Nanostructural Control Enables Optimized Photoacoustic–Fluorescence–Magnetic Resonance Multimodal Imaging and Photothermal Therapy of Brain Tumor

The performance of current multimodal imaging contrast agents is often constrained by the tunability of nanomaterial structural design. Herein, the influence of nanostructure on the overall imaging performance of a composite nanomaterial for multimodal imaging of brain tumors is studied. Newly designed near‐infrared molecules (TC1) are encapsulated into nanocomposites with ultrasmall iron oxide nanoparticles (UIONPs), forming stable nanoagents for multimodal imaging and photothermal therapy (PTT). Through a modified nanoprecipitation method, the synthesis of nanocomposites denoted as HALF is realized, in which UIONPs are restricted to half of the nanosphere. Such a unique nanostructure that physically separates TC1 and UIONPs is found with capabilities of mitigating fluorescence quenching, preserving the good performance of photoacoustic imaging, and enhancing the magnetic resonance imaging signals. Decorated with a peptide ligand cRGD for better brain tumor targeting, HALF‐cRGD is evaluated both in vitro and in vivo as imaging contrast agents and photothermal therapeutic agents. The good imaging performance and PTT effect of HALF‐cRGD in mice models indicate that the rational design and control of nanostructures could optimize multimodal imaging performance using the same components.     

Protease-Activatable Nanozyme with Photoacoustic and Tumor-Enhanced Magnetic Resonance Imaging for Photothermal Ferroptosis Cancer Therapy

Despite the promise of ferrotherapy in cancer treatment, current ferrous therapeutics suffer from compromised antitumor ferroptosis efficacy and low specificity for tumors. Herein, a protease-activatable nanozyme (Fe₃O₄@Cu_1.77Se) is reported for photoacoustic and tumor-enhanced magnetic resonance imaging (MRI)-guided second near-IR photothermal ferroptosis cancer therapy. Fe₃O₄@Cu_1.77Se remains stable in physiological conditions, but disintegrates to increase reactive intratumoral ferrous supply for elevated hydroxyl radical generation by Fenton reaction and GSH depletion in response to overexpressed matrix metalloproteinases in tumor microenvironment, leading to amplified ferroptosis of tumor cells as well as enhanced T₂-weighted MRI contrast. Further integration with second near-IR photoirradiation to generate localized heat not only triggers effective photothermal therapy and photoacoustic imaging but more importantly, potentiates Fenton reaction to promote ferroptotic tumor cell death. Such synergism leads to the polarization of tumor-associated macrophage from the tumor-promoting M2 type to the tumor-killing M1 type, and induces the immunogenic cells death of tumor cells, which in turn promotes the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes in tumor, contributing to significant tumor suppression. This study presents a novel activatable ferrous nanotheranostics for spatial-temporal control over antitumor ferroptosis responses.     

Silica‐Coated Manganese Oxide Nanoparticles as a Platform for Targeted Magnetic Resonance and Fluorescence Imaging of Cancer Cells

Monodisperse silica‐coated manganese oxide nanoparticles (NPs) with a diameter of ～35 nm are synthesized and are aminated through silanization. The amine‐functionalized core–shell NPs enable the covalent conjugation of a fluorescent dye, Rhodamine B isothiocyanate (RBITC), and folate (FA) onto their surface. The formed Mn₃O₄@SiO₂(RBITC)–FA core–shell nanocomposites are water‐dispersible, stable, and biocompatible when the Mn concentration is below 50 µg mL^?1 as confirmed by a cytotoxicity assay. Relaxivity measurements show that the core–shell NPs have a T₁ relaxivity (r₁) of 0.50 mM ^?1 s^?1 on the 0.5 T scanner and 0.47 mM ^?1 s^?1 on the 3.0 T scanner, suggesting the possibility of using the particles as a T₁ contrast agent. Combined flow cytometry, confocal microscopy, and magnetic resonance imaging studies show that the Mn₃O₄@SiO₂(RBITC)–FA nanocomposites can specifically target cancer cells overexpressing FA receptors (FARs). Findings from this study suggest that the silica‐coated Mn₃O₄ core–shell NPs could be used as a platform for bimodal imaging (both magnetic resonance and fluorescence) in various biological systems.     

