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 131 I-hypericin ( 131 I-Hyp), enabling tumor necrosis-targeted radiotherapy. 131 I-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@( 131 I-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 131 I-Hyp in necrotic regions. After intravenous injection into animals with residual tumors, HP-NPs accumulated in tumor tissue through the enhanced permeability and retention (EPR) effect and CD44/HA receptor-ligand interactions. The released 131 I-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. • Amphiphilic HA-PCL nanoparticles delivering necrosis-avid 131 I-hypericin for radiotherapy of residual lesions post-tumor-ablation. • HP-NPs exhibited 84.32% encapsulation efficiency, monodisperse spherical morphology (75.66 nm diameter), and rapid cytosolic degradation enabling 131 I-Hyp release in necrotic regions. • Dual targeting: passive accumulation via EPR effect & CD44 receptor-mediated uptake in residual tumors. • 131 I-Hyp selectively retained in necrotic tissues and continuously emitted β-rays, effectively suppressing growth of surrounding residual tumors via apoptosis induction. • HP-NPs reduce local tumor progression after ablation in rodent models of colorectal metastases.