Trimodal Imaging Research Articles

Strength in Numbers: A Giant NIR‐II AIEgen with One‐for‐All Phototheranostic Features for Exceptional Orthotopic Bladder Cancer Treatment

One‐for‐all phototheranostics that allows the simultaneous implementations of multiple optical imaging and therapeutic modalities by utilizing a single component, is growing into a sparkling frontier in cancer treatment. Of particular interest is phototheranostic agent with emission in the second near‐infrared (NIR‐II) window. Nevertheless, the practical uses of those conventional NIR‐II agents are severely impeded by their unsatisfactory features including insufficient stability, low synthetic yield, to be extended absorption/ emission wavelengths, and inefficient phototheranostic outcomes. Developing exceptional phototheranostic agents is thus highly desirable yet remains formidably challenging. Herein, we synthesized two novel N‐heteroacenes‐based NIR‐II luminogens, namely 2TT‐PPT and 4TT‐PBPT, by respectively employing pyrene‐fused phenaziothiadiazoles and pyrene‐fused bisphenaziothiadiazoles as acceptor skeletons. There is strength in numbers by increasing the fusing rings in N‐heteroacenes moieties and numbers of appended donors. Compared to less ring‐fused 2TT‐PPT, the giant molecule 4TT‐PBPT shows improved photophysical characteristics, such as enhanced light absorbance, red‐shifted wavelengths, higher brightness, favorable reactive oxygen species (ROS) generation, and elevated photothermal conversion efficiency, which render 4TT‐PBPT nanoparticles excellent fluorescence‐photoacoustic‐photothermal trimodal imaging guided photodynamic‐photothermal synergistic therapy for orthotopic bladder cancer.

Strength in Numbers: A Giant NIR-II AIEgen with One-for-All Phototheranostic Features for Exceptional Orthotopic Bladder Cancer Treatment.

One-for-all phototheranostics that allows the simultaneous implementations of multiple optical imaging and therapeutic modalities by utilizing a single component, is growing into a sparkling frontier in cancer treatment. Of particular interest is phototheranostic agent with emission in the second near-infrared (NIR-II) window. Nevertheless, the practical uses of those conventional NIR-II agents are severely impeded by their unsatisfactory features including insufficient stability, low synthetic yield, to be extended absorption/ emission wavelengths, and inefficient phototheranostic outcomes. Developing exceptional phototheranostic agents is thus highly desirable yet remains formidably challenging. Herein, we synthesized two novel N-heteroacenes-based NIR-II luminogens, namely 2TT-PPT and 4TT-PBPT, by respectively employing pyrene-fused phenaziothiadiazoles and pyrene-fused bisphenaziothiadiazoles as acceptor skeletons. There is strength in numbers by increasing the fusing rings in N-heteroacenes moieties and numbers of appended donors. Compared to less ring-fused 2TT-PPT, the giant molecule 4TT-PBPT shows improved photophysical characteristics, such as enhanced light absorbance, red-shifted wavelengths, higher brightness, favorable reactive oxygen species (ROS) generation, and elevated photothermal conversion efficiency, which render 4TT-PBPT nanoparticles excellent fluorescence-photoacoustic-photothermal trimodal imaging guided photodynamic-photothermal synergistic therapy for orthotopic bladder cancer.

Multi-responsive cascade enzyme-like catalytic nanoassembly for ferroptosis amplification and nanozyme-assisted mild photothermal therapy

