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BAG3 is a multifunctional protein that can bind to heat shock proteins (Hsp) 70 through its BAG domain and to other partners through its WW domain, proline-rich (PXXP) repeat and IPV (Ile-Pro-Val) motifs. Its intracellular expression can be induced by stressful stimuli, while is constitutive in skeletal muscle, cardiac myocytes and several tumour types. BAG3 can modulate the levels, localisation or activity of its partner proteins, thereby regulating major cell pathways and functions, including apoptosis, autophagy, mechanotransduction, cytoskeleton organisation, motility. A secreted form of BAG3 has been identified in studies on pancreatic ductal adenocarcinoma (PDAC). Secreted BAG3 can bind to a specific receptor, IFITM2, expressed on macrophages, and induce the release of factors that sustain tumour growth and the metastatic process. BAG3 neutralisation therefore appears to constitute a novel potential strategy in the therapy of PDAC and, possibly, other tumours.

Introduction Cancer remains still one of the major causes of death worldwide, therefore continuous improvements in tumor-fighting strategies are necessary. Targeting drugs directly to the tumour site, to overcome the systemic side effects, represents a great challenge. Nanoparticles have increasingly been used as drug delivery system showing intriguing therapeutic efficacies. Material and methods A genetically engineered nanocarrier based on human ferritin heavy chain (HFt) able to incorporate and deliver drugs was developed. These nanoparticles contain a short motif sequence (MP) cleavable by matrix metalloproteases between the HFt subunit and a masking sequence rich in proline (P), alanine (A) and serine (S): HFt-MP-PASE40. A topoisomerase I inhibitor was loaded into these nanocarriers (HFt-MP-PASE-Topo). Cell viability of different pancreatic cancer cell lines was evaluated in vitro. In vivo the therapeutic efficacy of HFt-MP-PASE-Topo was investigated on both a pancreatic cancer cell-line-derived xenograft and a patient-derived pancreatic cancer xenograft (PDX). Results and discussions In vitro studies showed a potent cytotoxic activity of HFt-MP-PASE-Topo with an IC50 that ranges between 0,005 µM to 0,05 µM. In vivo studies further demonstrated the therapeutic efficacy of HFt-MP-PASE-Topo in pancreatic cancer-bearing mice and in PDX model. In vivo treatments exhibited a robust decrease in tumour growth furthermore the animal overall survival significantly increased in HFt-MP-PASE-Topo treated mice. Conclusion Altogether, our results indicate that HFt-MP-PASE-Topo may constitute a promising tool in anticancer therapeutics.