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Dual Antibody-Conjugated Amyloid Nanorods to Promote Selective Cell-Cell Interactions.

ABSTRACT: Grafting biomolecules on nanostructures' surfaces is an increasingly used strategy to target pathogenic cells, with both diagnostic and therapeutic applications. However, nanomaterials monofunctionalized by conjugating a single type of ligand find limited uses in pathologies/therapies that require two or more targets/receptors to be targeted and/or activated with a single molecular entity simultaneously. Therefore, multivalent nanomaterials for dual- or multitargeting are attracting significant interest. This study provides a proof of concept of such nanostructures. We have recently developed a modular methodology that allows obtaining amyloid-based materials decorated with active globular domains. Here, this approach is exploited to generate functional amyloid fibrils displaying antibody capture moieties. A high antibody binding affinity and capacity for the resulting nanofibrils, whose size can be manipulated to obtain homogeneous nanorods with high biocompatibility, are demonstrated. These nanorods are then used for specific antibody-mediated targeting of different cell types. Simultaneous conjugation of these nanorods with different antibodies allows obtaining a mimic of a bispecific antibody that redirects T lymphocytes to tumoral cells, holding high potential for immunotherapy. Overall, the work illustrates a modular and straightforward strategy to obtain preparative quantities of multivalent antibody-functionalized nanomaterials with multitargeting properties without the need for covalent modification.

SUBMITTER: Wang W

PROVIDER: S-EPMC9262253 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Amyloid-? (A?) peptide is the main fibrillar component of plaque deposits found in brains affected by Alzheimer's disease (AD) and is related to the pathogenesis of AD. Passive anti-A? immunotherapy has emerged as a promising approach for the therapy of AD, based on the administration of specific anti-A? monoclonal antibodies (aA?mAbs) to delay A? aggregation in the brain. However, the main disadvantage of this approach is the required readministration of the aA?mAbs at frequent intervals. There are only a few reports describing in vitro study for the immobilization of aA?mAbs to nanoparticles as potential targeting agents of A? aggregates. In this article, we report the immobilization of the aA?mAb clone BAM10 to near-infrared fluorescent maghemite nanoparticles for the inhibition of A?40 fibrillation kinetics and the specific detection of A?40 fibrils. The BAM10-conjugated iron oxide nanoparticles were well-characterized, including their immunogold labeling and cytotoxic effect on PC-12 (pheochromocytoma cell line). Indeed, these antibody-conjugated nanoparticles significantly inhibit the A?40 fibrillation kinetics compared with the same concentration, or even five times higher, of the free BAM10. This inhibitory effect was confirmed by different assays such as the photo-induced crosslinking of unmodified proteins combined with sodium dodecyl sulfate- polyacrylamide gel electrophoresis. A cell viability assay also confirmed that these antibody-conjugated nanoparticles significantly reduced the A?40-induced cytotoxicity to PC-12 cells. Furthermore, the selective labeling of the A?40 fibrils with the BAM10-conjugated near-infrared fluorescent iron oxide nanoparticles enabled specific detection of A?40 fibrils ex vivo by both magnetic resonance imaging and fluorescence imaging. This study highlights the immobilization of the aA?mAb to dual-modal nanoparticles as a potential approach for aA?mAb delivery, eliminating the issue of readministration, and contributes to the development of multifunctional agents for diagnosis and therapy of AD.

Project description:Investigation of targeting inhibitors of A? aggregation, heme-A? peroxidase-like activity and efficient detectors of A? aggregation, are of therapeutic value and diagnostics significance for the treatment of Alzheimer's disease (AD). Due to the complex pathogenesis of AD, theranostics treatment with multiple functions are necessary. Herein we constructed the NIR absorption property of gold nanorods (GNRs) loaded with single chain variable fragment (scFv) 12B4 and thermophilic acylpeptide hydrolase (APH) ST0779 as a smart theranostic complex (GNRs-APH-scFv, GAS), which possesses both rapid detection of A? aggregates and NIR photothermal treatment that effectively disassembles A? aggregates and inhibits A?-mediated toxicity. Methods: We screened targeting anti-A? scFv 12B4 and thermophilic acylpeptide hydrolase as amyloid-degrading enzyme, synthesized GAS gold nanorods complex. The GAS was evalued by A? inhibition and disaggregation assays, A? detection assays, A? mediated toxicity assays in vitro. In vivo, delaying A?-induced paralysis in AD model of Caenorhabditis elegans was also tested by GAS. Results: In vitro, GAS has a synergistic effect to inhibit and disassociate A? aggregates, in addition to decrease heme-A? peroxidase-like activity. In cultured cells, treatment with GAS reduces A?-induced cytotoxicity, while also delaying A?-mediated paralysis in CL4176 C.elegans model of AD. Furthermore, the photothermal effect of the GAS upon NIR laser irradiation not only helps disassociate the A? aggregates but also boosts APH activity to clear A?. The GAS, as a targeting detector and inhibitor, allows real-time detection of A? aggregates. Conclusion: These results firstly highlight the combination of scFv, APH and nanoparticles to be theranostic AD drugs. Taken together, our strategy provides a new thought into the design of smart compounds for use as efficiently therapeutic and preventive agents against AD. Moreover, our design provides broad prospects of biomedical strategy for further theranostics application in those diseases caused by abnormal protein.

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Dual Antibody-Conjugated Amyloid Nanorods to Promote Selective Cell-Cell Interactions.

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