A pH-responsive photoacoustic imaging probe for tumor pH imaging in vivo based on polyaniline-bovine serum albumin.

Precise pH detection in tumors can guide the design of pH-responsive drugs and theranostic agents to improve treatment efficacy. However, most reported pH-responsive probes are fluorescent probes, for which in vivo application is limited by low probe penetration depth. In this study, a pH-responsive polyaniline-bovine serum albumin (BSA) probe was constructed for precise pH detection in tumors using photoacoustic imaging. The probe can be used to generate high-resolution images of deep biological tissues. The photoacoustic signal of the polyaniline-BSA probe exhibits a clear linear relationship with pH in the range of 5-6.8 both in vitro and in vivo, indicating that the probe is ideal for precise pH detection in most tumors. The polyaniline-BSA probe also exhibits satisfactory biocompatibility, low toxicity, fast response, and good reversibility. This work provides a useful in vivo pH detection probe for developing pH-responsive drugs and theranostic agents.

Ellagic acid-Fe nanoscale coordination polymer with higher longitudinal relaxivity for dual-modality T1-weighted magnetic resonance and photoacoustic tumor imaging.

Dual-modality contrast agents for T1-weighted magnetic resonance imaging (MRI) and photoacoustic imaging have attracted substantial attention as they combine the advantages of unlimited penetration depth and high sensitivity. However, most of the reported agents are Gd-based materials that exhibit nephrotoxicity, and few studies have focused on Fe-based materials owing to their lower relaxivity. This work describes the development of an ellagic acid (EA)-Fe nanoscale coordination polymer with high longitudinal relaxivity and strong near-infrared absorption for dual-modality T1-weighted MRI and photoacoustic imaging. The longitudinal relaxivity (r1) of the prepared EA-Fe@BSA nanoparticles was 2.54 mM-1 s-1, an increase of 185% compared with previously reported gallic acid-Fe nanoparticles. Furthermore, in vitro and in vivo experiments demonstrate that the EA-Fe@BSA NPs are an excellent T1-weighted MRI and photoacoustic dual-modality contrast agent with the advantages of convenient synthesis and low toxicity, exhibiting great potential for clinical use in tumor imaging.

Engineering polyvinyl alcohol microspheres with capability for use in photothermal/chemodynamic therapy for enhanced transarterial chemoembolization.

Transarterial chemoembolization (TACE) is widely recognized as a non-surgical treatment approach for advanced liver cancer, combining chemotherapy with the blockage of blood vessels supplying the tumor. To enhance the efficacy of TACE and address chemotherapy resistance, there is growing interest in the development of multifunctional embolic microspheres. In this study, multifunctional PVA microspheres, which encapsulate MIT as a chemotherapeutic drug, PPY as a photothermal agent, and Fe3O4 as a chemodynamic therapy agent, were prepared successfully. The results demonstrated that the developed multifunctional PVA microspheres not only exhibit favorable drug release, photothermal therapy, and chemodynamic therapy performance, but also show a promising synergistic therapeutic effect both in vitro and in vivo. Consequently, the engineered multifunctional PVA microspheres hold tremendous promise for enhancing TACE effectiveness and have the potential to overcome limitations associated with traditional liver cancer treatments.

Intelligent design of polymer nanogels for full-process sensitized radiotherapy and dual-mode computed tomography/magnetic resonance imaging of tumors.

