Transarterial chemoembolization with PD-(L)1 inhibitors plus molecular targeted therapies for hepatocellular carcinoma (CHANCE001).

There is considerable potential for integrating transarterial chemoembolization (TACE), programmed death-(ligand)1 (PD-[L]1) inhibitors, and molecular targeted treatments (MTT) in hepatocellular carcinoma (HCC). It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations. In this nationwide, retrospective, cohort study, 826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT (combination group, n = 376) or TACE monotherapy (monotherapy group, n = 450) were included from January 2018 to May 2021. The primary endpoint was progression-free survival (PFS) according to modified RECIST. The secondary outcomes included overall survival (OS), objective response rate (ORR), and safety. We performed propensity score matching approaches to reduce bias between two groups. After matching, 228 pairs were included with a predominantly advanced disease population. Median PFS in combination group was 9.5 months (95% confidence interval [CI], 8.4-11.0) versus 8.0 months (95% CI, 6.6-9.5) (adjusted hazard ratio [HR], 0.70, P = 0.002). OS and ORR were also significantly higher in combination group (median OS, 19.2 [16.1-27.3] vs. 15.7 months [13.0-20.2]; adjusted HR, 0.63, P = 0.001; ORR, 60.1% vs. 32.0%; P < 0.001). Grade 3/4 adverse events were observed at a rate of 15.8% and 7.5% in combination and monotherapy groups, respectively. Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS, OS, and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice, with an acceptable safety profile.

In situ self-assembly of amphiphilic dextran micelles and superparamagnetic iron oxide nanoparticle-loading as magnetic resonance imaging contrast agents.

Polymeric micelles have long been considered as promising nanocarrier for hydrophobic drugs and imaging probes, due to their nanoscale particle size, biocompatibility and ability to loading reasonable amount of cargoes. Herein, a facile method for dextran micelles preparation was developed and their performance as carriers of superparamagnetic iron oxide (SPIO) nanocrystals was evaluated. Amphiphilic dextran (Dex-g-OA) was synthesized via the Schiff base reactions between oxidized dextran and oleylamine, and self-assembled in situ into nano-size micelles in the reaction systems. The self-assembling behaviors of the amphiphilic dextran were identified using fluorescence resonance energy transfer technique by detection the energy transfer signal between the fluorophore pairs, Cy5 and Cy5.5. Hydrophobic SPIO nanoparticles (Fe3O4 NPs) were successfully loaded into the dextran micelles via the in situ self-assembly process, leading to a series of Fe3O4 NPs-loaded micelle nanocomposites (Fe3O4@Dex-g-OA) with good biocompatibility, superparamagnetism and strongly enhanced T 2 relaxivity. At the magnetic field of 0.5 T, the Fe3O4@Dex-g-OA nanocomposite with particle size of 116.2 ± 53.7 nm presented a higher T 2 relaxivity of 327.9 mM Fe - 1 ·s-1. The prepared magnetic nanocomposites hold the promise to be used as contrast agents in magnetic resonance imaging.

[Research progress on the fluorescence resonance energy transfer-based polymer micelles as drug carriers].

Polymer micelles formed by self-assembly of amphiphilic polymers are widely used in drug delivery, gene delivery and biosensors, due to their special hydrophobic core/hydrophilic shell structure and nanoscale. However, the structural stability of polymer micelles can be affected strongly by environmental factors, such as temperature, pH, shear force in the blood and interaction with non-target cells, leading to degradations and drug leakage as drug carriers. Therefore, researches on the structural integrity and in vivo distribution of micelle-based carriers are very important for evaluating their therapeutic effect and clinical feasibility. At present, fluorescence resonance energy transfer (FRET) technology has been widely used in real-time monitoring of aggregation, dissociation and distribution of polymer micelles ( in vitro and in vivo). In this review, the polymer micelles, characteristics of FRET technology, structure and properties of the FRET-polymer micelles are briefly introduced. Then, methods and mechanism for combinations of several commonly used fluorescent probes into polymer micelles structures, and progresses on the stability and distribution studies of FRET-polymer micelles ( in vitro and in vivo) as drug carriers are reviewed, and current challenges of FRET technology and future directions are discussed.

