Hyaluronic acid-modified polymeric nanoplatform delivering 131I-Hyp suppresses post-ablation residual lesions in colorectal cancer metastases via necrosis-targeted radiotherapy.

Despite serving as a radical alternative to surgery for inoperable colorectal hepatic metastases patients, thermal ablation faces local tumor progression rates up to 25% from residual tumors, seriously compromising treatment efficacy and survival of patients. We constructed hyaluronic acid (HA)-modified nanoparticles as carriers for the hydrophobic necrosis-avid agent 131I-hypericin (131I-Hyp), enabling tumor necrosis-targeted radiotherapy. 131I-Hyp was synthesized via iodogen-catalyzed electrophilic substitution and loaded into amphiphilic block copolymer hyaluronan-b-poly(ε-caprolactone) (HA-PCL) using dialysis, yielding HA-PCL@(131I-Hyp) nanoparticles (HP-NPs). HP-NPs were characterized in terms of size, stability, and drug release. Biodistribution and antitumor efficacy in vivo were evaluated in rodent models (nude mice and SRG rats bearing HT-29 subcutaneous tumors) with residual tumors induced by incomplete microwave ablation. HP-NPs showed 84.32% encapsulation efficiency, a uniform spherical shape with a hydrodynamic diameter of 75.66 nm, and rapid cytosolic degradation, enabling the release of 131I-Hyp in necrotic regions. After intravenous injection into animals with residual tumors, HP-NPs accumulated in tumor tissue through the enhanced permeability and retention effect and CD44/HA receptor-ligand interactions. The released 131I-Hyp remained selectively in necrotic areas, delivering localized β-radiation to the surrounding residual tumor tissue and significantly inhibiting tumor growth via induction of apoptosis. In conclusion, HP-NPs enable targeted radiotherapy to residual tumor tissue after ablation for colorectal metastases by leveraging necrosis avidity and CD44-mediated HA endocytosis, effectively reducing post-ablation tumor progression. This nanoplatform shows potential for clinical translation in colorectal metastasis treatment.