1. Therapeutic Discovery: total synthesis, structural remodeling, selective scaffold synthesis and biological evaluation
Natural products continue to be a dominant force in the development of therapeutic agents, either as sole identities or derivatives. Total synthesis campaigns will be undertaken towards therapeutically interesting compounds in the efforts of assessing their cytotoxicity and as potential lead drug candidates. Through these total syntheses campaigns many synthetically, and biologically, intriguing intermediates are accessed. These intermediates will then be subjected toward structural remodeling in the efforts of generating new interesting structures of varying biological properties. In addition to new total synthesis campaigns, already established routes towards natural products will be employed if structural remodeling upon the intermediates are interesting, feasible, and not step prohibitive.
All synthetically accessed compounds and ones obtained through collaborative efforts will be assessed for cytotoxicity, and modes of action will be determined for therapeutically relevant compounds. Cytotoxicity will be assessed through cell line selectivity (IC50 determinations) and flow cytometry for determination of assessment of cell cycle arrest, apoptotic pathway connection, ROS generation, and other phenotypes. Investigation into modes of actions will include transcript profiling, connectivity mapping techniques, and pull-down experiments with biotinylated derivatives.
2. Blood-Brain Barrier Penetration: Investigation of chemical physical properties effects upon penetration and improving the means at predicting penetration
Treatment of brain cancers remains one of the main challenges in oncology. The three major types of brain cancer, all classifications of gliomas, are: astrocytomas, oligodendrogliomas, and oligo-astrocytomas. Current standard of care consists of surgical removal, radiotherapy, and/or chemotherapy. Unfortunately, prognosis for patients with malignant brain tumors is poor. Surgical removal increases median survival by 20 weeks, radiotherapy incorporation extends to 36 weeks, and inclusion of chemotheraphy increases survival to 40-50 weeks. The failure to treat these tumors is due in part to the inability to deliver therapeutics across the blood-brain barrier (BBB).
The BBB is a formulation of multiple structural, cellular (endothelial, astrocyte and pericytes cells), and physiological components that govern movement of molecules and ions. Further protecting the brain, the cellular structure of the BBB is held together and guarded by tight junctions (TJ), forming a diffusion barrier. Presences of these junctions require that small molecules enter the brain through these cells, not between. In addition, the presence of multidrug resistant proteins (MRPs) and P-glycoproteins (P-gp), located at the apical side of the BBB, actively pump a variety of anticancer agents (e.g. paclitaxel and anthracyclilnes) back into the blood.
Studies have shown that the chemophysical properties of polar surface area (tPSA) and cLopP contributor a factor into penetration. While these properties aid in preliminary calculations to predict penetration, they fail to explain other effects and their roles in penetrating this complex barrier. Noting that glycylglycine fails to penetrate, but the cyclic/rigid form is penetrable suggests that rigidity is also an important property for penetration, along with others.
To investigate the various chemophysical properties roles in BBB penetration through the synthesis of a small molecules varying in single properties. Evaluation of compounds will be performed using a parallel artificial permeability assay, which mimics the BBB tight and adherent junctions. Scaffolds that penetrate the BBB-mimic will be compared evaluated in vivo for penetration and efficacy.
3. Selective Drug Delivery: Personalized therapeutics based on selective traits/expressions within cancerous verses normal cells
Targeted drug delivery plays a vital role in efficacy of anticancer agents, as these agents do not discriminate between cancerous and healthy cells. As a result, to achieve therapeutic concentrations of active therapeutics within a specific tissue/cell type, relatively large drug dosages are required. Therefore, this lack of selectivity translates to greater therapeutic expense and drug waste. Much attention has been given to this issue, and efforts toward selective drug delivery have been undertaken in various forms, including (but not limited to): 1) multifunctional envelope-type nanodevices (MEND), 2) peptide based delivery systems, 3) receptor-endocytosis vehicles, 4) antibody-directed enzyme prodrug therapy (ADEPT), and 5) multifunctional envelope-type mesoporous silica nanoparticle (MEMSN). The major flaw in these approaches is that the portion of the drug delivered to the tumor targets is less than 5%; circulator distribution and excretion prevent delivery of the remaining drug.
Selective drug delivery to cancerous versus healthy cells relies upon key differences in the cellular membranes, microenvironments, and intracellular machinery. Development of delivery systems will be undertaken that exploit these key characteristic differences. Selective targeting of overexpressed receptors within cancers, prodrug design based upon unique microenvironmental alterations, over/under expression of cellular proteins for activation of drugs will be undertaken.