Tuberculosis Treatment with Engineered Hydrogel Implants

How many times did you miss the medicines? Specially, when the treatments are lengthy and complicated. It is more difficult when they have side effects and are difficult to continue. Is there any alternative way to manage all these complications associated with treatments of complicated diseases such as cancer, tuberculosis, epilepsy, or diabetes? The answer is yes. In a recently published study in “Nanoscale” journal (of Royal Society of Chemistry) researchers from the RegionalCentre for Biotechnology (RCB) and the National Institute of Immunology (under the guidance of Dr. Avinash Bajaj from RCB and Dr. Vinay Nandicoori from NII) discovered a new approach to address this issue associated with tuberculosis disease.



Tuberculosis is a disease of the lungs, mainly caused by bacteria, and can be deadly. It can also infect other parts of the body like lymph nodes, the central nervous system, bones, joints, gastrointestinal organs, and genitourinary organs. Like COVID it can spread by air and cause severe harm to the patients. According to research and WHO reports almost 25% of the world’s population is latently (inactively) infected with TB and almost 3,816 people die everyday. While epidemiological figures of WHO, India accounts for almost 26% of total world TB cases, which is almost ~ 2,640,000 cases in 2020. Currently, doctors are using combination therapy to combat the tuberculosis infection and this includes four drugs (daily for months): rifampicin (RIF), isoniazid (INH), pyrazinamide (PYZ), and ethambutol (EMB). Although these methods are efficient to control TB to a great extent, but irregular medicine, ignorance of caregivers and patients, and inefficient drug delivery/management systems can give a rise to drug-resistant bacteria that are difficult to treat. Surprisingly India has the highestburden (total 465,000 cases) of tuberculosis (TB) patients with multidrug-resistant (MDR) TB and it is alarming to find out a different strategy.



Scientists, in this study, discovered a novel method that can deliver the complicated combinations of drugs against TB. With the help of a very safe, biodegradable, and robust hydrogel, this group of researchers has engineered this novel TB-Gel.

According to one of the first authors, Dr. Vijay Soni (currently working at Weill Cornell Medicine New York),we have developed a hydrogel-based delivery system (derived from a low molecular weight bile acid peptide) where we have entrapped four first-line anti-TB drugs (namely Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol) in it, and we called it TB-Gel. The TB-Gel maintained its integrity, elasticity, and strength, and can easily pass through the syringe. It is non-immunogenic (harmless) and implantable under the skin and can release these four drugs (in the therapeutic range) for a prolonged period (upto 15 days in mice).

In this extensive study,scientists found that they can easily control the rate of drug release from the TB-Gel and maintain the required and effective concentration of drugs in the body. They have also infected mice with tuberculosis and checked the efficacy of TB-Gel as compared to the oral drug delivery system.



Dr. Sanjay Pal (another first author, currently working at National Cancer Institute, USA) told that “in our “TB infection mice model”, TB-Gel treated mice showed significantly lower infection as compared to the group of mice that were administered with daily oral doses. As TB-Gel can maintain the optimum drug levels in the blood, without taking daily oral medications, therefore we found that it reduces the systematic toxicity and side effects of these drugs. Hence this system can lessen the requirement of regular dosing, it can be very helpful for TB treatment management and decreases the likelihood of drug resistance emergence.”

 

Novel TB-Gel can release four front-line anti-TB drugs and outperforms the oral doses of this combination. Thus reducing the TB infection in mice efficiently. (Image Credit: Nanoscale and Authors)

The main reason for tuberculosis treatment failures is long-term drug treatment. These long-term treatments with patient non-compliance pose a significant clinical risk for the evolution of multidrug-resistant tuberculosis. Therefore, discovering a simple way to deliver the desired amount of drugs over a prolonged period can increase patient acquiescence. Such implantable materials and devices are generating a huge impact on clinical treatments and diagnostics. However, designing an injectable soft material with desired mechanical and safety behavior at the biological interface is a considerable challenge. This research provided a needed direction towards the design and development of novel biomaterials for effective and safer drug delivery applications. It is easy to tune the porosity of this hydrogel (to control the desired drug release rate) therefore it is a favorable approach for the treatment of several other diseases using suchbiocompatible biomaterials.

“Soft synthetic materials generally disintegrate under stress and significantly impart undesirable toxicity at the implantable site. Surprisingly, our hydrogel exhibited superior mechanical properties like injectability, gel-like behavior even upon excessive load of chemotherapeutics medicines, and a controlled drug diffusion. Our hydrogel remained three weeks under the skin of the mouse without causing any rashes and other allergic or immune reactions. These were our desired results from the study, and then we started exploring this system further for drug delivery applications.” says Dr. Sandeep Kumar (currently working at Johns Hopkins University School of Medicine, Baltimore, USA)



Considering the safety profile and robustness of our hydrogel system, authors are aiming to develop and explore novel safer therapies against hard to treat brain tumors, topical hydrogel for skin infections, immunomodulatory local therapies for organ transplants, and a safer alternative to daily medication regimens in terms of weekly or monthly implantable formulation.

 

Reference: Sanjay Pal*, Vijay Soni*, Sandeep Kumar*, Somesh Kumar Jha, Nihal Medatwal, Kajal Rana, Poonam Yadav, Devashish Mehta, Dolly Jain, Raunak Kar, Aasheesh Srivastava, Veena S. Patil, Ujjaini Dasgupta, Vinay Nandicoori, and Avinash Bajaj. Hydrogel-mediated Temporal Delivery of Combination of Four Antituberculosis Drugs Outperforms Oral Delivery against Tuberculosis. Nanoscale (RSC Publication) 2021, 13, 13225–13230, DOI: 10.1039/d0nr08806d (* First Co-author)

 

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