Antitumor Platelet‐Mimicking Magnetic Nanoparticles

Nanoparticles possess the potential to revolutionize cancer diagnosis and therapy. The ideal theranostic nanoplatform should own long system circulation and active cancer targeting. Additionally, it should be nontoxic and invisible to the immune system. Here, the authors fabricate an all‐in‐one nanoplatform possessed with these properties for personalized cancer theranostics. Platelet‐derived vesicles (PLT‐vesicles) along with their membrane proteins are collected from mice blood and then coated onto Fe₃O₄ magnetic nanoparticles (MNs). The resulting core–shell PLT‐MNs, which inherit the long circulation and cancer targeting capabilities from the PLT membrane shell and the magnetic and optical absorption properties from the MN core, are finally injected back into the donor mice for enhanced tumor magnetic resonance imaging (MRI) and photothermal therapy (PTT). Meanwhile, it is found that the PTT treatment impels PLT‐MNs targeting to the PTT sites (i.e., tumor sites), and exactly, in turn, the enhanced targeting of PLT‐MNs to tumor sites can improve the PTT effects. In addition, since the PLT membrane coating is obtained from the mice and finally injected into the same mice, PLT‐MNs exhibit stellar immune compatibility. The work presented here provides a new angle on the design of biomimetic nanoparticles for personalized diagnosis and therapy of various diseases.     

Photoacoustic Imaging Guided Near‐Infrared Photothermal Therapy Using Highly Water‐Dispersible Single‐Walled Carbon Nanohorns as Theranostic Agents

The poly(maleic anhydride‐alt‐1‐octadecene‐poly(ethylene glycol)) (C₁₈PMH‐PEG) modified single‐walled carbon nanohorns (SWNHs) are designed with high stability and biocompatibility. The as‐prepared SWNHs/C₁₈PMH‐PEG not only can serve as an excellent photothermal agent but also can be used as a promising photoacoustic imaging (PAI) agent both in vitro and in vivo due to its strong absorption in the near infrared (NIR) region. The PAI result reveals that the SWNHs/C₁₈PMH‐PEG possesses ultra long blood circulation time and can significantly be accumulated at the tumor site through the enhanced penetration and retention (EPR) effect. The maximum accumulation of SWNHs/C₁₈PMH‐PEG at tumor site could be achieved at the time point of 24 h after intravenous injection, which is considered to be the optimal time for the 808 nm laser treatment. The subsequent photothermal ablation of tumors can be achieved without triggering any side effects. Therefore, a PAI guided PTT platform based on SWNHs is proposed and highlights the potential theranostic application for biomedical uses.     

PEGylated Polypyrrole Nanoparticles Conjugating Gadolinium Chelates for Dual‐Modal MRI/Photoacoustic Imaging Guided Photothermal Therapy of Cancer

Polypyrrole nanoparticles conjugating gadolinium chelates were successfully fabricated for dual‐modal magnetic resonance imaging (MRI) and photoacoustic imaging guided photothermal therapy of cancer, from a mixture of pyrrole and pyrrole‐1‐propanoic acid through a facile one‐step aqueous dispersion polymerization, followed by covalent attachment of gadolinium chelate, using polyethylene glycol as a linker. The obtained PEGylated poly­pyrrole nanoparticles conjugating gadolinium chelates (Gd‐PEG‐PPy NPs), sized around around 70 nm, exhibited a high T₁ relaxivity coefficient of 10.61 L mm ^?1 s^?1, more than twice as high as that of the relating free Gd³⁺ complex (4.2 L mm ^–1 s^?1). After 24 h intravenous injection of Gd‐PEG‐PPy NPs, the tumor sites exhibited obvious enhancement in both T₁‐weighted MRI intensity and photoacoustic signal compared with that before injection, indicating the efficient accumulation of Gd‐PEG‐PPy NPs due to the introduction of the PEG layer onto the particle surface. In addition, tumor growth could be effectively inhibited after treatment with Gd‐PEG‐PPy NPs in combination with near‐infrared laser irradiation. The passive targeting and high MRI/photo­acoustic contrast capability of Gd‐PEG‐PPy NPs are quite favorable for precise cancer diagnosing and locating the tumor site to guide the external laser irradiation for photothermal ablation of tumors without damaging the surrounding healthy tissues. Therefore, Gd‐PEG‐PPy NPs may assist in better monitoring the therapeutic process, and contribute to developing more effective “personalized medicine,” showing great potential for cancer diagnosis and therapy.     

