Nanoparticle-based target eliminators (NTEs) to guide and monitor protein degradation in hard-to-treat cancers and chemotherapy induced senescence

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Senescence is a state of cell-cycle arrest induced by damage or stress such as chemotherapeutics. If left uncleared, persistent senescent cells induce chronic local inflammation that exacerbates cancer. Current inhibitor-based therapeutics on persistent senescence, known as senolytics, are restricted by their cytotoxicity, which leads to the present proposal on senolysis via protein degradation. The proposed senolytic strategy conjugates specific proapoptotic peptide ligands onto F127 pluronic-polydopamine nanoparticle (F127-PDA NP). By proximity effect, the protein-specific ligands will selectively bind anti-apoptotic BCL proteins and bring them close to E3-ligase (also conjugated onto the NPs), allowing ubiquitination of the former and degradation via the ubiquitin-proteasome pathway. The projectwill first develop a protocol for surface attachment of BCL protein-binding peptide onto the NP, verified by material characterisation (e.g. electron microscopy, mass spectrometry) and in vitro biological evaluation (e.g. confocal microscopy, western blotting) techniques. Upon success, the protocol will be modified to incorporate E3-ligase-binding peptide onto the NP surface. Successful attachment of both ligands will initiate in vivo experiments that assess the nanotechnology's safety and pharmacokinetic properties in mice models. The proposed nanoparticle system has a modular capability and if successful will possess senolytic properties. We envision that this system applies to multiple senescent cell types, as well as the diseases these cells cause.