Dual‐Stimuli Responsive Nanotheranostics for Multimodal Imaging Guided Trimodal Synergistic Therapy

Multimodal imaging guided synergistic therapy promises more accurate diagnosis than any single imaging modality, and higher therapeutic efficiency than any single one or their simple “mechanical” combination. Herein, we report a dual‐stimuli responsive nanotheranostic based on a hierarchical nanoplatform, composed of mesoporous silica‐coated gold nanorods (GNR@SiO2), Indocyanine Green (ICG), and 5‐fluorouracil (5‐FU), for in vivo multimodal imaging guided synergistic therapy. The 5‐FU loaded ICG‐conjugated silica‐coated gold nanorods (GNR@SiO2‐5‐FU‐ICG) was able to response specifically to the two stimuli of pH change and near‐infrared (NIR) light irradiation. Both the NIR light irradiation and acidic environment accelerated the 5‐FU release. Meanwhile, the heat generation and singlet oxygen production can be induced by GNR@SiO2‐5‐FU‐ICG upon light irradiation. Most intriguingly, the nanoplatform also promises multimodal imaging such as two‐photon luminescence, fluorescence, photoacoustic, photothermal imaging, as well as trimodal synergistic therapy such as photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy. The cancer theranostic capability of GNR@SiO2‐5‐FU‐ICG was evaluated both in vitro and in vivo. The trimodal synergistic therapy with the guidance of multimodal imaging exhibited remarkably enhanced treatment efficacy. This concept of a hierarchical nanoplatform integrates multiple diagnostic/therapeutic modalities into one platform, which can potentially be applied as personalized nanomedicine with drug delivery, diagnosis, and treatment.     

Gadolinium‐Encapsulated Graphene Carbon Nanotheranostics for Imaging‐Guided Photodynamic Therapy

Photosensitizers (PS) are an essential component of photodynamic therapy (PDT). Conventional PSs are often porphyrin derivatives, which are associated with high hydrophobicity, low quantum yield in aqueous solutions, and suboptimal tumor‐to‐normal‐tissue (T/N) selectivity. There have been extensive efforts to load PSs into nanoparticle carriers to improve pharmacokinetics. The approach, however, is often limited by PS self‐quenching, pre‐mature release, and nanoparticle accumulation in the reticuloendothelial system organs. Herein, a novel, nanoparticle‐based PS made of gadolinium‐encapsulated graphene carbon nanoparticles (Gd@GCNs), which feature a high ¹O₂ quantum yield, is reported. Meanwhile, Gd@GCNs afford strong fluorescence and high T₁ relaxivity (16.0 × 10^?3m ^?1 s^?1, 7 T), making them an intrinsically dual‐modal imaging probe. Having a size of approximately 5 nm, Gd@GCNs can accumulate in tumors through the enhanced permeability and retention effect. The unbound Gd@GCNs cause little toxicity because Gd is safely encapsulated within an inert carbon shell and because the particles are efficiently excreted from the host through renal clearance. Studies with rodent tumor models demonstrate the potential of the Gd@GCNs to mediate image‐guided PDT for cancer treatment. Overall, the present study shows that Gd@GCNs possess unique physical, pharmaceutical, and toxicological properties and are an all‐in‐one nanotheranostic tool with substantial clinical translation potential.     

Activatable Hybrid Nanotheranostics for Tetramodal Imaging and Synergistic Photothermal/Photodynamic Therapy

A multifunctional core–satellite nanoconstruct is designed by assembling copper sulfide (CuS) nanoparticles on the surface of [⁸⁹Zr]‐labeled hollow mesoporous silica nanoshells filled with porphyrin molecules, for effective cancer imaging and therapy. The hybrid nanotheranostic demonstrates three significant features: (1) simple and robust construction from biocompatible building blocks, demonstrating prolonged blood retention, enhanced tumor accumulation, and minimal long‐term systemic toxicity, (2) rationally selected functional moieties that interact together to enable simultaneous tetramodal (positron emission tomography/fluorescence/Cerenkov luminescence/Cerenkov radiation energy transfer) imaging for rapid and accurate delineation of tumors and multimodal image‐guided therapy in vivo, and (3) synergistic interaction between CuS‐mediated photothermal therapy and porphyrin‐mediated photodynamic therapy which results in complete tumor elimination within a day of treatment with no visible recurrence or side effects. Overall, this proof‐of‐concept study illustrates an efficient, generalized approach to design high‐performance core–satellite nanohybrids that can be easily tailored to combine a wide variety of imaging and therapeutic modalities for improved and personalized cancer theranostics in the future.     

