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Tumor priming enhances particle delivery to and transport in solid tumors

Lu, Dan
http://rave.ohiolink.edu/etdc/view?acc_num=osu1144936804

Abstract Details

2006, Doctor of Philosophy, Ohio State University, Pharmacy.
The efficient delivery of particulate therapeutic agents to solid tumors is critical for exerting their therapeutic efficacy. Our laboratory has found that high tumor cell density is the major barrier of penetration for protein-bound chemotherapeutic agents in solid tumors, and tumor priming by apoptosis-inducing pretreatment enhances the delivery of these agents. Based on these findings, we further hypothesize that tumor priming by paclitaxel could promote the delivery and transport of particulate therapeutic agents in solid tumors. To evaluate this hypothesis, several questions are raised and answered by the research of this dissertation. The first question is whether tumor priming can promote particle delivery in vivo (inside out) after systemic administration. It was found that tumor priming enhanced the total uptake and interstitial dispersion of 100 and 200 nm particles. The second question is whether tumor priming can promote particle delivery in vivo (outside in) after regional administration. It was found that tumor priming by paclitaxel-loading microspheres (TPM) enhanced the penetration of 2 micron particles to peritoneal tumors after intraperitoneal delivery. The third question is whether tumor priming can produce therapeutic benefits. It was found that tumor priming enhanced tumor-selective uptake and efficacy of PEGylated liposomal doxorubicin (Doxil®). We further investigated the potential mechanisms of the priming effect. It was found that tumor priming enhanced particle diffusion in tumor histocultures after cell density reduction. Tumor priming also caused dilation of vessels and enhancement of perfusion in xenograft tumors. Considering the involvement of multiple transport parameters for the particle delivery in vivo, the convection-diffusion-based macroscopic and microscopic transport models were applied to predict the total uptake and interstitial dispersion of particles with or without priming. The model sensitivity analysis further suggested that the increased vessel surface area per unit volume and vessel diffusive permeability mainly contributed to the increased particle concentration in tumors, and the elevated interstitial diffusion coefficient mainly contributed to the enhanced dispersion of particles around a vessel after priming. In summary, the major finding of this dissertation research was that tumor priming by paclitaxel promoted particle delivery to and transport in solid tumors after systemic and regional administration, by increasing patent vessel diameters, diffusive extravasation and interstitial transport.
M. Guillaume Wientjes (Advisor)
202 p.
Health Sciences, Pharmacy
tumor priming; particle delivery; particle transport; particle penetration; solid tumor; paclitaxel; computational modeling; diffusion and convection

Recommended Citations

Citations

  • Lu, D. (2006). Tumor priming enhances particle delivery to and transport in solid tumors [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1144936804

    APA Style (7th edition)

  • Lu, Dan. Tumor priming enhances particle delivery to and transport in solid tumors. 2006. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1144936804.

    MLA Style (8th edition)

  • Lu, Dan. "Tumor priming enhances particle delivery to and transport in solid tumors." Doctoral dissertation, Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=osu1144936804

    Chicago Manual of Style (17th edition)

osu1144936804
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© 2006, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.