Sujatha Kannan, MD

Assistant Professor, Pediatrics

Division of Pediatric Critical Care
Children's Hospital of Michigan

Wayne State University
3901 Beaubien Detroit, MI 48201

Phone : (313)745-0122
Email: skannan@med.wayne.edu

Imaging and Targeted therapy in maternal inflammation induced perinatal brain injury

Brain injury is a major cause of morbidity and mortality in the perinatal period. Intrauterine infection is known to be a risk factor for brain damage in the neonate irrespective of the gestational age. Intrauterine infection may lead to a fetal systemic inflammatory response mediated by cytokines that has been implicated in the development of periventricular leukomalacia (PVL) leading to lifelong disabilities such as cerebral palsy and cognitive impairment in the infant. While in recent years a number of in vitro and in vivo studies have implicated microglial cells in the development of PVL in hypoxic-ischemic brain injuries, there is a knowledge gap in understanding and recognizing the progression of the cellular events leading to white matter injury. Lack of such knowledge is a critical problem because it prevents designing of effective therapy for arresting the progression of brain injury. The long-term goal of this research group is to understand the mechanism and progression of the cellular and metabolic derangements leading to brain injury during development, and to use this information to design specific targeted therapy using novel nanopolymers. The central hypothesis is that the fetal inflammatory response following endotoxin induced intra-uterine inflammation leads to activation and recruitment of microglial cells in the fetal brain that progresses over time with widespread production of pro-inflammatory mediators leading to the death of oligodendrocytes and white matter injury, and inhibiting the microglial cells will arrest this process. This work is done using a rabbit model of neuroinflammation and cerebral palsy induced by maternal intra-uterine endotoxin administration. Imaging of neuroinflammation and white matter injury is done using PET and MRI. Drugs are targeted to activated microglial cells using dendrimers for suppressing neuroinflammation and attenuation of white matter injury.

Relevent References

1. Kannan S*, Saadani-Makki F, Muzik O, Chakraborty P, Mangner TJ, Janisse J, Romero R, Chugani D. Microglial activation in perinatal rabbit brain induced by intrauterine inflammation: Detection with [11C](R)-PK11195 and microPET. Journal of Nuclear Medicine, 48(6), 946-54, 2007.


2. Saadani-Makki F, Kannan S*, Lu X, Janisse J, Dawe E, Edwin S, Romero R, Chugani D. Intrauterine administration of endotoxin leads to motor deficits in a rabbit model: a link between prenatal infection and cerebral palsy. E-pub, October 2008, AJOG.

Other recent references related to dendrimer targeted drug delivery:

1. Perumal O, Inapagolla R, Kannan S*, Kannan RM. The effect of surface functionality on cellular trafficking of dendrimers. Biomaterials. 2008 Aug-Sep;29(24-25):3469-76. Epub 2008 May 22.


2. Kohle P, Misra E, Kannan R, Kannan S, Lieh-Lai M. Drug Complexation, in vitro release and cellular entry of dendrimers and hyperbranched polymers, International Journal of Pharmaceutics, 259, 143-160, 2003.


3. Kannan S, Kohle P, Raykova V, Glibetic M, Kannan RM, Lieh-Lai M, Bassett D, J. Effect of dendrimer end functionality on the dynamics of cellular entry and drug delivery in lung epithelial cells, Biomater. Sci. Polymer Edn, Volume 15, No. 3, 311 – 330, March 2004.


4. Kolhe P, Khandare J, Kannan RM, Pillai O, Kannan S, Lieh-Lai M. Hyperbranched polymer-drug conjugates with high drug payload for enhanced cellular delivery, Pharm. Res. 2004: 21;2185-2195.


5. Khandare J, Kolhe P, Pillai O, Kannan S, Lieh-Lai M, Kannan RM. Synthesis, cellular transport and activity of PAMAM dendrimer-methylprednisolone conjugates, Bioconjugate Chem, 2005; 16(2); 330-337.


6. Khandare J, Kolhe P, Pillai O, Kannan S, Lieh-Lai M, Kannan RM. Preparation, cellular transport, and activity of polyamidoamine-based dendritic nanodevices with a high drug payload, Biomaterials, 2006; 27(4):660-9.


7. Wang X, Inapagolla R, Kannan S*, Lieh-Lai M, Kannan RM. Synthesis, Characterization and In vitro activity of Dendrimer-Streptokinase Conjugates, Bioconjugate Chem, May-Jun;18(3):791-9, 2007.