Large Hollow Cavity Luminous Nanoparticles with Near-Infrared Persistent Luminescence and Tunable Sizes for Tumor Afterglow Imaging and Chemo-/Photodynamic Therapies

Persistent luminous nanoparticles (PLNPs) have been capturing increasing attention in biomedical imaging because of their long-life emission and concomitant benefits (<i>e.g.</i>, zero-autofluorescence background, high signal-to-noise ratio). Although there are quite some synthetic methodologies to synthesize PLNPs, those for constructing functional structured PLNPs remain largely unexplored. Herein we report the design principle, synthesis route, and proof-of-concept applications of hollow structured PLNPs with near-infrared (NIR) persistent luminescence, namely afterglow, and tunable sizes for tumor afterglow imaging and chemical/photodynamic therapies. The design principle leverages on the crystallization of the immobilized parent ions on the purgeable carbon spheres. This strategy provides large and size-tunable hollow cavities to PLNPs after calcination. Building on the hollow cavity of PLNPs, high chemical drug (DOX) or photosensitizer (Si-Pc) loading can be achieved. The DOX/Si-Pc-loaded hollow PLNPs exhibit efficient tumor suppression based on the features of large cavity and afterglow of PLNPs. These hollow structured PLNPs, like traditional solid PLNPs, are quite stable and can be repeatedly activated, and particularly can selectively target tumor lesion, permitting rechargeable afterglow imaging in living mice. Our research supplies a strategy to synthesize hollow structured PLNPs, and hopefully it could inspire other innovative structures for cancer theranostics

Large Hollow Cavity Luminous Nanoparticles with Near-Infrared Persistent Luminescence and Tunable Sizes for Tumor Afterglow Imaging and Chemo-/Photodynamic Therapies

Persistent luminous nanoparticles (PLNPs) have been capturing increasing attention in biomedical imaging because of their long-life emission and concomitant benefits (<i>e.g.</i>, zero-autofluorescence background, high signal-to-noise ratio). Although there are quite some synthetic methodologies to synthesize PLNPs, those for constructing functional structured PLNPs remain largely unexplored. Herein we report the design principle, synthesis route, and proof-of-concept applications of hollow structured PLNPs with near-infrared (NIR) persistent luminescence, namely afterglow, and tunable sizes for tumor afterglow imaging and chemical/photodynamic therapies. The design principle leverages on the crystallization of the immobilized parent ions on the purgeable carbon spheres. This strategy provides large and size-tunable hollow cavities to PLNPs after calcination. Building on the hollow cavity of PLNPs, high chemical drug (DOX) or photosensitizer (Si-Pc) loading can be achieved. The DOX/Si-Pc-loaded hollow PLNPs exhibit efficient tumor suppression based on the features of large cavity and afterglow of PLNPs. These hollow structured PLNPs, like traditional solid PLNPs, are quite stable and can be repeatedly activated, and particularly can selectively target tumor lesion, permitting rechargeable afterglow imaging in living mice. Our research supplies a strategy to synthesize hollow structured PLNPs, and hopefully it could inspire other innovative structures for cancer theranostics

Furin-Catalyzed Enhanced Magnetic Resonance Imaging Probe for Differential Diagnosis of Malignant Breast Cancers

Molecular magnetic resonance imaging (mMRI) of biomarkers is essential for accurate cancer detection in precision medicine. However, the current clinically used contrast agents provide structural magnetic resonance imaging (sMRI) information only and rarely provide mMRI information. Here, a tumor-specific furin-catalyzed nanoprobe (NP) was reported for differential diagnosis of malignant breast cancers (BCs) in vivo. This NP with a compact structure of Fe3O4@Gd-DOTA NPs (FFG NPs) contains an “always-on” T2-weighted MR signal provided by the magnetic Fe3O4 core and a furin-catalyzed enhanced T1-weighted MR signal provided by the Gd-DOTA moiety. The FFG NPs were found to produce an activated T1 signal in the presence of furin catalysis and an “always-on” T2 signal, providing mMRI and sMRI information simultaneously. Ratiometric mMRI:sMRI intensity can be used for differential diagnosis of malignant BCs MDA-MB-231 and MCF-7, where the furin levels relatively differ. The proposed probe not only provides structural imaging but also enables real-time molecular differential visualization of BC through enzymatic activities of cancer tissues

Effective Reduction of Nonspecific Binding by Surface Engineering of Quantum Dots with Bovine Serum Albumin for Cell-Targeted Imaging

