The present invention concerns an oligonucleotide modified by substitution at the 3’ or the 5’ end by at least triple alkyl chain or at least one ketal functional group, wherein the ketal carbon bears two hydrocarbon chains. The invention also concerns the use of the hydrophobically modified oligonucleotides as a medicament, in particular for use for treating cancer. rnThe autors show lipid conjugate Antisense Oligonucleotide (L-ASO) are capable of inhibiting prostate cancer in vivo and have no toxicity in mice (Karaki S et al. 2017 J Control Release, 258:1-9). The addition of a lipid chain on the 5’ part of the antisense oligonucleotide enables inhibiting specifically “UD protein”, even in the absence of the transfection agent. The lipid modification strongly enhances the ability of ASO to reduce “UD protein” expression leading to a strong reduction of tumor progression in a murin xenograft model of Castration Resistant prostate cancer. The L-ASO have been validated in others therapeutic indications. rnThese modifications allow advantages over standard ASO: 1/ Delivery enhancement, Stability, biodisponibility; 2/ Internalisation without any transfection agents; 3/ Encapsulation of different molecules like chemotherapies (L-ASOs self-assembly give sphericals nanoparticles, which are prone to host drug molecules within their hydrophobic cores: for instance Paclitaxel).rnrn