSe/ZnS shell QD (QD490) as a carrier of A10 and Dox and as the second optical sensor. The two sensors (Dox and QD) generate an optical signal via formation of bi-molecular fluorescence resonance energy transfer (Bi-FRET) complex. FRET is a near-field dipole-dipole interaction that involves energy transfer between two molecules in close proximity (3-6 nm). In QD-Apt(Dox), there is a donor-acceptor relationship between QDs and Dox. The fluorescence of both QD and Dox is quenched ("OFF") when QD-Apt is loaded with Dox, and fluorescence is restored upon the release of Dox ("ON") after the uptake of QD-Apt(Dox) by prostate cancer cells. Thus, QD-Apt(Dox) can be used to image drug delivery to prostate cancer cells.ä |