"All in one" nanoprobe Au-TTF-1 for target FL/CT bioimaging, machine learning technology and imaging-guided photothermal therapy against lung adenocarcinoma.

The accurate preoperative diagnosis and tracking of lung adenocarcinoma is hindered by non-targeting and diffusion of dyes used for marking tumors. Hence, there is an urgent need to develop a practical nanoprobe for tracing lung adenocarcinoma precisely even treating them noninvasively. Herein, Gold nanoclusters (AuNCs) conjugate with thyroid transcription factor-1 (TTF-1) antibody, then multifunctional nanoprobe Au-TTF-1 is designed and synthesized, which underscores the paramount importance of advancing the machine learning diagnosis and bioimaging-guided treatment of lung adenocarcinoma. Bright fluorescence (FL) and strong CT signal of Au-TTF-1 set the stage for tracking. Furthermore, the high specificity of TTF-1 antibody facilitates selective targeting of lung adenocarcinoma cells as compared to common lung epithelial cells, so machine learning software Lung adenocarcinoma auxiliary detection system was designed, which combined with Au-TTF-1 to assist the intelligent recognition of lung adenocarcinoma jointly. Besides, Au-TTF-1 not only contributes to intuitive and targeted visualization, but also guides the following noninvasive photothermal treatment. The boundaries of tumor are light up by Au-TTF-1 for navigation, it penetrates into tumor and implements noninvasive photothermal treatment, resulting in ablating tumors in vivo locally. Above all, Au-TTF-1 serves as a key platform for target bio-imaging navigation, machine learning diagnosis and synergistic PTT as a single nanoprobe, which demonstrates attractive performance on lung adenocarcinoma.

Assessment of Prostate and Bladder Cancer Genomic Biomarkers Using Artificial Intelligence: a Systematic Review.

PURPOSE OF REVIEW: The aim of the systematic review is to assess AI's capabilities in the genetics of prostate cancer (PCa) and bladder cancer (BCa) to evaluate target groups for such analysis as well as to assess its prospects in daily practice. RECENT FINDINGS: In total, our analysis included 27 articles: 10 articles have reported on PCa and 17 on BCa, respectively. The AI algorithms added clinical value and demonstrated promising results in several fields, including cancer detection, assessment of cancer development risk, risk stratification in terms of survival and relapse, and prediction of response to a specific therapy. Besides clinical applications, genetic analysis aided by the AI shed light on the basic urologic cancer biology. We believe, our results of the AI application to the analysis of PCa, BCa data sets will help to identify new targets for urological cancer therapy. The integration of AI in genomic research for screening and clinical applications will evolve with time to help personalizing chemotherapy, prediction of survival and relapse, aid treatment strategies such as reducing frequency of diagnostic cystoscopies, and clinical decision support, e.g., by predicting immunotherapy response. These factors will ultimately lead to personalized and precision medicine thereby improving patient outcomes.

An Electroconductive Hydrogel Scaffold with Injectability and Biodegradability to Manipulate Neural Stem Cells for Enhancing Spinal Cord Injury Repair.

Spinal cord injury (SCI) generally leads to long-term functional deficits and is difficult to repair spontaneously. Many biological scaffold materials and stem cell treatment strategies have been explored, but very little research focused on the method of combining exogenous neural stem cells (NSCs) with a biodegradable conductive hydrogel scaffold. Here, a NSC loaded conductive hydrogel scaffold (named ICH/NSCs) was assembled by amino-modified gelatin (NH2-Gelatin) and aniline tetramer grafted oxidized hyaluronic acid (AT-OHA). Desirably, the well-conducting ICH/NSCs can be simply injected into the target site of SCI for establishing a good electrical signal pathway of cells, and the proper degradation cycle facilitates new nerve growth. In vitro experiments indicated that the inherent electroactive microenvironment of the hydrogel could better manipulate the differentiation of NSCs into neurons and inhibit the formation of glial cells and scars. Collectively, the ICH/NSC scaffold has successfully stimulated the recovery of SCI and may provide a promising treatment strategy for SCI repair.

Machine learning reveals mesenchymal breast carcinoma cell adaptation in response to matrix stiffness.

