Primary and secondary brain tumors are a leading cause of morbidity and mortality in the general American population. In recent years an enormous effort has been made to deliver drugs to the brain by targeting specific molecules or transport mechanisms across the blood brain barrier. Attempts to selectively deliver chemotherapeutic drugs to the brain by direct intra-arterial injection have not found wide clinical acceptance because of inadequate control of tissue drug concentrations, and the lack of a method to rigorously investigate the fast kinetics of intra-arterial drugs in pre-clinical studies. During the last decade considerable advances have been made in endovascular surgery. The development of microcatheters that are capable of manipulating blood flow and selectively delivering drugs to specific regions of the brain, can greatly improve the safety and efficacy of intra-arterial drugs. The application will show that modifying the blood flow and bolus injection characteristics can dramatically enhance intra-arterial delivery of drugs to the brain. We seek to investigate the effects of manipulating cerebral blood flow and bolus configuration on intra-arterial delivery of chemotherapeutic drugs to normal brain and tumor tissues, so as to maximize regional deposition of the drugs. We will further investigate the role of lipid solubility in enhancing drug delivery to the brain, particularly when the regional blood flow is transiently (30- 60s) reduced. Understanding the kinetics of intra-arterial drugs whose concentrations change rapidly after injection, requires high-speed in-situ measurements. Thus, insight into intra-arterial drug kinetics has hitherto been limited to only a few studies. This application uses the recently developed Optical Pharmacokinetics (OP) technique to measure regional drug concentrations in the brain. OP tracks tissue drug concentrations in virtual real time (50 ms/measurement). We will apply the OP measurements for the first time to the brain. OP measurements are made through the inner table of the skull; therefore, the brain tissue integrity is not compromised. In summary, the proposed research will improve methods of drug delivery to the brain. It will enhance the safety and efficacy of intra-arterial chemotherapeutic drugs. It will lead to new protocols for the treatment of brain cancers. ? ? Public Health Relevance: The proposed research which uses novel optical technology and new techniques of intraarterial drug delivery, will considerably advance the understanding of intraarterial drug kinetics. It will lead to new protocols for delivery of chemotherapeutic drugs for treating brain cancers. ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Baker, Houston
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Schools of Medicine
New York
United States
Zip Code
Joshi, Shailendra; Singh-Moon, Rajinder P; Ellis, Jason A et al. (2015) Cerebral hypoperfusion-assisted intra-arterial deposition of liposomes in normal and glioma-bearing rats. Neurosurgery 76:92-100
Joshi, Shailendra; Singh-Moon, Rajinder; Wang, Mei et al. (2014) Real-time hemodynamic response and mitochondrial function changes with intracarotid mannitol injection. Brain Res 1549:42-51
Joshi, Shailendra; Singh-Moon, Rajinder P; Wang, Mei et al. (2014) Transient cerebral hypoperfusion assisted intraarterial cationic liposome delivery to brain tissue. J Neurooncol 118:73-82
Singh-Moon, Rajinder P; Roblyer, Darren M; Bigio, Irving J et al. (2014) Spatial mapping of drug delivery to brain tissue using hyperspectral spatial frequency-domain imaging. J Biomed Opt 19:96003
Joshi, Shailendra; Singh-Moon, Rajinder; Wang, Mei et al. (2014) Cationic surface charge enhances early regional deposition of liposomes after intracarotid injection. J Neurooncol 120:489-97
Joshi, Shailendra; Ellis, Jason A; Emala, Charles W (2014) Revisiting intra-arterial drug delivery for treating brain diseases or is it ""déjà-vu, all over again""? J Neuroanaesth Crit Care 1:108-115
Romanov, Alexander; Moon, Rajinder-Singh; Wang, Mei et al. (2014) Paradoxical increase in the bispectral index during deep anesthesia in New Zealand white rabbits. J Am Assoc Lab Anim Sci 53:74-80
Ergin, Aysegul; Wang, Mei; Zhang, Jane Y et al. (2012) The feasibility of real-time in vivo optical detection of blood-brain barrier disruption with indocyanine green. J Neurooncol 106:551-60
Joshi, Shailendra; Ergin, Aysegul; Wang, Mei et al. (2011) Inconsistent blood brain barrier disruption by intraarterial mannitol in rabbits: implications for chemotherapy. J Neurooncol 104:11-9
Wang, Mei; Agarwal, Sachin; Mayevsky, Avraham et al. (2011) Optically measured NADH concentrations are unaffected by propofol induced EEG silence during transient cerebral hypoperfusion in anesthetized rabbits. Brain Res 1396:69-76

Showing the most recent 10 out of 11 publications