Comparison of Micro-flow Imaging and Contrast-Enhanced Ultrasound in Ultrasound-Guided Microwave Ablation of Benign Thyroid Nodules.

OBJECTIVE: The study described here was aimed at ascertaining the utility of micro-flow imaging (MFI) during ultrasound (US)-guided microwave ablation (MWA) of thyroid nodules by contrasting its effectiveness with that of contrast-enhanced ultrasound (CEUS). METHODS: Seventy-three patients with eighty-eight thyroid nodules who underwent US-guided MWA were included in our study from January 2020 to June 2023. Thirty-five patients underwent CEUS during the MWA process, and thirty-eight patients underwent MFI during the MWA process. We compared the two groups' baseline characteristics, tumor volume (V), volume reduction rate (VRR), complications and clinical characteristics. RESULTS: Both groups exhibited similar outcomes with respect to V and VRR at 1, 3, 6, 12 and 18 mo after MWA (p > 0.05). Consistency was observed with respect to post-operative complications, supplementary ablation times and surgical duration (p > 0.05). It is worth noting that the MFI group had lower treatment costs compared with the CEUS group (11,337.64 ± 80.93 yuan for the MFI group versus 12,971.23 ± 254.89 yuan for the CEUS group, p < 0.05). CONCLUSION: In the MWA procedure for thyroid nodules, MFI is similar to CEUS with respect to safety and efficacy. Simultaneously, it offers the advantage of reducing surgical expenses, which lessens the economic burden for patients.

GPX4 inhibition synergistically boosts mitochondria targeting nanoartemisinin-induced apoptosis/ferroptosis combination cancer therapy.

Artemisinin, originally used for its antimalarial activity, has received much attention in recent years for cancer therapy. The anticancer mechanisms of artemisinin are complicated and debatable. Challenges in the delivery of artemisinin also persist because the anticancer effect of artemisinin alone is often not satisfactory when used with traditional nanocarriers. We herein report the mitochondrial delivery of artemisinin with extremely high anticancer capacity. The action mode of artemisinin in the mitochondria of cancer cells includes heme-participating and oxygen-independent conversion of artemisinin into a carbon-centered radical, which is partly converted into ROS in the presence of molecular oxygen. We reveal that artemisinin alone in the mitochondria can induce strong cancer cell apoptosis. In addition, due to the weak inhibition of GPX4 activity by artemisinin, weak ferroptosis is also observed. We further discover that GPX4 activity in MCF-7 cells is greatly inhibited by RSL3 to synergistically enhance the anticancer capacity of artemisinin via enhancing ferroptosis. The synergistic anticancer activity of artemisinin and RSL3 in the mitochondria not only improves cancer cell-killing ability, but also inhibits the re-proliferation of residual cancer cells. This study provides a new insight into developing highly efficient and practical artemisinin nanomedicines for cancer therapy.

Removing the stumbling block of exosome applications in clinical and translational medicine: expand production and improve accuracy.

Although the clinical application and transformation of exosomes are still in the exploration stage, the prospects are promising and have a profound impact on the future transformation medicine of exosomes. However, due to the limitation of production and poor targeting ability of exosomes, the extensive and rich biological functions of exosomes are restricted, and the potential of clinical transformation is limited. The current research is committed to solving the above problems and expanding the clinical application value, but it lacks an extensive, multi-angle, and comprehensive systematic summary and prospect. Therefore, we reviewed the current optimization strategies of exosomes in medical applications, including the exogenous treatment of parent cells and the improvement of extraction methods, and compared their advantages and disadvantages. Subsequently, the targeting ability was improved by carrying drugs and engineering the structure of exosomes to solve the problem of poor targeting ability in clinical transformation. In addition, we discussed other problems that may exist in the application of exosomes. Although the clinical application and transformation of exosomes are still in the exploratory stage, the prospects are promising and have a profound impact on drug delivery, clinical diagnosis and treatment, and regenerative medicine.

Tumor-targeted AIE polymeric micelles mediated immunogenic sonodynamic therapy inhibits cancer growth and metastasis.

Aggregation-induced emission luminogens (AIEgens) exhibit potent sonosensitivity in nanocarriers compared with conventional organic sonosensitizers owing to the strong fluorescence emission in the aggregated state. However, the premature drug leakage and ineffective tumor targeting of current AIE nanosonosensitizers critically restrict their clinical applications. Here, an AIEgen-based sonosensitizer (AIE/Biotin-M) with excellent sonosensitivity was developed by assembling salicylaldazine-based amphiphilic polymers (AIE-1) and 4T1 tumor-targeting amphiphilic polymers (DSPE-PEG-Biotin) for the effective delivery of salicylaldazine to 4T1 tumor tissues, aiming to mediate immunogenic SDT. In vitro, AIE/Biotin-M were highly stable and generated plentiful singlet oxygen (1O2) under ultrasound (US) irradiation. After AIE/Biotin-M targeted accumulation in the tumor, upon US irradiation, the generation of 1O2 not only led to cancer cell death, but also elicited a systemically immune response by causing the immunogenic cell death (ICD) of cancer cells. In addition to mediating SDT, AIE/Biotin-M could chelate and reduce Fe3+, Cu2+ and Zn2+ by salicylaldazine for inhibiting neovascularization in tumor tissues. Ultimately, AIE/Biotin-M systemically inhibited tumor growth and metastasis upon US irradiation. This study presents a facile approach to the development of AIE nanosonosensitizers for cancer SDT.

