This dissertation will describe the design, characterization, biodistribution, and efficacy of peptide-targeted liposomes for use in selective treatment of multiple myeloma. Multiple myeloma (MM) is a plasma cell malignancy that forms solid lesions in the bone marrow. It is estimated that 86,000 new cases appear each year worldwide, and it is responsible for about 1% of all cancer deaths. It remains incurable with a median survival of 5 years due to recurrence and development of drug resistance. Actively targeted liposomal treatments have been shown to be able to overcome drug resistance in other types of cancers, including those in the bone marrow. In light of this, a targeted delivery system would be likely be effective in improving MM treatment outcomes.
Liposomes are a nanoparticle consisting of a spherical lipid bilayer with various elements either contained in the aqueous core, trapped in the lipophilic bilayer, or attached to a lipid to be presented on the surface. They are highly modifiable and can be designed to deliver a wide range of drugs and present molecules on the surface for targeting purposes. In order to selectively target MM cells, we discovered or designed short targeting peptide sequences that specifically bind to receptors frequently overexpressed in MM cases such as VLA-4, LPAM1, CD38, and CD138. Specifically, the design and evaluation of a liposomal system targeting both VLA-4 and LPAM-1 in vitro will be explored in Chapter 2. VLA-4 liposomes will then be further optimized for in vivo delivery to a tumor in Chapter 3. Then the knowledge gained from designing this in vivo system will be used in Chapter 3 to design additional liposomes for delivery of chemotherapeutics in vivo via targeting of CD38 and CD138. Finally, Chapter 4 will cover and compare all previously evaluated targeted liposomes as well as using the tumor-penetrating peptide iRGD and their uptake in vitro and biodistribution and tumor cell uptake in vivo.