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Title: Factors that influence tumour targeting by the enhanced permeability and retention (EPR) effect
Author: Sat, Yee Nee
ISNI:       0000 0001 3553 4780
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1999
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The enhanced permeability and retention (EPR) effect describes the selective passive tumour accumulation observed when polymer-drug conjugates and liposomal formulations are administered intravenously (i.v.). This effect is attributed to the increased vascular permeability of the angiogenic tumour blood vessels and poor lymphatic drainage within solid tumour tissue. The magnitude of tumour uptake of these polymer conjugates by the EPR effect will be vital in determining the clinical success of these approaches. Initially this study sought to characterise systematically the effect of tumour size and tumour type on the EPR effect in a number of murine and human tumour xenograft models. Two probes were used, the dye Evans blue and a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin conjugate (PKl). Approximately 50% of tumour models studied showed tumour size-dependent targeting, i.e. small tumours (<200 mg) displayed higher uptake when compared to larger tumours (>0.6 g), whilst the other models displayed size-independent targeting. Comparison of PKl levels after 1 h in a variety of tumour models of standardised size showed values in the range 2-18% dose/g tumour, a 10-fold variation. PKl contains a Gly-Phe-Leu-Gly spacer linking doxorubicin (DOX) to the polymer designed for intracellular cleavage by lysosomal cysteine proteases. In the same tumour models, the rate of PKl degradation at 1 h varied approximately 200-fold. When the tumour uptake of three DOX-carriers was compared in a standardised B16F10 murine melanoma model, highest accumulation was observed for Doxil (up to 13.2% dose/g tumour), > PKl (7.8% dose/g tumour) > a PAMAM dendrimer-DOX conjugate (2% dose/g tumour). Tumour levels showed a direct correlation with the plasma half-life of each carrier. To try and prolong the plasma half-life of PKl and thus improve the EPR mediated targeting, self-assembled PKl nanoparticles were prepared. However, preliminary experiments showed that these nanoparticles were not yet sufficiently stable to allow in vivo testing.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Polymer drug conjugates; Tissue