Ferroptosis is greatly restricted by low reactive oxygen species (ROS) generation efficiency, and the inherent self-protection mechanism originating in heat shock proteins (HSPs) seriously impedes the efficiency of photothermal therapy (PTT). Herein, we designed an intelligent strategy utilizing cascade catalytic nanoassemblies (Au@COF@MnO2) with triple-enzyme activity for amplifying ferroptosis therapy and improving the efficiency of PTT in tumor. Gold nanozyme was encapsulated within a hollow manganese dioxide (MnO2) shell with the help of covalent organic frameworks (COFs). The nanoassemblies possess the ability of photothermal conversion. Mechanism studies suggested that glutathione (GSH) depletion by Au@COF@MnO2 leads to the inactivation of glutathione peroxidase 4 (GPX4). This effect synergized with Mn2+-mediated reactive oxygen species (ROS) generation to enhance the accumulation of lipid peroxide (LPO), thereby inducing high-efficiency ferroptosis. Notably, gold nanozyme facilitated the conversion of glucose into gluconic acid and hydrogen peroxide (H2O2). This process augmented the endogenous H2O2 levels necessary for Fenton chemistry, which could effectively promote the generation of ROS. Simultaneously, glucose depletion downregulated the expression of HSPs induced by hyperthermia, consequently reducing cellular heat resistance for enhancing PTT. Therefore, the cascade catalytic nanoassembly not only exhibits high tumor inhibition and admirable biosafety, but also possesses trimodal imaging performance for imaging-guided tumor therapy in vivo, holding great potential for clinical application. Statement of significanceThis study engineered multi-responsive cascade catalytic nanoassembly (Au@COF@MnO2) with triple enzymatic functions for amplifying ferroptosis therapy and improving the efficiency of PTT in tumor. The nanoassembly exhibited multi-responsive release and great photothermal conversion performance. Glucose consumption-evoked starvation downregulated the hyperthermia-induced expression of HSPs in tumor cells, thereby improving the efficacy of PTT. Mechanism studies suggested that GSH depletion by Au@COF@MnO2 lead to the inactivation of GPX4, which synergized with Mn2+-mediated ROS generation to bolster the accumulation of LPO, thereby inducing high-efficiency ferroptosis. Moreover, the nanoassembly demonstrated trimodal (PT, PA, and MR) imaging in vivo, enabling the visualization of the tumor treatment with nanoassembly. Such nanoassembly exhibited high tumor inhibition and admirable biosafety in tumor therapy in vivo, holding a great potential for clinical application.

Phthalocyanine J-aggregate nanoparticles with enormous-redshifted and intense absorption: Potential structure-J-aggregation relationships and application in tumor-associated macrophages-targeted phototheranostics

Phthalocyanines (Pcs) are considered promising in cancer phototherapy. However, their maximum absorption wavelengths are only around 700 nm, which cannot allow deep tissue penetration and leads to poor therapeutic efficacy. To expand their clinical application, significantly shifting their absorption to longer wavelengths is urgently required. Dye J-aggregates exhibit a redshifted absorption relative to its monomer. However, Pc J-aggregates with enormous-redshifted and intense absorption is rarely reported, and little is known about the relationships between Pc structure and J-aggregation. Herein, such Pc J-aggregates are ingeniously conceived. With a yeast β-D-glucan-ursodeoxycholic acid conjugate as a potential tumor-associated macrophages (TAMs)-targeting carrier and 1-(4-carboxyethylphenoxy) zinc (II) phthalocyanine (Pc1) as a model, Pc1 J-aggregate nanoparticle (NanoPc1) is obtained via ultrasonication-aided emulsification-solvent evaporation technique. NanoPc1 displays strong absorption at 830 nm, with a 156 nm redshift. Further investigation on another twenty-four Pcs demonstrates that unsubstituted zinc (II) or magnesium (II) Pc and hydrophobic mono-substituted zinc (II) or magnesium (II) Pcs with mono-substituted phenoxy or phenylthio or naphthoxy as a substituent can readily form desired Pc J-aggregates with significant redshifts (140–165 nm). The other Pcs fail to form expected J-aggregates probably due to absence of central metals, steric hindrance on central metals (atoms), forming axial coordination on central metals, disorder tendency during self-assembly or hydrophilicity. The theoretical calculation indicates that Pc1 in its J-aggregates exhibits a spiral-like arrangement, and the reduction in the energy gap between HOMO and LUMO and variation of intermolecular π-π interaction caused by J-aggregate formation are responsible for the huge redshift. Additionally, using NanoPc1 as an exemplar, such Pc J-aggregate nanoparticles are substantiated to afford TAMs-targeted and efficient tri-modal imaging and photothermal therapy in a H22 mouse model.

Tri-modality in vivo imaging for tumor detection with combined ultrasound, photoacoustic, and photoacoustic elastography

A comprehensive understanding of a tumor is required for accurate diagnosis and effective treatment. However, currently, there is no single imaging modality that can provide sufficient information. Photoacoustic (PA) imaging is a hybrid imaging technique with high spatial resolution and detection sensitivity, which can be combined with ultrasound (US) imaging to provide both optical and acoustic contrast. Elastography can noninvasively map the elasticity distribution of biological tissue, which reflects pathological conditions. In this study, we incorporated PA elastography into a commercial US/PA imaging system to develop a tri-modality imaging system, which has been tested for tumor detection using four mice with different physiological conditions. The results show that this tri-modality imaging system can provide complementary information on acoustic, optical, and mechanical properties. The enabled visualization and dimension estimation of tumors can lead to a more comprehensive tissue characterization for diagnosis and treatment.

Pan-Canadian Analysis of Practice Patterns in Small Cell Carcinoma of the Cervix: Insights from a Multidisciplinary Survey.

