Development and High Throughput Screening of Targeted Anticancer Nanomedicines
The Project #4 belongs to the area of research focus “Multifunctional nano-therapeutics and post-therapy monitoring tools”. As an integral part of our CCNE project, it aims to pave the way to clinical trials of targeted nanomedicines by dramatically accelerating their screening at early steps of development by adapting the principals of combinatorial parallel synthesis of multiple liposomal nanostructures. In the proposed concept, the advanced pharmaceutical anocarriers – PEGylated “stealth” liposomes encapsulating one of the four representative drugs (doxorubicin, paclitaxel, Gemcitabine or vincristin) are targeted to the pancreatic and lung tumor cells by cancer cell-specific phage fusion proteins. The phages will be affinity selected from landscape phage libraries by their ability to bind very specifically cancer cells and/or penetrate into the cells. The selected tumor-specific phages will be amplified, stripped and converted into the drug-loaded vesicles, in which spontaneously inserted phage proteins span the lipid bilayer displaying the tumor-binding peptides on the surface of the vesicles. To demonstrate the power of the new approach, up to 100 phages demonstrating highest selectivity and affinity towards the target cancer cells will be combined with four “parental” liposomes containing different anticancer drugs and tested in high throughput format. The most efficient compositions of targeting proteins and drugs will be further optimized, prepared in large scale in GLP/GMP conditions at the Center’s Scaling up and Manufacturing Core and studied for antitumor activity in vivo in mouse models at the animal facilities of Northeastern University. In contrast to the traditional rational design of anticancer nanomedicines, the proposed combinatorial approach does not require preliminary identification of cancer-specific cellular receptors, development of peptide or antibody ligands to these receptors and idiosyncratic techniques for their conjugation to the drug-loaded nanoparticles. We hypothesize that proposed combinatorial approach to the development of targeted liposomal nanomedicines will lead to significant enhancement of their screening throughput by as much as 1000-fold, and result in dramatic acceleration of translational process.