Our proposed research addresses the full spectrum of challenges underlying nanocarriers as targeted delivery platforms for cancer therapy, it couples unique genomic insight and renowned clinical expertise on Acute Lymphoblastic Leukemia (ALL) with two new, powerful and versatile targeted nanoparticle delivery systems - protocells (nanoporous nanoparticle supported lipid bilayers) and virus-like particles - each directed with peptides identified by a high complexity virus-like particle (VLP) affinity selection technology. It promises the development of universal nanocarrier platforms enabling the delivery of therapeutics, imaging and contrast agents, sensors, etc. to arbitrary cancer cells with unprecedented selectivity and minimal side effects. Within the highly populated field of targeted drug delivery using nanocarriers, our proposed research is distinguished by three unique attributes: 1) The Pediatric Leukemia Program in the UNM Cancer Research and Treatment Center led by co-PI Cheryl Willman, MD, has pioneered the use of genomic technology in the analysis of the molecular mechanisms that underlie the leukemic phenotype. As part of this effort, her team has identified a number of proteins with extracellular epitopes that are differentially expressed on cells from high risk ALL patients. We will use this novel genomic information as the basis of the development of nanoparticles that specifically target a population of cells generally found to be resistant to standard intense chemotherapies. 2) Using virus like particles (VLPs) of bacteriophage MS2, David Peabody, PhD, created a new peptide display system, which integrates into a single platform the affinity selection capability of conventional filamentous phage display and the cargo carrying capacity of the hollow MS2 capsid. This display and affinity selection technology has the potential to create and evaluate libraries with complexities orders of magnitude greater than those used to date and therefore the potential to identify peptides with unprecedented targeting and delivery selectivities to arbitrary cell types. 3) Targeting peptides will be Implemented In protocells and VLPs. recently developed within the laboratory of co-PI, Jeff Brinker, PhD, through support by the NIIH Nanomedicine initiative. As demonstrated for hepatocarcinoma cells, both classes of nanocarriers achieve exceptionally high selectivity through multivalency effects engineered at the nanoscale, but they are complementary with respect to surface mobility, loading and release strategies.
The relevance of this research is its contribution to the successful treatment of the ~20% of ALL children who either fail therapy or relapse after entering an Initial remission and who have nearly a zero rate of survival. A further value of our proposed research will be the development of generic, universal nanoparticle platforms tailored to target, identify, and treat arbitrary, select, and often minute populations of diseased cells.
|Pascal, Jennifer; Ashley, Carlee E; Wang, Zhihui et al. (2013) Mechanistic modeling identifies drug-uptake history as predictor of tumor drug resistance and nano-carrier-mediated response. ACS Nano 7:11174-82|
|Kendall, Eric L; Ngassam, Viviane N; Gilmore, Sean F et al. (2013) Lithographically defined macroscale modulation of lateral fluidity and phase separation realized via patterned nanoporous silica-supported phospholipid bilayers. J Am Chem Soc 135:15718-21|
|Tarn, Derrick; Ashley, Carlee E; Xue, Min et al. (2013) Mesoporous Silica Nanoparticle Nanocarriers: Biofunctionality and Biocompatibility. Acc Chem Res :|
|Townson, Jason L; Lin, Yu-Shen; Agola, Jacob O et al. (2013) Re-examining the size/charge paradigm: differing in vivo characteristics of size- and charge-matched mesoporous silica nanoparticles. J Am Chem Soc 135:16030-3|
|Ashley, Carlee E; Carnes, Eric C; Epler, Katharine E et al. (2012) Delivery of small interfering RNA by peptide-targeted mesoporous silica nanoparticle-supported lipid bilayers. ACS Nano 6:2174-88|
|Ashley, Carlee E; Carnes, Eric C; Phillips, Genevieve K et al. (2011) Cell-specific delivery of diverse cargos by bacteriophage MS2 virus-like particles. ACS Nano 5:5729-45|
|Ashley, Carlee E; Carnes, Eric C; Phillips, Genevieve K et al. (2011) The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers. Nat Mater 10:389-97|