Principles of strategic drug delivery to the brain (SDDB): development of anorectic and orexigenic analogs of leptin

Abstract

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.

Fig. 1

Physiological condition: circulating leptin is transported across the blood-brain barrier by a saturable mechanism. Once in the brain, leptin interacts with its receptor at the arcuate nucleus to influence body weight.

Fig. 2

Drug development strategies: the leptin antagonist PEG-MLA binds to the leptin transporter at the blood–brain barrier but is not transported across by it. This binding blocks the ability of endogenous leptin in the blood from being transported into brain. Pluronic leptin crosses the BBB by way of an endocytic pathway (EP) to reach CNS receptors.

Fig. 3

Pluronic leptin transport is independent of the leptin BBB transporter: brain/serum ratios greater than 10 microl/g represent extravascular leptin (that is, leptin which has crossed the BBB). Radioactively labeled pluronic leptin (I-PL) and radioactively labeled leptin (I-Lep) are taken up by brain at similar rates. However, unlabeled leptin (Lep) inhibits the uptake of radioactively labeled leptin (I-Lep+Lep) but not of radioactively labeled pluronic leptin (I-PL+Lep). ***p<0.001. Adapted from [38].