Re-thinking mucus-penetrating nanoparticles using natural sugars

Significance 

Encapsulation of drug/small molecules in nanocarriers is a very promising approach for development of nanomedicine. Modern drug encapsulation methods allow efficient loading of drug molecules inside the nanocarriers thereby reducing systemic toxicity associated with drugs. Moreover, the possibility of direct and sustained delivery to the target epithelial cells in mucus covered tissues would be an invaluable development in the medical arena. Unfortunately, the impermeability of the mucus barrier and its entrapment of foreign particles have made the practical realization of such a therapeutic route challenging.

In fact, various reports have well documented the challenge that is encountered in maintaining the physiological stability of the mucosal matrix, and attributed it to the nanoparticle-induced reduction in the matrix diffusivity and promotion of mucin aggregation. In particular, such aggregation has also been established to adversely impact the permeability of the nanoparticles/nanocarriers and, thus, diminishes the efficacy of nanoparticle-based formulations. By contrast, a chemically tunable microenvironment would offer an attractive strategy to prevent nanoparticles from adversely reacting or adhering to the mucus hydrogel. However, reports on tuning the microenvironment of the mucus to make it more conducive for administration of drug formulations are limited.

To this end, given the considerable protein content of mucin, it is hypothesized that trehalose-induced prevention of adverse nanoparticle interactions combined with conservation of the coordinated water molecules could enhance mucus dispersion and, thus, retain the intrinsic matrix hydration. To confirm this, a group of researchers from the University College Dublin: Dr. Sourav Bhattacharjee, Dr. Sabine Harrison and Professor Dimitri Scholz, in collaboration with Dr. Soumik Siddhanta and Professor Ishan Barman at the Johns Hopkins University; proposed using trehalose to facilitate the transport of nonfunctionalized nanoparticles through the gut mucosal layer by lessening nanoparticle agglomeration as well as by precluding aggregation of the mucus components. Simply put, they sought to create an entirely complementary route to enhance nanoparticle transport through the mucus by expanding on the recently demonstrated bioprotectant attributes of trehalose in nanoparticle-cellular interactions. Their work is currently published in the research journal, Small.

In the study, such a role for trehalose is explored through molecular spectroscopic, rheological and nano-structural measurements using fresh undiluted porcine jejunal mucus under physiologically relevant conditions. Specifically, the researchers employed three types of nanoparticles classified according to the surface charge and reactivities—positively charged polystyrene nanoparticles, negatively charged silica nanoparticles, and negatively charged surface reactive silver nanoparticles. Their approach was unique in the way that the intrinsic molecular markers and far-red emission from the nanoparticle-mucin aggregates obviated the need to use any separate exogenous reporter molecules.

The research team reported that in the presence of a trehalose-rich milieu, the rheological properties of mucus did not show appreciable changes, even when the nanoparticles were introduced. In addition, the Raman and SERS measurements revealed that the mucoadhesive nanoparticles, such as, the positively charged polystyrene nanoparticles, interacted with the negatively charged MUC2 glycoproteins, and hence, were trapped within the mucus.

In summary, through the application of photonic and spectroscopic tools, Professor Ishan Barman and his colleagues were able—for the first time—to establish the role of preferential nanoparticle-induced aggregation of the globular domains of mucin and non-mucin proteins, in alteration of rheological properties. Overall, in contrast to the prevailing belief, the obtained results demonstrated that non-functionalized nanoparticles may rapidly penetrate through mucus barriers, and by leveraging the bioprotectant attributes of trehalose, an in vivo milieu for efficient mucosal drug delivery can be generated.

Re-thinking mucus-penetrating nanoparticles using natural sugars - Advances in Engineering Re-thinking mucus-penetrating nanoparticles using natural sugars - Advances in Engineering Re-thinking mucus-penetrating nanoparticles using natural sugars - Advances in Engineering

About the author

Dr. Soumik Siddhanta is a Post-Doctoral Fellow in the Department of Mechanical Engineering, Johns Hopkins University. His areas of interest include vibrational spectroscopy, plasmonics, biophotonics, and molecular imaging. Currently, he is trying to utilize the potent combination of engineered plasmonic nanoprobes and label-free plasmon-enhanced vibrational spectroscopy for various biological applications. During his Ph.D. at JNCASR, India, he had worked on developing label-free methods to probe small molecule-protein interactions through surface-enhanced Raman spectroscopy.

He was the recipient of the Indo-US Science and Technology Forum (IUSSTF) Student Research Fellowship, 2014, and the American Society for Laser Medicine & Surgery (ASLMS) Research Grant, 2016-’17. He was also a Hopkins Engineering Applications & Research Tutorials (HEART) program instructor and a Teaching-As-Research (TAR) Fellow at JHU.