Synthesis of magnetic/pH dual responsive dextran hydrogels as stimuli-sensitive drug carriers.

Hydrogels loaded with magnetic nanoparticles have been widely researched recently as biomaterials, due to their good biocompatibility and unique magnetic characteristics. In this study, water-soluble superparamagnetic iron oxide nanoparticles (Fe3O4) prepared by coprecipitation were physically doped into the dextran hydrogels which were formed via Schiff base reactions between ethylenediamine and oxidized dextran. The combination of magnetic nanoparticles and chemical cross-linked hydrogels leads to magnetic/pH dual-sensitive hydrogels which can be used as stimuli-responsive carrier. Magnetic properties, swelling, and rheology behaviors of the resulted magnetic hydrogels were strongly affected by the Fe3O4 nanoparticle content. Moreover, doxorubicin (DOX⋅HCl) was embedded into the magnetic hydrogels and pH/magnetic sensitive release profiles were identified. The release mechanism analysis indicated that the release behaviors of DOX⋅HCl were controlled by the diffusion, swelling, and erosion processes simultaneously. The prepared hydrogel/Fe3O4 composites with dual magnetic/pH stimuli-responsiveness hold the promise to be used in various applications such as drug release.

High-performance Fe-doped ZIF-8 adsorbent for capturing tetracycline from aqueous solution.

Efficient removal of antibiotics from aqueous solution is of fundamental importance due to the increasingly severe antibiotic-related pollution. Herein, a high-performance Fe-ZIF-8-500 adsorbent was synthesized by Fe-doping strategy and subsequent activation with high-temperature. In order to evaluate the feasibility of Fe-ZIF-8-500 as an adsorbent for tetracycline (TC) removal, the adsorption properties of Fe-ZIF-8-500 were systematically explored. The results showed that the Fe-ZIF-8-500 exhibited ultrahigh adsorption capacity for TC with a record-high value of 867 mg g-1. Additionally, the adsorption kinetics and isotherms for TC onto the Fe-ZIF-8-500 can be well-fitted by the pseudo-second-order kinetics model and the Freundlich model, respectively. The ultrahigh adsorption capacity of Fe-ZIF-8-500 can be explained by the synergistic effect of multi-affinities, i.e., surface complexation, electrostatic attraction, π-π interaction and hydrogen bonding. After being used for four cycles the adsorption capacity of Fe-ZIF-8-500 remains a high level, demonstrating its outstanding reusability. The ultrahigh adsorption capacity, excellent reusability, satisfactory water stability and easy-preparation nature of Fe-ZIF-8-500 highlight its bright prospect for removing tetracycline pollutant from wastewater.

Brachytherapy with Iodine-125 seeds for treatment of portal vein-branch tumor thrombus in patients with hepatocellular carcinoma.

BACKGROUND: There is currently no widely-accepted consensus for the management of hepatocellular carcinoma with portal vein tumor thrombus. We evaluate the safety and efficacy of ultrasound-guided percutaneous brachytherapy with iodine-125 seeds for the treatment of hepatocellular carcinoma with portal vein-branch tumor thrombus (PVBTT). METHODS: Sixty-nine hepatocellular carcinoma patients with PVBTT were enrolled; 34 received transarterial chemoembolization (TACE) combined with iodine-125 seeds implanted in the PVBTT; 35 were treated with TACE alone. Adverse events, objective response rate, disease control rate, progression-free survival, and overall survival were compared between the two groups. Tumor responses of PVBTT and intrahepatic tumor were correlated. Multivariate and subgroup analyses were conducted for overall survival. RESULTS: No grade 3 or 4 adverse events were recorded, and there was no difference in grade 1 or 2 adverse events between the two groups. Objective response rate and disease control rate for PVBTT were 58.9 and 91.2%, respectively, in the combined treatment group, which were significantly greater than the 5.7 and 54.3% rates, respectively, in the TACE-alone group (both p's ≤ 0.001). Intrahepatic tumor response was positively correlated with the PVBTT response (γ = 0.782, p < 0.01). Survival outcomes were better in the combined treatment group than in the TACE-alone group: the median progression-free survival for PVBTT was 9 months versus 3 months (HR = 0.187 [95% CI: 0.101, 0.345], p < 0.001), and the median overall survival was 11 months versus 7 months (HR = 0.448 [95% CI: 0.265, 0.758], p = 0.003). Multivariate analysis revealed that application of brachytherapy and lower grade PVBTT (Vp1 + Vp2 vs. Vp3) were protective predictors of overall survival. In stratified analysis, the benefit of overall survival was more significant in the subgroup of PVBTT Vp1 + Vp2 rather than in Vp3. CONCLUSIONS: The combination of iodine-125 seed brachytherapy guided by ultrasound and TACE is a convenient, safe, and effective treatment for patients with HCC and PVBTT, conferring a better survival benefit than TACE alone.

