One-Dose Bioorthogonal Gadolinium Nanoprobes for Prolonged Radiosensitization of Tumor

Abstract

Developing effective radiotherapy is impeded by tumor radioresistance, imprecise treatment, and the need for accurate imaging. Herein, a multifunctional gadolinium-based nanoprobe (GBD) is presented, integrating bioorthogonal click chemistry and theranostics to enhance tumor retention, magnetic resonance imaging (MRI) contrast, and radiosensitivity. GBD synthesis involved biomimetic mineralization of bovine serum albumin (BSA) with gadolinium ions to form nanoparticles (GB), followed by conjugation with dibenzocyclooctyne (DBCO). The optimized GBD exhibited an elevated longitudinal relaxivity (r1) of 25.54 mM⁻¹ s⁻¹, which represented a 6.7-fold enhancement compared to the clinical MRI contrast agent magnevist (Gd-DTPA, 3.81 mM⁻¹ s⁻¹). Notably, the application of bioorthogonal click chemistry enhanced the affinity and retention of GBD within tumor cells modified to express azide as an artificial receptor. This novel strategy enhanced tumor retention up to 16 days postinjection, outperforming DBCO-modified small molecule gadolinium (Gd-DBCO) with less than 1-day retention. Such prolonged retention facilitated continuous radiosensitization throughout the radiotherapy course, negating the need for multiple injections, and substantially boosted the effectiveness of radiotherapy. This study demonstrates the transformative potential of combining bioorthogonal click chemistry with nanotechnology in radiotherapy, offering a precise tumor targeting platform, real-time monitoring, and improved treatment outcomes.