An intelligent nanotheranostic agent for targeting, redox-responsive ultrasound imaging, and imaging-guided high-intensity focused ultrasound synergistic therapy.

A novel multifunctional nanotheranostic agent with targeting, redox-responsive ultrasound imaging and ultrasound imaging-guided high-intensity focused ultrasound (HIFU) therapy (MSNC-PEG-HA(SS)-PFH, abbreviated as MPH(SS)-PFH) capabilities is developed. The redox-responsive guest molecule release and ultrasound imaging functions can be both integrated in such a "smart" theranostic agent, which is accomplished by the redox-triggered transition from the crosslinking state to retrocrosslinking state of the grafted polyethylene glycol-disulfide hyaluronic acid molecules on the particle surface when reaching a reducing environment in vitro. More importantly, under the tailored ultrasound imaging guiding, in vivo Hela tumor-bearing nude mice can be thoroughly and spatial-accurately ablated during HIFU therapy, due to the targeted accumulation, responsive ultrasound imaging guidance and the synergistic ablation functions of nanotheranostic agent MPH(SS)-PFH in the tumors. This novel multifunctional nano-platform can serve as a promising candidate for further studies on oncology therapy, due to its high stability, responsive and indicative ultrasound imaging of tumors, and enhanced HIFU therapeutic efficiency and spatial accuracy under ultrasound-guidance.

Precision USPIO-PEG-SLex Nanotheranostic Agent Targeted Photothermal Therapy for Enhanced Anti-PD-L1 Immunotherapy to Treat Immunotherapy Resistance.

Background: The anti-Programmed Death-Ligand 1 (termed aPD-L1) immune checkpoint blockade therapy has emerged as a promising treatment approach for various advanced solid tumors. However, the effect of aPD-L1 inhibitors limited by the tumor microenvironment makes most patients exhibit immunotherapy resistance. Methods: We conjugated the Sialyl Lewis X with a polyethylene glycol-coated ultrasmall superparamagnetic iron oxide (USPIO-PEG) to form UPS nanoparticles (USPIO-PEG-SLex, termed UPS). The physicochemical properties of UPS were tested and characterized. Transmission electron microscopy and ICP-OES were used to observe the cellular uptake and targeting ability of UPS. Flow cytometry, mitochondrial membrane potential staining, live-dead staining and scratch assay were used to verify the in vitro photothermal effect of UPS, and the stimulation of UPS on immune-related pathways at the gene level was analyzed by sequencing. Biological safety analysis and pharmacokinetic analysis of UPS were performed. Finally, the amplification effect of UPS-mediated photothermal therapy on aPD-L1-mediated immunotherapy and the corresponding mechanism were studied. Results: In vitro experiments showed that UPS had strong photothermal therapy ability and was able to stimulate 5 immune-related pathways. In vivo, when the PTT assisted aPD-L1 treatment, it exhibited a significant increase in CD4+ T cell infiltration by 14.46-fold and CD8+ T cell infiltration by 14.79-fold, along with elevated secretion of tumor necrosis factor-alpha and interferon-gamma, comparing with alone aPD-L1. This PTT assisted aPD-L1 therapy achieved a significant inhibition of both primary tumors and distant tumors compared to the alone aPD-L1, demonstrating a significant difference. Conclusion: The nanotheranostic agent UPS has been introduced into immunotherapy, which has effectively broadened its application in biomedicine. This photothermal therapeutic approach of the UPS nanotheranostic agent enhancing the efficacy of aPD-L1 immune checkpoint blockade therapy, can be instructive to address the challenges associated with immunotherapy resistance, thereby offering potential for clinical translation.

Aptamer Functionalized Upconversion Nanotheranostic Agent With Nuclear Targeting as the Highly Localized Drug-Delivery System of Doxorubicin.

As a widely used anticancer drug, doxorubicin (DOX) could induce cell death mainly via interfering with DNA activity; thus, DOX could perform therapeutic effects mainly in the cell nucleus. However, most of the reported drug delivery systems lacked the well localization in the nucleus and released DOX molecules into the cytoplasm. Due to formidable barriers formed in the nuclear envelope, only around 1% of DOX could reach the nucleus and keep active. Therefore, DOX molecules were inevitably overloaded to achieve the desired therapeutic efficacy, which would induce serious side effects. Herein, we developed a highly localized drug nanocarrier for in situ release of DOX molecules to their action site where they could directly interfere with the DNA activity. In this work, we used cationic polymer-modified upconversion nanoparticles (UCNPs) as the luminescence core and gene carrier, while aptamers served as the DNA nanotrain to load DOX. Finally, the prepared nanotheranostic agent displayed good targetability, high cell apoptosis ratio (93.04%) with quite lower concentration than the LC50 of DOX, and obvious inhibition on tumor growth.

Functionalized polymeric hybrid micelles as an efficient nanotheranostic agent for thrombus imaging and thrombolysis.

Pathological thrombosis within a vessel hampers blood flow and is the mainspring of numerous fatal cardiovascular complications. In order to specifically image and dissolve a thrombus, we rationally designed a functionalized polymeric hybrid micelle (PHM) system self-assembled from amphiphilic polycaprolactone-polyethylenimine (PCL-PEI) and polycaprolactone-polyethylene glycol (PCL-PEG). Based on a biological component of thrombi, activated coagulation factor XIII (FXIIIa), which is responsible for fibrin crosslinking, we further developed FXIIIa-targeted near infrared imaging and thrombolytic nanoparticles, termed IR780/FPHM/LK NPs, through chemical conjugation of peptides to the system. In a ferric chloride (FeCl3)-induced mouse carotid thrombosis model, IR780/FPHM/LK NPs specifically targeted the thrombus and significantly enhanced the photoacoustic signal for an accurate diagnosis. When loaded with the fibrinolytic drug lumbrokinase (LK), FPHM remarkably dissociated the thrombus accompanied by an increase in the d-dimer level, a fibrin degradation product, and alleviation of fatal nonspecific hemorrhagic risk. Given its thrombus-specific imaging along with potent therapeutic activities, IR780/FPHM/LK NPs hold promise for developing nanotheranostic agents in preclinical thrombotic vascular disease models.

