4.2 Article

Synthesis of Site-Specific Antibody-[60]Fullerene-Oligonucleotide Conjugates for Cellular Targeting

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ACS APPLIED BIO MATERIALS
卷 6, 期 8, 页码 3189-3198

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AMER CHEMICAL SOC
DOI: 10.1021/acsabm.3c00318

关键词

Molecular Spherical Nucleic Acid; Antibody-OligonucleotideConjugate; [60]Fullerene Conjugate; Nanoparticle; Targeted Delivery

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An ideal therapeutic antibody-oligonucleotide conjugate (AOC) should have a uniform structure, a high oligonucleotide (ON) payload, and retain the antibody (Ab)-mediated binding properties for efficient delivery to the target site. In this study, [60]fullerene-based molecular spherical nucleic acids (MSNAs) were site-specifically conjugated to antibodies (Abs), and their Ab-mediated cellular targeting and binding properties were investigated. The AOCs obtained through glycan engineering and click chemistries showed uniformity, with a high ON:Ab ratio of 24:1 and retained antigen binding properties. Moreover, Ab-mediated endocytosis was demonstrated in HER2 overexpressing breast carcinoma cells, and the effect on cell proliferation was analyzed using live-cell imaging.
An ideal therapeutic antibody-oligonucleotideconjugate(AOC) would be a uniform construct, contain a maximal oligonucleotide(ON) payload, and retain the antibody (Ab)-mediated binding properties,which leads to an efficient delivery of the ON cargo to the site oftherapeutic action. Herein, [60]fullerene-based molecular sphericalnucleic acids (MSNAs) have been site-specifically conjugated to antibodies(Abs), and the Ab-mediated cellular targeting of the MSNA-Abconjugates has been studied. A well-established glycan engineeringtechnology and robust orthogonal click chemistries yielded the desireduniform MSNA-Ab conjugates (MW & SIM; 270 kDa), with an oligonucleotide(ON):Ab ratio of 24:1, in 20-26% isolated yields. These AOCsretained the antigen binding properties (Trastuzumab's bindingto human epidermal growth factor receptor 2, HER2), studied by biolayerinterferometry. In addition, Ab-mediated endocytosis was demonstratedwith live-cell fluorescence and phase-contrast microscopy on BT-474breast carcinoma cells, overexpressing HER2. The effect on cell proliferationwas analyzed by label-free live-cell time-lapse imaging.

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