Biomimetic Responsive Nanoconverters with Immune Checkpoint Blockade Plus Antiangiogenesis for Advanced Hepatocellular Carcinoma Treatment.

The first-line treatment for advanced hepatocellular carcinoma (HCC) combines immune checkpoint inhibitors and antiangiogenesis agents to prolong patient survival. Nonetheless, this approach has several limitations, including stringent inclusion criteria and suboptimal response rates that stem from the severe off-tumor side effects and the unfavorable pharmacodynamics and pharmacokinetics of different drugs delivered systemically. Herein, we propose a single-agent smart nanomedicine-based approach that mimics the therapeutic schedule in a targeted and biocompatible manner to elicit robust antitumor immunity in advanced HCC. Our strategy employed pH-responsive carriers, poly(ethylene glycol)-poly(ß-amino esters) amphiphilic block copolymer (PEG-PAEs), for delivering apatinib (an angiogenesis inhibitor), that were surface-coated with plasma membrane derived from engineered cells overexpressing PD-1 proteins (an immune checkpoint inhibitor to block PD-L1). In an advanced HCC mouse model with metastasis, these biomimetic responsive nanoconverters induced significant tumor regression (5/9), liver function recovery, and complete suppression of lung metastasis. Examination of the tumor microenvironment revealed an increased infiltration of immune effector cells (CD8+ and CD4+ T cells) and reduced immunosuppressive cells (myeloid-derived suppressor cells and T regulatory cells) in treated tumors. Importantly, our nanomedicine selectively accumulated in both small and large HCC occupying >50% of the liver volume to exert therapeutic effects with minimal systemic side effects. Overall, these findings highlight the potential of such multifunctional nanoconverters to effectively reshape the tumor microenvironment for advanced HCC treatment.

Optimal Irreversible Electroporation Combined with Nano-Enabled Immunomodulatory to Boost Systemic Antitumor Immunity.

In this work, we proposed nµPEF, a novel pulse configuration combining nanosecond and microsecond pulses (nµPEF), to enhance tumor ablation in irreversible electroporation (IRE) for oncological therapy. nµPEF demonstrated improved efficacy in inducing immunogenic cell death, positioning it as a potential candidate for next-generation ablative therapy. However, the immune response elicited by nµPEF alone was insufficient to effectively suppress distant tumors. To address this limitation, we developed PPR@CM-PD1, a genetically engineered nanovesicle. PPR@CM-PD1 employed a polyethylene glycol-polylactic acid-glycolic acid (PEG-PLGA) nanoparticle encapsulating the immune adjuvant imiquimod and coated with a genetically engineered cell membrane expressing programmed cell death protein 1 (PD1). This design allowed PPR@CM-PD1 to target both the innate immune system through toll-like receptor 7 (TLR7) agonism and the adaptive immune system through programmed cell death protein 1/programmed cell death-ligand 1 (PD1/PDL1) checkpoint blockade. In turn, nµPEF facilitated intratumoral infiltration of PPR@CM-PD1 by modulating the tumor stroma. The combination of nµPEF and PPR@CM-PD1 generated a potent and systemic antitumor immune response, resulting in remarkable suppression of both nµPEF-treated and untreated distant tumors (abscopal effects). This interdisciplinary approach presents a promising perspective for oncotherapy and holds great potential for future clinical applications.

Scheduled dosage regimen by irreversible electroporation of loaded erythrocytes for cancer treatment.