Dendritic Platinum–Copper Alloy Nanoparticles as Theranostic Agents for Multimodal Imaging and Combined Chemophotothermal Therapy

Theranostic nanoparticles that possess multiple diagnostic modalities and allow spatiotemporally controlled therapies can significantly improve therapeutic outcomes and reduce adverse effects. Here, an intelligent and biocompatible theranostic formulation is developed based on dendritic platinum–copper alloy nanoparticles (DPCN) for cancer therapy. DPCN have excellent photothermal effect, and can load anticancer drugs such as doxorubicin in their porous structure and release the loaded drugs in response to near infrared light or moderate acidic stimulus. They also inherently have multimodal imaging modalities. Upon the guidance of photoacoustic imaging, DPCN‐mediated photothermal treatment efficiently inhibits tumor growth in vivo. Furthermore, doxorubicin‐loaded DPCN completely suppress the tumor growth even under a low treatment temperature, which avoids hypothermia‐induced damage to normal tissues. Our study develops an excellent theranostic nanoparticle with inherent multimodal imaging and therapeutic modalities for chemophotothermal cancer therapy.     

Synthesis of PEOlated Fe3O4@SiO2 Nanoparticles via Bioinspired Silification for Magnetic Resonance Imaging

Inspired by the biosilification process, a highly benign synthesis strategy is successfully developed to synthesize PEOlated Fe₃O₄@SiO₂ nanoparticles (PEOFSN) at room temperature and near‐neutral pH. The success of such a strategy lies in the simultaneous encapsulation of Fe₃O₄ nanocrystals and silica precursors into the core of PEO‐based polymeric micelles. The encapsulation results in the formation of a silica shell being confined to the interface between the core and corona of the Fe₃O₄‐nanocrystal‐loaded polymeric micelles. Consequently, the surface of the Fe₃O₄@SiO₂ nanoparticle is intrinsically covered by a layer of free PEO chains, which enable the PEOFSN to be colloidally stable not only at room temperature, but also upon incubation in the presence of proteins under physiological conditions. In addition, the silica shell formation does not cause any detrimental effects to the encapsulated Fe₃O₄ nanocrystals with respect to their size, morphology, crystallinity, and magnetic properties, as shown by their physicochemical behavior. The PEOFSN are shown to be good candidates for magnetic resonance imaging (MRI) contrast agents as demonstrated by the high r₂/r₁ ratio with long‐term stability under high magnetic field, as well as the lack of cytotoxicity.     

Ultra‐Small Iron Oxide Doped Polypyrrole Nanoparticles for In Vivo Multimodal Imaging Guided Photothermal Therapy

Recently, near‐infrared (NIR) absorbing conjugated polymeric nanoparticles have received significant attention in photothermal therapy of cancer. Herein, polypyrrole (PPy), a NIR‐absorbing conjugate polymer, is used to coat ultra‐small iron oxide nanoparticles (IONPs), obtaining multifunctional IONP@PPy nanocomposite which is further modified by the biocompatible polyethylene glycol (PEG) through a layer‐by‐layer method to acquire high stability in physiological solutions. Utilizing the optical and magnetic properties of the yielded IONP@PPy‐PEG nanoparticles, in vivo magnetic resonance (MR) and photoacoustic imaging of tumor‐bearing mice are conducted, revealing strong tumor uptake of those nanoparticles after intravenous injection. In vivo photothermal therapy is then designed and carried out, achieving excellent tumor ablation therapeutic effect in mice experiments. These results promise the use of multifunctional NIR‐absorbing organic‐inorganic hybrid nanomaterials, such as IONP@PPy‐PEG presented here, for potential applications in cancer theranostics.     