Small-cell neuroendocrine carcinoma of the cervix (SCNECC) is a rare cancer with poor prognosis, with limited data to guide its treatment. The objective of this study was to evaluate practice patterns in the management of SCNECC. A 23-question online survey on management of SCNECC was disseminated to Canadian gynecologic oncologists (GO), radiation oncologists (RO) and medical oncologists (MO). In total, 34 practitioners from eight provinces responded, including 17 GO, 13 RO and four MO. During staging and diagnosis, 74% of respondents used a trimodality imaging approach, and 85% tested for neuroendocrine markers. In early-stage (1A1-1B2) SCNECC, 87% of practitioners used a surgical-based approach with various adjuvant and neoadjuvant treatments. In locally advanced (1B3-IVA) SCNECC, 53% favored primary chemoradiation, with cisplatin and etoposide, with the remainder using surgical or radiation-based approaches. In metastatic and recurrent SCNECC, the most common first-line regimen was etoposide and platinum, and 63% of practitioners considered clinical trials in the first line setting or beyond. This survey highlights diverse practice patterns in the treatment of SCNECC. Interdisciplinary input is crucial to individualizing multimodality treatment, and there is a need for prospective trials and intergroup collaboration to define the optimal approach towards managing this rare cancer type.

Abstract PO4-19-10: Selective Avoidance of Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy In HER-2 Positive/Triple Negative Breast Cancer Patients With Excellent Radiologic Response to the Breast and Axilla

Abstract Background Neoadjuvant chemotherapy (NACT) for breast cancer (BC) is downstaging inoperable tumors into operable tumors and de-escalating breast/axillary surgery. According to advanced NACT, dual human epidermal growth factor-2 (HER2) blockage in HER2-positive BC, carboplatin, and immunotherapy in triple-negative breast cancer (TNBC) revealed pathologic complete response (ypCR) rates of up to 68% and 80%, the indications for NACT have expanded to early BC and the expected ypCR rate has increased. Therefore, it may be reasonable to consider omitting surgery in cases with excellent responses to NACT. Although sentinel lymph node biopsy (SLNB) is minimally invasive, some patients still experience complications such as lymphedema, pain, sensory loss, and axillary web syndrome. Several recent retrospective studies and pilot prospective studies have reported axillary pathologic complete response (ApCR) is highly correlated with breast pathologic complete response (BpCR). In cN0 with HER2+ BC and TNBC, the ApCR rate in BpCR after NACT was reported up to 100%, and in cN1 with HER2+ BC and TNBC, the ApCR rate in BpCR after NACT was reported about 85%. There are many studies predicting BpCR using radiologic imaging such as breast mammography (MMG), ultrasonography (USG), and magnetic resonance imaging (MRI). However, the combination of tri-modality (MMG, USG, MRI) could not confirm BpCR. The current study is screened in cT1-3N0-1M0, HER2+ or TNBC, and planned breast-conserving surgery (BCS) patients after NACT with excellent response at the combination of tri-modality imaging (breast MMG, breast USG, breast MRI) and with expected BpCR at physical examination. Methods Trial design The ASLAN trial is a prospective, multicenter, single-arm, clinical study. The five tertiary care hospitals in South Korea are participating which are members of the Korean Breast Cancer Study Group (KBCSG). Eligibility Inclusion criteria: women aged 20-69; cT1-3N0-1M0; HER2+ or TNBC (defined by ER-negative (< 10% positive cells in IHC) and PR-negative (< 10% positive cells in IHC)); expected complete remission at physical examination and radiological expected Tumor size ≤ 2cm or non-mass enhancement ≤ 4cm at breast MRI after standard NACT; planned breast-conserving surgery (BCS) with whole-breast irradiation; ECOG performance status 0-1. Exclusion criteria: SLNB before NACT; previous axillary surgery; bilateral BC; pregnancy. Intervention In eligible patients, BCS was performed. After BCS, patients who showed BpCR are enrolled with the omission of SLNB. Patients with no BpCR proceed with routine axillary surgery. Sample size calculation The assumption for an acceptable 5-year RFS ≥84% is based on previous study findings. The calculated total case number for per-protocol analysis is N=178. By Jun 2023, 153 patients had been enrolled and the target accrual of 178 patients is expected to be complete by Dec 2023. Study outcomes Primary endpoint: 5-year recurrence-free survival. Secondary endpoint: local recurrence-free survival, breast cancer-specific survival, overall survival, ipsilateral axillary recurrence interval, distant metastasis-free survival, contralateral breast-free survival, re-operation rate according to breast biopsy after NACT, adverse event, and quality of life. Accrual Plans The first patient was enrolled on Sep 2021. Among 223 patients who were screened, 153 patients have been enrolled in Jun 2023. We plan to complete the target accrual by Dec 2023. Conclusion The primary aim of the ASLAN trial is to demonstrate the oncologic safety of omitting axillary surgery for the excellent response after NACT in HER2+ or TNBC, early breast cancer patients undergoing BCS and adjuvant RT ASLAN trial, altogether with the EUBREAST-01 and ASCIS trials, will answer the very important question that may alter the axillary surgery in highly selected patients after NACT Citation Format: Jai Min Ryu, Wonshik Han, Han-Byoel Lee, Sung Gwe Ahn, Hee Jeong Kim, Hyung Seok Park, Ji Soo Choi, Hyunjun Lee, Hae Young Kim, Jeong Eon Lee. Selective Avoidance of Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy In HER-2 Positive/Triple Negative Breast Cancer Patients With Excellent Radiologic Response to the Breast and Axilla [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-10.