Quantum dots (QDs) have been widely used as fluorescent probes in cell-targeted imaging. However, nonspecific binding to cellular membranes has been a major challenge. In this study, a new approach is developed for effective reduction of nonspecific binding by bovine serum albumin (BSA)-coated QDs in cell targeting. The experimental results show efficient transfer of hydrophobic QDs from organic to aqueous phase in the presence of BSA aqueous solution under ultrasonication. This ultrasonication-based approach is facile, rapid, and efficient. Stabilization of QDs is mainly achieved by multiple mercapto groups in BSA macromolecules as multidentate ligands and partially by hydrophobic interaction between BSA and pending fatty ligands on QDs. The water solubility of QDs is enhanced by the surface amino and carboxyl groups, which also provide reaction sites for conjugation of targeting ligands. The BSA-coated QDs, with an overwhelming majority of hydrodynamic diameter size of ca. 18 nm, are colloidally stable under both acidic and basic conditions and found to exhibit strong fluorescent intensities. The nonspecific cellular binding is effectively reduced by BSA-coated QDs, compared with the mercaptopropionic acid (MPA)-coated CdTe QDs. BSA-coated QDs are further functionalized with cyclic Arg-Gly-Asp (cRGD) peptide. The cell assays indicate their high target-selectivity in integrin α_vβ₃-expressed cell imaging

Silk Nanofibers as Robust and Versatile Emulsifiers

Peptides have been extensively studied as emulsifiers due to their sequence and size control, biocompatibility, versatility, and stabilizing capacity. However, cost and mass production remain the challenges for broader utility for these emulsifiers. Here we demonstrate the utility of silk fibroin nanofibers as emulsifiers, with superior functions to the more traditional peptide emulsifiers. This silk nanofiber system is universal for different oil phases with various polarities and demonstrates control of microcapsule size through tuning the ratio of silk fibroin nanofiber solutions to oils. Besides the improved stabilizing capacity to peptides, these silk fibroin nanofibers endow additional stability to the emulsions formed under high salt concentration and low pH. Highly efficient encapsulation of biomarkers through interfacial networks suggests potential applications in therapeutics, food, and cosmetics. Compared to peptide emulsifiers, these silk fibroin nanofibers offer advantages in terms of cost, purification, and production scale, without compromising biocompatibility, stabilizing capacity, and versatility

Site-Specific Biomimetic Precision Chemistry of Bimodal Contrast Agent with Modular Peptides for Tumor-Targeted Imaging

Various biomimetic nanoparticles have been fabricated for cancer nanotheranostics with a diverse range of proteins. However, the operating mechanisms of these reactions are still unclear, especially on the interaction between metal ions and protein, the precise binding sites, and the existence format of nanoparticles. Assuming the shortening of the amino acids sequence into several, namely short peptides, it would be much easier to investigate the biomimetic reaction mechanism. In this study, a modular peptide, possessing Au³⁺ ion coordination motifs and a Gd³⁺ ion chelation sequence, is designed and synthesized. This peptide is experimentally found effective in site-specific biomimetic synthesis of paramagnetic fluorescent gold nanoclusters (pAuNCs) with a quantum yield of 6.8%, deep red emission at 676 nm, and potent relaxivity. The gel electrophoresis result declares that the two imaging motifs in pAuNCs are quite stable. In vivo fluorescence–magnetic resonance bimodal imaging show significant tumor enhancement by pAuNCs in tumor-bearing mice. In vivo biodistribution and toxicity studies reveal that pAuNCs can be gradually cleared from the body without damage. This study presents a modular peptide that can incubate multifunctional nanoparticles in a biomimetic fashion and hopefully provides a strategy for the investigation of the mechanism of protein-mediated biomimetic synthesis

Albumin-Mediated Biomineralization of Paramagnetic NIR Ag₂S QDs for Tiny Tumor Bimodal Targeted Imaging <i>in Vivo</i>

Bimodal imaging has captured increasing interests due to its complementary characteristics of two kinds of imaging modalities. Among the various dual-modal imaging techniques, MR/fluorescence imaging has been widely studied owing to its high 3D resolution and sensitivity. There is, however, still a strong demand to construct biocompatible MR/fluorescence contrast agents with near-infrared (NIR) fluorescent emissions and high relaxivities. In this study, BSA-DTPA^Gd derived from bovine serum albumin (BSA) as a novel kind of biotemplate is employed for biomineralization of paramagnetic NIR Ag₂S quantum dots (denoted as Ag₂S@BSA-DTPA^Gd pQDs). This synthetic strategy is found to be bioinspired, environmentally benign, and straightforward. The obtained Ag₂S@BSA-DTPA^Gd pQDs have fine sizes (ca. 6 nm) and good colloidal stability. They exhibit unabated NIR fluorescent emission (ca. 790 nm) as well as high longitudinal relaxivity (<i>r</i>₁ = 12.6 mM^–1 s^–1) compared to that of commercial Magnevist (<i>r</i>₁ = 3.13 mM^–1 s^–1). <i>In vivo</i> tumor-bearing MR and fluorescence imaging both demonstrate that Ag₂S@BSA-DTPA^Gd pQDs have pronounced tiny tumor targeting capability. <i>In vitro</i> and <i>in vivo</i> toxicity study show Ag₂S@BSA-DTPA^Gd pQDs are biocompatible. Also, biodistribution analysis indicates they can be cleared from body mainly via liver metabolism. This protein-mediated biomineralized Ag₂S@BSA-DTPA^Gd pQDs presents great potential as a novel bimodal imaging contrast agent for tiny tumor diagnosis

pH-Dependent Assembly of Porphyrin–Silica Nanocomposites and Their Application in Targeted Photodynamic Therapy