Precise control of cargo release is essential but still a great challenge for any drug delivery system. Irreversible electroporation (IRE), utilizing short high-voltage pulsed electric fields to destabilize the biological membrane, has been recently approved as a non-thermal technique for tumor ablation without destroying the integrity of adjacent collagenous structures. Due to the electro-permeating membrane ability, IRE might also have great potential to realize the controlled drug release in response to various input IRE parameters, which were tested in a red blood cell (RBC) model in this work. According to the mathematical simulation model of a round biconcave disc-like cell based on RBC shape and dielectric characteristics, the permeability and the pore density of the RBC membrane were found to quantitatively depend on the pulse parameters. To further provide solid experimental evidence, indocyanine green (ICG) and doxorubicin (DOX) were both loaded inside RBCs (RBC@DOX&ICG) and the drug release rates were found to be tailorable by microsecond pulsed electric field (µsPEF). In addition, µsPEF could effectively modulate the tumor stroma to augment therapy efficacy by increasing micro-vessel density and permeability, softening extracellular matrix, and alleviating tumor hypoxia. Benefiting from these advantages, this IRE-responsive RBC@DOX&ICG achieved a remarkably synergistic anti-cancer effect by the combination of µsPEF and chemotherapy in the tumor-bearing mice model, with the survival time increasing above 90 days without tumor burden. Given that IRE is easily adaptable to different plasma membrane-based vehicles for delivering diverse drugs, this approach could offer a general applicability for cancer treatment.

Nanoplatform Self-Assembly from Small Molecules of Porphyrin Derivatives for NIR-II Fluorescence Imaging Guided Photothermal-Immunotherapy.

Combinatorial photothermal and immunotherapy have demonstrated great potential to remove primary tumors, suppress metastases, and prevent tumor recurrence. However, this strategy still confronts patients with many limitations, such as complex components, sophisticated construction, and inadequate therapeutic efficacy. In this work, small molecules of porphyrin derivatives (PPor) which can self-assemble into monodispersed nanoparticles without supplement of any other ingredients or surfactants are developed. The formed PPor nanoparticles (PPor NPs) exhibit highly photothermal conversion efficiency of 70% and NIR-II luminous abilities originate from the strong intramolecular charge transfer (ICT) effect of D-A structure under 808 nm laser irradiation, thus achieving NIR-II fluorescence imaging guided photothermal therapy (PTT) against primary tumors with a high cure rate. More importantly, tumor-associated antigens (TAAs), together with damage-associated molecular patterns (DAMPs) released from PTT-treated cancer cells, are proved to elicit immune responses to some degree. After combination with programmed cell death-1 (PD-1) antibodies, a robust systematic antitumor immunity is generated to restrain both primary and abscopal tumors growth, prolong survival, and prevent pulmonary metastasis on an aggressive 4T1 murine breast tumor model. Thus, this study provides a promising therapeutic paradigm with porphyrin derivatives nano-assembly as phototheranostic agents for the treatment of aggressive tumors with high efficiency.

Red Blood Cell-Mimic Nanocatalyst Triggering Radical Storm to Augment Cancer Immunotherapy.

Red blood cells (RBCs) have recently emerged as promosing candidates for cancer treatment in terms of relieving tumor hypoxia and inducing oxidative damage against cancer cells, but they are still far from satisfactory due to their limited oxygen transport and reactive oxygen species generation rate in tumor tissue. Herein, artificial RBCs (designated FTP@RBCM) with radical storm production ability were developed for oncotherapy through multidimensional reactivity pathways of Fe-protoporphyrin-based hybrid metal-organic frameworks (FTPs, as the core), including photodynamic/chemodynamic-like, catalase-like and glutathione peroxidase-like activities. Meanwhile, owing to the advantages of long circulation abilities of RBCs provided by their cell membranes (RBCMs), FTP with a surface coated with RBCMs (FTP@RBCM) could enormously accumulate at tumor site to achieve remarkably enhanced therapeutic efficiency. Intriguingly, this ROS-mediated dynamic therapy was demonstrated to induce acute local inflammation and high immunogenic cancer death, which evoked a systemic antitumor immune response when combined with the newly identified T cell immunoglobulin and mucin-containing molecule 3 (Tim-3) checkpoint blockade, leading to not only effective elimination of primary tumors but also an abscopal effect of growth suppression of distant tumors. Therefore, such RBC-mimic nanocatalysts with multidimensional catalytic capacities might provide a promising new insight into synergistic cancer treatment.

Tracking Cell Viability for Adipose-Derived Mesenchymal Stem Cell-Based Therapy by Quantitative Fluorescence Imaging in the Second Near-Infrared Window.