[Preparation and applications of the polymeric micelle/hydrogel nanocomposites as biomaterials].

Polymeric hydrogels have been widely researched as drug delivery systems, wound dressings and tissue engineering scaffolds due to their unique properties such as good biocompatibility, shaping ability and similar properties to extracellular matrix. However, further development of conventional hydrogels for biomedical applications is still limited by their poor mechanical properties and self-healing properties. Currently, nanocomposite hydrogels with excellent properties and customized functions can be obtained by introducing nanoparticles into their network, and different types of nanoparticles, including carbon-based, polymer-based, inorganic-based and metal-based nanoparticle, are commonly used. Nanocomposite hydrogels incorporated with polymeric micelles can not only enhance the mechanical properties, self-healing properties and chemical properties of hydrogels, but also improve the in vivo stability of micelles. Therefore, micelle-hydrogel nanocomposites have been recently considered as promising biomaterials. In this paper, the structure, properties and methods for preparation of the micelle-hydrogel nanocomposite systems are introduced, and their applications in drug delivery, wound treatment and tissue engineering are reviewed, aiming to provide reference for further development and application of the nanocomposites.

Dextran hydrogels via disulfide-containing Schiff base formation: Synthesis, stimuli-sensitive degradation and release behaviors.

Dextran hydrogels (Dex-SS) containing both disulfide and Schiff base bonds were developed via facile method based on the dextran oxidation and subsequent formation of Schiff base linkages between polyaldehyde dextran and cystamine, denoted as the disulfide-containing Schiff base reactions. Results of rheology, swelling and 13C CP/MAS NMR study indicated that cross-linking degree of Dex-SS hydrogels depended strongly on the molar ratio of -CHO/-NH2. Acidic and reductive (GSH) environment sensitive degradation behaviors of Dex-SS hydrogels were then evidenced by SEM, rheology study and Ellman's assay. Moreover, doxorubicin (DOX) was loaded into the hydrogel matrix and pH/GSH-responsive release behaviors were demonstrated. Cytocompatibility of Dex-SS hydrogel and effective cell uptake of released DOX was finally proved by transwell assay with HepG2 cells. Take advantages of the abundance of vicinal hydroxyl on a variety of polysaccharides, the disulfide-containing Schiff base reactions is considered as versatile method to develop stimuli-sensitive hydrogels for local drug delivery.

Evaluation of the efficacy and postoperative outcomes of hydrodissection-assisted microwave ablation for subcapsular hepatocellular carcinoma and colorectal liver metastases.

