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The Effect of Particle Size and Shape on the In Vivo Journey of Nanoparticles

Toy, Randall
http://rave.ohiolink.edu/etdc/view?acc_num=case1396887959

Abstract Details

2014, Doctor of Philosophy, Case Western Reserve University, Biomedical Engineering.
Although several formulations of nanomedicines are approved to treat cancer, their therapeutic efficacy has been limited in the clinic. The delivery of nanoparticles, which is driven by blood flow, is hindered by high interstitial pressures in primary tumors. Moreover, clinically approved nanoparticles are not well designed to target metastasis, which is the leading cause of death from cancer. To effectively treat tumors, it is essential to improve a nanoparticle's ability to marginate (drift) to the blood vessel wall, overcome interstitial pressures, and bind to overexpressed receptors at a tumor. We assert that nanoparticle size and shape are both design parameters which must be optimized to target and treat tumors effectively. Shape, in particular, heavily influences a nanoparticle's pharmacokinetics, margination, and binding avidity to receptors. To evaluate the effect of size and shape on nanoparticle margination, the wall deposition of different classes of nanoparticles was compared under flow in a microfluidic chamber. With the knowledge that flow influences nanoparticle intravascular transport, we then employed an in vivo multimodal imaging protocol to evaluate the effect of blood flow on the intratumoral deposition of untargeted and targeted nanoparticles of unique sizes. These studies established that convection heavily influences the deposition of large nanoparticles, while active targeting to cell receptors improves the retention of smaller nanoparticles. Furthermore, these studies allowed us to derive design rules to improve the site-specific performance of nanoparticles for hard-to-treat cancers. For example, in contrast to primary tumors, micrometastatic lesions lack the hyperpermeable vasculature that allows nanoparticles to passively accumulate in the tumor interstitium. Thus, we developed a chain of iron oxide nanoparticles targeted to the alpha-v-beta-3 integrin, which is overexpressed on the vascular wall in metastatic lesions. The chain-shaped nanoparticle was identified to have high margination behavior and binding avidity, which enabled it to detect liver and lung micrometastases in a metastatic breast tumor model. Attachment of a doxorubicin liposome to the nanochain and use of a radiofrequency triggered drug release mechanism created an approach to treat metastatic breast cancer. This work demonstrates that rational selection of a nanoparticle's size and shape can positively impact the efficacy of nanoparticle chemotherapies against the aggressive forms of cancer.
Efstathios Karathanasis, Ph.D. (Advisor)
James Basilion, Ph.D. (Committee Chair)
Stanton Gerson, M.D. (Committee Member)
Harihara Baskaran, Ph.D. (Committee Member)
Mark Griswold, Ph.D. (Committee Member)
182 p.
Biomedical Engineering; Nanotechnology
nanoparticle, size, shape, triple-negative breast cancer, metastasis, margination, nanochain, liposomes, blood flow, multi-modal imaging, tumor deposition, integrin, triggered drug release, chemotherapy

Recommended Citations

Citations

  • Toy, R. (2014). The Effect of Particle Size and Shape on the In Vivo Journey of Nanoparticles [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1396887959

    APA Style (7th edition)

  • Toy, Randall. The Effect of Particle Size and Shape on the In Vivo Journey of Nanoparticles. 2014. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1396887959.

    MLA Style (8th edition)

  • Toy, Randall. "The Effect of Particle Size and Shape on the In Vivo Journey of Nanoparticles." Doctoral dissertation, Case Western Reserve University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1396887959

    Chicago Manual of Style (17th edition)

case1396887959
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© 2014, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.