(5bb) Functional Nanotechnology for Imaging and Therapy

Nanoscale control in fabricating nanoparticles allows for multi-functional carriers that can potentially enable personalized therapies that facilitate diagnosing, sensing, treating and monitoring the progress of treatment for each individual patient. To realize this vision, my research has focused on the development of (1) imaging nanoprobes and methods of use for early cancer detection and prediction/monitoring of cancer therapies by non-invasively probing vascular permeability and molecular markers (postdoctoral work), and (2) nanostructured glucose-sensing particles for insulin delivery (doctoral work).

Imaging nanoprobes for prediction of chemotherapy outcomes: Besides the cytotoxic effect at the molecular level, the success of nanoparticle-based cancer chemotherapy is primarily dependent on the access these agents have to tumors via the tumor leaky vasculature. Yet, the extent of vascular permeability to nanoparticles in individual tumors varies widely resulting in a correspondingly wide range of responses to the therapy. To address this need, we developed a long-circulating liposomal contrast nanoprobe for X-ray imaging. Imaging of a breast tumor model in rats using this nanoprobe and a clinical mammography system, demonstrated a wide range of vascular permeability. The same animals, when treated with a long circulating liposomal doxorubicin preparation exhibited a range of responses, which strongly correlated with the vascular permeability measured by the nanoprobe imaging. Such prediction can therefore facilitate personalized therapy, and spare potential non-responders from the rigors of a chemotherapy regimen. In a subsequent study, a multifunctional nanocarrier was developed co-encapsulating a contrast agent and a chemotherapeutic to predict and monitor chemotherapy. Following multiple treatments, it was observed that specific tumors that exhibited high uptake of the nanocarrier as visualized by imaging were mostly benefited from the treatment showing low tumor growth and long survival. In other efforts, nanoprobes for x-ray and MR imaging have been advanced to characterize brain tumors and cardiovascular diseases by probing vasculature and molecular markers.

Nanostructured glucose-sensing particles for insulin delivery: Recognizing the need for a system able to adapt a release rate based on the occasion, an inhalable glucose-sensing insulin nanostructured particle was developed with long residence times in the deep lungs. The nanostructured particle consists of insulin-loaded nanoparticles with glycosyl-presenting external leaflets which were agglomerated by a sugar binding moiety, con A . Upon exposure of the particle to elevated glucose, the release of insulin was triggered by binding of con A to free glucose and liberation of nanoparticles. The glucose-sensing particle was intratracheally instilled in the lungs of rats with suppressed pancreatic functions. Hyperglycemic events triggered an acceleration of the release of insulin achieving normoglycemia shortly after ?sensing? the elevated systemic glucose. This work is a demonstration of glucose-sensing insulin release mimicking the function of a healthy pancreas.

Future research plans: My research interests lie in the intersection of nanotechnology with molecular markers and imaging to enable non-invasive characterization of angiogenesis and pathology of diseased vasculature. My laboratory will exploit the multifunctionality of nanoparticles to design nanoscale contrast agents for vascular anatomical, functional and molecular imaging to provide prognostic and diagnostic tools enabling personalized therapies. Among the numerous diseases where vasculature plays a critical role such as cancer, atherosclerosis, stroke, aneurism, and ischemia, my research will focus on solid tumors and vulnerable atherosclerotic plaques.

Selected publications

1. E. Karathanasis, L. Chan, S.R. Balusu, I. Sechopoulos, R.V. Bellamkonda, Multifunctional nanocarriers for mammographic quantification of tumor dosing and prognosis of breast cancer therapy, Biomaterials (accepted)

2. E. Karathanasis, S. Suryanarayanan, S.R. Balusu, K. McNeeley, I. Sechopoulos, A. Karellas, A.V. Annapragada, R.V. Bellamkonda, Imaging nanoprobe for prediction of nanoparticle chemotherapy using mammography, Radiology (accepted)

3. E. Karathanasis, J. Park, A. Agarwal, V. Patel, F. Zhao, A.V. Annapragada, X. Hu, R.V. Bellamkonda, MRI mediated, non-invasive tracking of intratumoral distribution of nanocarriers in rat glioma, Nanotechnology 19 315101 (9pp) 2008

4. E. Karathanasis, A. Agarwal, A.V. Annapragada, Triggered release of post-administered drugs, In: Handbook of Particulate Drug Delivery, R. Kumar Ed., American Scientific Publishers 2007, 243-260

5. E. Karathanasis, R. Bhavane, A.V. Annapragada, Glucose-sensing pulmonary delivery of human insulin to the systemic circulation of rats, International Journal of Nanomedicine 2(3) (2007) 501-513

6. R. Bhavane, E. Karathanasis, A.V. Annapragada, Triggered release of ciprofloxacin from nanostructured agglomerated vesicles, International Journal of Nanomedicine 2(3) (2007) 407-418

7. E. Karathanasis, R. Bhavane, A.V. Annapragada, Triggered release of inhaled insulin from the agglomerated vesicles: Pharmacodynamic studies in rats, Journal of Controlled Release 113(2) (2006) 117-127

8. E. Karathanasis, A. Ayyagari, R. Bhavane, R. Bellamkonda, A.V. Annapragada, Preparation of in vivo cleavable agglomerated liposomes suitable for modulated pulmonary drug delivery, Journal of Controlled Release 103(1) (2005) 159-175

9. R. Bhavane, E. Karathanasis, A.V. Annapragada, Agglomerated Vesicle Technology: A new class of particles for controlled and modulated pulmonary drug delivery, Journal of Controlled Release 93(1) (2003) 15-28