Polyetheylenimine-polyplexes of Spiegelmer NOX-A50 directed against intracellular high mobility group protein A1 (HMGA1) reduce tumor growth in vivo.
High mobility group A1 (HMGA1) proteins belong to a group of architectural transcription factors that are overexpressed in a range of human malignancies, including pancreatic adenocarcinoma. They promote anchorage-independent growth and epithelial-mesenchymal transition and are therefore suggested as potential therapeutic targets. Employing in vitro selection techniques against a chosen fragment of HMGA1, we have generated biostable l-RNA oligonucleotides, so-called Spiegelmers, that specifically bind HMGA1b with low nanomolar affinity. We demonstrate that the best binding Spiegelmers, NOX-A50 and NOX-f33, compete HMGA1b from binding to its natural binding partner, AT-rich double-stranded DNA. We describe a formulation method based on polyplex formation with branched polyethylenimine for efficient delivery of polyethylene glycol-modified Spiegelmers and show improved tissue distribution and persistence in mice. In a xenograft mouse study using the pancreatic cancer cell line PSN-1, subcutaneous administration of 2 mg/kg per day NOX-A50 formulated in polyplexes showed an enhanced delivery of NOX-A50 to the tumor and a significant reduction of tumor volume. Our results demonstrate that intracellular targets can be successfully addressed with a Spiegelmer using polyethylenimine-based delivery and underline the importance of HMGA1 as a therapeutic target in pancreatic cancer.
NOXXON Pharma AG, Max-Dohrn-Strasse 8-10, D-10589 Berlin, Germany.
Christian
C
Maasch
Axel
A
Vater
Klaus
K
Buchner
Werner G
WG
Purschke
Dirk
D
Eulberg
Stefan
S
Vonhoff
Sven
S
Klussmann
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D052157:Aptamers, Nucleotide / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D024003:HMGA Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011485:Protein Binding; D023041:Xenograft Model Antitumor Assays
D052157:Aptamers, Nucleotide; D004273:DNA, Neoplasm; D024003:HMGA Proteins