One-pot synthesis of AuPd@FexOy nanoagent with the activable Fe species for enhanced Chemodynamic-photothermal synergetic therapy.

Facile fabrication of Fe-based nanotheranostic agents with the enhanced Chemodynamic therapy (CDT) effect and multiple functions is important for oncotherapy. In this report, noble-metal@FexOy core-shell nanoparticles (Au@FexOy NPs, AuRu@FexOy NPs, AuPt@FexOy NPs and AuPd@FexOy NPs) are one-pot constructed by a simply redox self-assembly strategy. As a typical example, AuPd@FexOy NPs are applied for oncotherapy. Compared to their crystalline counterparts (e.g., AuPd@c-Fe2O3 nanocrystals (NCs)), AuPd@FexOy NPs with the metastable FexOy shell can be activated by a small amount of NaBH4 to obviously enhance the production of ·OH in subsequent Fenton reaction (these activated products are termed as r-AuPd@FexOy NPs). In addition, a favorable photothermal effect (63.5% photothermal conversion efficiency) of r-AuPd@FexOy NPs can further promote the ·OH generation. Moreover, r-AuPd@FexOy NPs also show a pH-responsive T1-weighted MRI contrast property, CT imaging capacity and the function of regulating tumor microenvironment. This work presents an attractive route to prepare versatile nanotheranostic agents.

Construction of Multicolor Upconversion Nanotheranostic Agent for in-situ Cooperative Photodynamic Therapy for Deep-Seated Malignant Tumors.

Upconversion nanoparticles (UCNPs)-based photodynamic nanotheranostic agents could address the main drawbacks of photosensitizer molecules (PSs) including instability in aqueous solution and rapid clearance. Due to the relatively weak luminescence intensity of UCNPs and insufficient reactive oxygen species (ROSs), UCNPs-based photodynamic therapy (UCNPs-PDT) was discounted for deep-seated tumors. Thus, we proposed a PSs-modulated sensitizing switch strategy. Indocyanine green (ICG) as an NIR organic dye was proved to effectively enhance the luminescence intensity of UCNPs. Herein, four-color UCNPs were coated with a silica layer which loaded ICG and PSs while the thickness of silica layer was controlled to assist the sensitization function of ICG and activation of PSs. Under the drive of mitochondria-targeting ligand, the prepared nanotheranostic agent would accumulate in the mitochondria where ROSs were in-situ produced and then cell apoptosis was induced. Due to the cooperative PDT and high tissue-penetration depth of NIR laser, the prepared upconversion nanotheranostic agent could achieve significant inhibition on the deep-seated tumors.

Oxygen Vacancy Defect-Induced Activity Enhancement of Gd Doping Magnetic Nanocluster for Oxygen Supplying Cancer Theranostics.

This work finds that Fe3O4 nanoclusters can rearrange by Gd doping and then self-assemble to a hollow magnetic nanocluster (HMNC), providing larger magnetic moments to obtain an excellent MRI capability and increasing the number of oxygen vacancies in HMNC. The hollow structure makes platinum(IV) prodrugs effectively load into HMNC. Second, plenty of oxygen vacancy defects can capture oxygen molecules, enhance the catalytic activity of HMNC, and then promote intracellular ROS generation. On the basis of this, a targeting iRGD-labeled HMNC nanosystem (iHMNCPt-O2) is developed through loading oxygen molecules and platinum(IV) prodrugs for chemo- and chemodynamic therapy of cancer. This nanosystem shows an excellent response ability to weak acid and GSH, which can cause a series of cascade reactions in a cell. These cascade reactions are dramatically enhanced at the intracellular ROS level, cause mitochondria and DNA damage, and then induce cancer cell death. Besides, systemic delivery of iHMNCPt-O2 significantly enhanced the MRI contrast signal of tumors and improved the quality of MR images, accurately diagnosing tumors. Therefore, this work provides a novel method for accelerating the Fenton-like reaction and enhancing the MRI capability and fabricates a promising "all-in-one" system to overwhelm the problems of cancer theranostic.

Manganese (II) Chelate Functionalized Copper Sulfide Nanoparticles for Efficient Magnetic Resonance/Photoacoustic Dual-Modal Imaging Guided Photothermal Therapy.

The integration of diagnostic and therapeutic functionalities into one nanoplatform shows great promise in cancer therapy. In this research, manganese (II) chelate functionalized copper sulfide nanoparticles were successfully prepared using a facile hydrothermal method. The obtained ultrasmall nanoparticles exhibit excellent photothermal effect and photoaoustic activity. Besides, the high loading content of Mn(II) chelates makes the nanoparticles attractive T1 contrast agent in magnetic resonance imaging (MRI). In vivo photoacoustic imaging (PAI) results showed that the nanoparticles could be efficiently accumulated in tumor site in 24 h after systematic administration, which was further validated by MRI tests. The subsequent photothermal therapy of cancer in vivo was achieved without inducing any observed side effects. Therefore, the copper sulfide nanoparticles functionalized with Mn(II) chelate hold great promise as a theranostic nanomedicine for MR/PA dual-modal imaging guided photothermal therapy of cancer.