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// Zoi Diamantopoulou 1, * , Maud-Emmanuelle Gilles 1, * , Maha Sader 1 , Melissande Cossutta 1 , Benoit Vallee 1 , Claire Houppe 1 , Damien Habert 1 , Blandine Brissault 2 , Eric Leroy 2 , Federica Maione 3 , Enrico Giraudo 3 , Damien Destouches 1 , Jacques Penelle 2 , Jose Courty 1, ** and Ilaria Cascone 1, ** 1 Laboratory of Growth, Reparation and Tissue Regeneration (CRRET), University of Paris Est, ERL-CNRS 9215, 94010 Creteil, France 2 East Paris Institute of Chemistry and Materials Science, CNRS & University Paris-Est, 94320 Thiais, France 3 Department of Oncological Sciences and Laboratory of Transgenic Mouse Models, Institute for Cancer Research and Treatment, University of Torino School of Medicine, I-10060 Candiolo, Torino, Italy * These authors have contributed equally to this work ** These authors are considered as co-senior author Correspondence to: Jose Courty, email: courty@u-pec.fr Keywords: nanoparticles, antitumour activity, polyplex, nucleolin, pancreatic ductal adenocarcinoma Received: June 21, 2017 Accepted: August 27, 2017 Published: September 30, 2017 ABSTRACT In this study, a novel anticancer reagent based on polyplexes nanoparticles was developed. These nanoparticles are obtained by mixing negatively charged polyelectrolytes with the antitumour cationically-charged pseudopeptide N6L. Using two in vivo experimental tumor pancreatic models based upon PANC-1 and mPDAC cells, we found that the antitumour activity of N6L is significantly raised via its incorporation in polyplexed nanoparticles. Study of the mechanism of action using affinity isolation and si-RNA experiments indicated that N6L-polyplexes are internalized through their interaction with nucleolin. In addition, using a very aggressive model of pancreatic cancer in which gemcitabine, a standard of care for this type of cancer, has a weak effect on tumour growth, we observed that N6L-polyplexes administration has a stronger efficacy than gemcitabine. Biodistribution studies carried out in tumour-bearing mice indicated that N6L-polyplexes localises in tumour tissue, in agreement with its antitumour effect. These results support the idea that N6L nanoparticles could develop into a promising strategy for the treatment of cancer, especially hard-to-treat pancreatic cancers.

Despite the advent of several new treatment options over the past years, advanced/metastatic prostate carcinoma (PCa) still remains incurable, which justifies the search for novel targets and therapeutic molecules. Nucleophosmin (NPM1) is a shuttling nucleoprotein involved in tumor growth and its targeting could be a potential approach for cancer therapy. We previously demonstrated that the multivalent pseudopeptide N6L binds to NPM1 potently affecting in vitro and in vivo tumor cell growth of various tumor types as well as angiogenesis. Furthermore, NPM1 binds to androgen receptor (AR) and modulate its activity. In this study, we first investigated the implication of the NPM1 and its Thr199 and Thr234/237 phosphorylated forms in PCa. We showed that phosphorylated forms of NPM1 interact with androgen receptor (AR) in nucleoplasm. N6L treatment of prostate tumor cells led to inhibition of NPM1 phosphorylation in conjunction with inhibition of AR activity. We also found that total and phosphorylated NPM1 were overexpressed in castration-resistant PCa. Assessment of the potential therapeutic role of N6L in PCa indicated that N6L inhibited tumor growth both in vitro and in vivo when used either alone or in combination with the standard-of-care first- (hormonotherapy) and second-line (docetaxel) treatments for advanced PCa. Our findings reveal the role of Thr199 and Thr234/237 phosphorylated NPM1 in PCa progression and define N6L as a new drug candidate for PCa therapy.