This paper presents our most recent investigations on the effect of a soluble, inert polymer as a conjugating agent for synthetic oligonucleotides. In particular, we studied in detail the influence of a high-molecular weight unit of poly(ethylene glycol) (PEG) on both natural and chimeric oligonucleotides acting as antisense andanti-gene effectors. The attachment of a fluorophore at one end of the PEG-oligonucleotideconjugateallowedtrackingofthe intracellular path of these large chemical moieties in order for us to better understand their biological activity. Also evaluated were the substitution of PEG with other chemically and biologically compatible polymer as supporting units. As an extension of these studies, a particular effort was made to prepare orthogonally protected, bifunctional PEG to obtain mixed oligonucleotide PEG-conjugates bearing at the other extremity a peptide as a targeting cellular moiety, or other bioactive molecules able to improve the biological properties of the starting oligonucleotides.
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