Nanoparticles of Chlorin Dimer with Enhanced Absorbance for Photoacoustic Imaging and Phototherapy

Nanoparticle assembled from organic molecules is a versatile platform to integrate various functionalities for theranostics. In this work, nanoparticles are constructed from chlorin dimers that are synthesized by reducing porphyrin molecules. Chlorin dimers can assemble into nanoscale aggregates in the absence of surfactants or other auxiliary agent. The resulting nanoparticles of chlorin dimer exhibit much higher absorbance than the porphyrin counterparts, resulting in enhanced photodynamic and photothermal activity upon irradiation. The forming nanoparticles can be effectively endocytosed by the tumor cells, inducing apoptosis under irradiation. Tumor growth on mice model is inhibited by the photodynamic and photothermal treatment in vivo. Furthermore, this nanoparticle can be used for photoacoustic imaging. It is believed that the integrated imaging and phototherapeutic capability in one nanoparticle is beneficial for future cancer diagnosis, therapy, and molecular imaging.     

Engineering of Multifunctional Nano‐Micelles for Combined Photothermal and Photodynamic Therapy Under the Guidance of Multimodal Imaging

The integration of diagnostic and therapeutic functionalities on a single theranostic nano‐system holds great promise to enhance the accuracy of diagnosis and improve the efficacy of therapy. Herein, a multifunctional polymeric nano‐micelle system that contains a photosensitizer chlorin e6 (Ce6) is successfully fabricated, at the same time serving as a chelating agent for Gd³⁺, together with a near‐infrared (NIR) dye, IR825. With a r₁ relativity 7 times higher than that of the commercial agent Magnevist, strong fluorescence offered by Ce6, and high NIR absorbance attributed to IR825, these theranostic micelles can be utilized as a contrast agent for triple modal magnetic resonance (MR), fluorescence, and photoacoustic imaging of tumors in a mouse model. The combined photothermal and photodynamic therapy is then carried out, achieving a synergistic anti‐tumor effect both in vitro and in vivo. Different from single photo treatment modalities which only affect the superficial region of the tumor under mild doses, the combination therapy at the same dose using this agent is able to induce significant damage to both superficial and deep parts of the tumor. Therefore, this work presents a polymer based theranostic platform with great potential in multimodal imaging and combination therapy of cancer.     

Magnetic/Silica Nanocomposites as Dual‐Mode Contrast Agents for Combined Magnetic Resonance Imaging and Ultrasonography

A simple and efficient method for synthesizing a range of hybrid nanocomposites based on a core of silica nanospheres (160, 330, and 660 nm in diameter) covered by an outer shell of superparamagnetic nanoparticles, either iron oxide or heterodimeric FePt‐iron oxide nanocrystals, is presented. The magnetic and ultrasound characterization of the resulting nanocomposites shows that they have great potential as contrast agents for dual‐mode imaging purposes, combining magnetic resonance imaging (MRI) and ultrasonography (US).     

Novel Au–SiO2–WO3 Core–Shell Composite Nanoparticles for Surface‐Enhanced Raman Spectroscopy with Potential Application in Cancer Cell Imaging