Rationale: Development of intelligent radiosensitization nanoplatforms for imaging-guided tumor radiotherapy (RT) remains challenging. We report here the construction of an intelligent nanoplatform based on poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) co-loaded with gold (Au) and manganese dioxide (MnO2) nanoparticles (NPs) for dual-mode computed tomography (CT)/magnetic resonance (MR) imaging-guided "full-process" sensitized RT of tumors. Methods: PVCL NGs were synthesized via precipitation polymerization and in situ loaded with Au and MnO2 NPs. The created PVCL-Au-MnO2 NGs were well characterized and systematically examined in their cytotoxicity, cellular uptake, intracellular oxygen and ·OH production, and cell cycle arrest in vitro, evaluated to disclose their RT sensitization effects of cancer cells and a tumor model, and assessed to validate their dual-mode CT/MR imaging potential, pharmacokinetics, biodistribution, and biosafety in vivo. Results: The formed PVCL-Au-MnO2 NGs with a size of 121.5 nm and good stability can efficiently generate reactive oxygen species through a Fenton-like reaction to result in cell cycle distribution toward highly radiosensitive G2/M phase prior to X-ray irradiation, sensitize the RT of cancer cells under X-ray through the loaded Au NPs to induce the significant DNA damage, and further prevent DNA-repairing process after RT through the continuous production of O2 catalyzed by MnO2 in the hybrid NGs to relieve the tumor hypoxia. Likewise, the in vivo tumor RT can also be guided through dual mode CT/MR imaging due to the Au NPs and Mn(II) transformed from MnO2 NPs. Conclusion: Our study suggests an intelligent PVCL-based theranostic NG platform that can achieve "full-process" sensitized tumor RT under the guidance of dual-mode CT/MR imaging.

Fe3O4 assembly for tumor accurate diagnosis by endogenous GSH responsive T2/T1 magnetic relaxation conversion.

Superparamagnetic iron oxide nanoparticles with high magnetization strength and good biological safety have been widely used as magnetic resonance imaging (MRI) contrast agents for tumors. However, the accuracy of tumor diagnosis is still low due to the lack of tumor targeting and the interference signals from normal tissues. Endogenous substances in tumor (such as high levels of GSH and pH) stimuli-responsive contrast agents could offer higher sensitivity for tumor diagnosis. Herein, based on the characteristic of overexpression of GSH in tumors, we propose an ultra-small Fe3O4 assembly as an endogenous GSH responsive MRI contrast agent. The ultra-small superparamagnetic Fe3O4 are bonded to the crosslinker cystamine to synthesize Fe3O4 nanoclusters, which exhibit a T2 imaging effect. When the contrast agent reaches the tumor tissue, the disulfide bond in cystamine is induced by GSH to break, the Fe3O4 nanoclusters are disassembled into ultra-small Fe3O4 nanoparticles, and the relaxation signal changes from T2 to T1, which is helpful for accurate diagnosis of tumors. In vivo experiments have shown that Fe3O4 nanoclusters can rapidly respond to overexpressed GSH in tumor sites for T2/T1 switchable imaging. This work not only designed an endogenous GSH responsive platform through simple synthesis methods, but also improved the accuracy of tumor diagnosis through the transformation of T2/T1 MRI signals.

A chelator-free multifunctional [64Cu]CuS nanoparticle platform for simultaneous micro-PET/CT imaging and photothermal ablation therapy.

We synthesized and evaluated a novel class of chelator-free [(64)Cu]CuS nanoparticles (NPs) suitable both for PET imaging and as photothermal coupling agents for photothermal ablation. These [(64)Cu]CuS NPs are simple to make, possess excellent stability, and allow robust noninvasive micro-PET imaging. Furthermore, the CuS NPs display strong absorption in the near-infrared (NIR) region (peak at 930 nm); passive targeting prefers the tumor site, and mediated ablation of U87 tumor cells occurs upon exposure to NIR light both in vitro and in vivo after either intratumoral or intravenous injection. The combination of small diameter (∼11 nm), strong NIR absorption, and integration of (64)Cu as a structural component makes these [(64)Cu]CuS NPs ideally suited for multifunctional molecular imaging and therapy.

Bioinspired, biocompatible and peptide-decorated silk fibroin coatings for enhanced osteogenesis of bioinert implant.

