Influence Of Size And Specificity On Pharmacokinetics, Biodistribution, And Tumor Targeting Of Widely Used Biologics: Fundamental Understanding To Applications
Specific and efficient targeting to tumors as well as many other diseases is a key to the success in several therapeutic interventions. The specificity offers the ideal way to transport and deliver a variety of biomedical entities for diagnosis, prevention, and treatment, selectively to the targeted sites. These specific targeting and delivery potentially lead to the advancement of noninvasive diagnostics and provide safer therapeutic options. Numerous factors can effectuate and determine the accomplishment of the site-specific targeting. In this dissertation, I have comprehensively investigated the influence of size and specificity on pharmacokinetics, biodistribution and tumor targeting of commonly used biologics. Six different fluorescently-labeled biologics, including two antibodies, two antibody fragments, serum albumin, and streptavidin, were used in the study to examine their distribution at whole body, ex-vivo tissue, and cellular levels in mice bearing human cervical cancer cells. The understanding of these pharmacokinetic parameters and tumor targeting outcomes would assist not only in future molecular imaging design but also therapeutic intervention development. Thereby it could render opportunity for novel treatment regimens. Utilizing the fundamental understanding in pharmacokinetics and biodistribution from our study, we have engineered two different targeted delivery systems for both imaging and delivery applications. The first system is super paramagnetic iron oxide (SPIO) nanoparticle for magnetic resonance imaging (MRI) application. The second system is polyplex nanoparticle for large genetic content delivery. Among a wide range of targeting molecules, intercellular adhesion molecule (ICAM)-1 is of great interest as a versatile targeting molecule due to its constitutively over-expressed in many carcinomas including breast, colon, non-small cell lung, and gastric tumors compared to corresponding normal epithelial cells, in tumor vasculature within an inflammatory network, and in inflammation sites. Targeting ICAM-1 would offer a great benefit through combinatorial targeting strategies to both tumor cells and tumor-associated endothelial cells. Validated in in vivo mouse models, our targeted delivery systems localized preferentially to the tumors, inflamed vasculature, as well as systemic and subcutaneous inflammation. The studies presented here demonstrate a comprehensive understanding of size and specificity parameters to tumor targeting outcomes, along with two examples of targeted delivery systems for imaging and therapeutic implications. We anticipate this work may greatly contribute to successful translation of the molecular imaging and therapeutic delivery systems into the clinic.
targeted drug delivery systems; pharmacokinetics and biodistribution; BIOLOGICS
Daniel, Susan; Zarnegar, Rasa
Ph.D. of Biomedical Engineering
Doctor of Philosophy
dissertation or thesis