唾液腺保护策略与未来方向

4.2 Strategies and Future Directions 4.2.1 Salivary Gland Protection Strategies For salivary gland toxicity, emerging solutions include: 1) Epigenetic modulators: Histone deacetylase (HDAC) inhibitors can upregulate PSMA expression in tumors while reducing PSMA levels in salivary glands, thereby expanding the therapeutic window by 3.2 times (Ref. 30). 2) Precision dose adjustment: Individualized dosimetry guided by SPECT/CT to reduce the cumulative radiation dose to the salivary glands. 3) Novel ligand design: Development of PSMA ligands with low affinity for salivary glands, such as the PSMA-D5 variant in preclinical studies (Ref. 10). 4.2.2 Overcoming Target Heterogeneity For PSMA-low or PSMA-negative lesions, various innovative strategies are being explored, including: dual-targeting approaches, epigenetic modulation, and multi-probe imaging guidance. 4.2.3 Reversing Resistance Mechanisms To overcome secondary resistance, several combination strategies are under clinical development: 1) DNA repair inhibition: The synergistic effect of PARP inhibitors combined with PSMA-targeted radiotherapy is being evaluated in multiple Phase II trials (e.g., Olaparib + ¹⁷⁷Lu-PSMA-617). 2) Ferroptosis induction: Dual-target nanoparticles simultaneously deliver PSMA ligands and ferroptosis inducers (such as RSL3), enhancing radiosensitivity through lipid peroxidation (Refs. 5, 31).