PURPOSE: To explore the effect of hydrodissection assisted percutaneous microwave ablation (MWA) on the primary technique efficacy (PTE) and local tumor progression (LTP) of subcapsular hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM). METHODS: A retrospective review of 135 patients with 181 hepatic subcapsular HCC and CRLM that underwent MWA with (hydrodissection group) and without the use of hydrodissection (control group). The PTE, cumulative LTP rate, and postoperative complications were compared between the two groups. RESULTS: Amongst the 135 patients with 181 tumors, 60 patients with 72 tumors were in the hydrodissection group and 75 patients with 109 tumors were in the control group. The PTEs were 97.2% and 85.3% in hydrodissection and control groups, respectively (P = 0.019). Multivariate analysis showed that hydrodissection significantly improved the PTE of MWA [odds ratio (OR) 0.147; 95% confidence interval (CI) 0.031-0.703; P = 0.016). Among the tumors which achieved complete response at the first (1 month) follow-up, the overall LTP rates were 8.6% (6/70) and 11.8% (11/93) in the hydrodissection and control groups, respectively. The 1- and 2-year cumulative LTP rates were 3.0% and 5.0% for the hydrodissection group and 6.8% and 13.5% in the control group, respectively (P = 0.391). No significant differences were observed in major postoperative complications between the two groups. CONCLUSION: Hydrodissection-assisted MWA had a significantly higher PTE than MWA alone in hepatic subcapsular HCC and CRLM. Hydrodissection did not significantly impact the cumulative LTP rate or the incidence of postoperative complications.

Nuclear receptor FXR impairs SK-Hep-1 cell migration and invasion by inhibiting the Wnt/ß-catenin signaling pathway.

Recently, the nuclear receptor farnesoid X receptor (FXR) has been considered to be a liver tumor suppressor. However, the role of FXR in liver cancer invasion and metastasis remains unclear. The results of the current study demonstrated that FXR suppressed the migratory and invasive capacities of SK-Hep-1 cells in vitro and that FXR overexpression inhibited local invasion and lung metastasis of SK-Hep-1 ×enografts in vivo. Bioinformatics analysis of the gene expression profile of SK-Hep-1 cells with different FXR levels indicated that FXR may regulate the Wnt/ß-catenin pathway. Compared with controls, FXR-overexpressing SK-Hep-1 cells exhibited decreased expression of ß-catenin target genes and reduced nuclear translocation of ß-catenin proteins in vitro and in vivo. In conclusion, these results indicated that FXR may suppress SK-Hep-1 cell invasion and metastasis by suppressing the Wnt/ß-catenin signaling pathway. The current study provided novel insight into the diagnosis and treatment of liver cancer.

Elevated procalcitonin levels in primary hepatic neuroendocrine carcinoma: Case report and literature review.

RATIONALE: Procalcitonin (PCT) has been identified as a tumor biomarker in medullary thyroid carcinoma. Other neuroendocrine carcinomas with elevated PCT levels are relatively rare, and are mainly reported in the lung, digestive tract, and pancreas. No studies in the literature have reported a case of primary hepatic carcinoma complicated with unexpectedly elevated PCT levels. PATIENT CONCERNS: A 78-year-old man with persistent fatigue and mild fever was complicated with an extremely high PCT level. Radiological examination revealed a single hypodense lesion in the left lobe of the liver with a "rapid enhancement and rapid washout" pattern. Pathological analysis showed a poorly differentiated neuroendocrine carcinoma (grade 3) with multiple genetic mutations. DIAGNOSIS: Primary hepatic neuroendocrine carcinoma. INTERVENTIONS: The patient received antibiotic therapy and subsequent transcatheter hepatic arterial chemoembolization; a PCT assessment and computed tomography were performed during the follow-up. OUTCOMES: The PCT level did not decline after antibiotic therapy but greatly declined in response to effective transcatheter hepatic arterial chemoembolization. The patient survived and is still being followed up. LESSONS: An extremely elevated PCT level may raise a suspicion of a neuroendocrine carcinoma and plays an indicative role as a biomarker during therapy.

Targeted inhibition of ACK1 can inhibit the proliferation of hepatocellular carcinoma cells through the PTEN/AKT/mTOR pathway.

