Abstract Gadolinium-based nanoparticles (GdNP) are sub-5 nm particles designed for radiosensitization and MRI contrast enhancement. The high atomic number of Gd (Z = 64) enables efficient X-ray absorption and dose deposition within tumors, with tumor accumulation facilitated by the enhanced permeability and retention effect. Previous clinical trials have provided preliminary evidence for the safety and potential therapeutic benefit of intravenous GdNP in patients with cervical cancer and brain metastases. To improve tumor specificity, we conjugated GdNP with pH-low insertion peptide (pHLIP), which targets the acidic tumor microenvironment through pH-dependent membrane insertion. Previous work demonstrated that pHLIP conjugated to GdNP enhanced gadolinium uptake and radiosensitization in vitro. In vitro experiments were performed with cultured A549 human lung adenocarcinoma cells at pH 6.2 (tumor-like) and pH 7.4 (physiologic) conditions. Clonogenic assays and ICP-MS analysis revealed that while pHLIP-GdNP (0.17 mM dose) did not significantly alter cell survival, it increased intracellular gadolinium levels by approximately 18-fold under acidic conditions compared to unconjugated GdNP. In vivo, mice bearing subcutaneously implanted A549 tumors received 10 Gy X-ray irradiation with or without unconjugated GdNP or pHLIP-GdNP pretreatment (300 mg/kg; n = 7 mice/group). All irradiated groups exhibited significant tumor growth delay compared to controls (P 0.013), but no additional radiosensitization was observed in the nanoparticle-treated cohorts, despite Gd accumulation in the tumor. MRI T1 mapping demonstrated shortened T1 relaxation times following GdNP administration, with greater reduction following pHLIP-GdNP injection, indicating enhanced contrast agent delivery. These findings suggest that pHLIP conjugation improves gadolinium uptake and MRI visibility but does not enhance radiotherapeutic efficacy under current conditions. Departing from previous work, this study used a simpler covalent bond to conjugate pHLIP to GdNP rather than a disulfide bridge, which may explain the decreased efficacy. Reintroducing the disulfide linkage might be critical, as it allows the conjugate to remain stable in circulation while releasing nanoparticle cargo upon insertion into acidic tumor cells, potentially increasing therapeutic efficacy. Citation Format: Jessica Wen, Yuwei Xue, Wu Liu, Guillem Pratx, . pH-targeted gadolinium-based nanoparticles for enhanced radiotherapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5815.
Wen et al. (2026) studied this question.