Recent studies are confirming that differences exist between the normal and diseased endothelium, in cancer as well as for other diseases, in the organization of the vascular network, mean blood velocity and vascular permeability; and in the expression of specific vascular markers.

Nano-sized particulate systems (nPS), sufficiently small to be administered at the systemic level, transported by the blood flow can reach potentially any site within the macro– and microvascular systems carrying simultaneously imaging and therapeutic agents. In addition, their geometry (size and shape) and surface physico-chemical properties (3S problem) can be tailored to enhance the specific recognition of biological targets and escape the sequestration by the reticular-endothelial system (RES).

The objective of this ANH proposal is two-fold: i) develop a nPS for imaging and treating the inflamed vasculature with superior specificity and MRI contrast, and through this ii) develop an integrated framework for the rational design of nPSs combining mathematical modeling and in-vivo live animal imaging.

These goals will be achieved by integrating expertise pertaining to different fields such as engineering, chemistry, physics, biology and medicine. Four cores/groups will be involved: (i) a chemistry core for the development of single walled carbon nanotubes loaded with Gd3+ ions (Gadonanotubes – GdNT) at Rice University; (ii) a molecular biology core for the development and selection of filamentous phages display peptides (Phages) at the MD Anderson Cancer Center; (iii) an engineering core for the mathematical design, fabrication and in-vitro testing of silicon-based nano-porous particles (Si-nPS) at the University of Texas – HSCH; and (iv) a vascular biology core for analyzing the behavior of particulate systems within the vasculature of live animals at the Baylor College of Medicine.

The nPS to be developed will comprise the silicon-based nano-porous particles (Si-nPS) (engineering core) loaded with the Gadonanotubes (GdNT) (chemistry core) located within their porous structure and coated with a network of filamentous phage display peptides (Phages) (molecular biology core). The selectivity of the Phages will provide the Si-nPS with superior vascular targeting properties; whereas the loaded GdNTs will serve simultaneously as MRI contrast enhancers and therapeutic agents through magnetic hyperthermia. Within this proposal RGD-4C peptides will be used for targeting integrins on the inflamed tumor endothelium.

Mathematical models will be developed (engineering core) to identify the optimal combination of Size, Shape and Surface properties for maximizing vascular targeting while minimizing RES sequestration of nPS. Intravital microscopy (vascular biology core) and adhoc in-vitro apparata will be used to validate and refine the predictive models. Discoidal, dome–shaped and cylindrical Si-nPS with nominal diameters ranging from about 0.6 to 1.6 μm will be considered.

The results and interdisciplinary knowledge originated from this ANH proposal are expected to fuel the development of a research center for the optimal design and development of nPS to be employed in the early detection and treatment of a variety of diseases involving vascular alterations (cancer, cardiovascular, infectious, hemorrhaging, gynecological to cite a few).