(579a) Analysis of Transport Mechanisms Governing Efficient Tumor Penetration and siRNA Delivery by RGD-PAMAM Dendrimers

The inability of macromolecular drugs and nanoscale drug delivery systems to penetrate into solid tumors represents a major barrier to efficient drug delivery in these malignancies. A complex network of abnormal cells, extracellular matrix (ECM) proteins and a limited number of blood vessels within solid tumors render efficient diffusion of drug molecules particularly challenging. In this work, poly(amidoamine) (PAMAM) dendrimers presenting varying numbers of cyclic(RGD) targeting peptides were generated to facilitate siRNA delivery to malignant glioblastoma cells. The presence of RGD peptides on PAMAM dendrimers was found to enhance the penetration of siRNA cargo through an in vitro three-dimensional tumor spheroid model of malignant glioma in a manner that depends on the number of RGD peptides present[1]. The mechanisms governing efficient nanoparticle transport including integrin-binding affinity and cell internalization kinetics were studied quantitatively in this work. Surface plasmon resonance (SPR) biosensor experiments showed that a decreased binding affinity to integrin protein receptors was observed with increasing RGD number. The effect of dendrimer functionalization with RGD on cellular internalization kinetics was also determined. Incorporation of these experimental parameters into a mathematical diffusion model of tumor spheroid drug penetration provides a quantitative understanding of the mechanisms governing efficient tumor penetration by PAMAM-RGD conjugates. This work provides a framework for the rational design of drug-delivery systems to balance cellular binding and internalization rates to facilitate efficient drug delivery into solid tumors.

1. Waite, C. L.; Roth, C. M., PAMAM-RGD Conjugates Enhance siRNA Delivery Through a Multicellular Spheroid Model of Malignant Glioma. Bioconjugate Chemistry 2009, 20, (10), 1908-1916.