Abstract
Many proteins can be used to treat brain diseases; however, the presence of the blood–brain barrier (BBB) creates an obstacle to delivering them into the brain. Previously, various molecules were delivered through the paracellular pathway of the BBB via its modulation, using ADTC5 and HAV6 peptides. This study goal was to design new cyclic peptides with N-to-C terminal cyclization for better plasma stability and modulation of the BBB. Cyclic HAVN1 and HAVN2 peptides were derived from a linear HAV6 peptide. Linear and N-to-C terminal cyclic ADTHAV peptides were designed by combining the sequences of ADTC5 and HAV6. These novel cyclic peptides were used to deliver an IRdye800CW-labeled IgG monoclonal antibody into the brain. Cyclic HAVN1 and HAVN2 peptides deliver IgG into the brain, while the parent linear HAV6 peptide does not. Cyclic and linear ADTHAV and ADTC5 peptides enhanced brain delivery of IgG mAb, in which cyclic ADTHAV peptide was better than linear ADTHAV (p = 0.07). Cyclic ADTHAV and ADTC5 influenced the distribution of IgG mAb in other organs while HAV6, HAVN1 and HAVN2 did not. In summary, the novel cyclic peptides are generally better BBB modulators than their linear counterparts for delivering IgG mAb into the brain.
Highlights
Insufficient delivery of drugs across the blood–brain barrier (BBB) has become the major challenge in diagnosing and treating brain-related diseases [1,2,3]
We have designed and synthesized novel cyclic peptides that can effectively modulate the BBB to enhance the delivery of monoclonal antibodies (mAbs) into the brains of C57BL/6 mice
The new peptides were designed based on HAV6 and ADTC5 peptides, which modulate cadherin–cadherin interactions in the BBB to improve the delivery of small, medium, and large molecules, including proteins
Summary
Insufficient delivery of drugs across the blood–brain barrier (BBB) has become the major challenge in diagnosing and treating brain-related diseases [1,2,3]. The BBB is one of the major hurdles for brain delivery of large therapeutic agents such as proteins. Most large molecules, such as monoclonal antibodies (mAbs) with a molecular weight around 150 kDa, have a low ability to enter the brain because any molecule that crosses the BBB requires appropriate physicochemical properties for passive diffusion or a specific transporter for an active transport mechanism. The transcellular pathway, which many hydrophobic drugs utilize to cross the BBB, is limited to molecules with physicochemical properties that at least satisfy Lipinski’s rule of five [4]. Even if a molecule satisfies Lipinski’s rules, efflux pumps can still prevent it from crossing the BBB [2]
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