Activated Cdc42-associated kinase 1 (ACK1) expression is upregulated in hepatocellular carcinoma (HCC) tissues and other tumour tissues. However, the function and regulatory mechanism of ACK1 in HCC remains unclear. In this study, the expression of pTyr284-ACK1, pSer473-AKT and PTEN in HCC was detected by immunohistochemistry, and its clinicopathological significance was analysed. Then, ACK1-targeted small molecule inhibitors AIM-100 and Dasatinib were used to treat cells SK-Hep-1 and HepG2, and changes in activity and biological behaviours of PTEN/AKT/mTOR signalling pathway were observed. The results showed that pTyr284-ACK1 protein was highly expressed in HCC tissues and was related to the poor prognosis of patients; the expression of pTyr284-ACK1 protein was positively correlated with pSer473-AKT and negatively correlated with PTEN. In addition, after treatment either with AIM-100 or Dasatinib, both proliferation of two cells and migration, invasion of SK-Hep-1 cells were all significantly inhibited. Meanwhile, ACK1, pTyr284-ACK1, pSer473-AKT, mTOR and EGFR were down-regulated; PTEN was up-regulated when analysed by western-blot in SK-Hep-1 cells. These results demonstrated that ACK1 may promote HCC development via PTEN/AKT/mTOR pathway. Targeted inhibition of ACK1 may be a novel therapeutic strategy for HCC. SIGNIFICANCE OF THE STUDY: Hepatocellular carcinoma (HCC) is a common malignant tumour with high mortality. Our study showed that ACK1 and pTyr284-ACK1 are highly expressed in HCC and may promote HCC development through the PTEN/AKT/mTOR signalling pathway. Targeted inhibition of ACK1 expression with small inhibitors AIM-100 and Dasatinib may weaken tumour cells ability of proliferation, migration and invasion. Our results suggested that downregulation of ACK1 may be a potential therapeutic strategy for HCC.

Synthesis and characterization of magnetic dextran nanogel doped with iron oxide nanoparticles as magnetic resonance imaging probe.

Magnetic hybrid nanogels composed of magnetic nanoparticles and polymer hydrogel matrix have drawn much attention because of their unique superparamagnetic properties and biocompatibility as biomaterials. In this study, a facile method was developed for the preparation of iron oxide nanoparticle-loaded magnetic dextran nanogel as magnetic resonance imaging (MRI) probe. Water soluble superparamagnetic iron oxide nanocrystals (Fe3O4) was pre-synthesized and physically doped into a Schiff base-containing dextran nanogel formed using W/O microemulsion as nanoreactor. Magnetic dextran nanogel (Fe3O4@Dex) with particle size of 300-1000 nm was obtained with multiple Fe3O4 nanoparticles randomly encapsulated in the hydrogel networks. Magnetization and T2 relaxivity study shows that the resulted magnetic nanogel has similar superparamagneitc behaviors with single Fe3O4 nanocrystals, and relatively higher T2 relaxivity (277.2 mMFe-1·s-1) as MRI probe. Notably, Schiff base linkages and aldehyde groups on the dextran hydrogel matrix endow the magnetic nanogel with pH-sensitiveness and reactive groups for further modifications, which make the magnetic dextran nanogel a promising nanoplatform as MRI-guided drug delivery system with acid environment-responsiveness.

Schiff base-containing dextran nanogel as pH-sensitive drug delivery system of doxorubicin: Synthesis and characterization.

Stimuli-responsive hydrogels have been widely researched as carrier systems, due to their excellent biocompatibility and responsiveness to external physiologic environment factors. In this study, dextran-based nanogel with covalently conjugated doxorubicin (DOX) was developed via Schiff base formation using the inverse microemulsion technique. Since the Schiff base linkages are acid-sensitive, drug release profile of the DOX-loaded nanogel would be pH-dependent. In vitro drug release studies confirmed that DOX was released much faster under acidic condition (pH 2.0, 5.0) than that at pH 7.4. Approximately 66, 28, and 9% of drug was released in 72 h at pH 2.0, 5.0, and 7.4, respectively. Cell uptake by the human breast cancer cell (MCF-7) demonstrated that the DOX-loaded dextran nanogel could be internalized through endocytosis and distributed in endocytic compartments inside tumor cells. These results indicated that the Schiff base-containing nanogel can serve as a pH-sensitive drug delivery system. And the presence of multiple aldehyde groups on the nanogel are available for further conjugations of targeting ligands or imaging probes.

