Development of Fibrinolytic Platelet Systems for the Reduction of Cancer Metastasis and in vitro Feasibility of Targeting Thrombosis
Open Access DepositedThe objective of this dissertation is to develop a fibrinolytic platelet system capable of disassociating circulating tumor cell clusters and enhancing the lysis of thrombi by leveraging platelet interactions for targeted delivery. Platelets play a key role in the metastasis of circulating tumor cell (CTC) clusters and the formation of thrombi largely through receptor mediated interactions. As such, a platelet-based carrier approach provides a promising opportunity to address these critical medical challenges. To explore this fibrinolytic platelet approach, we first characterized lyophilized platelets (LPs) and their effect on unaltered platelet function. The LPs have an inhibitory effect on platelet aggregation but promote platelet adhesion, which could be leveraged in promising drug delivery applications. These LPs also maintain some of the critical surface receptors necessary to interact with CTC clusters or thrombi. We then developed a platelet-based system to target circulating tumor cell (CTC) clusters and deliver a fibrinolytic agent to dissociate the fibrin bound clusters into single cells with lower metastatic potential. We characterized the tPA loading onto platelet-decoy and LPs carriers and assessed the enhanced fibrinolytic activity of the system. We then demonstrated that the fibrinolytic platelets can effectively disassociate tumor cell clusters in vitro and assessed the efficacy of this system for reducing cancer metastasis in vivo. Finally, we applied a modified fibrinolytic platelet approach to the need for an effective method of delivering tPA to thrombi, which can increase the efficacy of smaller fibrinolytic doses and reduce the risk of severe complications such hemorrhage. Using partially activated platelet decoys, we demonstrated that the system can adhere on a thrombogenic surface and can effectively lyse fibrin in vitro. Through these analyses this dissertation demonstrates the viability and efficacy of a fibrinolytic platelet approach for the reduction of cancer metastasis and the lysis of thrombi.
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