With the rapid development of nanotechnology during the last decades, the ability to detect and control individual objects at the nanoscale has enabled us to deal with complex biomedical challenges. In cancer imaging, novel nanoparticles (NPs) offer promising potential to identify single cancer cells and precisely label larger areas of cancer tissues. Herein, a new class of size tunable core–shell composite (Au–SiO₂–WO₃) nanoparticles is reported. These nanoparticles display an easily improvable ≈10³ surface‐enhanced Raman scattering (SERS) enhancement factor with a double Au shell for dried samples over Si wafers and several orders of magnitude for liquid samples. WO₃ core nanoparticles measuring 20–50 nm in diameter are sheathed by an intermediate 10–60 nm silica layer, produced by following the Stöber‐based process and Turkevich method, followed by a 5–20 nm thick Au outer shell. By attaching 4‐mercaptobenzoic acid (4‐MBA) molecules as Raman reporters to the Au, high‐resolution Raman maps that pinpoint the nanoparticles' location are obtained. The preliminary results confirm their advantageous SERS properties for single‐molecule detection, significant cell viability after 24 h and in vitro cell imaging using coherent anti‐stokes Raman scattering. The long‐term objective is to measure SERS nanoparticles in vivo using near‐infrared light.     

A Multi‐Gradient Targeting Drug Delivery System Based on RGD‐l‐TRAIL‐Labeled Magnetic Microbubbles for Cancer Theranostics

The accurately and efficiently targeted delivery of therapeutic/diagnostic agents into tumor areas in a controllable fashion remains a big challenge. Here, a novel cancer targeting magnetic microbubble is elaborately fabricated. First, the γ‐Fe₂O₃ magnetic iron oxide nanoparticles are optimized to chemically conjugate on the surface of polymer microbubbles. Then, arginine‐glycine‐aspartic acid‐l ‐tumor necrosis factor‐related apoptosis‐inducing ligand (RGD‐l ‐TRAIL), antitumor targeting fusion protein, is precisely conjugated with magnetic nanoparticles of microbubbles to construct RGD molecularly targeted magnetic microbubble, which is defined as RGD‐l ‐TRAIL@MMBs. Such RGD‐l ‐TRAIL@MMBs is endowed with the multigradient cascade targeting ability following by magnetic targeting, RGD, as well as enhanced permeability and retention effect regulated targeting to result in high cancerous tissue targeting efficiency. Due to the highly specific accumulation of RGD‐l ‐TRAIL@MMBs in the tumor, the accurate diagnostic information of tumor can be obtained by dual ultrasound and magnetic resonance imaging. After imaging, the TRAIL molecules as anticancer agent also get right into the cancer cells by nanoparticle‐ and RGD‐mediated endocytosis to effectively induce the tumor cell apoptosis. Therefore, RGD‐l ‐TRAIL conjugated magnetic microbubbles could be developed as a molecularly targeted multimodality imaging delivery system with the addition of chemotherapeutic cargoes to improve cancer diagnosis and therapy.     

Mitochondria‐Targeted Small‐Molecule Fluorophores for Dual Modal Cancer Phototherapy

Mitochondria are recognized as the ideal target for cancer treatment because they play a central role in oxidative metabolism and apoptosis. In this work, a mitochondria‐targeted near‐infrared (NIR) photosensitizer (PS) for synchronous cancer photodynamic therapy (PDT) and photothermal therapy (PTT) is synthesized. This multifunctional small‐molecule PS is developed from a variety of synthesized heptamethine cyanine dyes, which are modified with various N‐alkyl side chains on the lipophilic cationic heptamethine core. It is demonstrated to preferentially accumulate in cancer cells by organic‐anion transporting polypeptide mediated active transport and retain in mitochondria by its lipophilic cationic property. As mitochondria are susceptible to hyperthermia and excessive reactive oxygen species, this new PS integrating PTT and PDT treatment exhibits highly efficient phototherapy in multiple cancer cells and animal xenograft models. Furthermore, this targeted PS with NIR imaging property also enables tumors and their margins clearly visualized, providing the potential for precisely imaging‐guided phototherapy and treatment monitoring. This is the first report that a small‐molecule PS integrates both cancer PTT and PDT treatment by targeting mitochondria, significantly increasing the photosensitization. This work may also present a practicable strategy to develop small‐molecule‐based cancer theranostic agents for simultaneous cancer targeting, imaging, and therapy.