Treating TB with engineered hydrogel implants: A fresh approach to drug delivery raises hopes

New Delhi: According to various reports, almost 25% of the world’s population is latently (inactively) infected with tuberculosis (TB) and almost 3,816 people die every day. The epidemiological data from World Health Organization (WHO) suggests that 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 TB 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 highest burden (total 465,000 cases) of TB patients with multidrug-resistant (MDR) TB and it is alarming to find out a different strategy.

In a recently published study in “Nanoscale” journal (of Royal Society of Chemistry), the researchers from the Regional Centre for Biotechnology (RCB) and the National Institute of Immunology (NII) (under the guidance of Dr. Avinash Bajaj from RCB and Dr. Vinay Nandicoori from NII) discovered a new approach to address this issue.

What is TB-Gel and how can it be useful?

TB-Gel is a novel drug delivery method, with which these drug combinations can be released in a controlled manner for a long period. 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 (up to 15 days in mice).

Is it biocompatible?

Researchers have done extensive studies in mice and checked the drug release rate with changing porosity of the hydrogel. 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) mentioned that in their “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)

Why TB-Gel is needed?

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 such biocompatible 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)