Poly(propylene imine) dendrimers modified with maltose or maltotriose protect phosphorothioate oligodeoxynucleotides against nuclease activity

Abstract

The antisense oligonucleotides are promising agents for application in anti-HIV therapies. The antiretroviral nucleoside analogues administrated into circulatory system are vulnerable to nuclease degradation and require a vehicle which would not only facilitate therapeutic nucleotides into host cells, but would also provide protection against enzymatic degradation. Such potential is exhibited by poly(propylene imine) dendrimers - the branched cationic polymers easily interacting with oligonucleotides to form complexes called "dendriplexes". The aim of the present study was to evaluate the abilities of the fourth generation poly(propylene imine) dendrimers partially modified with maltose (PPI-Mal G4) or maltotriose (PPI-Mal-III G4) to protect anti-HIV antisense oligonucleotides (ODNs) from nucleolytic degradation. The ODNs (AT, GEM91, SREV) were complexed with dendrimers and subjected to cleavage by serum nucleases or endonuclease S1. The results showed that all examined dendrimers protected ODNs against nucleases contained in FBS. Both PPI-Mal G4 and PPI-Mal-III G4 dendrimers completely prevented ODNs digestion by nuclease S1 at neutral pH. The protective capabilities of investigated dendrimers were significantly weaker in acidic environment. The time stability assay showed that the dendriplexes formed by AT, GEM91, SREV and carbohydrate-modified PPI G4 dendrimers still existed after 12h incubation both in low and at neutral pH buffers. The conformational change of dendriplexes in acidic environment was proposed as possible phenomenon leading to exposition of ODNs to nuclease attack and significantly diminishing dendriplexes' resistance to nucleolitic digestion.