NIR‐Responsive Polycationic Gatekeeper‐Cloaked Hetero‐Nanoparticles for Multimodal Imaging‐Guided Triple‐Combination Therapy of Cancer

Responsive multifunctional organic/inorganic nanohybrids are promising for effective and precise imaging‐guided therapy of cancer. In this work, a near‐infrared (NIR)‐triggered multifunctional nanoplatform comprising Au nanorods (Au NRs), mesoporous silica, quantum dots (QDs), and two‐armed ethanolamine‐modified poly(glycidyl methacrylate) with cyclodextrin cores (denoted as CD‐PGEA) has been successfully fabricated for multimodal imaging‐guided triple‐combination treatment of cancer. A hierarchical hetero‐structure is first constructed via integration of Au NRs with QDs through a mesoporous silica intermediate layer. The X‐ray opacity and photoacoustic (PA) property of Au NRs are utilized for tomography (CT) and PA imaging, and the imaging sensitivity is further enhanced by the fluorescent QDs. The mesoporous feature of silica allows the loading of a typical antitumor drug, doxorubicin (DOX), which are sealed by the polycationic gatekeepers, low toxic hydroxyl‐rich CD‐PGEA/pDNA complexes, realizing the co‐delivery of drug and gene. The photothermal effect of Au NRs is utilized for photothermal therapy (PTT). More interestingly, such photothermal effect also induces a cascade of NIR‐triggered release of DOX through the facilitated detachment of CD‐PGEA gatekeepers for controlled chemotherapy. The resultant chemotherapy and gene therapy for glioma tumors are complementary for the efficiency of PTT. This work presents a novel responsive multifunctional imaging‐guided therapy platform, which combines fluorescent/PA/CT imaging and gene/chemo/photothermal therapy into one nanostructure.     

Gadolinium‐Conjugated Gold Nanoshells for Multimodal Diagnostic Imaging and Photothermal Cancer Therapy

Multimodal imaging offers the potential to improve diagnosis and enhance the specificity of photothermal cancer therapy. Toward this goal, gadolinium‐conjugated gold nanoshells are engineered and it is demonstrated that they enhance contrast for magnetic resonance imaging, X‐ray, optical coherence tomography, reflectance confocal microscopy, and two‐photon luminescence. Additionally, these particles effectively convert near‐infrared light to heat, which can be used to ablate cancer cells. Ultimately, these studies demonstrate the potential of gadolinium‐nanoshells for image‐guided photothermal ablation.     

A Versatile Theranostic Nanoemulsion for Architecture‐Dependent Multimodal Imaging and Dually Augmented Photodynamic Therapy

To design a clinically translatable nanomedicine for photodynamic theranostics, the ingredients should be carefully considered. A high content of nanocarriers may cause extra toxicity in metabolism, and multiple theranostic agents would complicate the preparation process. These issues would be of less concern if the nanocarrier itself has most of the theranostic functions. In this work, a poly(ethylene glycol)‐boron dipyrromethene amphiphile (PEG‐F₅₄‐BODIPY) with 54 fluorine‐19 (¹⁹F) is synthesized and employed to emulsify perfluorohexane (PFH) into a theranostic nanoemulsion (PFH@PEG‐F₅₄‐BODIPY). The as‐prepared PFH@PEG‐F₅₄‐BODIPY can perform architecture‐dependent fluorescence/photoacoustic/¹⁹F magnetic resonance multimodal imaging, providing more information about the in vivo structure evolution of nanomedicine. Importantly, this nanoemulsion significantly enhances the therapeutic effect of BODIPY through both the high oxygen dissolving capability and less self‐quenching of BODIPY molecules. More interestingly, PFH@PEG‐F₅₄‐BODIPY shows high level of tumor accumulation and long tumor retention time, allowing a repeated light irradiation after a single‐dose intravenous injection. The “all‐in‐one” photodynamic theranostic nanoemulsion has simple composition, remarkable theranostic efficacy, and novel treatment pattern, and thus presents an intriguing avenue to developing clinically translatable theranostic agents.     

