Bio Patrika interviews Dr. Sreekanth and Mr. Kar on their thoughts about “bile based nanomicelles as delivery platform for anticancer agents”

Dr. Vedagopuram Sreekanth and Mr. Animesh Kar’s joint interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews. Work described here is done in the lab of Dr. Avinash Bajaj at Regional Centre for Biotechnology, Faridabad, Dr. Ujjaini Dasgupta at Amity University, Haryana, Dr. Sagar Sengupta and Dr. Arnab Mukhopadhyay at National Institute of Immunology, New Delhi. Currently Dr. Sreekanth is a Postdoctoral research fellow at Brigham and Women’s Hospital, Harvard Medical School, USA and Mr. Kar is a Ph.D. Scholar at Regional Centre for Biotechnology, Faridabad, India. They published a paper titled “Bile Acid Tethered Docetaxel‐based Nanomicelles Mitigate Tumor Progression through Epigenetic Changes” as joint first authors in Angew. Chem. Int. Ed. journal (2020).

How would you explain your paper’s key results to the non-scientific community?

Fundamentally, all living cells in the body work on a set of instructions for their normal function. When some of these instructions go wrong, our cells divide rapidly and grow uncontrollably to form a malignant tumor. Selective killing of the cancer cells while not harming the healthy cells is the ideal treatment goal. But current chemotherapeutic drugs/formulations fail to achieve this ideal goal as they cause multi-organ toxicity. For example, Taxotere®, a formulation of Docetaxel, approved for treatment of breast, cancer suffer from formulation instability and organ toxicity. These problems are attributed to hydrophobic nature of the drug, chemical components used in the formulation, availability of the free drug in blood and vital organs other than the tumor site.

To alleviate these problems, we chose a nanotechnology platform that offered a ray of hope for cancer therapy over the past decade. Due to their altered vasculature, solid tumors such as breast cancer have the property of retaining nanoparticles known as Enhanced Permeation and Retention (EPR) effect. Surprisingly, this EPR property is not documented in the healthy organs of the body or circulating blood cells. We capitalized on this EPR property to make sub-100 nanometer-size micelles from a phospholipid-drug conjugate (Figure 1). By chemically conjugating docetaxel to a phospholipid, we limited the availability of free docetaxel in the circulation and the other healthy organs. This phospholipid-docetaxel conjugate (LCA-DTX-PC) readily forms nanomicelles in presence of accessory lipid (LCA-PEG). When we evaluated these nanomicelles in a mouse breast cancer model, we observed a selective trapping and drug release in the tumors compared to other organs, as well as no systemic toxicity. One of the big lacunae in the cancer nanomedicine field is lack of understanding of molecular mechanism of action of nanomedicine. Using in-depth RNA and Bisulfite-sequencing method, we further demonstrated that these nanomicelles suppresses DNA methyltransferase activity and targets the demethylation of CpG islands of tumor suppressor genes, like Sparcl1 and increases their expression which leads to tumor regression. Several drugs/formulations show their effectiveness in mouse models, but they fail to show efficacy in higher organisms such as monkeys and humans. Apart from high tumor inhibition capacity, most striking findings are the superior safety profile and increased blood circulation time of our nanomicelles across different animal models including monkeys. The superiority of our non-toxic nonmicellar formulation in monkeys raised a big hope for the next level studies.

Figure 1. Bile acid based nanomicelles mitigates tumor progression through epigenetic modulation, and show superior pharmacokinetics in higher model organisms.

“[…] we hope to see our drug delivery method find use in clinical applications.”

What are the possible consequences of these findings for your research area?

Our findings open up the door for new possibility of cancer treatment. The adaptive nature of our delivery method allows us to accommodate more than one chemotherapeutic drug to increase the effectiveness of the individual drug. A single dose of the drug to treat tumors over extended period without causing major toxicity is one of the big aims to reduce the economic and mental burden of cancer patient and hospitalizations. Further, our molecular studies gave us insight into a plethora of tumor suppressor genes targeted by docetaxel nanomicelles giving in-depth knowledge about the mechanism of action. With our continuous exploration in this area, one day we hope to see our drug delivery method find use in clinical applications.

