(202a) Drug Delivery for Cancer Therapy: Emerging Importance of Definition at the Nanoscale

One area of active exploration is to exploit advances in nanotechnology for targeted treatment of cancer where efficacy is maximized, adverse effects are minimized and as a consequence quality of life and life expectancy for patients are enhanced. Such approaches often utilize nanoscale polymeric or inorganic constructs to target tumor cells passively (by the enhance permeability and retention effect) or actively by attaching targeting moieties. Advances in nanotechnology and materials science have provided unique opportunities to fabricate drug carriers with a high degree of definition in terms of chemical structure, size, shape, surface properties, etc. The emerging question is whether such high degree of control will enable the design and development of novel drug delivery systems with superior properties compared to existing constructs. To address this question detailed studies at the interface of nano- (materials/characteristics) and biotechnology (whole animal, tissue, cells and subcellular compartments) need to be carried out. Over the past few years we have focused on the design and development of multifunctional nanoconstructs for delivery of bioactive agents to solid tumors. This presentation will be an overview of our efforts in the design and development of recombinant polymers for cancer gene therapy [1], evaluating the toxicity and cellular uptake of inorganic nanoconstructs as a function of geometry, size, charge, and surface properties [2], assessing the influence of generation, concentration, incubation time, and surface properties of poly amido amine dendrimers on their cellular transport and toxicity in the context of oral drug delivery [3], and finally design and development of water-soluble polymer-peptide conjugates for targeted drug delivery to sites of tumor angiogenesis [4].

References: [1] J. Gustafson and H. Ghandehari, Silk-Elastinlike Protein Polymers for Cancer Gene Therapy, Advanced Drug Delivery Reviews, e-pub ahead of print. [2] A. Gormley, and H. Ghandehari, Evaluation of Toxicity of Nanostructures in Biological Systems, In: Nanotoxicity-From In Vivo and In Vitro Models to Health Risks (Sahu, S. C., and Casciano, D. A., eds.), John Wiley & Sons, Ltd, West Sussex, pp 115-159, (2009). [3] D. Sweet Goldberg, H. Ghandehari, and P.W. Swaan, Cellular Entry of G3.5 PAMAM Dendrimers by Clathrin- and Dynamin-Dependent Endocytosis Promotes Tight Junctional Opening in Intestinal Epithelia, Pharmaceutical Research, 27:1547-57 (2010). [4] D.B. Pike, H. Ghandehari, HPMA Copolymer-Cyclic RGD Conjugates for Tumor Targeting. Adv Drug Deliv Rev. 62: 167-183 (2010).

Acknowledgement: Efforts of many present and past lab members as well as collaborators are deeply appreciated. Financial support is made possible by NIH (2R01 CA107621, R01 EB007171, R01 EB007470, R01 ES01625501), NSF (NIRT-0608906) and the Utah Science Technology and Research (USTAR) Initiative.