Chakravarthy: edging toward breakthroughs in nanomedicine

Krishnan Chakravarthy is a resident physician in the Department of Anesthesiology and Critical Care Medicine at the Johns Hopkins Hospital. He is also the founder of a company called NanoAxis. He is seeking potential faculty collaborators through Johns Hopkins Institute for NanoBioTechnology, where he is a recently affiliated faculty member.

Krishnan Chakravarthy

Krishnan Chakravarthy

Chakravarthy launched NanoAxis in 2009 while earning an MD and PhD at SUNY Buffalo. He won the Henry A. Panasci Jr. Technology Entrepreneurship Competition sponsored by the University of Buffalo School of Management with a business plan for creating a new drug delivery mode for seasonal and pandemic flu using quantum dots and gold nano particles.

He is the remaining founder and owner of NanoAxis and says the company has grown significantly since 2009. NanoAxis now has active labs and collaborators both nationally and internationally. The company is now taking root in Maryland, and Chakravarthy says he is actively working on collaborating with local biotech businesses in the area.

INBT: Can you briefly summarize your company’s main goals?

KC: At inception, we were primarily interested as a business to commercialize quantum dot technology for various industrial applications. Over the course of six years, our business goals have shifted from large-scale nano materials manufacturing to being the world leader in developing paradigm-shifting technologies in the field of nano medicine. For us, this comprises nano particle enabled advances in drug delivery and smart design point-of-care devices using nanotechnology.

At present, we have four main preclinical candidates that we are working on with the eventual goal of beginning FDA clinical trials. One project involves a novel antiviral therapy for seasonal and pandemic influenza that we are actively developing with the US Centers for Disease Control. This antiviral therapy also has shown to have therapeutic benefits in the treatment of Ebola virus.

In the realm of neuroscience, we have efforts to target Alzheimer’s disease, chronic pain, and depression using nano particles that deliver micro RNA and signal interference RNA designed to up-regulate and down-regulate key proteins. The preclinical data from both in vitro and in vivo studies look extremely promising.

Furthermore, we are currently in developing of two hand-held devices for screening for infections related to prosthetic implants (such as joint replacement). They could be used in the operating room and clinics across the US. Our goal is for orthopedic surgeons to be able to measure specific infection markers at their fingertips to enable them to make safe and cost-effective medical management decisions based on an accurate and precise screening tool. One of the devices will be iPhone compatible, while the other we are developing as a stand-alone device that would be ideal for markets in developing countries.

Our hope is that our platform will extend to diagnosing infectious diseases, be used in the Intensive Care Unit for basic metabolic panel measurements and be extended to a host of other medical applications. We will likely begin FDA clinical trials for these devices by early 2016.  I am also working on developing a platform for detection of various disease processes using nanotechnology and breath as a medium for detecting specific breath-based biomarkers.

INBT: What sort of collaborations are you hoping to establish?

KC: I am hoping to use the extensive knowledge at INBT and at Hopkins to help further our development efforts. As an affiliated faculty, I feel honored to be part of such an impressive think tank of scientists and entrepreneurs. I believe nanotechnology is at the heart of the bench-to-bedside paradigm. It is one component of the growing medical revolution that is happening around the world. In addition, unlike any other industry or science, nano medicine advances are going to be interdisciplinary and collaborative. So teamwork, collaboration, and collective ideas are going to push ongoing advances and development.

INBT: What are the main research challenges you would like to address?

KC: At present, the main stumbling block will be pushing our technology through FDA clinical trials. The process is long, tedious, and expensive. In addition, preclinical data has to be sound. So refinement of the nano materials to find the ideal candidate to deliver the gene or drug will require creativity and repeated experimentation. In addition, when thinking about the ultimate goal of seeing these drugs being used in patients, large-scale production becomes an important component to address.  It has to be of consistent quality, safe, and easily reproducible in large quantities.  So these are things we need to think about from an industrial perspective when you are no longer in the academic realm.

INBT: Anything else people should know?

KC: I am looking forward to working with other INBT faculty.  We are always open to new ideas, and my research team would be more than willing to start new projects.  Likewise, we will also try and suggest areas that we think specific faculty would be suitable for project development.