A tumor microenvironment responsive mesoporous polydopamine theranostic probe embedded with Gd/I-doped carbon nanodots for CT/MR/FL imaging and chemo/photothermal synergistic therapy

This study reports a smart theranostic probe, designated as DMCR, designed for simultaneous CT/MR/FL imaging and chemo/photothermal synergistic therapy. Gd/I-doped carbon nanodots (designed as Gd/I-CDs) are synthesized for the first time using a straightforward one-step solvent thermal approach, serving as the efficient FL/MR/CT trimodal imaging component of DMCR. Subsequently, chemical drug doxorubicin (DOX), diagnostic moiety Gd/I-CDs and tumor-targeting peptide CRGD are successively conjugated onto mesoporous polydopamine (MPDA) to prepare DMCR. Besides its role as versatile scaffold for loading various functional moieties, MPDA serves two additional functions: as an efficient fluorescence quencher for Gd/I-CDs, and an effective photo-sensitizer for photothermal therapy. Therefore, loading DOX into MPDA facilitates the resulting DMCR for chemo/photothermal synergistic tumor therapy. DMCR exhibits excellent water-solubility, biocompatibility, and strong tumor-targeting capability. The decomposition of MPDA by over-expressed glutathione (GSH) and H+ in the tumor microenvironment leads to the GSH/H+-responsive release of diagnostic moieties Gd/I-CDs and therapeutic moieties DOX, triggering the fluorescence turn-on of Gd/I-CDs. In addition, DMCR exhibits a high r1 relaxation rate (38.3 mM−1s−1) and X-ray absorption capability (153.8 Hu mM−1). Both in vitro and in vivo experiments confirm DMCR's high effectiveness in FL/MR/CT triple-modal imaging of tumors and synergistically inhibiting tumor growth with improved efficacy.

Rare-earth-based polymeric nanobubbles as tri-modal imaging contrast agent

Medical imaging plays an important role in providing sufficient guidance for disease diagnosis and treatment. Among them, multimodal contrast agents can combine with a variety of imaging technologies to obtain comprehensive information on the lesion. It is an important development direction of medical imaging for accurate diagnosis of most diseases. In this study, we have designed and prepared a novel nanocomposite (i.e. NaGdF4:Eu@PLGA NBs) by combining sulfur hexafluoride (SF6) loaded polylactic acid-co-glycolic acid (PLGA) nanobubbles (NBs) with NaGdF4:Eu nanoparticles (NPs), which is the first research work on the composite assembly of ultrasound contrast bubbles with rare earth nanomaterials. Results show that NaGdF4:Eu@PLGA NBs with a diameter of appropriately 220 nm had uniform size and good in vitro stability. Combined with PLGA NBs’ superior ultrasound (US) imaging characteristics and NaGdF4:Eu NPs’ excellent magnetic resonance imaging (MRI) and computed tomography (CT) imaging characteristics, NaGdF4:Eu@PLGA NBs have exhibited significant and long-term in vitro US imaging, MRI and CT tri-modal contrast enhancement capability. Taken together, NaGdF4:Eu@PLGA NBs have great potential to be utilized in biomedical applications of US/MRI/CT tri-modal imaging.

The Down-Shifting Luminescence of Rare-Earth Nanoparticles for Multimodal Imaging and Photothermal Therapy of Breast Cancer.