What was the exciting moment (eureka moment) during your research?

Research is always hypothesis based, however all hypotheses cannot be always proved. Fortunately, we could prove our hypothesis. First, we were excited to see the aggregation of the lipid-drug conjugate to form nanomicelles under an electron microscope. That excitement went up when we saw the tumors getting shrunk with our nanomicelle treatment. Not every researcher gets an opportunity to see several steps of translational path in their Ph.D. time. Luckily, we witnessed these steps, starting from chemistry, formulations, murine studies, and eventually to monkey models. Finally, the silver lining happened when we could go to the core of its mechanistic impact on tumor suppressor genes making the picture complete as to how the docetaxel nanomicelles work.

What do you hope to do next?

Research is a continuous learning process by improving old things and discovering/ inventing new things. Although we found interesting findings, there are still several milestones to achieve before making it to the clinical stage. The short-term goal is to optimize several parameters of our nanomicelle technology to be compatible with good manufacturing practice (GMP) capacity by optimizing the drug-linker-lipid chemistry, enhancing process and stability parameters. Our long-term goal is to optimize the technology further to bring it to the clinical stage.

Where do you seek scientific inspiration?

Vedagopuram Sreekanth: My passion for science and inspiration comes from Nature. Very early on, few notable figures like Sir David Attenborough, Austin Stevens, Jane Goodall opened my curiosity filled mind to study and learn the principles from our co-habitants on this beautiful planet earth. Starting from my school days, I was mesmerized by the evolution and the ability of birds, reptiles, and higher primates. For years, our co-habitants are a continuous source of inspiration for scientists to mimic and engineer different gadgets/machines from waterproof clothes to aeroplanes. The science behind every aspect of the nature inspires me and motivates me to think critically and explore deeply.

Animesh Kar: My scientific inspiration started when, for the first time, I saw a plant cell under a microscope, which augmented my curiosity to comprehend the complex mechanisms responsible for the existence of all living beings. Since then, it gives me immense pleasure and joy to find new things, solve unanswered questions or develop a cure which would be beneficial as knowledge and hope for humanity. Renowned planetary scientist and communicator, Neil DeGrasse Tyson always makes me fall in love with science all over again. Both my principal investigator Dr. Avinash Bajaj & co-principal investigator Dr. Ujjaini Dasgupta are the continuous source of inspiration for me to take upon new challenges and do good science.

How do you intend to help Indian science improve?

Indian science sector is continuously progressing and expanding its capability in basic science, technology, medicine, agriculture, engineering, space and climate research. There is a valley of death that exist between patients, clinicians, scientists, industries, and regulatory authorities. We will also focus to bridging the valley of death to enhance the knowledge transfer and foster the technologies to tackle the diseases. The sustained scientific growth of a country needs generations of curious young minds. We are passionate to train the next generation scientists, who can take the challenging problems in different fields.

Reference

Sreekanth V and Kar A, Kumar S, Pal S, Yadav P, Sharma Y, Komalla V, Sharma H, Shyam R, Sharma R D, Mukhopadhyay A, Sengupta S, Dasgupta U and Bajaj A. Bile Acid Tethered Docetaxel‐based Nanomicelles Mitigate Tumor Progression through Epigenetic Changes. Angew. Chem. Int. Ed. 2020. https://doi.org/10.1002/anie.202015173.

Author current affiliation

Vedagopuram Sreekanth, Ph.D. Currently Postdoctoral research fellow at Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. Visiting fellow at Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Email: svedagopuram@bwh.harvard.edu

Animesh Kar currently Ph.D. Scholar, Regional Centre for Biotechnology, Faridabad, India. Visiting scholar at National Institute of Immunology, New Delhi, India.

Email: animesh@rcb.res.in

Learn more about Dr. Avinash Bajaj lab research interest here https://sites.google.com/site/lncbgrp/pi

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