Abstract
The targeting of specific tissue is a major challenge for the effective use of therapeutics and agents mediating this targeting are strongly demanded. We report here on an in vivo selection technology that enables the de novo identification of pegylated DNA aptamers pursuing tissue sites harbouring a hormone refractory prostate tumour. To this end, two libraries, one of which bearing an 11 kDa polyethylene glycol (PEG) modification, were used in an orthotopic xenograft prostate tumour mouse model for the selection process. Next-generation sequencing revealed an in vivo enriched pegylated but not a naïve DNA aptamer recognising prostate cancer tissue implanted either subcutaneous or orthotopically in mice. This aptamer represents a valuable and cost-effective tool for the development of targeted therapies for prostate cancer. The described selection strategy and its analysis is not limited to prostate cancer but will be adaptable to various tissues, tumours, and metastases. This opens the path towards DNA aptamers being experimentally and clinically engaged as molecules for developing targeted therapy strategies.
Highlights
Prostate cancer is the most common cancer among men, with approximately 1.1 million new cases diagnosed per year worldwide[1]
Spectroscopic data indicate that the conformation of the DNA aptamer is not impaired by the polyethylene glycol (PEG) moiety, it might directly interact with the target structures, explaining D3P-21’s PEG-dependent interaction properties
Tumours from mice injected with phosphate buffered saline (PBS) were used as negative tumours during the library extraction and amplification steps to discard contamination of the samples
Summary
Prostate cancer is the most common cancer among men, with approximately 1.1 million new cases diagnosed per year worldwide[1]. Tomasetti and Vogelstein recently described occurrence of random mutations during DNA replication in cancer stem cells playing an important role in the development of certain types of tumours[8]. Developing new therapeutic strategies with high specificity for the malignant tissue is of strong interest but challenging once prostate cancer progresses to an androgen-independent, hormone refractory state. A prostate cancer targeting RNA aptamer selected in an internalisation cell-SELEX procedure was successfully used, in combination with two highly toxic drugs, for the inhibition of tumour growth in vivo[20]. An in vivo selection approach is described, employing DNA libraries for the identification of aptamers targeting androgen independent prostate tumours in an orthotopic xenograft mouse model. Spectroscopic data indicate that the conformation of the DNA aptamer is not impaired by the PEG moiety, it might directly interact with the target structures, explaining D3P-21’s PEG-dependent interaction properties
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