Cooperative Cellular Uptake and Activity of Octaarginine Antisense Peptide Nucleic acid (PNA) Conjugates

TY - JOUR

T1 - Cooperative Cellular Uptake and Activity of Octaarginine Antisense Peptide Nucleic acid (PNA) Conjugates

AU - Ghavami, Mahdi

AU - Shiraishi, Takehiko

AU - Nielsen, Peter E.

PY - 2019/10

Y1 - 2019/10

N2 - Cellular uptake and antisense activity of d-octaarginine conjugated peptide nucleic acids (PNAs) is shown to exhibit pronounced cooperativity in serum-containing medium, in particular by being enhanced by analogous mis-match PNA-cell-penetrating peptide (PNA-CPP) conjugates without inherent antisense activity. This cooperativity does not show cell or PNA sequence dependency, suggesting that it is a common effect in cationic CPP conjugated PNA delivery. Interestingly, our results also indicate that Deca-r8-PNA and r8-PNA could assist each other and even other non-CPP PNAs as an uptake enhancer agent. However, the peptide itself (without being attached to the PNA) failed to enhance uptake and antisense activity. These results are compatible with an endosomal uptake mechanism in which the endocytosis event is induced by multiple CPP-PNA binding to the cell surface requiring a certain CPP density, possibly in terms of nanoparticle number and/or size, to be triggered. In particular the finding that the number of endosomal events is dependent on the total CPP-PNA concentration supports such a model. It is not possible from the present results to conclude whether endosomal escape is also cooperatively induced by CPP-PNA.

AB - Cellular uptake and antisense activity of d-octaarginine conjugated peptide nucleic acids (PNAs) is shown to exhibit pronounced cooperativity in serum-containing medium, in particular by being enhanced by analogous mis-match PNA-cell-penetrating peptide (PNA-CPP) conjugates without inherent antisense activity. This cooperativity does not show cell or PNA sequence dependency, suggesting that it is a common effect in cationic CPP conjugated PNA delivery. Interestingly, our results also indicate that Deca-r8-PNA and r8-PNA could assist each other and even other non-CPP PNAs as an uptake enhancer agent. However, the peptide itself (without being attached to the PNA) failed to enhance uptake and antisense activity. These results are compatible with an endosomal uptake mechanism in which the endocytosis event is induced by multiple CPP-PNA binding to the cell surface requiring a certain CPP density, possibly in terms of nanoparticle number and/or size, to be triggered. In particular the finding that the number of endosomal events is dependent on the total CPP-PNA concentration supports such a model. It is not possible from the present results to conclude whether endosomal escape is also cooperatively induced by CPP-PNA.

KW - antisense

KW - cell-penetrating peptides

KW - octaarginine conjugate

KW - PNA delivery

KW - self-assembled nanoparticles

U2 - 10.3390/biom9100554

DO - 10.3390/biom9100554

M3 - Journal article

C2 - 31581514

AN - SCOPUS:85072910905

SN - 2218-273X

VL - 9

JO - Biomolecules

JF - Biomolecules

IS - 10

M1 - 554

ER -