## 2 Results and Discussion  
In order to implement cell delivery of the DNA mimic foldamers, several targeting strategies were considered, including the synthesis of an ADC. This class of therapeutic agents where a cytotoxic drug is grafted onto a monoclonal antibody with a fixed DAR has emerged in the last decade and is rapidly expanding with the recent approval of several molecules [17; 20]. Trastuzumab is a monoclonal antibody targeting HER2 that is approved for the treatment of HER2-positive breast cancers. After the binding of trastuzumab on its HER2 specific antigen, the trastuzumab-HER2 complex is able to internalize efficiently. Therefore, trastuzumab has been conjugated to highly cytotoxic drugs such as the tubulin polymerization inhibitor emtansine or the DNA topoisomerase I poison deruxtecan, leading respectively to the two ADCs, ado-trastuzumab emtansine (T-DM1 or Kadecyla(r)) and famtrastuzumab deruxtecan-nxki (DS-8201a or Enhertu(r)), that are approved by the FDA against HER2-positive breast cancer [17]. A third ADC, vic-tratuzumab duocarmazine (SYD985), using the alkylating agent duocarmycin as a payload, was also developed [23] and is currently in phase 3 trial. Based on this background, we selected trastuzumab to graft a 16-mer DNA mimic foldamer composed of 8-amino-2-quinolinesarboxylic acid monomers each bearing a negatively charged phosphonate residue in position 4 (Figure 1A) to produce an ADC able to specifically target the surface of HER2-positive cancer cells and then internalize to deliver its payload. To achieve this goal, we designed a site-specific ADC **4** (Figure 1C) using a bifunctional non-cleavable linker. Considering the size of the payload and its potential mechanism of action [15], we decided to use a non-cleavable linker to graft payload **3** (Figure 1B) as the most straightforward strategy. Indeed, after internalization of the ADC, trastuzumab will be completely digested in the lysosome. Since the foldamer resists degradation by both nucleases and proteases [15], the generated metabolite will be very close in structure to the precursor **3**[17; 24]. This approach thus does not compromise the foldamer's mechanism of action. The selected linker included a diphenylthiomaleimide bioconjugation function as a next generation maleimide, able to rebridge previously reduced interchain disulfide bridges of an antibody while incorporating up to four desired payloads for an IgGI [25; 26; 27; 28]. The diphenylthio-maleimidocaproic acid **2** (diphenylthio-Mal-Cap, Figure 1B) was synthesized according to previously reported procedures [28]. We then prepared the protected 16-mer **1** (Figure 1B) on a low loading Wang resin via acid chloride activation of the monomers under neutral conditions using the [PERSON] reagent (1-chloro-_N_,\(N\),2-trimethylpropenylamine) [29], following microwave assisted foldamer solid phase synthesis (SPS) procedures [30; 31; 32]. The \(N\)-terminal functionalization of the foldamer with the diphenylthio-Mal-Cap linker **2** was performed on solid phase by activating in situ the caproic acid moiety of the linker as an acid chloride using triphenyl-phosphine, trichloroacetonitrile and colliding as a base [33]. Removal from the resin with concomitant cleavage of the _tert_-butyl phosphonate ester groups was performed by treatment with 95:2.5:2.5 TFA/H\({}_{2}\)O/\(i\)P\({}_{3}\)SiH (vol/vol/vol). The crude material was analyzed and purified by RP-HPLC. The pure product was characterized by \({}^{1}\)H NMR in H\({}_{2}\)O/D\({}_{2}\)O and mass spectrometry (Figures S1-S3). Precursor **3** was then conjugated onto trastuzumab. Trastuzumab in BBS buffer was first incubated with a solution of TCEP in BBS under argon at 37 \({}^{\circ}\)C for 75 min to allow complete reduction of the interchain disulfide bridges. Then, a solution of diphenylthio-Mal-Cap-foldamer **3** in water was added and the reaction mixture was incubated for 2 h at 4 \({}^{\circ}\)C under stirring.