Glucose-Functionalized Silver Nanoparticles as a Potential New Therapy Agent Targeting Hormone-Resistant Prostate Cancer cells

Abstract

Mariana Morais,1,2,* Vera Machado,1,* Francisca Dias,1 Patrícia Figueiredo,3 Carlos Palmeira,4– 6 Gabriela Martins,4,5 Rui Fernandes,7,8 Ana Rita Malheiro,7,8 Kirsi S Mikkonen,3,9 Ana Luísa Teixeira,1,2 Rui Medeiros1,2,6,10,11 1Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Research Center-LAB2, Porto, 4200-072, Portugal; 2ICBAS, Abel Salazar Institute for the Biomedical Sciences, University of Porto, Porto, 4050-513, Portugal; 3Department of Food and Nutrition, Faculty of Agriculture and Forestry, University of Helsinki, Helsinki, FI-00014, Finland; 4Department of Immunology, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, 4200-072, Portugal; 5Experimental Pathology and Therapeutics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Research Center-LAB2, Porto, 4200-072, Portugal; 6Biomedical Research Center (CEBIMED, Faculty of Health Sciences, Fernando Pessoa University (UFP), Porto, 4249-004, Portugal; 7HEMS-Histology and Electron Microscopy, i3S-Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, 4200-135, Portugal; 8IBMC, Instituto de Biologia Molecular e Celular da Universidade do Porto, Porto, Portugal; 9Helsinki Institute of Sustainability Science (HELSUS), University of Helsinki, Helsinki, FI-00014, Finland; 10Research Department, LPCC- Portuguese League Against Cancer (NRNorte), Porto, Portugal; 11Faculty of Medicine, University of Porto (FMUP), Alameda Prof. Hernâni Monteiro, University of Porto, Porto, 4200-319, Portugal*These authors contributed equally to this workCorrespondence: Rui Medeiros; Ana Luísa Teixeira, Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Research Center-LAB2, E Bdg 1st floor, Rua Dr António Bernardino de Almeida, Porto, 4200-072, Portugal, Tel [phone] Ext:5115, Fax [phone], Email [email protected]; [email protected]: Silver nanoparticles (AgNPs) have shown great potential as anticancer agents, namely in therapies’ resistant forms of cancer. The progression of prostate cancer (PCa) to resistant forms of the disease (castration-resistant PCa, CRPC) is associated with poor prognosis and life quality, with current limited therapeutic options. CRPC is characterized by a high glucose consumption, which poses as an opportunity to direct AgNPs to these cancer cells. Thus, this study explores the effect of glucose functionalization of AgNPs in PCa and CRPC cell lines (LNCaP, Du-145 and PC-3).Methods: AgNPs were synthesized, further functionalized, and their physical and chemical composition was characterized both in water and in culture medium, through UV-visible spectrum, dynamic light scattering (DLS), transmission electron microscopy (TEM) and Fourier-transform infrared spectroscopy (FTIR). Their effect was assessed in the cell lines regarding AgNPs’ entering pathway, cellular proliferation capacity, ROS production, mitochondrial membrane depolarization, cell cycle analysis and apoptosis evaluation.Results: AgNPs displayed an average size of 61nm and moderate monodispersity with a slight increase after functionalization, and a round shape. These characteristics remained stable when redispersed in culture medium. Both AgNPs and G-AgNPs were cytotoxic only to CRPC cells and not to hormone-sensitive ones and their effect was higher after functionalization showing the potential of glucose to favor AgNPs’ uptake by cancer cells. Entering through endocytosis and being encapsulated in lysosomes, the NPs increased the ROS, inducing mitochondrial damage, and arresting cell cycle in S Phase, therefore blocking proliferation, and inducing apoptosis.Conclusion: The nanoparticles synthesized in the present study revealed good characteristics and stability for administration to cancer cells. Their uptake through endocytosis leads to promising cytotoxic effects towards CRPC cells, revealing the potential of G-AgNPs as a future therapeutic approach to improve the management of patients with PCa resistant to hormone therapy or metastatic disease.Keywords: castration-resistant prostate cancer, hormonal therapy, therapy resistance, Warburg Effect

Keywords

• castration resistant prostate cancer
• hormonal therapy
• therapy resistance
• warburg effect