Targeted delivery of TB therapeutics

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Project Abstract: Tuberculosis (TB) causes an estimated 10 million new cases each year and remains one of the leading causes of infectious death. While the current “short” chemotherapy regimen is generally effective, it must be delivered for an extended period and the evolution of resistant clones is common. Treatment options for drug- resistant infections requires the use of less effective or more toxic agents. Current evidence suggests that limited drug exposure within the TB granuloma is responsible for these deficiencies. Thus, concentrating TB drugs within the granuloma has been a long-standing goal that could enhance bacterial clearance, reduce the emergence of drug resistance, and facilitate the use of second-line drugs that are limited by their systemic toxicity. Our group has developed a flexible delivery platform technology for the high efficiency encapsulation of compounds within glucan particles (GP), which are avidly taken up by macrophages via glucan receptors, selectively targeting cargo to these cells. Using this strategy, we found that we can efficiently concentrate both isoniazid and clofazimine in Mtb-infected macrophages ex vivo, increasing the potency of these drugs by up to 100-fold. We now plan to expand these studies by optimizing the encapsulation and delivery of additional drugs using the ex vivo macrophage model, and perform a proof of principle animal study to determine if we can effectively target drugs to the site of infection and enhance bacterial killing. If successful, this exploratory project will lay the groundwork for a longer-term project with the potential to transform TB therapy.