Overcoming Transport Barriers in Tuberculosis Granulomas to Improve Drug Delivery
Tuberculosis (TB) is the leading cause of infectious disease-related death, afflicting
nearly one-third of the global population. Intriguingly, the hallmark of TB infection -
the pulmonary granuloma - is not unlike a solid malignant tumor. In fact, cancerous
tumors and TB granulomas share strikingly similar aberrant features in their
microenvironments, including densely packed cells, ... read morean overabundance of extracellular
matrix components, and an associated atypical vasculature. The abnormal physiology of
these masses leads to significant transport barriers that result not only in a paucity
of oxygen and nutrients, but also in ineffective drug delivery, which together
compromise the anti-TB immune response and treatment efficacy. Therefore, I propose to
overcome the transport barriers resulting from physiological abnormalities in the TB
granuloma microenvironment in order to enhance drug delivery and improve treatment
response. The work presented in this Thesis is motivated by insights gained from the
rich research field of tumor biology, and utilizes this knowledge to explore and exploit
similar features found in TB granulomas to improve therapeutic outcome. In our
preclinical studies with the experimental rabbit TB model, we have discovered for the
first time that the TB granuloma vasculature is structurally and functionally abnormal.
Furthermore, we have demonstrated that we can effectively "normalize" vessel function by
targeting the abnormal granuloma vasculature and dense matrix to improve small molecule
delivery to these lesions. Combined, these strategies have the potential to serve as
"host-directed therapies" that can improve anti-TB drug delivery and treatment outcome.
Additionally, the distribution of small molecules (e.g., oxygen) in granulomas can be
described using basic chemical engineering principles of transport and reaction. Thus,
by focusing on physiological abnormalities in the TB granuloma microenvironment, the
novel treatment avenues discovered here may prove efficacious in reducing the global
health burden of this devastating infectious
Thesis (Ph.D.)--Tufts University, 2018.
Submitted to the Dept. of Chemical and Biological Engineering.
Advisors: Rakesh Jain, and Kyongbum Lee.
Committee: Nikhil Nair, Harry Bernheim, Clifton Barry, and Laura Via.
Keyword: Chemical engineering.read less