Epithelial-mesenchymal transition (EMT) and its reverse process, mesenchymal-epithelial transition (MET), are believed to play key roles in facilitating the metastatic cascade. Metastatic lesions often exhibit a similar epithelial-like state to that of the primary tumour, in particular, by forming carcinoma cell clusters via E-cadherin-mediated junctional complexes. However, the factors enabling mesenchymal-like micrometastatic cells to resume growth and reacquire an epithelial phenotype in the target organ microenvironment remain elusive. In this study, we developed a workflow using image-based cell profiling and machine learning to examine morphological, contextual and molecular states of individual breast carcinoma cells (MDA-MB-231). MDA-MB-231 heterogeneous response to the host organ microenvironment was modelled by substrates with controllable stiffness varying from 0.2kPa (soft tissues) to 64kPa (bone tissues). We identified 3 distinct morphological cell types (morphs) varying from compact round-shaped to flattened irregular-shaped cells with lamellipodia, predominantly populating 2-kPa and >16kPa substrates, respectively. These observations were accompanied by significant changes in E-cadherin and vimentin expression. Furthermore, we demonstrate that the bone-mimicking substrate (64kPa) induced multicellular cluster formation accompanied by E-cadherin cell surface localisation. MDA-MB-231 cells responded to different substrate stiffness by morphological adaptation, changes in proliferation rate and cytoskeleton markers, and cluster formation on bone-mimicking substrate. Our results suggest that the stiffest microenvironment can induce MET.

Construction of Intelligent Responsive Drug Delivery System and Multi-Mode Imaging Based on Gold Nanodots.

Cancer remains a formidable global problem with a high mortality rate. There are many effective anti-cancer drugs in clinical use, among which paclitaxel (PTX) has good effects on non-small cell lung cancer, ovarian cancer, and breast cancer. However, when applied to the clinic, PTX still has many limitations, such as poor water solubility, drug resistance, and side effects on healthy tissues. A gold nanodots-paclitaxel-polylysine (AuNDs-PTX-PLL) core-shell nano-system of integrated diagnosis and treatment is constructed to achieve intelligent responsive drug delivery. On the one hand, the problem of poor water-solubility and drug resistance of PTX are solved. On the other hand, the nano-system has an excellent intelligent response effect. Drugs can only be released in the weakly acidic environment of the tumor, which reduces the damage and side effects to normal tissues. Moreover, the nano-system can be used for real-time tracking and auxiliary diagnosis for the tumor through the multi-mode imaging mode, such as fluorescence, photoacoustic, and computed tomography to achieve accurate visualization. The photothermal effect of AuNDs is beneficial to promote the release of drugs. The nano-system integrates multi-mode imaging, chemotherapy, intelligent drug release in tumor weakly acidic environment, and has excellent practical application prospects in tumor diagnosis and treatment.

Hydrogel Composites with Different Dimensional Nanoparticles for Bone Regeneration.

The treatment of large segmental bone defects and complex types of fractures caused by trauma, inflammation, or tumor resection is still a challenge in the field of orthopedics. Various natural or synthetic biological materials used in clinical applications cannot fully replicate the structure and performance of raw bone. This highlights how to endow materials with multiple functions and biological properties, which is a problem that needs to be solved in practical applications. Hydrogels with outstanding biocompatibility, for their casting into any shape, size, or form, are suitable for different forms of bone defects. Therefore, they have been used in regenerative medicine more widely. In this review, versatile hydrogels are compounded with nanoparticles of different dimensions, and many desirable features of these materials in bone regeneration are introduced, including drug delivery, cell factor vehicle, cell scaffolds, which have potential in bone regeneration applications. The combination of hydrogels and nanoparticles of different dimensions encourages better filling of bone defect areas and has higher adaptability. This is due to the minimally invasive properties of the material and ability to match irregular defects. These biological characteristics make composite hydrogels with different dimensional nanoparticles become one of the most attractive options for bone regeneration materials.

Radioactive (90Y) upconversion nanoparticles conjugated with recombinant targeted toxin for synergistic nanotheranostics of cancer.

We report combined therapy using upconversion nanoparticles (UCNP) coupled to two therapeutic agents: beta-emitting radionuclide yttrium-90 (90Y) fractionally substituting yttrium in UCNP, and a fragment of the exotoxin A derived from Pseudomonas aeruginosa genetically fused with a targeting designed ankyrin repeat protein (DARPin) specific to HER2 receptors. The resultant hybrid complex UCNP-R-T was tested using human breast adenocarcinoma cells SK-BR-3 overexpressing HER2 receptors and immunodeficient mice, bearing HER2-positive xenograft tumors. The photophysical properties of UCNPs enabled background-free imaging of the UCNP-R-T distribution in cells and animals. Specific binding and uptake of UCNP complexes in SK-BR-3 cells was observed, with separate 90Y- and PE40-induced cytotoxic effects characterized by IC50 140 µg/mL (UCNP-R) and 5.2 µg/mL (UCNP-T), respectively. When both therapeutic agents were combined into UCNP-R-T, the synergetic effect increased markedly, ∼2200-fold, resulting in IC50 = 0.0024 µg/mL. The combined therapy with UCNP-R-T was demonstrated in vivo.