Cell survival rate determines engraftment efficiency in adipose-derived mesenchymal stem cell (ADSC)-based regenerative medicine. In vivo monitoring of ADSC viability to achieve effective tissue regeneration is a major challenge for ADSC therapy. Here, we developed an activated near-infrared II (NIR-II) fluorescent nanoparticle consisting of lanthanide-based down-conversion nanoparticles (DCNPs) and IR786s (DCNP@IR786s) for cell labeling and real-time tracking of ADSC viability in vivo. In dying ADSCs due to excessive ROS generation, absorption competition-induced emission of IR786s was destroyed, which could turn on the NIR-II fluorescent intensity of DCNPs at 1550 nm by 808 nm laser excitation. In contrast, the NIR-II fluorescent intensity of DCNPs was stable at 1550 nm by 980 nm laser excitation. This ratiometric fluorescent signal was precise and sensitive for tracking ADSC viability in vivo. Significantly, the nanoparticle could be applied to quantitively evaluate stem cell viability in real-time in vivo. Using this method, we successfully sought two small molecules including glutathione and dexamethasone that could improve stem cell engraftment efficiency and enhance ADSC therapy in a liver fibrotic mouse model. Therefore, we provide a potential strategy for real-time in vivo quantitative tracking of stem cell viability in ADSC therapy.

Presentation of gallbladder torsion at an abnormal position: A case report.

BACKGROUND: Gallbladder torsion is a rare acute abdominal condition that requires emergency surgery. It occurs more commonly in elderly people and in women in the adult population. Diagnosis is a challenge as non-specific symptoms and signs have been reported on ultrasonography, computed tomography and magnetic resonance imaging. Prompt cholecystectomy can decrease the mortality and morbidity of perforation due to gallbladder torsion. CASE SUMMARY: An 82-year-old woman with upper-right quadrant pain and associated nausea and vomiting was diagnosed with ectopic acute calculus cholecystitis. Magnetic resonance cholangiopancreatography (MRCP) showed a V-shaped distortion of the extrahepatic bile ducts and a particularly extended twisted cystic duct, which indicated the presence of gallbladder torsion. Emergency laparoscopic cholecystectomy confirmed the diagnosis and the patient recovered without incident. CONCLUSION: Gallbladder torsion can be diagnosed pre-operatively by MRCP. The specific signs are a V-shaped distortion of the extrahepatic bile ducts and a particularly extended twisted cystic duct which can be called twisting signs.

Multifunctional theranostic nanosystems enabling photothermal-chemo combination therapy of triple-stimuli-responsive drug release with magnetic resonance imaging.

Theranostic nanosystems are emerging as a promising approach for controlled drug delivery, diagnosis and multimodal therapeutics. Herein, a multifunctional theranostic nanoplatform is reported for photothermal-chemo combination therapy functioned with magnetic and thermal imaging. Hyaluronic acid (HA) coated Fe3O4@polydopamine nanoparticles equipped with redox-sensitive disulfide linkers have been subsequently deposited with an anticancer drug, doxorubicin (DOX) (termed as FPCH-DOX NPs). These nanocomposites possess an average diameter of 120 nm, a saturation magnetization of 28.5 emu g-1, DOX loading capacity of 7.13% and a transverse relaxation rate of 171.76 mM-1 s-1. The drug release could be triggered by pH, glutathione (GSH) concentration and light irradiation. Prussian blue staining and confocal microscopy demonstrate that these nanoplatforms have improved biocompatibility and cellular uptake in CD44-positive HeLa cell lines rather than in CD44-negative NIH 3T3 normal cell lines. In vitro evaluations demonstrate that the combination therapy of FPCH-DOX NPs lowers the cell viability to 16.2%, less than that of individual chemotherapy (55.3%) or PTT (52.1%). In vivo MRI indicates that the tumor accumulation of FPCH-DOX NPs provides enhanced MRI contrast, and in vivo thermal imaging verified their localized photothermal conversion effect in tumor tissues. Importantly, FPCH-DOX NPs present remarkable anti-tumor efficacy by photothermal-chemo combination therapy. H&E and Ki67 staining tests show obvious necrosis and weak cell proliferation at the region of the tumor. Thus, FPCH-DOX NPs are promising multifunctional nanoplatforms for highly effective cancer theranostics.

