Lehot Victor, Neuberg Patrick, Ripoll Manon, Daubeuf François, Erb Stéphane, Dovgan Igor, Ursuegui Sylvain, Cianférani Sarah, Kichler Antoine, Chaubet Guilhem, Wagner Alain
Bio-Functional Chemistry (UMR 7199), Institut du Médicament de Strasbourg, University of Strasbourg, 74 Route du Rhin, 67400 Illkirch-Graffenstaden, France.
UAR3286, Plate-Forme de Chimie Biologique Intégrative de Strasbourg, ESBS, CNRS-Strasbourg University, 67400 Illkirch-Graffenstaden, France.
Pharmaceutics. 2023 Jun 2;15(6):1643. doi: 10.3390/pharmaceutics15061643.
Despite their clinical success, Antibody-Drug Conjugates (ADCs) are still limited to the delivery of a handful of cytotoxic small-molecule payloads. Adaptation of this successful format to the delivery of alternative types of cytotoxic payloads is of high interest in the search for novel anticancer treatments. Herein, we considered that the inherent toxicity of cationic nanoparticles (cNP), which limits their use as oligonucleotide delivery systems, could be turned into an opportunity to access a new family of toxic payloads. We complexed anti-HER2 antibody-oligonucleotide conjugates (AOC) with cytotoxic cationic polydiacetylenic micelles to obtain Antibody-Toxic-Nanoparticles Conjugates (ATNPs) and studied their physicochemical properties, as well as their bioactivity in both in vitro and in vivo HER2 models. After optimising their AOC/cNP ratio, the small (73 nm) HER2-targeting ATNPs were found to selectively kill antigen-positive SKBR-2 cells over antigen-negative MDA-MB-231 cells in serum-containing medium. Further in vivo anti-cancer activity was demonstrated in an SKBR-3 tumour xenograft model in BALB/c mice in which stable 60% tumour regression could be observed just after two injections of 45 pmol of ATNP. These results open interesting prospects in the use of such cationic nanoparticles as payloads for ADC-like strategies.
尽管抗体药物偶联物（ADCs）在临床上取得了成功，但它们仍然仅限于递送少数几种具有细胞毒性的小分子payload。在寻找新型抗癌治疗方法的过程中，将这种成功的形式应用于递送其他类型的细胞毒性payload具有很高的研究价值。在此，我们认为阳离子纳米颗粒（cNP）的固有毒性限制了它们作为寡核苷酸递送系统的应用，但这也可以转化为一个机会，用于开发一类新的毒性payload。我们将抗HER2抗体-寡核苷酸偶联物（AOC）与具有细胞毒性的阳离子聚二乙炔胶束复合，以获得抗体-毒性-纳米颗粒偶联物（ATNPs），并研究了它们的物理化学性质以及在体外和体内HER2模型中的生物活性。在优化了它们的AOC/cNP比例后，发现小尺寸（73 nm）的靶向HER2的ATNPs在含血清培养基中能够选择性地杀死抗原阳性的SKBR-2细胞，而不是抗原阴性的MDA-MB-231细胞。在BALB/c小鼠的SKBR-3肿瘤异种移植模型中进一步证明了其体内抗癌活性，在注射两次45 pmol的ATNP后，即可观察到肿瘤稳定消退60%。这些结果为将此类阳离子纳米颗粒用作类似ADC策略的payload开辟了有趣的前景。
