Modified translationally controlled tumor protein-derived protein transduction domain enhances nasal delivery of exendin-4 as shown with insulin

Abstract

Protein transduction domains (PTDs) have been shown to promote the delivery of therapeutic proteins or peptides into the living cells. In a previous study, we showed that the double mutant of TCTP-PTD 13, TCTP-PTD 13M2, was more effective in the delivery of insulin than the wild-type TCTP-PTD 13. In this study, we applied this approach to the nasal delivery of a different peptide, exendin-4, using as carriers, several modified TCTP-PTDs, such as TCTP-PTD 13M1, 13M2, and 13M3. Nasal co-administration of TCTP-PTD 13M2 with exendin-4 showed the highest exendin-4 uptake among the three analogs in normal rats, and also decreased blood glucose levels by 43.3% compared with that of exendin-4 alone and by 18.6% compared with that of exendin-4 plus TCTP-PTD 13 in diabetic mice. We also designed an additional covalently linked conjugate of TCTP-PTD 13M2 and exendin-4 and evaluated its hypoglycemic effect after subcutaneous or intranasal delivery. Subcutaneous administration of exendin-4 that its C-terminus is covalently linked to TCTP-PTD 13M2 showed hypoglycemic effect of 42.2% compared to that in untreated group, whereas intranasal delivery was not successful in diabetic mice. We conclude that a simple mixing TCTP-PTD 13M2 with peptide/protein drugs can be potentially a generally applicable approach for intranasal delivery into animals.

Systemic and brain delivery of antidiabetic peptides through nasal administration using cell-penetrating peptides

“…Moreover, mounting evidence has demonstrated the feasibility of several types of CPPs, including TAT-PTD, TCTP-PTD, polyarginine, and penetratin and analogs thereof ( Table 1 ), in the transepithelial delivery through nasal and intestinal epithelium ( Kamei et al, 2008 ; Khafagy et al, 2010a , 2012 ; Kamei et al, 2013a ; Bae and Lee, 2013 ; Bae et al, 2018a ) and of their potential for use as advanced drug delivery vehicles ( Zhu et al, 2014 ; Shan et al, 2015 ; Zhang et al, 2015 ; Kristensen and Nielsen, 2016 ). Although the exact mechanism by which CPPs translocate the epithelium is not fully elucidated, these motifs are regarded as promising vectors for transepithelial transport and the basis for developing more advanced drug delivery strategies ( Kristensen and Nielsen, 2016 ).…”

Nucleus-selective codelivery of proteins and drugs for synergistic antitumor therapy

“…[12][13][14][15][16][17] To date, plenty of protein delivery technologies have been explored for assisting cytosolic delivery, such as polymeric nanoparticles, [18][19][20] lipid nanoparticles, [21][22][23] inorganic nanoparticles, [24][25][26][27] DNA nanomaterials, 28,29 and the direct incorporation of cell penetrating peptides (CPPs). 30 However, most of these methods are delivering protein just to the cytoplasm. Therefore, it is of great signicance to develop carriers which can deliver proteins to the nucleus.…”

Nucleus‐Targeted Delivery of Multi‐Protein Self‐Assembly for Combined Anticancer Therapy

“…[3] One promising strategy to address these problems is to develop an effective delivery system. [4][5][6][7][8] Up to now, a series of protein formulation approaches have been developed to improve protein therapy, such as inorganic nanoparticles, [9][10][11][12] liposomes, [13] polymeric nanoparticles, [14][15][16][17][18][19] DNA materials, [20] cell-penetrating peptides (CPP), [21] and protein-transduction domains (PTD). [22] Although significant progress has been made, these methods also have their shortcomings, such as tedious and lengthy synthetic procedures and cumbersome preparation process, Protein therapy has the potential to revolutionize medicine, but the delivery of multiple proteins is challenging because it requires the development of a strategy that enables different proteins to be combined together and transported not only into cells, but also to the desired cell compartments, such as the nucleus.…”

“…[ 3 ] One promising strategy to address these problems is to develop an effective delivery system. [ 4–8 ] Up to now, a series of protein formulation approaches have been developed to improve protein therapy, such as inorganic nanoparticles, [ 9–12 ] liposomes, [ 13 ] polymeric nanoparticles, [ 14–19 ] DNA materials, [ 20 ] cell‐penetrating peptides (CPP), [ 21 ] and protein‐transduction domains (PTD). [ 22 ] Although significant progress has been made, these methods also have their shortcomings, such as tedious and lengthy synthetic procedures and cumbersome preparation process, which inevitably lead to poor treatment effects.…”