This award by the Biomaterials Program in the Division of Materials Research, and co-funded by the Thermal Transport Processes Program (CBET/ENG) to the University of Illinois, Chicago, is to create a class of novel dendrimer-polymer hybrid nano-particles that utilizes a combination of biomimetic tumor targeting strategies of cell rolling and multivalent binding. The present project will mimic naturally occurring processess (cell rolling and multivalent binding) for enhanced tumor targeting, integrated within a signle hybrid NP system. This "mothership" approach will have major implications and potentially high reward in the emerging area of biomimetic nanotechnology. Successful achievement of the proposed study will: i) significantly advance the understanding of cancer targeting using multiple targeting mechanisms in a kinetically controlled manner; ii) establish a database describing the effects of spatial construction of targeting agents, targeting kinetics, particle properties, polymer degradation rates, multivalent effect, nanoparticle rolling, and tumor penetration on targeting efficacy; and potentially iii) present a novel, transformative platform technology for targeted cancer therapy. The PI will develop and expand education and outreach activities involving, among others, high-school internship programs in underserved areas, and research experiences for undergraduates and teachers. Additionally, the research results and experimental techniques developed in this program will be disseminated via publications and proceedings at international conferences as well as via integration into classroom instruction, both at the undergraduate and graduate levels.
Technical Part:
Although recent advances in nanotechnology have culminated in a number of promising delivery platforms for tumor targeting, successful clinical implementation of such technologies has been hindered largely due to a lack of fundamental understanding on nano-bio interactions, resulting in clinically unmet targeting efficacy. The multifaceted nature of cancer has often caused ineffective targeting of nanocarriers that rely on one, or less commonly two, of currently available targeting strategies, i.e., passive and active targeting. This award is to support an effort to develop a new nanocarrier system that integrates multiple targeting mechanisms within a single delivery platform through hybridization of poly(amidoamine) (PAMAM) dendrimers and polymeric nanoparticles (NPs). It is hypothesized that overall targeting efficacy of the novel hybrid nanoparticles (NPs), or nanohybrids, will be substantially enhanced using biomimetic targeting approaches in a kinetically controlled manner. Through chemical, physical, and biological studies, sequential utilization of three targeting mechanisms will be explored: i) Recruiting of the hybrid NPs from bloodstream to angiogenic endothelia through leukocyte-mimicking rolling; ii) Extravasation of the size-controlled hybrid NPs (~100 nm in diameter) to tumors, facilitated by the dynamic rolling and the enhanced permeability and retention effect; and iii) Multivalent targeting and efficient tumor penetration of targeted dendrimers to individual tumor cells upon release through diffusion from and degradation of the NP shell. The new design of the nanocarriers will be validated through a series of physicochemical and biological assays.
