Cell-penetrating peptides in cargo delivery : In vitro studies on uptake and in vivo studies on tumor targeting
Sammanfattning: The capability of cell-penetrating peptides (CPPs) to transport cargos over different cellular membranes both in vitro and in vivo have drawn major attention in the past decade. Three main topics on the application of CPPs have been studied in this thesis.First, several well-known CPPs, with fluorescein as a cargo, were shown to translocate into Nicotiana tabacum cultivar SR-1 protoplasts. By coupling different cargos to CPP it might be possible to effectively transport them inside the plant protoplasts. The translocation of CPPs into plant protoplasts might open up a new method for transformation of plant cells.Next, the cell-penetrating ability of the novel peptide YTA2 was characterized and it was established that chemical coupling between YTA2 and the protein cargo is not needed for the transport of the cargo over the cellular membrane in vitro. The delivery of proteins into cells by mere coincubation with CPPs is an improvement, since the chemical coupling between the CPP and the cargo molecule, which adds time-consuming synthesis and purification steps, can be omitted.Finally, by conjugating each of the two breast tumor homing peptides, the cyclic cCPGPEGAGC (PEGA) or the linear CREKA peptide, to the CPP pVEC, two cell-penetrating peptides with homing properties were obtained. Both, PEGA-pVEC and CREKA-pVEC were taken up by different breast cancer cells in vitro. Moreover, the homing capacity of the PEGA-pVEC and CREKA-pVEC was conserved in vivo, where the conjugates mainly accumulated in blood vessels in breast tumor tissue and were subsequently translocated into cells. Conjugating the anti-cancer drug chlorambucil to PEGA-pVEC or CREKA-pVEC markedly improved its efficiency. Furthermore, systemic treatment of tumor-bearing mice with chlorambucil-CREKA-pVEC significantly reduced tumor growth compared to control groups. These tumor-homing CPPs might improve both diagnosis and treatment of breast cancer tumors, by conjugation to therapeutic agents.
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