A Novel Top‐Down Synthesis of Ultrathin 2D Boron Nanosheets for Multimodal Imaging‐Guided Cancer Therapy

Single atom nonmetal 2D nanomaterials have shown considerable potential in cancer nanomedicines, owing to their intriguing properties and biocompatibility. Herein, ultrathin boron nanosheets (B NSs) are prepared through a novel top‐down approach by coupling thermal oxidation etching and liquid exfoliation technologies, with controlled nanoscale thickness. Based on the PEGylated B NSs, a new photonic drug delivery platform is developed, which exhibits multiple promising features for cancer therapy and imaging, including: i) efficient NIR‐light‐to‐heat conversion with a high photothermal conversion efficiency of 42.5%, ii) high drug‐loading capacity and triggered drug release by NIR light and moderate acidic pH, iii) strong accumulation at tumor sites, iv) multimodal imaging properties (photoacoustic, photothermal, and fluorescence imaging), and v) complete tumor ablation and excellent biocompatibility. As far as it is known, this is the first report on the top‐down fabrication of ultrathin 2D B NSs by the combined thermal oxidation etching and liquid exfoliation, as well as their application as a multimodal imaging‐guided drug delivery platform. The newly prepared B NSs are also expected to provide a robust and useful 2D nanoplatform for various biomedical applications.     

Nebulized Gadolinium‐Based Nanoparticles: A Theranostic Approach for Lung Tumor Imaging and Radiosensitization

Lung cancer is the most common and most fatal cancer worldwide. Thus, improving early diagnosis and therapy is necessary. Previously, gadolinium‐based ultra‐small rigid platforms (USRPs) were developed to serve as multimodal imaging probes and as radiosensitizing agents. In addition, it was demonstrated that USRPs can be detected in the lungs using ultrashort echo‐time magnetic resonance imaging (UTE‐MRI) and fluorescence imaging after intrapulmonary administration in healthy animals. The goal of the present study is to evaluate their theranostic properties in mice with bioluminescent orthotopic lung cancer, after intrapulmonary nebulization or conventional intravenous administration. It is found that lung tumors can be detected non‐invasively using fluorescence tomography or UTE‐MRI after nebulization of USRPs, and this is confirmed by histological analysis of the lung sections. The deposition of USRPs around the tumor nodules is sufficient to generate a radiosensitizing effect when the mice are subjected to a single dose of 10 Gy conventional radiation one day after inhalation (mean survival time of 112 days versus 77 days for irradiated mice without USRPs treatment). No apparent systemic toxicity or induction of inflammation is observed. These results demonstrate the theranostic properties of USRPs for the multimodal detection of lung tumors and improved radiotherapy after nebulization.     

Advanced Nanotechnology Leading the Way to Multimodal Imaging‐Guided Precision Surgical Therapy

Surgical resection is the primary and most effective treatment for most patients with solid tumors. However, patients suffer from postoperative recurrence and metastasis. In the past years, emerging nanotechnology has led the way to minimally invasive, precision and intelligent oncological surgery after the rapid development of minimally invasive surgical technology. Advanced nanotechnology in the construction of nanomaterials (NMs) for precision imaging‐guided surgery (IGS) as well as surgery‐assisted synergistic therapy is summarized, thereby unlocking the advantages of nanotechnology in multimodal IGS‐assisted precision synergistic cancer therapy. First, mechanisms and principles of NMs to surgical targets are briefly introduced. Multimodal imaging based on molecular imaging technologies provides a practical method to achieve intraoperative visualization with high resolution and deep tissue penetration. Moreover, multifunctional NMs synergize surgery with adjuvant therapy (e.g., chemotherapy, immunotherapy, phototherapy) to eliminate residual lesions. Finally, key issues in the development of ideal theranostic NMs associated with surgical applications and challenges of clinical transformation are discussed to push forward further development of NMs for multimodal IGS‐assisted precision synergistic cancer therapy.     