Dual-step irradiation strategy to sequentially destroy singlet oxygen-responsive polymeric micelles and boost photodynamic cancer therapy.

Nanotechnology provides a powerful tool to overcome many disadvantages of small-molecule photosensitizers for photodynamic cancer therapy, such as hydrophobicity, rapid blood clearance, low accumulation in tumor tissue and low cell penetration, etc. The occurrence of quench in photosensitizer-loaded nanoparticle greatly downregulates the ability to generate singlet oxygen with light irradiation. Stimuli-responsive nanocarriers can improve the efficacy of PDT to a certain extent. However, insufficient release of photosensitizer from either endogenous or exogenous stimuli responsive nanocarriers in the short period of light irradiation restricts full usage of the photosensitizer delivered into cancer cells. We here report a dual-step light irradiation strategy to enhance the efficacy of cancer PDT. Ce6 as a photosensitizer is loaded in singlet oxygen-sensitive micelles (Ce6-M) via self-assembly of amphiphilic polymer mPEG2000-TK-C16. After co-incubation of Ce6-M with cancer cells or i.v. injection of Ce6-M, cancer cells or tumor tissues are irradiated with light for a short time to trigger Ce6 release, and 2 h later, re-irradiated for relatively long time. The sufficient release of Ce6 in the period between twice light irradiation significantly improves the generation of singlet oxygen, leading to more efficient cancer therapeutic effects of dual-step irradiation than that of single-step irradiation for the same total irradiation time.

Multi-functional carboxymethyl chitin-based nanoparticles for modulation of tumor-associated macrophage polarity.

Current challenge of using cytokines is its poor distribution and systemic side effects. To avoid this issue, we prepared the tumor-targeted and microenvironment-responsive nanocarriers (TRN), which were consisted of α-tocopheryl succinate (α-TOS) loaded mesoporous silica nanoparticles as cores, and surface-modified by thioketal-linkage, electrostatically coated with carboxymethyl chitin, and further anchored glucose-regulated protein 78-binding peptide as shells for encapsulating IL-12. TRN showed a size of 260 nm after encapsulated IL-12 and α-TOS with loading content of 0.0206% and 7.21%, respectively, and exhibited good biocompatibility to 4 T1 cells and macrophages. Moreover, IL-12/α-TOS loaded TRN displayed obvious anti-tumor efficacy on BALB/c nude mice bearing 4 T1 tumors, which was derived from promoted targeting to tumor tissue, endocytosed by macrophages and locally release IL-12 to subsequently repolarize tumor-associated macrophages into tumoricidal M1 phenotype with reduced side effects. The nanosystem exhibited as a promising strategy with functional conversion of macrophages in tumor microenvironment for anti-tumor therapy.

An Oxidation-Enhanced Magnetic Resonance Imaging Probe for Visual and Specific Detection of Singlet Oxygen Generated in Photodynamic Cancer Therapy In Vivo.

Singlet oxygen is regarded as the primary cytotoxic agent in cancer photodynamic therapy (PDT). Despite the advances in optical methods to image singlet oxygen, it remains a challenge for in vivo application due to the limited tissue penetration depth of light. Up to date, no singlet oxygen-specific magnetic resonance imaging (MRI) probe has been reported. Herein, a T2 -weighted MRI probe is reported to visually detect singlet oxygen generated in PDT in vitro and in vivo. The MRI probe Ce6/Fe3 O4 -M is constructed by co-encapsulation of photosensitizer Ce6 and Fe3 O4 nanoparticles in mPEG2000 -TK-C16 micelles. Thioketal (TK) linker in the probe is highly sensitive to singlet oxygen, but lowly sensitive to other reactive oxygen species (ROS) existing in physiological and pathological environments. Singlet oxygen, generated with light irradiation, triggers the cleavage of TK, which leads to loss of surface polyethylene glycol, increment of the hydrophobicity, and aggregation of Fe3 O4 nanoparticles. Subsequently, negatively enhanced T2 -weighted MRI signal is obtained for visual detection of singlet oxygen in the solution, cancer cells, and in vivo. This oxidation responsive MRI probe is expected to hold great promise in evaluating the ability of photosensitizers to generate singlet oxygen and in predicting the therapeutic efficacies of PDT in vivo.

Tumor acidity activated triphenylphosphonium-based mitochondrial targeting nanocarriers for overcoming drug resistance of cancer therapy.