Glypican-1 as a target for fluorescence molecular imaging of bladder cancer.

OBJECTIVES: To investigate whether anti-glypican-1 antibody Miltuximab conjugated with near-infrared dye IRDye800CW can be used for in vivo fluorescence imaging of urothelial carcinoma. METHODS: The conjugate, Miltuximab-IRDye800CW, was produced and characterized by size exclusion chromatography and flow cytometry with glypican-1-expressing cells. Balb/c nude mice bearing subcutaneous urothelial carcinoma xenografts were intravenously injected with Miltuximab-IRDye800CW or control IgG-IRDye800CW and imaged daily by fluorescence imaging. After 10 days, tumors and major organs were collected for ex vivo study of the conjugate biodistribution, including its accumulation in the tumor. RESULTS: The intravenous injection of Miltuximab-IRDye800CW to tumor-bearing mice showed its specific accumulation in the tumors with the tumor-to-background ratio of 12.7 ± 2.4, which was significantly higher than that in the control group (4.6 ± 0.9, P < 0.005). The ex vivo imaging was consistent with the in vivo findings, with tumors from the mice injected with Miltuximab-IRDye800CW being significantly brighter than the organs or the control tumors. CONCLUSIONS: The highly specific accumulation and retention of Miltuximab-IRDye800CW in glypican-1-expressing tumors in vivo shows its high potential for fluorescence imaging of urothelial carcinoma and warrants its further investigation toward clinical translation.

Human Epidermal Zinc Concentrations after Topical Application of ZnO Nanoparticles in Sunscreens.

Zinc oxide nanoparticle (ZnO NP)-based sunscreens are generally considered safe because the ZnO NPs do not penetrate through the outermost layer of the skin, the stratum corneum (SC). However, cytotoxicity of zinc ions in the viable epidermis (VE) after dissolution from ZnO NP and penetration into the VE is ill-defined. We therefore quantified the relative concentrations of endogenous and exogenous Zn using a rare stable zinc-67 isotope (67Zn) ZnO NP sunscreen applied to excised human skin and the cytotoxicity of human keratinocytes (HaCaT) using multiphoton microscopy, zinc-selective fluorescent sensing, and a laser-ablation inductively coupled plasma-mass spectrometry (LA-ICP-MS) methodology. Multiphoton microscopy with second harmonic generation imaging showed that 67ZnO NPs were retained on the surface or within the superficial layers of the SC. Zn fluorescence sensing revealed higher levels of labile and intracellular zinc in both the SC and VE relative to untreated skin, confirming that dissolved zinc species permeated across the SC into the VE as ionic Zn and significantly not as ZnO NPs. Importantly, the LA-ICP-MS estimated exogenous 67Zn concentrations in the VE of 1.0 ± 0.3 µg/mL are much lower than that estimated for endogenous VE zinc of 4.3 ± 0.7 µg/mL. Furthermore, their combined total zinc concentrations in the VE are much lower than the exogenous zinc concentration of 21 to 31 µg/mL causing VE cytotoxicity, as defined by the half-maximal inhibitory concentration of exogenous 67Zn found in human keratinocytes (HaCaT). This speaks strongly for the safety of ZnO NP sunscreens applied to intact human skin and the associated recent US FDA guidance.

UCNP-based Photoluminescent Nanomedicines for Targeted Imaging and Theranostics of Cancer.

Theranostic approach is currently among the fastest growing trends in cancer treatment. It implies the creation of multifunctional agents for simultaneous precise diagnosis and targeted impact on tumor cells. A new type of theranostic complexes was created based on NaYF4: Yb,Tm upconversion nanoparticles coated with polyethylene glycol and functionalized with the HER2-specific recombinant targeted toxin DARPin-LoPE. The obtained agents bind to HER2-overexpressing human breast adenocarcinoma cells and demonstrate selective cytotoxicity against this type of cancer cells. Using fluorescent human breast adenocarcinoma xenograft models, the possibility of intravital visualization of the UCNP-based complexes biodistribution and accumulation in tumor was demonstrated.

Incoherent wavefront reconstruction by a retroemission device containing a thin fluorescent film: theory.