Correlation of lysosome-associated protein transmembrane-4ß gene overexpression with the malignant phenotypes of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and rapidly fatal malignancies, for which hepatitis B virus (HBV) chronic infection constitutes a major risk factor. The lysosome-associated protein transmembrane-4 ß gene (LAPTM4B) is a recently identified gene that was found to be overexpressed in several types of cancer. However, the role of LAPTM4B in HCC tumorigenesis and progression has not been clearly determined. The present study demonstrated that the mRNA as well as the protein levels of LAPTM4B were significantly upregulated in HCC specimens. Patients with higher levels of LAPTM4B mRNA in their HCC tissues tended to be of a younger age, HBsAg+, with an advanced Barcelona Clinic Liver Cancer stage. Moreover, LAPTM4B mRNA expression was positively associated with serum α -fetoprotein levels. We also observed that LAPTM4B was able to promote HCC cell proliferation, migration and invasion in vitro. In conclusion, our results indicated that LAPTM4B plays an important role in the promotion of hepatocarcinogenesis and cancer progression and may serve as a biomarker for the diagnosis and monitoring of HCC.

Outcome of decompression using a transnasal ileus tube in malignant adhesive bowel obstruction: A retrospective study.

Malignant adhesive bowel obstruction caused by peritoneal carcinomatosis is a common complication of advanced abdominal malignancies, and surgical treatment provides little benefit. The present study was undertaken to evaluate the decompression efficacy of a transnasal ileus tube under X-ray guidance, with benign adhesive bowel obstruction patients serving as the control group. A total of 21 patients with malignant adhesive bowel obstruction and 60 patients with benign conditions were enrolled between February 2011 and March 2015. All the patients were treated with transnasal ileus intubation under X-ray guidance. A total of 9 of the 21 malignant cases and 44 of the 60 benign cases were successfully treated with transnasal ileus intubation (42.9 vs. 73.3%, respectively; P=0.01). Treatment in 8 malignant and 4 benign cases failed due to death, tube discharge, and/or therapy abandonment, all of which contributed to a significant difference between the two groups (38.1 vs. 6.7%, respectively; P=0.01). A total of 4 malignant cases and 12 benign adhesion cases received further surgical treatment, the success rate of which was 50 vs. 91.7%, respectively. The rate of successfully treated intubation cases in all resolution patients was similar between the two groups (81.8% in the malignant group and 80% in the benign group; P=0.89). In conclusion, ileus tube decompression in patients with malignant conditions was associated with a lower success rate and lower further surgical intervention success rate compared with that observed in patients with benign conditions. However, insertion of an ileus tube may successfully cure ~80% of all resolution patients in both groups; thus, it may be used as a feasible therapy in malignant adhesive bowel obstruction patients, similar to patients with benign obstruction.

Long Noncoding RNAs Act as Novel Biomarkers for Hepatocellular Carcinoma: Progress and Prospects.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and confers a poor prognosis. Novel diagnostic or prognostic biomarkers and effective therapeutic targets for HCCs are urgently needed. Currently, dozens of long noncoding RNAs (lncRNAs) have been identified as playing critical roles in cancer development and progression. Advanced studies have shown that several well-known lncRNAs are dysregulated in HCC tissue as compared to adjacent noncancerous tissue. Furthermore, highly stable cell-free circulating nucleic acids (cfCNAs), including lncRNAs, aberrantly expressed in the plasma of HCC patients, have been detected. In this review, we focus on the most extensively investigated lncRNAs in HCC and discuss the potential of HCC-related lncRNAs as novel biomarkers for early diagnosis and prognosis.

Imaging-guided synergetic therapy of orthotopic transplantation tumor by superselectively arterial administration of microwave-induced microcapsules.