The drug resistance in cancer treatment with DOX is mainly related to the overexpression of drug efflux proteins, residing in the plasma and nuclear membranes. Delivering DOX into the mitochondria, lacking drug efflux proteins, is an interesting method to overcome DOX resistance. To solve the problem of positively charged triphenylphosphonium (TPP) for mitochondrial targeting in vivo, a charge reversal strategy was developed. Methods: An acidity triggered cleavable polyanion PEI-DMMA (PD) was coated on the surface of positively charged lipid-polymer hybrid nanoparticle (DOX-PLGA/CPT) to form DOX-PLGA/CPT/PD via electrostatic interaction. The mitochondrial localization and anticancer efficacy of DOX-PLGA/CPT/PD was evaluated both in vitro and in vivo. Results: The surface negative charge of DOX-PLGA/CPT/PD prevents from rapid clearance in the blood and improved the accumulation in tumor tissue through the enhanced permeability and retention (EPR) effect. The hydrolysis of amide bonds in PD in weakly acidic tumor tissue leads to the conversion of DOX-PLGA/CPT/PD to DOX-PLGA/CPT. The positive charge of DOX-PLGA/CPT enhances the interaction with tumor cells, promotes the uptake and improves DOX contents in tumor cells. Once endocytosed by tumor cells, the exposed TPP in nanomedicine results in effective mitochondrial localization of DOX-PLGA/CPT. Afterward, DOX can release from the nanomedicine in the mitochondria, target mtDNA, induce tumor cells apoptosis and overcome DOX resistance of MCF-7/ADR breast cancer. Conclusion: Tumor acidity triggered charge reversal of TPP-containing nanomedicine and activation of mitochondrial targeting is a simple and effective strategy for the delivery of DOX into the mitochondria of cancer cells and overcoming DOX resistance of MCF-7/ADR tumor both in vitro and in vivo, providing new insight in the design of nanomedicines for cancer chemotherapy.

Dendrimer-grafted bioreducible polycation/DNA multilayered films with low cytotoxicity and high transfection ability.

Controlled release of incorporated foreign DNA from multilayered films plays an important role in surface-mediated gene delivery. Herein, multilayered polyelectrolyte complex thin films, composed of dendrimer-grafted bio-reducible cationic poly(disulfide amine) and plasmid DNA, were fabricated via layer-by-layer (LBL) assembly for in vitro localized gene delivery. The UV absorbance and thickness of the LBL films were found to have linear correlation with the numbers of poly(disulfide amine)/DNA bilayers. Although LBL films were stable in PBS buffer, their degradation could be triggered by reducing agents (i.e. glutathione, GSH). The degradation rate of the films is directly proportional to the GSH concentration, which in turn affected the corresponding gene expression. All poly(disulfide amine)/DNA films exhibited lower cytotoxicity and higher transfection activity in comparison with PEI/DNA multilayered films. Moreover, LBL films showed the highest transfection efficiency in the presence of 2.5 mM GSH when cultured with 293T cells, with ~36% GFP-positive 293T cells after 5-days of co-culture. These DNA-containing reducible films could potentially be useful in gene therapy and tissue engineering by controlling the release of incorporated DNA.

Fluorinated polymeric micelles to overcome hypoxia and enhance photodynamic cancer therapy.

Photodynamic therapy (PDT) as an alternative choice of cancer treatment method has attracted increasing attention in the past few decades. A sufficient amount of oxygen is essential for the production of singlet oxygen (1O2) in successful PDT; however, hypoxia is a typical hallmark of cancer, which is one of the most important limitation factors of PDT. To overcome the hypoxic tumour microenvironment and achieve highly efficient photodynamic cancer therapy, herein, a photosensitizer Ce6-loaded fluorinated polymeric micelle (Ce6-PFOC-PEI-M) was constructed via the self-assembly of an amphiphilic polymer prepared from perfluorooctanoic acid and branched polyethyleneimine (10 kDa). The introduction of perfluoroalkyl groups in the polymeric micelle Ce6-PFOC-PEI-M retained the oxygen-carrying capacity similar to perfluorocarbon, increased the oxygen level and overcame the hypoxia in C6 glioma cells under oxygen-deficient conditions. As a control, Ce6-OC-PEI-M without a perfluoroalkyl group could not increase the oxygen level in C6 glioma cells under the same conditions. With laser irradiation, Ce6-PFOC-PEI-M generated much more reactive oxygen species (ROS) in C6 glioma cells than Ce6-OC-PEI-M, leading to a higher phototoxicity in vitro and photodynamic tumour growth inhibition in vivo than Ce6-OC-PEI-M. Furthermore, there were no differences in the contents of Ce6 in tumour tissue between Ce6-PFOC-PEI-M and Ce6-OC-PEI-M. The higher efficacy of Ce6-PFOC-PEI-M in PDT is ascribed to its oxygen-carrying ability rather than higher content of Ce6 in the tumour. The presented fluorinated polymeric micelle could provide a new platform in the delivery of various photosensitizers and has great potential to improve the efficacy of PDT cancer therapy.