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DNA-triggered release liposomes : a pharmaceutical strategy for improving the tumor exposure of chemotherapeutic agents

University of British Columbia

Long circulating liposomes have been demonstrated to be an attractive delivery system for anticancer agents with favorable tumor drug accumulation. However, the slow rate of drug release from these liposomes may limit the level of drug exposure in the tumor available for cell uptake and one strategy to address this problem is to develop long circulating liposomes with selective drug release at the tumor. With the well-known propensity of fusogenic cationic liposomes to associate with DNA and strong evidences indicating selective localization of extracellular DNA in solid tumors, it is hypothesized that a fusogenic cationic liposome formulation containing DOTAP and DOPE would exhibit selective drug release in the tumor. This thesis presents a stepwise approach to the design of such liposomes. In order to develop a triggered release liposome that selectively targets the extracellular DNA in the tumor, the characteristic features of these DNA are first studied. In vivo results in Chapter 2 demonstrate an elevated level of extracellular DNA in the tumor in comparison with other organs and that they are in the size range of 200-3000 bp. Secondly, it is essential for an optimum triggered release liposome to remain stable in the circulation before reaching the tumor. Results from Chapter 3 demonstrate that the incorporation of DSPE-PEG 350 into DOTAP/DOPE liposomes prevents their characteristic salt-induced aggregations in physiological solutions while retaining the capacity to be triggered by extracellular DNA to release its entrapped contents. The in vivo results from Chapter 4 demonstrate the prolonged circulation time of DOTAP/DOPE/DSPE-350 (50:35:15) liposomes in H460 tumor bearing mice. These liposomes were stable in the circulation with selective tumor release of the entrapped contents. The results from these studies provide the basis for developing DNA triggered release liposomes that can selectively release their entrapped therapeutic agents in the tumor.

Thesis/Dissertation

application/pdf

2009-11-02

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http://hdl.handle.net/2429/14583

Pharmaceutical Sciences

University of British Columbia

UBCV

DSpace