It is an ambitious target to improve overall Hepatocellular Carcinoma therapeutic effects. Recently, MW ablation has emerged as a powerful thermal ablation technique, affording favorable survival with excellent local tumor control. To achieve better therapeutic effects of MW ablation, MW sensitizers are prepared for enhanced MW ablation to preferentially heat tumor territory. However, it is still not practicable for treatment of the orthotopic transplantation tumor. Herein, biocompatible and degradable methoxy poly(ethylene glycol)-poly(lactic-co-glycolic acid) (mPEG-PLGA) microcapsules with hierarchical structure have been designed for microwave-induced tumor therapy. Chemical drug doxorubicin hydrochloride (DOX·HCl), microwave (MW) sensitizers and CT imaging contrast MoS2 nanosheets and MR imaging contrast Fe3O4 nanoparticles are co-incorporated into the microcapsules. In vitro/vivo MR/CT dual-modal imaging results prove the potential application for guiding synergetic therapy and predicting post-therapy tumor progression in the orthotopic transplantation tumor model. After blocking the tumor-feeding arteries, these microcapsules not only exclude the cooling effect by cutting off the blood flow but also enhance MW heating conversion at tumor site. The focused MW heating makes microcapsules mollescent or ruptured and releases DOX·HCl from the microcapsules, achieving the controlled release of drugs for chemical therapy. Compared with MW ablation, 29.4% increase of necrosis diameter of normal liver in rabbit is obtained under MW ablation combined with transcatheter arterial blocking, and the average size of necrosis and inhibition rate of VX-2 liver orthotopic transplantation tumor in rabbit has increased by 129.33% and 73.46%. Moreover, it is proved that the superselectively arterial administration of the as-prepared microcapsules has no recognizable toxicity on the animals. Therefore, this research provides a novel strategy for the construction of MW-induced microcapsules for orthotopic transplantation tumor ablation with the properties of MW sensitizing, superselective arterial blocking, control release and enhanced accumulation of DOX·HCl, and MR/CT dual-modal imaging, which exhibits great potential applications in the field of HCC therapy.

Therapeutic efficacy of novel microwave-sensitized mPEG-PLGA@ZrO2@(DOX + ILS) drug-loaded microspheres in rabbit VX2 liver tumours.

The use of nanomaterials as drug delivery systems shows good effects in treating tumors. However, the effective dose of drugs targeted to tumor tissues is very low because of the effect of the reticuloendothelial system (RES) in removing such foreign substances. In order to eliminate the RES effect, we developed mPEG-PLGA@ZrO2@(DOX + ILS) (mPEG-PLGA@ZrO2@[DOX + ILS]) drug-loaded microspheres. These microwave (MW)-sensitized microspheres directly embolized the blood-supply vessels of tumors to induce tumor ischemia and hypoxia, as well as to aggregate drugs within tumor tissues in a long-lasting manner. Additionally, combination with MW ablation can triple the effects for the inhibition of tumor growth. The MW sensitive ionic liquid (ILS) in microspheres can rapidly produce a high temperature in a MW field on the basis of MW sensitization, thus accelerating the degradation of microspheres to release DOX-loaded ZrO2 into the lesions to kill tumors. Microspheres can also prolong the pharmacological time and effect of drugs through the enhanced permeability and retention (EPR) effect of nanocarriers, as well as the sustained release of nanomaterials. Studies performed in vivo revealed that mPEG-PLGA@ZrO2@(DOX + ILS) showed good biosafety. We undertook sensitized microsphere embolism therapy using novel mPEG-PLGA@ZrO2@(DOX + ILS) microspheres in a rabbit VX2 liver tumor model. Three, 6 and 9 d after treatment, computed tomography indicated no significant change in tumor size, and diffusion weighted imaging showed a marked decrease of residual tumor tissues. With the multiple functions of inducing embolisms, sensitization, and the sustained release of chemotherapeutics, novel mPEG-PLGA@ZrO2@(DOX + ILS) microspheres can achieve good therapeutic efficacy, in combination with MW ablation and chemotherapy, while embolizing the blood vessels of arterial tumors.