A retroemission device (REM) is an incoherent holographic device that represents a lenslet array situated on a substrate containing fluorescent material. Each lenslet focuses each wavelet of an optical wavefront incident on the REM device into a diffraction-limited volume (voxel) in the fluorescent material, so that the voxel coordinates encode the angle of incidence and curvature of the wavelet. The back-propagating fraction of the excited fluorescence is collected by the lenslet and quasi-collimated into a back-propagating wavelet. All wavelets are combined to reconstruct the incident wavefront propagating in the backward direction. We present a theoretical model of REM based on Fresnel-Kirchhoff approximation describing the reconstructed 3D image characteristics versus the thickness of the fluorescence film at the focal plane of the lenslets. Results of the computer simulations of the REM-based images of a point source, two axially separated point sources and an extended object (a circular rim) situated in the sagittal plane are presented. These results speak in favor of using a fluorescence film of minimum diffraction-limited thickness at the lenslet back focal plane. This REM structure minimizes the fluorescence background and improves the 3D imaging resolution in virtue of the exclusion of out-of-voxel fluorescence contributions to the reconstructed wavefront.

Incoherent wavefront reconstruction by a retroemission device.

This Letter addresses wavefront reconstruction by a retroemission device (REM). REM represents a lenslet array mounted on a substrate made of photoluminescent optical material, such as a polymer film impregnated with upconversion nanoparticles. An excitation light wavefront incident on the REM was sampled by the lenslet array piece-wise. Each wavelet at the lenslet aperture was converged into a voxel in the substrate, with its coordinates encoding the angle of incidence and curvature of the wavelet. Photoluminescence excited in the voxel was radiated isotropically, its back-propagating fraction was captured by the lenslet and transformed into a back-propagating wavelet, which contributed to reproduction of the entire incident wavefront with some fidelity. We experimentally proved the wavefront reconstruction based on REM, and present its theoretical model based on a Fresnel-Kirchhoff approximation.

Targeted Radionuclide Therapy of Human Tumors.

Targeted radionuclide therapy is one of the most intensively developing directions of nuclear medicine. Unlike conventional external beam therapy, the targeted radionuclide therapy causes less collateral damage to normal tissues and allows targeted drug delivery to a clinically diagnosed neoplastic malformations, as well as metastasized cells and cellular clusters, thus providing systemic therapy of cancer. The methods of targeted radionuclide therapy are based on the use of molecular carriers of radionuclides with high affinity to antigens on the surface of tumor cells. The potential of targeted radionuclide therapy has markedly grown nowadays due to the expanded knowledge base in cancer biology, bioengineering, and radiochemistry. In this review, progress in the radionuclide therapy of hematological malignancies and approaches for treatment of solid tumors is addressed.

Somatostatin and its 2A receptor in dorsal root ganglia and dorsal horn of mouse and human: expression, trafficking and possible role in pain.

BACKGROUND: Somatostatin (SST) and some of its receptor subtypes have been implicated in pain signaling at the spinal level. In this study we have investigated the role of SST and its sst2A receptor (sst2A) in dorsal root ganglia (DRGs) and spinal cord. RESULTS: SST and sst2A protein and sst2 transcript were found in both mouse and human DRGs, sst2A-immunoreactive (IR) cell bodies and processes in lamina II in mouse and human spinal dorsal horn, and sst2A-IR nerve terminals in mouse skin. The receptor protein was associated with the cell membrane. Following peripheral nerve injury sst2A-like immunoreactivity (LI) was decreased, and SST-LI increased in DRGs. sst2A-LI accumulated on the proximal and, more strongly, on the distal side of a sciatic nerve ligation. Fluorescence-labeled SST administered to a hind paw was internalized and retrogradely transported, indicating that a SST-sst2A complex may represent a retrograde signal. Internalization of sst2A was seen in DRG neurons after systemic treatment with the sst2 agonist octreotide (Oct), and in dorsal horn and DRG neurons after intrathecal administration. Some DRG neurons co-expressed sst2A and the neuropeptide Y Y1 receptor on the cell membrane, and systemic Oct caused co-internalization, hypothetically a sign of receptor heterodimerization. Oct treatment attenuated the reduction of pain threshold in a neuropathic pain model, in parallel suppressing the activation of p38 MAPK in the DRGs CONCLUSIONS: The findings highlight a significant and complex role of the SST system in pain signaling. The fact that the sst2A system is found also in human DRGs and spinal cord, suggests that sst2A may represent a potential pharmacologic target for treatment of neuropathic pain.

