Doctoral Themes

Ru Nanozymes - peptide conjugates for target metastatic cancer

Supervisors

Carla Nunes, cmnunes@fc.ul.pt

Tânia S. Morais, tsmorais@fc.ul.pt

Registration Institution

Faculdade de Ciências, Universidade de Lisboa

Project description

The growing burden of cancer incidence and mortality worldwide is one of the most important public health challenges of this century. Tumor microenvironment(TME) exhibits hypoxia, which is associated with multidrug resistance, recurrence, and metastasis in solid tumors[1,2]. Nanozymes –nanomaterials with enzyme-mimetic activities have attracted interest due to their higher physiochemical stability against harsh environments, durability and lower costs [2]. Metal nanozymes that catalyze H₂O₂ to generate hydroxyl radicals or oxygen have emerged as agents to overcome tumor hypoxia. Ruthenium hollow mesoporous nanomaterials(RuNPs) are candidates due to their high photothermal conversion rate, valence, and multiple oxidation states showing potential to overcome this. Their advantages include facile synthesis, high ability to drug loading, release behavior and multifunctionalization[6]. Nanozymes face challenges, as unsatisfied low catalytic activity and poor specificity.

This PhD proposal focus on the development of functionalized ruthenium nanozymes (with peroxidase-like activity), that will be loaded with Ru organometallic complex (TM34 or TM90) that already proved to be highly effective in vitro/in vivo[3,4]. Then they will be conjugated with specific tumor-targeting peptides with high affinity/selectivity for receptors overexpressed on cellular membranes of primary and metastatic cancer cells[5]. These all-in-one systems are an innovative generation of Ru highly specific and cytotoxic drugs, that are inactive during delivery, but stimuli- responsive at the TME.

The PhD student will acquire a strong knowledge in inorganic/organometallic synthesis and several characterization techniques. The biological evaluation will be carried out at FCT.NOVA under ongoing collaborations. A short-term visit(4/5 months) to CSIC/Spain is planned to determine the 3D-molecular structure of the peptides by NMR.

References: [1] C. Yao, et.al, Adv. Mater., 2018, 30, 1704833. [2] C.C. Huang, et.al, J. Am. Chem. Soc., 2016, 138, 5222. [3] N. Mendes et.al, Anti-Cancer Agents Med. Chem., 2017, 17, 126. [4] T. S. Morais et.al, Future Med. Chem., 2016, 8, 527. [5] J. F. Machado et.al, Dalton Trans., 2020, 49, 5974.

Keywords

Ru Nanozymes-peptide conjugate; Nanoparticles; Targeted therapy; Drug delivery

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