Targeted Inhibition of Prostate Cancer Metastases with an RNA Aptamer to Prostate-specific Membrane Antigen

Dassie, Justin P.; Hernandez, Luiza I.; Thomas, Gregory S.; Long, Matthew E.; Rockey, William M.; Howell, Craig A.; Chen, Yani; Hernandez, Frank J.; Liu, Xiu Ying; Wilson, Mary E.; Allen, Lee‐Ann H.; Vaena, Daniel A.; Meyerholz, David K.; Giangrande, Paloma H.

doi:10.1038/mt.2014.117

Cited by 90 publications

(64 citation statements)

References 42 publications

(72 reference statements)

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“…Although this minimized molecule has previously been shown to inhibit PSMA enzymatic activity with an IC50 of *10 nM [14,15], to inhibit PSMA cell migration with an IC50 of *200 nM [21] and even to localize to tumors following systemic administration to mice bearing PSMA-positive tumors [21], assays characterizing the direct cell binding capabilities of this molecule and its specificity for PSMA in the literature were lacking detail. Therefore, we performed a set of analyses using a fluorescently labeled aptamer (AF488-A9.min) to directly determine the cell binding characteristics of this molecule.…”

Section: Discussionmentioning

confidence: 99%

Improved Synthesis andIn VitroEvaluation of an Aptamer Ribosomal Toxin Conjugate

Kelly

Kratschmer

Maier

et al. 2016

Nucleic Acid Therapeutics

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Delivery of toxins, such as the ricin A chain, Pseudomonas exotoxin, and gelonin, using antibodies has had some success in inducing specific toxicity in cancer treatments. However, these antibody-toxin conjugates, called immunotoxins, can be bulky, difficult to express, and may induce an immune response upon in vivo administration. We previously reported delivery of a recombinant variant of gelonin (rGel) by the full-length prostate-specific membrane antigen (PSMA) binding aptamer, A9, to potentially circumvent some of these problems. Here, we report a streamlined approach to generating aptamer-rGel conjugates utilizing a chemically synthesized minimized form of the A9 aptamer. Unlike the full-length A9 aptamer, this minimized variant can be chemically synthesized with a 5¢ terminal thiol. This facilitates the large scale synthesis and generation of aptamer toxin conjugates linked by a reducible disulfide linkage. Using this approach, we generated aptamertoxin conjugates and evaluated their binding specificity and toxicity. On PSMA(+) LNCaP prostate cancer cells, the A9.min-rGel conjugate demonstrated an IC 50 of *60 nM. Additionally, we performed a stability analysis of this conjugate in mouse serum where the conjugate displayed a t 1/2 of *4 h, paving the way for future in vivo experiments.

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Section: Discussionmentioning

confidence: 99%

Improved Synthesis andIn VitroEvaluation of an Aptamer Ribosomal Toxin Conjugate

Kelly

Kratschmer

Maier

et al. 2016

Nucleic Acid Therapeutics

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“…[19][20][21] Early aptamers including A10 and A9 were screened from the synthesized RNA aptamer library, and can both effectively bind to PSMA. 22,23 However, they both consist of 79 nucleotides, which leads to a very high molecular weight and severely restricts their role as targeting molecules. Researchers have continued to shorten their sequences in their subsequent experiments and the A10-3 aptamer molecule with only 59 nucleotides was developed.…”

Section: Introductionmentioning

confidence: 99%

Diagnosis of prostate cancer using anti-PSMA aptamer A10-3.2-oriented lipid nanobubbles

Fan

Guo

Wang

et al. 2016

IJN

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In this study, the lipid targeted nanobubble carrying the A10-3.2 aptamer against prostate specific membrane antigen was fabricated, and its effect in the ultrasound imaging of prostate cancer was investigated. Materials including 2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphatidic acid, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol, carboxyl-modified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, and polyethyleneglycol-2000 were for mechanical oscillation, and nanobubbles were obtained through the centrifugal flotation method. After mice were injected with nanobubbles, abdominal color Doppler blood flow imaging significantly improved. Through left ventricular perfusion with normal saline to empty the circulating nanobubbles, nanobubbles still existed in tumor tissue sections, which demonstrated that nanobubbles could enter tissue spaces via the permeability and retention effect. Fluorinated A10-3.2 aptamers obtained by chemical synthesis had good specificity for PSMA-positive cells, and were linked with carboxyl-modified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine lipid molecules from the outer shell of nanobubbles via amide reaction to construct targeted nanobubbles. Gel electrophoresis and immunofluorescence confirmed that targeted nanobubbles were fabricated successfully. Next, targeted nanobubbles could bind with PSMA-positive cells (C4-2 cells), while not with PSMA-negative cells (PC-3 cells), using in vitro binding experiments and flow cytometry at the cellular level. Finally, C4-2 and PC-3 xenografts in mice were used to observe changes in parameters of targeted and non-targeted nanobubbles in the contrast-enhanced ultrasound mode, and the distribution of Cy5.5-labeled targeted nanobubbles in fluorescent imaging of live small animals. Comparison of ultrasound indicators between targeted and non-targeted nanobubbles in C4-2 xenografts showed that they had similar peak times ( P >0.05), while the peak intensity, half time of peak intensity, and area under the curve of ½ peak intensity were significantly different ( P <0.05). In PC-3 xenografts, there were no differences in these four indicators. Fluorescent imaging indicated that targeted nanobubbles had an aggregation ability in C4-2 xenograft tumors. In conclusion, targeted nanobubbles carrying the anti-PSMA A10-3.2 aptamer have a targeted imaging effect in prostate cancer.

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“…5 A wide variety of imaging agents that target PSMA have been described with many currently in clinical trials (www.clinicaltrials.gov), highlighting the continued interest in PSMA in biomedical, translational medicine and pharmaceutical fields. 6 While we have previously shown that endothelial-expressed PSMA regulates angiogenesis 7 and retinal neovascularization 8 primarily via b1 integrin-mediated cell adhesion, an important functional role for PSMA in PC had not yet been established.…”

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confidence: 99%

PSMA redirects MAPK to PI3K-AKT signaling to promote prostate cancer progression

Caromile

Shapiro

2017

Molecular & Cellular Oncology

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Increased Prostate Specific Membrane Antigen expression promotes tumor progression in prostate epithelium by dysregulating the b1-integrin/type I insulin-like growth factor receptor axis, resulting in a shift in signaling from the less aggressive mitogen-activated protein kinase-extracellular signal-regulated kinases 1 and 2 pathway to the pro-survival protein kinase B(AKT)/phosphatidylinositol 3-kinase pathway.

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Targeted Inhibition of Prostate Cancer Metastases with an RNA Aptamer to Prostate-specific Membrane Antigen

Cited by 90 publications

References 42 publications

Improved Synthesis andIn VitroEvaluation of an Aptamer Ribosomal Toxin Conjugate

Improved Synthesis andIn VitroEvaluation of an Aptamer Ribosomal Toxin Conjugate

Diagnosis of prostate cancer using anti-PSMA aptamer A10-3.2-oriented lipid nanobubbles

PSMA redirects MAPK to PI3K-AKT signaling to promote prostate cancer progression

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