Hybrid NIR-responsive liposome/hydrogel platform mediating chemo-photothermal therapy of retinoblastoma enhanced by quercetin as an adjuvant

Rationale: Retinoblastoma is one of the most aggressive paediatric cancers originating from retina and finally invades vitreous humour or other tissues if treated improperly. Current interventions often fail due to the complexities of tumour progression and drug resistance driven by frequent intravitreal injection and epithelial-mesenchymal transition (EMT). Consequently, there is an unmet need for more effective, less invasive treatments. Methods: A near-infrared (NIR)-responsive liposome/hydrogel platform that incorporates quercetin (QUE) and doxorubicin (DOX) co-loaded liposomes (QD Lipo), and indocyanine green (ICG) in a low-gelling temperature agarose hydrogel (LAgel) was developed to improve efficacy through localized, on-demand delivery of chemo-photothermal therapy directly at the site of tumour. The initial phase of the study examined the injectability, reversibility and stability of QD Lipo/ICG/LAgel under NIR using cryo -SEM technique and rheological measurement. Following this, photothermal conversion capability and controlled release of QD Lipo, alongside the mobility and penetration of QD Lipo was investigated using infrared thermal imaging, nanoparticle tracking analysis and fluorescence microscope. Moreover, retinoblastoma orthotopic model was established to corroborate the anti-tumour effectiveness in vivo . Flow cytometry, H&E, immunohistochemical staining, animal imaging and western blotting were performed to identify the underling mechanism of QD Lipo/ICG/LAgel to improve the treatment. Results: The thermosensitivity and photothermal conversion capabilities of QD Lipo/ICG/LAgel enable precise, on-demand drug delivery in vitreous, significantly reducing the need for frequent intravitreal injections. In vitro and in vivo evaluation demonstrated that with facilitation of QUE, our platform effectively targets the rapid tumour progression and overcome therapeutic resistance of mild photothermal therapy (PTT), by modulating EMT process and inhibiting heat shock protein (HSP) level. Conclusions: This innovative approach not only mitigates the current challenges of repeated invasive medication, but also sets new strategies for treating complex ocular diseases.