The blood-brain barrier (BBB) presents a tremendous challenge for the delivery of drugs to the central nervous system (CNS). This includes drugs that target brain receptors for the treatment of
obesity and
anorexia. Strategic
drug delivery to brain (SDDB) is an approach that considers in depth the relations among the BBB, the candidate therapeutic, the CNS target, and the disease state to be treated. Here, we illustrate principles of SDDB with two different approaches to developing drugs based on
leptin. In normal body weight humans and in non-obese rodents,
leptin is readily transported across the BBB and into the CNS where it inhibits feeding and enhances thermogenesis. However, in
obesity, the transport of
leptin across the BBB is impaired, resulting in a resistance to
leptin. As a result, it is difficult to treat
obesity with
leptin or its analogs that depend on the
leptin transporter for access to the CNS. To treat
obesity, we developed a
leptin agonist modified by the addition of
pluronic block copolymers (P85-leptin). P85-leptin retains
biological activity and is capable of crossing the BBB by a mechanism that is not dependent on the
leptin transporter. As such, P85-leptin is able to cross the BBB of obese mice at a rate similar to that of native
leptin in lean mice. To treat
anorexia, we developed a
leptin antagonist modified by pegylation (PEG-MLA) that acts primarily by blocking the BBB transporter for endogenous, circulating
leptin. This prevents blood-borne, endogenous
leptin from entering the CNS, essentially mimicking the
leptin resistance seen in
obesity, and resulting in a significant increase in adiposity. These examples illustrate two strategies in which an understanding of the interactions among the BBB, CNS targets, and candidate
therapeutics under physiologic and diseased conditions can be used to develop drugs effective for the treatment of
brain disease.