Nanotheranostic agents capable of simultaneously enabling real-time tracking and precise treatment at tumor sites play an increasingly pivotal role in the field of medicine. In this article, we report a novel near-infrared-II window (NIR-II) emitting downconversion rare-earth nanoparticles (RENPs) to improve image-guided therapy for breast cancer. The developed α-NaErF4@NaYF4 nanoparticles (α-Er NPs) have a diameter of approximately 24.1 nm and exhibit superior biocompatibility and negligible toxicity. RENPs exhibit superior imaging quality and photothermal conversion efficiency in the NIR-II range compared to clinically approved indocyanine green (ICG). Under 808 nm laser irradiation, the α-Er NPs achieve significant tumor imaging performance and photothermal effects in vivo in a mouse model of breast cancer. Simultaneously, it combines X-ray computed tomography (CT) and ultrasound (US) tri-modal imaging to guide therapy for cancer. The integration of NIR-II imaging technology and RENPs establishes a promising foundation for future medical applications.

Fluorinated Hafnium and Zirconium Coenable the Tunable Biodegradability of Core-Multishell Heterogeneous Nanocrystals for Bioimaging.

Upconversion (UC)/downconversion (DC)-luminescent lanthanide-doped nanocrystals (LDNCs) with near-infrared (NIR, 650-1700 nm) excitation have been gaining increasing popularity in bioimaging. However, conventional NIR-excited LDNCs cannot be degraded and eliminated eventually in vivo owing to intrinsic "rigid" lattices, thus constraining clinical applications. A biodegradability-tunable heterogeneous core-shell-shell luminescent LDNC of Na3HfF7:Yb,Er@Na3ZrF7:Yb,Er@CaF2:Yb,Zr (abbreviated as HZC) was developed and modified with oxidized sodium alginate (OSA) for multimode bioimaging. The dynamic "soft" lattice-Na3Hf(Zr)F7 host and the varying Zr4+ doping content in the outmoster CaF2 shell endowed HZC with tunable degradability. Through elaborated core-shell-shell coating, Yb3+/Er3+-coupled UC red and green and DC second near-infrared (NIR-II) emissions were, respectively, enhanced by 31.23-, 150.60-, and 19.42-fold when compared with core nanocrystals. HZC generated computed tomography (CT) imaging contrast effects, thus enabling NIR-II/CT/UC trimodal imaging. OSA modification not only ensured the exemplary biocompatibility of HZC but also enabled tumor-specific diagnosis. The findings would benefit the clinical imaging translation of LDNCs.

A Contrast-Enhanced Tri-Modal MRI Technique for High-Performance Hypoxia Imaging of Breast Cancer.

Personalized radiotherapy strategies enabled by the construction of hypoxia-guided biological target volumes (BTVs) can overcome hypoxia-induced radioresistance by delivering high-dose radiotherapy to targeted hypoxic areas of the tumor. However, the construction of hypoxia-guided BTVs is difficult owing to lack of precise visualization of hypoxic areas. This study synthesizes a hypoxia-responsive T1, T2, T2 mapping tri-modal MRI molecular nanoprobe (SPION@ND) and provides precise imaging of hypoxic tumor areas by utilizing the advantageous features of tri-modal magnetic resonance imaging (MRI). SPION@ND exhibits hypoxia-triggered dispersion-aggregation structural transformation. Dispersed SPION@ND can be used for routine clinical BTV construction using T1-contrast MRI. Conversely, aggregated SPION@ND can be used for tumor hypoxia imaging assessment using T2-contrast MRI. Moreover, by introducing T2 mapping, this work designs a novel method (adjustable threshold-based hypoxia assessment) for the precise assessment of tumor hypoxia confidence area and hypoxia level. Eventually this work successfully obtains hypoxia tumor target and accurates hypoxia tumor target, and achieves a one-stop hypoxia-guided BTV construction. Compared to the positron emission tomography-based hypoxia assessment, SPION@ND provides a new method that allows safe and convenient imaging of hypoxic tumor areas in clinical settings.

CT- and MRI-Aided Fluorescence Tomography Reconstructions for Biodistribution Analysis.

