Copy number profiling of circulating free DNA predicts transarterial chemoembolization response in advanced hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is the most commonly used treatment for advanced hepatocellular carcinoma (HCC), but still lacks accurate real-time biomarkers for monitoring its therapeutic efficacy. Here, we explored whether copy number profiling of circulating free DNA (cfDNA) could be utilized to predict responses and prognosis in HCC patients with TACE treatment. In total, 266 plasma cfDNA samples were collected from 64 HCC patients, 57 liver cirrhosis (LC) patients and 32 healthy volunteers. We performed low-depth whole-genome sequencing (LD-WGS) on cfDNA samples to conduct copy number variant (CNV) analysis and tumour fraction (TFx) quantification. Then, the correlation between TFx/CNVs and therapeutic efficacy, treatment outcomes and lipiodol deposition were explored. The change in TFx during TACE treatment was associated with patients' tumour burden, and could accurately and earlier predict treatment response and prognosis, providing an alternative strategy other than mRECIST. Meanwhile, the chromosomal 16q/NQO1 amplification indicated worse therapeutic response; in patients who underwent multiple TACE sessions, TFx change during their first TACE treatment reflected the long-term survival; additionally, the copy number amplification of chromosome 1q, 3p, 6p, 8q, 10p, 12q, 18p or 18q affected lipiodol deposition. Overall, we have provided a new liquid biopsy approach for future TACE management of HCC patients.

Glutathione responsive micelles incorporated with semiconducting polymer dots and doxorubicin for cancer photothermal-chemotherapy.

Nanoplatform integrated with photothermal therapy (PTT) and chemotherapy has been recognized a promising agent for enhancing cancer therapeutic outcomes, but still suffer from less controllability for optimizing their synergistic effects. We fabricated glutathione (GSH) responsive micelles incorporated with semiconducting polymer dots and doxorubicin (referred as SPDOX NPs) for combining PTT with chemotherapy to enhance cancer therapeutic efficiency. These micelles, with excellent water dispersibility, comprises of three distinct functional components: (1) the monomethoxy-poly(ethylene glycol)-S-S-hexadecyl (mPEG-S-S-C16), which forms the micelles, can render hydrophobic substances water-soluble and improve the colloidal stability; (2) disulfide linkages can be cleaved in a reductive environment for tumor specific drug release due to the high GSH concentrations of tumor micro-environment; (3) PCPDTBT dots and anti-cancer drug DOX that are loaded inside the hydrophobic core of the micelle can be applied to simultaneously perform PTT and chemotherapy to achieve significantly enhanced tumor killing efficiency both in vitro and in vivo. In summary, our studies demonstrated that our SPDOX NPs with simultaneous photothermal-chemotherapy functions could be a promising platform for a tumor specific responsive drug delivery system.

Smart Cu(II)-aptamer complexes based gold nanoplatform for tumor micro-environment triggered programmable intracellular prodrug release, photodynamic treatment and aggregation induced photothermal therapy of hepatocellular carcinoma.

This study describes smart Cu(II)-aptamer complexes based gold nanoplatform for tumor micro-environment triggered programmable prodrug release, in demand photodynamic therapy and aggregation induced photothermal ablation of hepatocellular carcinoma. The nanoplatform is consist of monodispersed gold nanoparticle (GNP) that is binding to HCC cell specific targeting aptamers (TLS11a) through Au-S bond; the aptamer is labeled with Ce6 at the 5'end and coordinated with Cu(II) through (GA)10 repeating bases to load AQ4N at the 3' end. In normal physiological conditions, the fluorescence and ROS generation ability of Ce6 are quenched by GNPs via RET; but in cancerous cells, the fluorescence and the ROS generation of Ce6 could be recovered by cleavage of Au-S bond through high level of intracellular GSH for real-time imaging and in demand PDT. Meanwhile, the prodrug AQ4N release could be triggered by acid-cleavage of coordination bonds, then accompanied by a release of Cu(II) that would induce the electrostatic aggregation of GNPs for photo-thermal ablation; furthermore, the significantly enhanced chemotherapy efficiency could be achieved by PDT produced hypoxia to convert AQ4N into AQ4. In summary, here described nanoplatform with tumor cell specific responsive properties and programmable PDT/PTT/chemotherapy functions, might be an interesting synergistic strategy for HCC treatment.

Lipid micelles packaged with semiconducting polymer dots as simultaneous MRI/photoacoustic imaging and photodynamic/photothermal dual-modal therapeutic agents for liver cancer.

Incorporating multiple imaging modalities and simultaneous therapeutic functions together into one single nano-formulation is of great importance for developing high-performance clinical-translatable theranostic agents. Herein, we fabricated multifunctional lipid-micelles incorporated with semiconducting polymer dots and a photosensitizer (referred as Pdots/Ce6@lipid-Gd-DOTA micelles) for combined magnetic resonance imaging (MRI)/photoacoustic imaging (PAI) and photodynamic (PDT)/photothermal (PTT) dual-modal therapy that induced by a single laser to achieve enhanced cancer therapeutic efficiency. The Pdots/Ce6@lipid-Gd-DOTA micelles with excellent water dispersibility were comprised of a core with poly[2,6-(4,4-bis-(2-ethylhexyl)-4H-cyclopenta[2,1-b;3,4-b']-dithiophene)-alt-4,7-(2,1,3-benzo-thiadiazole)] dots (Pdots) and Ce6 molecules inside, and a lipid-PEG outlayer conjugated with gadolinium-1,4,7,10-tetraacetic acid. The prepared Pdots/Ce6@lipid-Gd-DOTA micelles exhibited extremely low cytotoxicity, and had excellent MR- and PA-imaging contrast-enhancement ability, which could synchronously offer anatomical information and morphological information of tumors. Moreover, both Pdots and Ce6 photosensitizer, encapsulated inside the lipid-Gd-DOTA micelles, exhibited high NIR absorption at 670 nm and were applied to combine photothermal and photodynamic therapy simultaneously to achieve enhanced synergistic cancer therapeutic efficiency both in vitro and in vivo. In summary, our studies demonstrated that Pdots/Ce6@lipid-Gd-DOTA micelles with multi-diagnosis modalities and simultaneous dual-modal photo-therapy functions might be a potential interesting theranostic platform for tumor treatment.