|
Perinatology Research Branch(PRB) Nanotechnology Lab
|
There are a wide range of dendrimers with differing building blocks. PAMAM dendrimers are
the most widely studied dendrimers. Our research focuses on three aspects, to build tailored dendrimer nanodevices for specific clinical applications: (1) understanding the intrinsic biodistribution properties of dendrimers, to learn about the cells types and disease processes that are natural targets for dendrimers. We do this by a combination of in vivo imaging techniques such as Positron emission tomography, MRI, and confocal microscopy of tissues; (2) understanding the cellular release profiles needs to design delivery systems. For example, we have designed glutathione sensitive linkers that will release the drug only intracellularly, but not during blood circulation (Bioconjugate Chemistry 2008); (3) develop platform technologies that have common themes, such as neuroinflammation
The Kannan group is focused on developing dendrimer nanodevices starting from the preparation of nanodevices, in vitro release and cellular characterization, testing in animal models, and translation. The application platforms include:
 Neuroinflammation in chorioamnionitis (collaboration with S. Kannan and R. Romero): We are establishing a translational nanomedicine lab in the NIH Perinatology Research Branch (PRB) for developing maternal-fetal applications. A group of 6 post-docs and two graduate students are working in an inter-disciplinary setting to develop and implement these strategies. More opportunities exist for additional researchers to be added in this exciting area.
Neuroinflammation associated with Macular degeneration (collaboration with R. Iezzi): This collaboration with the Kresge Eye Institute has led to the development of a patented sustained release intravitreal delivery device
Neuroinflammation associated with Spinal Cord Injuries (collaboration with Harry Goshgarian – Anatomy and Cell Biology): This effort seeks to develop sustained brain delivery strategies for functional recovery following spinal cord injuries.
Nanotoxicology/genomics of dendrimers (Collaboration with Ray Novak – Institute of Environment and Health Science): In preparation for pre-clinical studies, we seek to understand the effects of dendrimers and dendrimer nanodevices at the gene level.
|
|
|
Some salient features of the research are explained below:
- Nanodevice preparation: our group has the capability to conjugate a wide range of functional moieties (drugs, peptides, imaging agents, targeting ligands). We use linking chemistries for drugs that can release them at different rates (very fast or sustained), and at different subcellular compartments (please see publications below).
- The glutathione (GSH) sensitive linkers enable fast drug release from dendrimer conjugates at intracellular glutathione levels, but not in blood circulation. As shown below, the conjugates can release more than 50% of the drug in about one hour at intracellular GSH levels, but they do not release any drug in the absence of GSH:
- The dendrimer-drug conjugates enter the target cells for neuroinflammation (microglial cells) and deliver drugs significantly better, producing efficacies several fold better than the free drug, enabled by superior intracellular transport and drug release from conjugates.
|
|
|
 
Confocal microscopy images (630x) after 2 hours of treatment with (Figure-A) control, (Figure-B) FITC-PAMAM-NH-CO-Pr-S-S-NAC. The FITC-PAMAM-NH-CO-Pr-S-S-NAC conjugates appear to be mainly localized in the cytoplasm while the nucleus appears to be relatively free of the presence of any fluorescence at this time scale.
|
|
|
The nitrite assay shows that the dendrimer-n-actyl cysteine (D-NAC) conjugates more than a 20-fold improvement in efficacy compared to free drug. At the lowest dose (0.5 mM), the conjugate was significantly better than the free drug at the highest administered dose (8 mM) .
[14]'Drug release characteristics of PAMAM dendrimer–drug conjugates with different linkers.',Yunus E. Kurtoglu, Manoj K. Mishra, Sujatha Kannan, Rangaramanujam M. Kannan, International Journal of Pharmaceutics (In Press)
[13]'Multifunctional Dendrimer-templated Antibody Presentation on Biosensor Surfaces for Improved Biomarker Detection’, H.Han, R.M.Kannan, S.Wang, G.Z.Mao, J.P.Kusanovic, R.Romero, Advanced Functional Materials, in press, Oct (2009), 19, 1–13
[12]'Stimuli-responsive star polyethylene glycol conjugates for improved intracellular delivery of N-acetyl cysteine in neuroinflammation.',Raghavendra S. Navath, Bing Wang, Sujatha Kannan, Roberto Romero, Rangaramanujam M. Kannan, Journal of Controlled Release (In Press)
[11]'Anti-inflammatory and anti-oxidant activity of anionic dendrimer-N-acetyl cysteine conjugates in activated microglial cells',Wang, Bing; Navath, Raghavendra S.; Romero, Roberto; Kannan, Sujatha; Kannan, Rangaramanujam. International Journal of Pharmaceutics (2009), 377(1-2), 159-168.
[10]'Effects of Branching Architecture and Linker on the Activity of Hyperbranched Polymer-Drug Conjugates.',Perumal, Omathanu; Khandare, Jayant; Kolhe, Parag; Kannan, Sujatha; Lieh-Lai, Mary; Kannan, Rangaramanujam M., Bioconjugate Chemistry (2009), 20(5), 842-846.
[9]'Dendrimer-based diagnostic nanodevices for improved detection of inflammatory markers in the amniotic fluid.', Han, Hye Jung; Romero, Roberto; Kannan, Rangaramanujam M., PMSE Preprints (2009), 100 710-711.
[8]'Development of PAMAM-dendrimer based nanodevice for targeted delivery to chlamydia trachomatis infection.',Mishra, Manoj K.; Hudson, Judith W.; Kannan, Rangaramanujam M. PMSE Preprints (2009), 100 702.
[7]'Structure and mechanical properties of supercritical carbon dioxide processed porous resorbable polymer constructs', Baker, KC, R. Bellair, M. Manitiu, HN Herkowitz, RM Kannan. Journal of Mechanical Behavior of Biomedical Materials (2009), 2(6) 620-626
[6]'Poly(amidoamine) dendrimer-drug conjugates with disulfide linkages for intracellular drug delivery.', Kurtoglu, Yunus E.; Navath, Raghavendra S.; Wang, Bing; Kannan, Sujatha; Romero, Robert; Kannan, Rangaramanujam M., Biomaterials (2009), 30(11), 2112-2121.
[5]'Dendrimer-drug conjugates for tailored intracellular drug release based on glutathione levels.', Navath, R; Y. Kurtoglu; B. Wang; S. Kannan;R. Romero; R.M. Kannan. Bioconjugate Chemistry (2008), 19(12), 2446-2455.
[4]'The effect of surface functionality on cellular trafficking of dendrimers.', Perumal, Omathanu P.; Inapagolla, Rajyalakshmi; Kannan, Sujatha; Kannan, Rangaramanujam M. Biomaterials (2008), 29(24-25), 3469-3476.
[3]'Dendrimers and hyperbranched polymers for drug delivery.', Kannan, Rangaramanujam M.; Perumal, Omathanu P.; Kannan, Sujatha. Biomedical Applications of Nanotechnology (2007), 105-129
[2]'Synthesis, characterization and in vitro release of dendrimer-streptokinase conjugates', X. Wang, R. Inapagolla, M. Lieh-Lai, R. M. Kannan, S. Kannan, Bioconjugate Chem.(2007), 18(3), 791-799
[1]'Cellular interactions of nano drug delivery systems.', Kannan, Rangaramanujam M.; Perumal, Omathanu Pillai; Kannan, Sujatha. Force Microscopy (2006), 113-136
Primary Researchers:
|
|
|
|
|
|
|
| |
 |
| |
|
| |
|
|