Optical fluorescence imaging can track the biodistribution of fluorophore-labeled drugs, nanoparticles, and antibodies longitudinally. In hybrid computed tomography-fluorescence tomography (CT-FLT), CT provides the anatomical information to generate scattering and absorption maps supporting a 3-dimensional reconstruction from the raw optical data. However, given the CT's limited soft tissue contrast, fluorescence reconstruction and quantification can be inaccurate and not sufficiently detailed. Magnetic resonance imaging (MRI) can overcome these limitations and extend the options for tissue characterization. Thus, we aimed to establish a hybrid CT-MRI-FLT approach for whole-body imaging and compared it with CT-FLT. The MRI-based hybrid imaging approaches were established first by scanning a water and coconut oil-filled phantom, second by quantifying Cy7 concentrations of inserts in dead mice, and finally by analyzing the biodistribution of AF750-labeled immunoglobulins (IgG, IgA) in living SKH1 mice. Magnetic resonance imaging, acquired with a fat-water-separated mDixon sequence, CT, and FLT were co-registered using markers in the mouse holder frame filled with white petrolatum, which was solid, stable, and visible in both modalities. Computed tomography-MRI fusion was confirmed by comparing the segmentation agreement using Dice scores. Phantom segmentations showed good agreement, after correction for gradient linearity distortion and chemical shift. Organ segmentations in dead and living mice revealed adequate agreement for fusion. Marking the mouse holder frame and the successful CT-MRI fusion enabled MRI-FLT as well as CT-MRI-FLT reconstructions. Fluorescence tomography reconstructions supported by CT, MRI, or CT-MRI were comparable in dead mice with 60 pmol fluorescence inserts at different locations. Although standard CT-FLT reconstruction only considered general values for soft tissue, skin, lung, fat, and bone scattering, MRI's more versatile soft tissue contrast enabled the additional consideration of liver, kidneys, and brain. However, this did not change FLT reconstructions and quantifications significantly, whereas for extending scattering maps, it was important to accurately segment the organs and the entire mouse body. The various FLT reconstructions also provided comparable results for the in vivo biodistribution analyses with fluorescent immunoglobulins. However, MRI additionally enabled the visualization of gallbladder, thyroid, and brain. Furthermore, segmentations of liver, spleen, and kidney were more reliable due to better-defined contours than in CT. Therefore, the improved segmentations enabled better assignment of fluorescence signals and more differentiated conclusions with MRI-FLT. Whole-body CT-MRI-FLT was implemented as a novel trimodal imaging approach, which allowed to more accurately assign fluorescence signals, thereby significantly improving pharmacokinetic analyses.

Gold-Crowned Bismuth-Based Nanocomposites for Sonodynamic, Photothermal, and Chemotherapeutic Cancer Therapy.

Conventional inorganic semiconductor nanoparticles have emerged as photothermal agents in photothermal therapy and as sonosensitizers in sonodynamic therapy. However, their weak drug-loading capabilities and the deficient techniques for multifunctional inorganic nanoparticles limit their applications. A bismuth-based gold-crowned nanocomposite (BACN) was rationally designed and successfully synthesized and could then be used to prepare nanoplatforms with excellent biocompatibilities for synergistic therapy and real-time imaging. Because of the constituent gold nanoparticles and pyridine, the nanoplatforms functioned as drug delivery vehicles, ultrasonically activated sonosensitizers, and photothermal agents. The BACNs exhibited excellent photothermal conversion efficiency (79.1%) in the second near-infrared biowindow (1064 nm). Cellular and mouse experiments demonstrated that under laser and ultrasound irradiation bufalin-loaded BACNs significantly reduced cancer cell counts and completely eradicated tumors, along with great therapeutic biosafety and no discernible recurrence. Additionally, BACNs were also used as contrast agents in computed tomography-photoacoustic imaging. The versatile BACN nanoplatform with multitreatment effects and trimodal imaging properties shows immense potential as an antitumor nanotherapeutic system.

Multi-shell structured nanomaterials with strong red upconversion emission for trimodal biomedical imaging

Upconversion nanomaterials show promising applications in multimodal imaging due to their advantages such as sharp emission bands and non-autofluorescence in tissue. Obtaining intense red upconversion emission is crucial for fluorescence imaging. Herein, we designed a multi-shell structured NaErF4:0.5%Tm3+@NaYF4:20%Yb3+ @NaLuF4 upconversion nanomaterial exhibiting strong red emission and high red-to-green ratio under 980 nm irradiation. The main mechanism of the strong emission is attributed to the inert NaLuF4 shell which serves to block the energy transfer from Yb3+ to surface defects. In addition, a NaGdF4 shell is further cladded considering the property of Gd3+ of facilitating longitudinal relaxation rate of water. The properties of X-ray attenuation, longitudinal relaxation rate, and the upconversion emission of the measured sample suggest that our designed nanomaterial possesses potential for X-ray computed tomography (CT), magnetic resonance imaging (MRI), and fluorescence trimodal imaging.

Covalent Organic Framework-Based Nanomotor for Multimodal Cancer Photo-Theranostics.