Visit the Chakravarthy Research Group Website: www.nanoaxisllc.com

Recent Publications:

Jacob A, Chakravarthy K (2014-04-06 14:52:34 UTC) Engineering Magnetic Nanoparticles for Thermo-Ablation and Drug Delivery in Neurological Cancers. Cureus 6(4): e170. doi:10.7759/cureus.170

Jacob A, Chakravarthy K, Law M, et al. (2014-04-21 18:33:15 UTC) Neuroradiology, Anesthesia, Bioengineering, and Hardware Programming in the Clinical Applications of Deep Brain Stimulation. Cureus 6(4): e172. doi:10.7759/cureus.172

Upcoming Invited Talks:

Designing smart nano-systems for effective gene and drug delivery across the blood brain barrier.  12th Annual World Brain Mapping and Therapeutics Congress.  March 6-8, 2015, Los Angeles, USA

Selective abrogation of IL-12/IL-23 production provides novel therapeutic modality in combating lethal synergism of influenza and secondary pneumonia.  5th World Congress on Cell Science and Stem cell research.  March 23-25, 2015, Chicago, USA

Periodically Johns Hopkins Institute for NanoBioTechnology (INBT) features a brief profile on one of its affiliated faculty members. If you are an affiliated faculty member of INBT and would like to be featured, contact INBT’s science writer, Mary Spiro at mspiro@jhu.edu. If you wish to become an affiliated faculty member visit this link. http://inbt.jhu.edu/apps/faculty/join/

 

 

 

 

Making therapeutic proteins last longer

Happy TRAILs to you: PEGylation of proteins through complementary interactions between a His-tag and a Ni2+ complex of nitrilotriacetic acid (NTA, see picture), a well-established practice in protein research, was used to improve the half-life of therapeutic proteins in the blood following systemic administration in vivo. Animal models show that this site-specific modification improves the efficacy of modified TRAIL proteins.

Happy TRAILs to you: PEGylation of proteins through complementary interactions between a His-tag and a Ni2+ complex of nitrilotriacetic acid (NTA, see picture), a well-established practice in protein research, was used to improve the half-life of therapeutic proteins in the blood following systemic administration in vivo. Animal models show that this site-specific modification improves the efficacy of modified TRAIL proteins.

Proteins are responsible for pretty much everything in the human body. When there is a problem with the proteins, it usually leads to disease.

Protein therapy shows enormous potential for treating disease. But sometimes the proteins in a therapeutic treatment break down or are metabolized before they ever reach their target destination.

In a recent paper published in Angewandte Chemie, researchers from the laboratories of Martin Pomper (radiology oncology) and Seulki Lee (radiology, Center for Nanomedicine) at the Johns Hopkins School of Medicine and developed a simple method to validate protein drugs in animal models, said Lee. An illustration related to the paper appeared on the cover of the journal.

“We show that we can extend the half-life, that is, the amount of time the drug stays in the blood, while maintaining the activity of the model protein drug, TRAIL,” said one of the lead authors Maggie Swierczewska. “This has great implications for drug screening and validation methods, especially for the growing protein drug market.”

According to the paper, by attaching a molecule of  polyethylene glycol (PEG) to certain sites on the TRAIL protein drugs through an already well known method, the half-life of the drug could be extended without affecting its beneficial activity.

Authors on this paper include Tae Hyung Kim, Magdalena Swierczewska, Yumin Oh, AeRyon Kim, Dong Gyu Jo, Jae Hyung Park,  Youngro Byun, Scheherazade Sadegh-Nasseri, Martin G. Pomper, Kang Choon Lee, Seulki Lee. Author affiliations include the departments of Radiology and Pathology at the Johns Hopkins School of Medicine, the Johns Hopkins Center of Cancer Nanotechnology Excellence, the Johns Hopkins Institute for NanoBioTechnology, Center for Nanomedicine and collaborators at Sungkyunkwan University and Seoul National University, both in Korea.

Reference: Kim, T. H., Swierczewska, M., Oh, Y., Kim, A., Jo, D. G., Park, J. H., Byun, Y., Sadegh-Nasseri, S., Pomper, M. G., Lee, K. C. and Lee, S. (2013), Mix to Validate: A Facile, Reversible PEGylation for Fast Screening of Potential Therapeutic Proteins In Vivo. Angew. Chem. Int. Ed.. Vol. 52, Issue 27, pages 6880-6884, doi: 10.1002/anie.201302181

Nanoparticles slip through mucus barrier to protect against herpes virus

“Thick, sticky mucus layers limit effectiveness of drug delivery to mucosal tissues. Mucus-penetrating particles or MPPs (in red) are able to penetrate mucus, covering the entire surface of the mouse vagina (in blue). Improved distribution and retention of MPPs led to significantly increased protection in a mouse model for herpes simplex virus infection. Image by Laura Ensign.

Johns Hopkins researchers say they have demonstrated for the first time, in animals, that nanoparticles can slip through mucus to deliver drugs directly to tissue surfaces in need of protection.

The researchers used these mucus-penetrating particles, or MPPs, to protect against vaginal herpes infections in mice. The goal is to create similar MPPs to deliver drugs that protect humans against sexually transmitted diseases or even treat cancer.

