Research

Dendrimer Nanomedicine

Our group focuses on using dendrimers as a nanoscale platform for drug delivery and diagnosis.  To achieve this, we utilize PAMAM dendrimers enhanced with desired functionalities.  At the Center for Nanomedicine of the Wilmer Eye Institute of Johns Hopkins Medicine, we are developing translational applications for dendrimer-based drug delivery approaches. Our research focuses on three aspects to build tailored dendrimer nanodevices for specific clinical applications:

(1) We seek to understand disease biologies and the key designing parameters for our dendrimer-based nanodevice that determine their intrinsic targeting properties to those diseases.  We have shown that dendrimers can target activated glial cells in the presence of neuroinflammation, excitotoxicity, and brain tumors.  This knowledge has become a powerful tool as we develop drug delivery systems.

(2)  Our in vitro and in vivo studies inform the rational design of dendrimer nanoparticles.  This allows us to imbue or enhance dendrimers with desired properties by conjugating them to functionalized groups, imaging agents, and drug molecules.  We are developing a variety of dendrimer conjugates to suit specific applications, such as tailoring drug release profiles and targeting specific cell types.

(3)  Due to their ability to target inflammation, we are developing dendrimer technologies to treat a wide range of inflammatory disorders.  Our dendrimer therapeutics are being applied to a wide range of animal models, including models of cerebral palsy, glioblastoma, macular degeneration, Rett syndrome, stroke, ALS, and many others.  Our overall focus is on developing dendrimer-mediated therapies for two major categories of diseases: central nervous system disorders and ophthalmic diseases.

Dendrimer-based targeted therapies for central nervous system disorders

Glial cells, such as microglia and astrocytes, and their activation during brain injury play central roles in the pathogenesis of central nervous system (CNS) disorders and in the events following brain injury.  Thus, they are attractive targets for treating such disorders and have received significant scientific attention among the drug delivery community in the last decade.  Targeting injured glial cells may provide a potent strategy to fight against brain injury, enabling the development of novel targeted drug delivery therapies for unmet clinical needs.  The unique physiochemical, cellular, and in vivo properties of PAMAM dendrimers provide advantages in targeting the activated glial cells.  We have shown that these dendrimers localize to regions of inflamed tissue.  Additionally, dendrimer conjugated drug molecules exhibit beneficial properties such as increased solubility, decreased toxicity, and resistance to degradation and clearance versus free drug formulations, which allow for systemic administration.  Our group combines bio-conjugation therapy and neuroscience approaches to develop and translate dendrimer-based therapeutics and diagnostics for the treatment of neuroinflammatory disorders and cancer.

FITC conjugated dendrimer localizes to cerebral palsy brains (neuroinflammation), specifically microglia and astrocytes.
FITC conjugated dendrimer localizes to cerebral palsy brains (neuroinflammation), specifically microglia and astrocytes.
In cerebral palsy, the blood brain barrier is compromised, allowing our dendrimers to pass through and target neuroinflammation.
In cerebral palsy, the blood brain barrier is compromised, allowing our dendrimers to pass through and target neuroinflammation.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Dendrimer-based targeted therapies for ophthalmic inflammatory disorders

 

 

Selected Recent Publications:

  1. ‘Dendrimer-based targeted intravitreal therapy for sustained attenuation of neuroinflammation in retinal degeneration’, R. Iezzi, B. Raja Guru, I. Glybina, M. Mishra, A.Kennedy, R.M. Kannan. Biomaterials, 33(3) 978 (2011)
  2. ‘Dendrimer-Based Drug and Imaging Conjugates: Design Considerations for Nanomedical Applications’, A.Menjoge, R.M.Kannan, D.Tomalia, Invited Foundation review, Drug Discovery Today, 15(5),171-185 (2010).
  3. ‘Injectable PAMAM dendrimer-PEG hydrogels for the treatment of ascending genital infections: Formulation, in-vitro and in-vivo evaluation’, A. Menjoge, R. Navath, H.Dai, A. Abbas, R.Romero, S.Kannan, R.M.Kannan, Molecular Pharmaceutics, 8(4):1209-1223 (2011).
  4. ’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, 19, 1–13 (2009).
  5. ‘Drug release mechanisms and kinetics from dendrimer-drug conjugates with glutathione sensitive linkers’, Emre, YK, R. Navath, B. Wang, R. Romero, S. Kannan, RM Kannan, Biomaterials, 30, 2112-2121 (2009).
  6. ‘PAMAM dendrimer-azithromycin conjugate nanodevices for the treatment of Chlamydia trachomatis Infections’, M. Mishra, K. Kotta, M. Hali, S. Wykes, I. Benchaala, H. Gerard, A. Hudson, J. Whittum-Hudson, R M. Kannan, Nanomedicine (NBM), 7(6), 935 (2011).
  7. ‘Transfer of PAMAM dendrimers across the human placenta: prospects for use as drug carrier during pregnancy’, A.R.Menjoge, A. Rinderknecht, R.Navath, M.Faridnia, R.Romero, R.Miller, R.M. Kannan, Journal of Controlled Release, 150(3), 326-338 (2011)
  8. ’Intrinsic targeting of neuroinflammation by polyamidoamine dendrimers in a rabbit model of cerebral palsy’ H.Dai, R.Navath, B.Balakrishnan, B.Raja Guru, M.Mishra, R.Romero, R.M.Kannan, S.Kannan, Future Medicine:Nanomedicine,5(9), 1317-1329 (2010)
  9. ‘Inhibition of bacterial growth and intramniotic infection in a guinea pig model of chorioamnionitis using PAMAM dendrimers’, B. Wang, R.Navath, A.Menjoge, B.Balakrishnan, R.Bellair, H.Dai, R.Romero, S.Kannan, R.M.Kannan, Int. J. Pharm., 395(1-2), 298-308 (2010).
  10. ‘Amino acid functionalized dendrimers with hetero-bifunctional chemoselective peripheral groups for drug delivery’, R.Navath, A.Menjoge, B.Wang, R.Romero, S.Kannan, R.M.Kannan, Biomacromolecules, 11 (6), 1544–1563 (2010)
  11. ‘Transport and Biodistribution of Dendrimers Across Human Fetal Membranes: Implications for Intravaginal Administration of Dendrimers’, A. R. Menjoge, R. S. Navath, A. Asad, S. Kannan, C. J. Kim, R.Romero, R. M. Kannan, Biomaterials, 31(8), 5007-5021 (2010).