Structurally controlled nanoparticles, such as core–shell nanocomposite particles by combining two or more compositions, possess enhanced or new functionalities that benefited from the synergistic coupling of the two components. Here we report new nanocomposite particles with self-assembled porphyrin arrays as the core surrounded by amorphous silica as the shell. The synthesis of such nanocomposite nanoparticles was conducted through a combined surfactant micelle confined self-assembly and silicate sol–gel process using optically active porphyrin as a functional building block. Depending on kinetic conditions, these particles exhibit structure and function at multiple length scales and locations. At the molecular scale, the porphyrins as the building blocks provide well-defined macromolecular structures for noncovalent self-assembly and unique chemistry for high-yield generation of singlet oxygen for photodynamic therapy (PDT). On the nanoscale, controlled noncovalent interactions of the porphyrin building block result in an extensive self-assembled porphyrin network that enables efficient energy transfer and impressive fluorescence for cell labeling, evidenced by absorption and photoluminescence spectra. Finally, the thin silicate shell on the nanoparticle surface allows easy functionalization, and the resultant targeting porphyrin-silica nanocomposites can selectively destroy tumor cells upon receiving light irradiation

Albumin-Bioinspired Gd:CuS Nanotheranostic Agent for <i>In Vivo</i> Photoacoustic/Magnetic Resonance Imaging-Guided Tumor-Targeted Photothermal Therapy

Photothermal therapy (PTT) is attracting increasing interest and becoming more widely used for skin cancer therapy in the clinic, as a result of its noninvasiveness and low systemic adverse effects. However, there is an urgent need to develop biocompatible PTT agents, which enable accurate imaging, monitoring, and diagnosis. Herein, a biocompatible Gd-integrated CuS nanotheranostic agent (Gd:CuS@BSA) was synthesized <i>via</i> a facile and environmentally friendly biomimetic strategy, using bovine serum albumin (BSA) as a biotemplate at physiological temperature. The as-prepared Gd:CuS@BSA nanoparticles (NPs) with ultrasmall sizes (<i>ca.</i> 9 nm) exhibited high photothermal conversion efficiency and good photostability under near-infrared (NIR) laser irradiation. With doped Gd species and strong tunable NIR absorbance, Gd:CuS@BSA NPs demonstrate prominent tumor-contrasted imaging performance both on the photoacoustic and magnetic resonance imaging modalities. The subsequent Gd:CuS@BSA-mediated PTT result shows high therapy efficacy as a result of their potent NIR absorption and high photothermal conversion efficiency. The immune response triggered by Gd:CuS@BSA-mediated PTT is preliminarily explored. In addition, toxicity studies <i>in vitro</i> and <i>in vivo</i> verify that Gd:CuS@BSA NPs qualify as biocompatible agents. A biodistribution study demonstrated that the NPs can undergo hepatic clearance from the body. This study highlights the practicality and versatility of albumin-mediated biomimetic mineralization of a nanotheranostic agent and also suggests that bioinspired Gd:CuS@BSA NPs possess promising imaging guidance and effective tumor ablation properties, with high spatial resolution and deep tissue penetration

Facile Synthesis of Gd–Cu–In–S/ZnS Bimodal Quantum Dots with Optimized Properties for Tumor Targeted Fluorescence/MR <i>In Vivo</i> Imaging

Dual-modal imaging techniques have gained intense attention for their potential role in the dawning era of tumor early accurate diagnosis. Chelate-free robust dual-modal imaging nanoprobes with high efficiency and low toxicity are of essential importance for tumor targeted dual-modal <i>in vivo</i> imaging. It is still a crucial issue to endow Cd-free dual-modal nanoprobes with bright fluorescence as well as high relaxivity. Herein, a facile synthetic strategy was developed to prepare Gd-doped CuInS/ZnS bimodal quantum dots (GCIS/ZnS, BQDs) with optimized properties. The fluorescent properties of the GCIS/ZnS BQDs can be thoroughly optimized by varying reaction temperature, aging time, and ZnS coating. The amount of Gd precursor can be well-controlled to realize the optimized balance between the MR relaxivity and optical properties. The obtained hydrophobic GCIS/ZnS BQDs were surface engineered into aqueous phase with PEGylated dextran-stearyl acid polymeric lipid vesicles (PEG-DS PLVs). Upon the phase transfer, the hydrophilic GCIS/ZnS@PLVs exhibited pronounced near-infrared fluorescence as well as high longitudinal relaxivity (<i>r</i>₁ = 9.45 mM^–1 S^–1) in water with good colloidal stability. <i>In vivo</i> tumor-bearing animal experiments further verified GCIS/ZnS@PLVs could achieve tumor-targeted MR/fluorescence dual-modal imaging. No toxicity was observed in the <i>in vivo</i> and <i>ex vivo</i> experiments. The GCIS/ZnS@PLVs present great potential as bimodal imaging contrast agents for tumor diagnosis