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. 2016 Jul;6(4):352-8.
doi: 10.1016/j.apsb.2016.04.001. Epub 2016 May 26.

Nose-to-brain delivery of macromolecules mediated by cell-penetrating peptides

Tingting Lin  1 , Ergang Liu  1 , Huining He  2 , Meong Cheol Shin  3 , Cheol Moon  4 , Victor C Yang  5 , Yongzhuo Huang  6
Affiliations

Nose-to-brain delivery of macromolecules mediated by cell-penetrating peptides

Tingting Lin et al. Acta Pharm Sin B. 2016 Jul.

Abstract

Brain delivery of macromolecular therapeutics (e.g., proteins) remains an unsolved problem because of the formidable blood-brain barrier (BBB). Although a direct pathway of nose-to-brain transfer provides an answer to circumventing the BBB and has already been intensively investigated for brain delivery of small drugs, new challenges arise for intranasal delivery of proteins because of their larger size and hydrophilicity. In order to overcome the barriers and take advantage of available pathways (e.g., epithelial tight junctions, uptake by olfactory neurons, transport into brain tissues, and intra-brain diffusion), a low molecular weight protamine (LMWP) cell-penetrating peptide was utilized to facilitate nose-to-brain transport. Cell-penetrating peptides (CPP) have been widely used to mediate macromolecular delivery through many kinds of biobarriers. Our results show that conjugates of LMWP-proteins are able to effectively penetrate into the brain after intranasal administration. The CPP-based intranasal method highlights a promising solution for protein therapy of brain diseases.

Keywords: Blood–brain barrier; Brain targeting; Cell-penetrating peptide; Intranasal protein delivery; Low molecular weight  protamine.

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Figures

fx1
Graphical abstract
Fig. 1
Figure 1
The cell-penetrating LMWP peptide-mediated protein drug from nose to brain delivery.
Fig. 2
Figure 2
SDS-PAGE characterization of the LMWP–BSA conjugates.
Fig. 3
Figure 3
Q-TOF mass spectrum of the LMWP–BSA conjugates.
Fig. 4
Figure 4
In vivo imaging after intranasal administration (up panel) and the fluorescence imaging of the brain tissues at experimental endpoint (bottom panel).
Fig. 5
Figure 5
LMWP–BSA conjugates were intranasally administered to mice. One hour later, the olfactory bulbs were removed and processed cryosection. Slides were observed using fluorescent microscope. (A) LMWP–BSA–FITC; (B) BSA–FITC.
Fig. 6
Figure 6
Enzymatic activity of HPR (left panel) and β-gal (right panel). LMWP-linked proteins were represented by grey bars, and native proteins white bars. LMWP-enzymes were significantly higher than their non-modified counterparts (n=3).
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