A Self‐Assembled Biocompatible Nanoplatform for Multimodal MR/Fluorescence Imaging Assisted Photothermal Therapy and Prognosis Analysis

The need for better imaging assisted cancer therapy calls for new biocompatible agents with excellent imaging and therapeutic capabilities. This study successfully fabricates albumin‐cooperated human serum albumin (HSA)‐GGD‐ICG nanoparticles (NPs), which are comprised of a magnetic resonance (MR) contrast agent, glycyrrhetinic‐acid‐modified gadolinium (III)‐1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetate (GGD), and a fluorescence (FL) dye, indocyanine green (ICG), for multimodal MR/FL imaging assisted cancer therapy. These HSA‐GGD‐ICG NPs with excellent biocompatibility are stable under physiological conditions, and exhibit enhanced T₁ contrast capability and improved fluorescence imaging capacity. In vitro experiments reveal an apparent effect of the NPs in killing tumor cells under low laser irradiation, due to the enhanced photothermal conversion efficiency (≈85.1%). Importantly, multimodal MR/FL imaging clearly shows the in vivo behaviors and the efficiency of tumor accumulation of HSA‐GGD‐ICG NPs, as confirmed by a pharmacokinetic study. With the guidance of multimodal imaging, photothermal therapy is subsequently conducted, which demonstrates again high photothermal conversion capability for eliminating tumors without relapse. Notably, real‐time monitoring of tumor ablation for prognosis and therapy evaluation is also achieved by MR imaging. This strategy of constructing nanoplatforms through albumin‐mediated methods is both convenient and efficient, which would enlighten the design of multimodal imaging assisted cancer therapy for potential clinical translation.     

Cancer‐Associated,Stimuli‐Driven,Turn on Theranostics for Multimodality Imaging and Therapy

Advances in bioinformatics, genomics, proteomics, and metabolomics have facilitated the development of novel anticancer agents that have decreased side effects and increased safety. Theranostics, systems that have combined therapeutic effects and diagnostic capabilities, have garnered increasing attention recently because of their potential use in personalized medicine, including cancer‐targeting treatments for patients. One interesting approach to achieving this potential involves the development of cancer‐associated, stimuli‐driven, turn on theranostics. Multicomponent constructs of this type would have the capability of selectively delivering therapeutic reagents into cancer cells or tumor tissues while simultaneously generating unique signals that can be readily monitored under both in vitro and in vivo conditions. Specifically, their combined anticancer activities and selective visual signal respond to cancer‐associated stimuli, would make these theranostic agents more highly efficient and specific for cancer treatment and diagnosis. This article focuses on the progress of stimuli‐responsive turn on theranostics that activate diagnostic signals and release therapeutic reagents in response to the cancer‐associated stimuli. The present article not only provides the fundamental backgrounds of diagnostic and therapeutic tools that have been widely utilized for developing theranostic agents, but also discusses the current approaches for developing stimuli‐responsive turn on theranostics.     

Photosensitizer–Gold Nanorod Composite for Targeted Multimodal Therapy

In this work, a DNA inter‐strand replacement strategy for therapeutic activity is successfully designed for multimodal therapy. In this multimodal therapy, chlorin e6 (Ce6) photosensitizer molecules are used for photodynamic therapy (PDT), while aptamer‐AuNRs, are used for selective binding to target cancer cells and for photothermal therapy (PTT) with near infrared laser irradiation. Aptamer Sgc8, which specifically targets leukemia T cells, is conjugated to an AuNR by a thiol‐Au covalent bond and then hybridized with a Ce6‐labeled photosensitizer/reporter to form a DNA double helix. When target cancer cells are absent, Ce6 is quenched and shows no PDT effect. However, when target cancer cells are present, the aptamer changes structure to release Ce6 to produce singlet oxygen for PDT upon light irradiation. Importantly, by combining photosensitizer and photothermal agents, PTT/PDT dual therapy supplies a more effective therapeutic outcome than either therapeutic modality alone.