GMP-grade nanoparticle targeted to nucleolin downregulates tumor molecular signature, blocking growth and invasion, at low systemic exposure

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GMP-grade nanoparticle targeted to nucleolin downregulates tumor molecular signature, blocking growth and invasion, at low systemic exposure

Thursday, 18.02.2021

Authors and Affiliations:

Nuno A.Fonsecaab1, Ana C.Gregórioab1, Vera M.Mendesa, Rui Lopesa, Teresa Abreua, Nélio Gonçalvesa, Bruno Manadasa, Manuela Lacerdac, Paulo Figueiredod, Marta Pereirae, Manuela Gasparf, Fabiana Colellig, Daniela Pesceg, Giacomo Signorinog, Laura Focaretag, Alessandra Fuccig, Francesco Cardileg, Claudio Pisanog, Tony Cruzb, Luís Almeidah, Vera Mourab, Sérgio Simõesai e João N.Moreiraai

a CNC – Center for Neurosciences and Cell Biology, Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Faculty of Medicine (Polo 1), Rua Larga, 3004-504 Coimbra, Portugal

b TREAT U, SA, Parque Industrial de Taveiro, Lote 44, 3045-508 Coimbra, Portugal

c IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal

d IPOFG-EPE - Portuguese Institute of Oncology Francisco Gentil, Coimbra, Portugal

e CHUC – Coimbra’s Hospital and University Center, Praceta Prof. Mota Pinto, 3000-075 Portugal

f FFUL – Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal

g Biogem, Istituto di Biologia e Genetica Molecolare, Via Camporeale, 83031 Ariano Irpino, AV, Italy

h Blueclinical, Ltd, Senhora da Hora, 4460-439 Matosinhos, Portugal

i UC – University of Coimbra, CIBB, Faculty of Pharmacy, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal



Patients with breast or ovarian cancer have not benefited from improved efficacy with pegylated liposomal doxorubicin relative to free drug, likely due to the limited extent of the enhanced permeability and retention (EPR) effect, further compromising drug bioavailability in the tumor. Herein it is hypothesized that targeting nucleolin overexpressed in tumor endothelial cells (readily accessible from the vascular compartment), besides cancer cells, with PEGASEMP (doxorubicin hydrochloride in a lipid-based pegylated nanoparticle functionalized with a 31-aminoacid peptide targeting nucleolin), lessens the dependence on high systemic exposures and EPR effect for successful tumor targeting. This strategy has resulted in improved intracellular tumor bioavailability of doxorubicin, at low systemic exposure, associated with a safe toxicological profile. Levels of cell surface nucleolin dictated the antitumor activity of PEGASEMP against nucleolin-overexpressing solid tumors of diverse histological origin, evidencing a significant growth inhibition of malignant mesothelioma over the standard of care. Those observations were paralleled by an impairment of the nucleolin-positive vasculature and downregulation of typically overexpressed genes. Patient stratification based on nucleolin mRNA expression correlated with prognosis and enabled identification of breast and mesothelioma tumors that may potentially benefit from PEGASEMP. Overall, a novel principle of drug delivery is presented with potential therapeutic impact across nucleolin-overexpressing human cancers.


Journal: NanoToday