Photoacoustic-Raman Imageable Embolic Microspheres for Depth-Dependent Laser-Dosage Guidance of Photothermal Therapy of Hepatocellular Carcinoma

Abstract

Transarterial embolization in combination with photothermal therapy (PTT) represents a promising strategy for unresectable hepatocellular carcinoma (HCC). However, its clinical application is hindered by the lack of accurate laser-dosage guidance regimens, which results in tumor recurrence from insufficient irradiation or complications from excessive ablation. Here, we develop a depth-dependent laser-dosage guidance strategy for photothermal therapy via dual photoacoustic (PA)-Raman imaging using BBTPPRO-loaded poly(lactic-co-glycolic acid) microspheres (BBTPPRO MPs) as a theranostic embolic platform. The BBTPPRO MPs have a uniform spherical morphology (53.21 μm average diameter) with a drug loading of 4.73% and an encapsulation efficiency of 99.23%. The aggregated state of BBTPPRO through microsphere encapsulation offers substrate-free Raman signals via the stacking-induced intermolecular charge transfer-enhanced Raman scattering effect and enhances PA signals and photothermal conversion efficiency (29.7%) through the aggregation-caused quenching effect. By calibrating the required irradiation time to reach the temperature threshold required for complete thermal ablation under a fixed laser power density at various tissue depths, we establish a depth-dependent laser-dosage guidance strategy. In the orthotopic N1S1 rat liver tumor model after hepatic arterial embolization of BBTPPRO MPs, the PA imaging noninvasively assesses tumor depth to guide laser dosage, while the intraoperative Raman imaging provides tumor localization and delineation for the laser irradiation field. This dual-modal strategy has exhibited superior antitumor efficacy evidenced by a significantly lower maximum standardized uptake value via 18F-fluorodeoxyglucose positron emission tomography-computed tomography (1.68 ± 0.30) at 14 days post-treatment compared to conventional PTT group (6.92 ± 3.63). Overall, this PA-Raman image-guided strategy integrates pretreatment laser-dosage guidance with intraoperative spatial targeting, highlighting its potential to improve the safety and efficacy of HCC ablation.