Developing efficient integrated diagnosis and treatment agents based on fuel-free self-movement nanomotors remains challenging in antitumor therapy. In this study, a covalent organic framework (COF)-based biomimetic nanomotor composed of polypyrrole (PPy) core, porphyrin-COF shell, and HCT116 cancer cell membrane coating is reported. Under near-infrared (NIR) light irradiation, the obtained mPPy@COF-Por can overcome Brownian motion and achieves directional motion through self-thermophoretic force generated from the PPy core. The HCT116 cancer cell membrane coating enables the nanomotor to selectively recognize the source cell lines and reduces the bio-adhesion of mPPy@COF-Por in a biological medium, endowing with this NIR light-powered nanomotor good mobility. More importantly, such multifunctional integration allows the COF-based nanomotor to be a powerful nanoagent for cancer treatment, and the high infrared thermal imaging/photoacoustic imaging/fluorescence trimodal imaging-guided combined photothermal/photodynamic therapeutic effect on HCT116 tumor cell is successfully achieved. The results offer considerable promise for the development of COF nanomotors with integrated imaging/therapy modalities in biomedical applications.

2-Methoxyestradiol loaded mesoporous polydopamine nanoprobes for hypoxia alleviation and sorafenib synergistic treatment of hepatocellular carcinoma

Hepatocellular carcinoma is a common and highly malignant disease. As a currently designated systemic chemotherapeutic agent for advanced Hepatocellular carcinoma, sorafenib has been confronted with dilemma of drug-resistance caused by tumor hypoxia, which hinders the therapeutic efficacy of the drug. Based on this, a multifunctional mesoporous polydopamine nanoprobe 2Me-SPIO-CY5.5@AAZ-MPDA with a mesoporous frame loaded 2-Methoxyestradiol, Superparamagnetic Iron Oxide Nanoparticles and the near-infrared dye cyanine 5.5, conjugated with hypoxia Hepatocellular carcinoma-specific targeting molecule of sulfonamides acetazolamide, is fabricated for hypoxic region targeting, sorafenib resistance reversion and photothermal therapy of Hepatocellular carcinoma. In addition, the magnetic resonance imaging/fluorescence/photoacoustic tri-modal imaging ability enables the tracing of the nanoprobes and monitoring the treatment procedure in vivo, providing a new methods of imaging-guided Hepatocellular carcinoma synergic treatment which improves the long-term therapeutic effects of sorafenib.

Redox ferrocenylseleno compounds modulate longitudinal and transverse relaxation times of FNPs-Gd MRI contrast agents for multimodal imaging and photo-Fenton therapy.

Developing a feasible way to feature longitudinal (T1) and transverse (T2) relaxation performance of contrast agents for magnetic resonance imaging (MRI) is important in cancer diagnosis and therapy. Improved accessibility to water molecule is essential for accelerating the relaxation rate of water protons around the contrast agents. Ferrocenyl compounds have reversible redox property for modulating the hydrophobicity/hydrophilicity of assemblies. Thus, they could be the candidates that can change water accessibility to the contrast agent surface. Herein, we incorporated ferrocenylseleno compound (FcSe) with Gd3+-based paramagnetic UCNPs, to obtain FNPs-Gd nanocomposites using T1-T2 MR/UCL trimodal imaging and simultaneous photo-Fenton therapy. When the surface of NaGdF4:Yb,Tm UNCPs was ligated by FcSe, the hydrogen bonding between hydrophilic selenium and surrounding water molecules accelerated their proton exchange to initially endow FNPs-Gd with high r1 relaxivity. Then, hydrogen nuclei from FcSe disrupted the homogeneity of the magnetic field around the water molecules. This facilitated T2 relaxation and resulted in enhanced r2 relaxivity. Notably, upon the near-infrared light-promoted Fenton-like reaction in the tumor microenvironment, hydrophobic ferrocene(II) of FcSe was oxidized into hydrophilic ferrocenium(III), which further increased the relaxation rate of water protons to obtain r1=1.90±0.12 mM-1 s-1 and r2=12.80±0.60 mM-1 s-1. With an ideal relaxivity ratio (r2/r1) of 6.74, FNPs-Gd exhibited high contrast potential of T1-T2 dual-mode MRI in vitro and in vivo. This work confirms that ferrocene and selenium are effective boosters that enhance the T1-T2 relaxivities of MRI contrast agents, which could provide a new strategy for multimodal imaging-guided photo-Fenton therapy of tumors. STATEMENT OF SIGNIFICANCE: T1-T2 dual-mode MRI nanoplatform with tumor-microenvironment-responsive features has been an attractive prospect. Herein, we designed redox ferrocenylseleno compound (FcSe) modified paramagnetic Gd3+-based UCNPs, to modulate T1-T2 relaxation time for multimodal imaging and H2O2-responsive photo-Fenton therapy. Selenium-hydrogen bond of FcSe with surrounding water molecules facilitated water accessibility for fast T1 relaxation. Hydrogen nucleus in FcSe perturbed the phase coherence of water molecules in an inhomogeneous magnetic field and thus accelerated T2 relaxation. In tumor microenvironment, FcSe was oxidized into hydrophilic ferrocenium via NIR light-promoted Fenton-like reaction which further increased both T1 and T2 relaxation rates; Meanwhile, the released toxic •OH performed on-demand cancer therapy. This work confirms that FcSe is an effective redox mediate for multimodal imaging-guided cancer therapy.