About the author

Dr. Sourav Bhattacharjee graduated with M.B.B.S. (Bachelor of Medicine and Surgery) in 2004 from the Medical College and Hospital, Kolkata (India). After a brief period of resident training in Orthopedic Surgery, he joined M.Sc. in Biomolecular Sciences/Cell Biology in 2006 at the Vrije Universiteit Amsterdam (Netherlands). In the meanwhile, he moved to the Edinburgh (UK), where he worked under the supervision of Prof. Vicki Stone in the Napier University. Upon completion of M.Sc., he began his Ph.D. in the Wageningen University (Netherlands) in 2008 which he successfully defended in 2012. Following that, he worked for a year as a postdoc in the University of Twente (Netherlands). From March 2014 he joined University College Dublin (UCD) in Dublin (Ireland) as a postdoc working on the EU FP7 funded TRANS-INT consortium.

From February 2016 he joined the UCD School of Veterinary Medicine as an Assistant Professor in Veterinary Anatomy while also trying to develop his own niche of research encompassing a broad range of nanobiotechnology and advanced microscopy tools for effective diagnostic and drug delivery platforms.

About the author

Dr. Harrison is a Senior Technical Officer in the School of Agriculture & Food Science at the University College Dublin (UCD) in Dublin (Ireland). She previously received her M.Sc. in analytical chemistry from the University of Vienna (Austria) for her research on the composition of binding media in works of art. She then obtained her Ph.D. from UCD for her research on food authentication and diet reconstruction using lamb and cattle tissues. Following the completion of her Ph.D., she worked in the pharmaceutical industry where she further honed her skills in the development and validation of analytical methods.

In her current role, Dr. Harrison’s main interest lies in the development and validation of robust analytical methods for the determination of bio-active compounds including fatty acids and polyphenols in food. She is also applying her understanding of analytical chemistry to headspace-GC-MS analysis in order to determine the impact of food production on the volatile profiles of food materials. Dr. Harrison is also involved in rheology for the determination of physico-chemical properties of a variety of samples.

About the author

Dr. Scholz is currently the Director of Biological Imaging in the Conway Institute, University College Dublin (UCD) in Dublin (Ireland). Dr. Scholz completed his Ph.D. from the National Medical University, Moscow (Russia), and his Habilitation (Dr. of Sciences) at the Goethe University Frankfurt/Main, (Germany) for cell biology and microscopical anatomy. After academic positions at Max-Planck Institute for Experimental Cardiology in Bad Nauheim (Germany) and at Medical University of South Caroline (MUSC, Charleston SC, USA), he joined UCD in Dublin (Ireland) as the founder and head of the Imaging facility.

His research interests belong to pushing frontiers of microscopy for cell biology, developing of new microscopical tools, systems and approaches.

About the author

Ishan Barman is Associate Professor in the Department of Mechanical Engineering at Johns Hopkins University with joint appointments in the Departments of Oncology, and Radiology and Radiological Science. He graduated from the Indian Institute of Technology Kharagpur, before moving to Massachusetts Institute of Technology for his Ph.D., where he investigated transcutaneous blood analyte detection using vibrational spectroscopy. By combining optical spectroscopy, chemical imaging and nanoplasmonics, the Barman lab develops approaches in which structural and molecular data converge to provide integrated insight into disease mechanisms. The optical tools generated from the laboratory’s investigations have been successfully adopted in diverse biomedical environments such as in automated recognition of biopsy specimen, real-time diagnosis of middle ear pathology, and as a customized monoclonal antibody identification platform.

His work has been extensively featured in leading scientific (Technology Review, Physics Today, Physics World, C&E News) and popular media (Wall St. Journal, CNN Newsroom with Ali Velshi) outlets. Dr. Barman’s awards for his research contributions include the NIH Director’s New Innovator Award, Emerging Leader in Molecular Spectroscopy Award, Maryland Outstanding Young Engineer Award, American Society for Lasers in Surgery and Medicine (ASLMS) Dr. Horace Furumoto Innovations Young Investigator Award, and the Tomas Hirschfeld Award by the Federation of Analytical Chemistry and Spectroscopy Societies.

Reference

Soumik Siddhanta, Sourav Bhattacharjee, Sabine M. Harrison, Dimitri Scholz, Ishan Barman. Shedding Light on the Trehalose-Enabled Mucopermeation of Nanoparticles with Label-Free Raman Spectroscopy. Small 2019, volume 15, Article number: 1901679.

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