In this study, we develop an osteopromotive polyetheretherketone (PEEK) implant decorated with silk fibroin and bone forming peptide, in which the surface of bioinert PEEK implant is firstly sulfonated to form a three-dimensional, porous topography and then is functionalized with silk fibroin via spin-coating process and peptide decoration. The bio-test results show that cells on the functional bioinert implants exhibit better cell adhesion, proliferation and spreading, when compared with the uncoated ones. Moreover, the peptide-decorated silk fibroin coatings have ability to hasten the osteogenic differentiation and maturation of osteoblast-like cells. Our findings show the potential of the functional PEEK implants with superior bioactivity and osteoinductive property in orthopedics and dentistry. Besides, the facile, bioinspired, osteopromotive modification strategy can be used in other orthopedic and dental implants, such as titanium, zirconium dioxide.

131I-Labeled Copper Sulfide-Loaded Microspheres to Treat Hepatic Tumors via Hepatic Artery Embolization.

Purpose: Transcatheter hepatic artery embolization therapy is a minimally invasive alternative for treating inoperable liver cancer but recurrence is frequent. Multifunctional agents, however, offer an opportunity for tumor eradication. In this study, we were aim to synthesized poly (lactic-co-glycolic acid) (PLGA) microspheres encapsulating hollow CuS nanoparticles (HCuSNPs) and paclitaxel (PTX) that were then labeled with radioiodine-131 (131I) to produce 131I-HCuSNPs-MS-PTX. This compound combines the multi-theranostic properties of chemotherapy, radiotherapy and photothermal therapy. In addition, it can also be imaged with single photon emission computed tomography (SPECT) imaging and photoacoustic imaging. Methods: We investigated the value of therapeutic and imaging of 131I-HCuSNPs-MS-PTX in rats bearing Walker-256 tumor transplanted in the liver. After the intra-arterial (IA) injection of 131I-HCuSNPs-MS-PTX, 18F-Fluorodeoxyglucose (18F-FDG) micro-positron emission tomography/computed tomography (micro-PET/CT) imaging was used to monitor the therapeutic effect. PET/CT findings were verified by immunohistochemical analysis. SPECT/CT and photoacoustic imaging were performed to demonstrate the distribution of 131I-HCuSNPs-MS-PTX in vivo. Results: We found that embolization therapy in combination with chemotherapy, radiotherapy and photothermal therapy offered by 131I-HCuSNPs-MS-PTX completely ablated the transplanted hepatic tumors at a relatively low dose. In comparison, embolization monotherapy or combination with one or two other therapies had less effective anti-tumor efficacy. The combination of SPECT/CT and photoacoustic imaging effectively confirmed microsphere delivery to the targeted tumors in vivo and guided the near-infrared laser irradiation. Conclusion: Our study suggests that there is a clinical theranostic potential for imaging-guided arterial embolization with 131I-HCuSNPs-MS-PTX for the treatment of liver tumors.

Receptor-mediated transcytosis: a mechanism for active extravascular transport of nanoparticles in solid tumors.

Targeted nanoparticle-based delivery systems have been used extensively to develop effective cancer theranostics. However, how targeting ligands affect extravascular transport of nanoparticles in solid tumors remains unclear. Here, we show, using B16/F10 melanoma cells expressing melanocortin type-1 receptor (MC1R), that the nature of targeting ligands, i.e., whether they are agonists or antagonists, directs tumor uptake and intratumoral distribution after extravasation of nanoparticles from tumor vessels into the extravascular fluid space. Pegylated hollow gold nanospheres (HAuNS, diameter=40 nm) coated with MC1R agonist are internalized upon ligand-receptor binding, whereas MC1R antagonist-conjugated HAuNS remain attached on the cell surface. Transcellular transport of agonist-conjugated HAuNS was confirmed by a multilayer tumor cell model and by transmission electron microscopy. MC1R agonist- but not MC1R antagonist-conjugated nanoparticles exhibit significantly higher tumor uptake than nontargeted HAuNS and are quickly dispersed from tumor vessels via receptor-mediated endocytosis and subsequent transcytosis. These results confirm an active transport mechanism that can be used to overcome one of the major biological barriers for efficient nanoparticle delivery to solid tumors.