Facile phase transfer of hydrophobic Fe3O4@Cu2-xS nanoparticles by red blood cell membrane for MRI and phototherapy in the second near-infrared window.

The development of nanotheranostic agents integrating diagnosis and therapy has gained tremendous attention in the past few decades, but many of them are inherently hydrophobic and need complicated phase-transfer and tedious surface modifications. This work proposed a facile method of transferring hydrophobic Fe3O4@Cu2-xS nanoparticles from oil to water by using red blood cell membrane to create theranostic nanobeads for T2-weighted MRI and second near-infrared photothermal ablation. The obtained nanoplatform, namely SCS@RBCM, showed a core-shell structure with the inner core densely packed with Fe3O4@Cu2-xS nanoclusters and the surface coated with a layer of RBCM. SCS@RBCM displayed a stable nanostructure, high NIR II light absorption and photothermal conversion ability, T2-weighted MR imaging and magnetic field targeting ability. Meanwhile, the RBCM cloaking endowed SCS with reduced elimination by macrophages. With the navigation of an external magnetic field (MF), the tumor accumulation of SCS@RBCM was dramatically increased, thus achieving good performance of MR imaging and antitumor efficacy through the PTT effect under NIR II irradiation. Therefore, our strategy presents a new and desirable paradigm in the phase-transfer of hydrophobic nanotheranostics for optimizing their biomedical performance.

Multifunctional theranostic agents based on prussian blue nanoparticles for tumor targeted and MRI-guided photodynamic/photothermal combined treatment.

The independence of photodynamic or photothermal modality create difficulties in the success of tumor therapy. In this current study, a multifunctional nanotheranostic agent of PDE-Ce6-HA was developed for tumor targeted and MRI-guided photodynamic/photothermal combined therapy (PDT/PTT). For this purpose, the near-infrared-absorbing nanoparticles of prussian blue were coated with polydopamine and successively conjugated with chlorin e6 (Ce6) for reactive oxygen species (ROS) generation. The resultant nanoparticles, denoted as PDE-Ce6, were then modified with hyaluronic acid (HA) through electrostatic interaction to yield the final therapeutic agent of PDE-Ce6-HA NPs. PDE-Ce6-HA NPs not only exhibited high colloid stability, good biocompatibility and suitable transverse relaxation rate (0.54 mM-1 s-1), but also high photothermal conversion efficiency (40.4%) and excellent ROS generation efficiency under NIR light irradiation. The confocal microscopy images demonstrated a selective uptake of PDE-Ce6-HA by CD44 overexpressed HeLa cells via HA-mediated endocytosis. Meanwhile, in vitro anti-cancer evaluation verified the significant photodynamic and photothermal combined effects of PDE-Ce6-HA on cancer cells. Moreover, PDE-Ce6-HA led to an increase of T1-MRI contrast in tumor site. Furthermore, in vivo anti-tumor evaluation proved that the PDE-Ce6-HA under both 808 and 670 nm laser showed significantly high tumor growth inhibition effects compared with individual PTT or PDT. Hence, PDE-Ce6-HA is applicable in tumor targeted and MRI-guided photodynamic/photothermal combined treatment.

Vehicle-saving theranostic probes based on hydrophobic iron oxide nanoclusters using doxorubicin as a phase transfer agent for MRI and chemotherapy.

A simple approach for constructing theranostic nanobeads is developed by using doxorubicin as a phase transfer agent to solubilize small iron oxide nanoclusters. The nanobeads can be specifically internalized into cancer cells with the guidance of an external magnetic field, resulting in good MRI and chemotherapy.

Correction: Vehicle-saving theranostic probes based on hydrophobic iron oxide nanoclusters using doxorubicin as a phase transfer agent for MRI and chemotherapy.

Correction for 'Vehicle-saving theranostic probes based on hydrophobic iron oxide nanoclusters using doxorubicin as a phase transfer agent for MRI and chemotherapy' by Yanbing Cao et al., Chem. Commun., 2019, DOI: .