“This is the first in vivo proof that MPPs can improve distribution, retention, and protection by a drug applied to a mucosal surface, said Justin Hanes, Ph.D., a professor of ophthalmology at the Johns Hopkins Wilmer Eye Institute and director of the Center for Nanomedicine at the Johns Hopkins University School of Medicine.

Hanes also is a principal investigator with the Johns Hopkins Center of Cancer Nanotechnology Excellence. Results of his team’s experiments are described in the June 13 issue of the journal Science Translational Medicine.

The moist mucosal surfaces of the body, like the eyes, lungs, intestines and genital tract, are protected from pathogens and toxins by layers of moist sticky mucus that is constantly secreted and shed, forming our outermost protective barrier.

“Although many people associate mucus with disgusting cold and cough symptoms, mucus is in fact a sticky barrier that helps keep you healthy,” says Laura Ensign, a doctoral student affiliated with the Center for Nanomedicine at the School of Medicine and with the Department of Chemical and Biomolecular Engineering at Johns Hopkins’ Whiting School of Engineering. She is the lead author of the journal report.

Unfortunately, Ensign noted, mucus barriers also stop helpful drug delivery, especially conventional nanoparticles intended for sustained drug delivery. In a Johns Hopkins laboratory, researchers developed nanoparticles that do not stick to mucus so they can slip through to reach the cells on the mucosal surface, in this case the surface of the mouse vagina, she added.

Ensign explained that conventional nanoparticles actually stick to mucus before releasing their drug payload and are then removed when the mucus is replenished, often within minutes to hours. Working with researchers in the laboratory of Richard Cone, Ph.D., in the Department of Biophysics in the university’s Krieger School of Arts and Sciences, the Hanes team fabricated particles with surface chemistry that mimics a key feature of viruses that readily infect mucosal surfaces.

“Richard Cone’s lab found that viruses, such as the human papilloma virus, could diffuse through human cervical mucus as fast as they diffuse through water. These ‘slippery viruses’ have surfaces that are ‘water-loving,’ ” Hanes said. “In contrast, many nanoparticles intended to deliver drugs to mucosal surfaces are ‘mucoadhesive’ and ‘oil-loving,’ but these nanoparticles stick to the superficial layers of the mucus barrier, the layers that are most rapidly removed.”

To make their mucus-penetrating particles, the team transformed conventional ‘oil-loving’ nanoparticles by coating them with a substance used in many commercial pharmaceutical products: polyethylene glycol. PEG makes the particles “water-loving,” like the viruses that slip right through mucus.

“The key is that the nanoparticles, like viruses, have to be small enough to go through the openings in the mucus mesh, and also have surfaces that mucus can’t stick to. If you think about it,” said Ensign, “mucus sticks to almost everything.”

“Viruses have evolved over millions of years to become slippery pathogens that readily penetrate our protective mucus barriers,” said Cone, “and engineering nanoparticles that penetrate the mucus barrier just like viruses is proving to be a clever way to deliver drugs.”

Hanes emphasized that the MPPs provided greatly improved protective efficacy while at the same time reducing the effective dose of drug needed 10-fold. Furthermore, Hanes added, the MPPs “continue to supply drug for at least a day and provide nearly 100 percent coverage of the mucosal surface of the vagina and ectocervix” in their laboratory mice.

“We’ve shown that mucus-penetrating particles are safe for vaginal administration in mice. Our next move will be to show that they are safe for vaginal administration in humans,” Ensign said. “Now our laboratory currently is working on an MPP formulation of a drug that protects against HIV infection that we hope will be tested in humans.”

Their technology could lead to a once-daily treatment for preventing sexually transmitted diseases, for contraception and for treatment of cervico-vaginal disorders, Ensign said.

Ensign added that MPP technology has the potential to prevent a wide range of mucosal diseases and infections, including chronic obstructive pulmonary disease, lung cancer, and cystic fibrosis,” Ensign said.

Additional authors on the paper include postdoctoral fellow Ying-Ying Wang and research specialist Timothy Hoen from the Department of Biophysics; former master’s student Terence Tse from the Department of Chemical and Biomolecular Engineering; and Benjamin Tang, formerly of Johns Hopkins School of Medicine and currently at the Massachusetts Institute of Technology.

Under a licensing agreement between Kala Pharmaceuticals and the Johns Hopkins University, Hanes is entitled to a share of royalties received by the university on sales of products used in the study.

Hanes and the university own Kala Pharmaceuticals stock, which is subject to certain restrictions under university policy. Hanes is also a founder, a director and a paid consultant to Kala Pharmaceuticals. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.”

Story by Mary Spiro

Additional news coverage of this research may be found at the following links:

Phys.org

WYPR: The Mucus Ruse

Scientific American