Tumor Cell Targeting and Responsive Nanoplatform for Multimodal-Imaging Guided Chemodynamic/Photodynamic/Photothermal Therapy toward Triple Negative Breast Cancer.

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with ineffective treatment and poor prognosis. It is in great demand to develop a novel theranostic strategy for accurate diagnosis and targeted treatment of TNBC. In the present study, one nanoplatform (HA-ICG-Fe-PDA), endowed with multimodal imaging-guided chemodynamic/photodynamic/photothermal (CDT/PDT/PTT) synergistic therapy capacity toward TNBC, was innovatively constructed. The nanoplatform was prepared by covalently conjugating ICG-decorated hyaluronic acid (HA) on Fe3+-chelated polydopamine (PDA). HA facilitated the targeting and accumulating of the nanoplatform in tumor tissue and cells of TNBC, thus producing enhanced magnetic resonance signal. Upon entering into TNBC cells, the intracellular hyaluronidase-catalyzed cleavage of HA-ICG-Fe-PDA activated the prequenched near-infrared (NIR) fluorescence signal, allowing for the activatable NIR fluorescence imaging. On the other hand, Fe3+ in the nanoplatform could be reduced to reactive Fe2+ in tumor microenvironment, guaranteeing efficient Fenton reaction-mediated CDT. The combination of ICG with Fe-PDA enhanced the NIR absorption of the nanoplatform so that considerable PTT/PDT and photothermal imaging were achieved under 808 nm laser irradiation. In vitro and in vivo experiments have verified that the proposed nanoplatform integrates the potential of TNBC-targeting, precise NIR fluorescence/magnetic resonance/photothermal trimodal imaging, efficient treatment via synergistic CDT/PDT/PTT, as well as excellent biocompatibility. Therefore, this multifunctional nanoplatform provides a simple and versatile strategy for imaging-guided theranostics of TNBC.

Tetramodal Chemical Imaging Delineates the Lipid-Amyloid Peptide Interplay at Single Plaques in Transgenic Alzheimer's Disease Models.

Beta-amyloid (Aβ) plaque pathology is one of the most prominent histopathological feature of Alzheimer's disease (AD). The exact pathogenic mechanisms linking Aβ to AD pathogenesis remain however not fully understood. Recent advances in amyloid-targeting pharmacotherapies highlight the critical relevance of Aβ aggregation for understanding the molecular basis of AD pathogenesis. We developed a novel, integrated, tetramodal chemical imaging paradigm for acquisition of trimodal mass spectrometry imaging (MSI) and interlaced fluorescent microscopy from a single tissue section. We used this approach to comprehensively investigate lipid-Aβ correlates at single plaques in two different mouse models of AD (tgAPPSwe and tgAPPArcSwe) with varying degrees of intrinsic properties affecting amyloid aggregation. Integration of the multimodal imaging data and multivariate data analysis identified characteristic patterns of plaque-associated lipid- and peptide localizations across both mouse models. Correlative fluorescence microscopy using structure-sensitive amyloid probes identified intra-plaque structure-specific lipid- and Aβ patterns, including Aβ 1-40 and Aβ 1-42 along with gangliosides (GM), phosphoinositols (PI), conjugated ceramides (CerP and PE-Cer), and lysophospholipids (LPC, LPA, and LPI). Single plaque correlation analysis across all modalities further revealed how these distinct lipid species were associated with Aβ peptide deposition across plaque heterogeneity, indicating different roles for those lipids in plaque growth and amyloid fibrillation, respectively. Here, conjugated ceramide species correlated with Aβ core formation indicating their involvement in initial plaque seeding or amyloid maturation. In contrast, LPI and PI were solely correlated with general plaque growth. In addition, GM1 and LPC correlated with continuous Aβ deposition and maturation. The results highlight the potential of this comprehensive multimodal imaging approach and implement distinct lipids in amyloidogenic proteinopathy.