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Final Report Summary - MIPC (Microsphere Based Cellular Manipulation – From Protein Delivery to Intracellular Palladium Catalysis)

Summary description of the project objectives: The objectives of the project were the application, exploitation and development of a generic microsphere cellular delivery system for the efficient and benign delivery of a broad range of cargos into cells.

Description of the work performed since the beginning of the project:

(1). Microspheres were covalently functionalised with nitrilotriacetic acid (NTA) and imido diaceticacid (IDA) to allow His-tag protein capture and subsequent cellular delivery. Model peptides based on hexa-His attached to a nuclear localisation sequence were successfully delivered to HeLa and HEK 293T cells. However cellular delivery of His-tag-enhanced green fluorescent protein (GFP) met with limited success with loss of the GFP from the microspheres (in the media) and non-specific binding of the GFP observed to the cell membrane. Effort to optimise the properties of microspheres led to the synthesis of two unique nanaoparticles: Fluorescent nanoparticles with enhanced fluorescence properties1 and Dual fiunctionalised nanaoparticles.

(2). Loading and intra-cellular release of cargos using palladium mediated coupling reactions were explored. The boronic acid groups on the dual functionalised particles allowed the conjugation of complex peptide-reporter cargos by Pd-mediated Suzuki–Miyaura cross coupling and allowed the delivery of a range of cargos into specific organelle targets.

(3). Various polymer supported Pd(0) catalyst system were prepared (see Figure 3) for “in-situ” controlled synthesis of drugs from inert intermediates or prodrugs. The catalytic activities of the Pd0 catalysts, under physiological conditions, were investigated using caged fluorophore (non-fluoroscent). As a result of Pd(0) catalytic activity of biocompatible catalysts, the decaging of fluorophore was quantified via fluorescence measurements. Further, the application of biocompatible Pd(0) catalysts was explored by a cell-based experiments for “in-situ” synthesis of various inhibitors that resulted in inhibition of the proliferation of cervical carcinoma (HeLa) and prostate cancer (PC3) cells and induces apoptosis in vitro.

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THE UNIVERSITY OF EDINBURGH
United Kingdom
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