VEGF-loaded ROS-responsive nanodots improve the structure and function of sciatic nerve lesions in type II diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes mellitus (DM), significantly contributing to the risk of amputation and mortality. Reactive oxygen species (ROS) can induce both neurological and structural harm through direct impact and pyroptosis, underscoring the critical role of ROS regulation in mitigating DPN. In this research endeavor, we propose harnessing the inherent antioxidant properties of sulfhydryl groups by grafting them onto gold nanodots through an amidation reaction, resulting in the creation of ROS-responsive AuNDs. Additionally, we aim to synthesize AuNDs-VEGF, wherein VEGF is attached to AuNDs via electrostatic interactions, as a therapeutic strategy for addressing DPN in rat models. The results of in vivo experiments showed that AuNDs and AuNDs-VEGF nanoparticles could increase the nerve conduction velocity, shorten the latency of nerve conduction in the sciatic nerve, promote the regeneration of nerve trophectodermal vessels, improve the structure and function of the sciatic nerve, reduce the apoptosis of neural cells, and alleviate the atrophy of the gastrocnemius muscle. Thus, VEGF-loaded ROS-responsive nanodots present a promising avenue for ameliorating diabetic peripheral neuropathy. This innovative approach not only extends the application possibilities of nanodots but also introduces a novel avenue for the treatment of diabetic neuropathy.

"All-in-one" tea polyphenol-modified injectable hyaluronic acid-based hydrogel for diabetic wound healing.

Refractory diabetic wounds are a devastating and rapidly growing clinical problem, which is associated with high incidence rates, mortality, and recurrence rates. Therapeutic angiogenesis in wound tissues is essential to the healing of diabetic wounds. However, the presence of excessive oxidative stress in diabetic wounds hinders angiogenesis, and conventional anti-oxidative approaches are inefficient to compensate for the systematically impaired angiogenesis. Here, a multifunctional supramolecular hyaluronic acid hydrogel dressing for diabetic wounds is successfully designed and constructed (GHPM). The GHPM hydrogel features outstanding properties, including excellent tissue adhesion, antibacterial ability, conductivity, and antioxidant properties. Based on the dynamic crosslinking structure, the GHPM hydrogel also presents adequate injectable and self-healing capabilities, which play a vital role in covering irregular or deep wounds. Additionally, diabetic wounds treated with GHPM hydrogel showed a significant acceleration of wound closure by preventing wound infection, reducing oxidative stress, and accelerating collagen deposition. More interestingly, the combination of electrical stimulation and GHPM hydrogel can effectively promote angiogenesis and neurogenesis, further accelerating diabetic wound healing in an all-around way. This advanced collaborative strategy opens a new avenue in treating diabetic wounds.

Enhancing glioma treatment with 3D scaffolds laden with upconversion nanoparticles and temozolomide in orthotopic mouse model.

Targeted drug delivery for primary brain tumors, particularly gliomas, is currently a promising approach to reduce patient relapse rates. The use of substitutable scaffolds, which enable the sustained release of clinically relevant doses of anticancer medications, offers the potential to decrease the toxic burden on the patient's organism while also enhancing their quality of life and overall survival. Upconversion nanoparticles (UCNPs) are being actively explored as promising agents for detection and monitoring of tumor growth, and as therapeutic agents that can provide isolated therapeutic effects and enhance standard chemotherapy. Our study is focused on the feasibility of constructing scaffolds using methacrylated hyaluronic acid with additional impregnation of UCNPs and the chemotherapeutic drug temozolomide (TMZ) for glioma treatment. The designed scaffolds have been demonstrated their efficacy as a drug and UCNPs delivery system for gliomas. Using the aggressive orthotopic glioma model in vivo, it was found that the scaffolds possess the capacity to ameliorate neurological disorders in mice. Moreover, upon intracranial co-implantation of the scaffolds and glioma cells, the constructs disintegrate into distinct segments, augmenting the release of UCNPs into the surrounding tissue and concurrently reducing postoperative damage to brain tissue. The use of TMZ in the scaffold composition contributed to restraining glioma development and the reduction of tumor invasiveness. Our findings unveil promising prospects for the application of photopolymerizable biocompatible scaffolds in the realm of neuro-oncology.

Laser-Synthesized Germanium Nanoparticles as Biodegradable Material for Near-Infrared Photoacoustic Imaging and Cancer Phototherapy.

Biodegradable nanomaterials can significantly improve the safety profile of nanomedicine. Germanium nanoparticles (Ge NPs) with a safe biodegradation pathway are developed as efficient photothermal converters for biomedical applications. Ge NPs synthesized by femtosecond-laser ablation in liquids rapidly dissolve in physiological-like environment through the oxidation mechanism. The biodegradation of Ge nanoparticles is preserved in tumor cells in vitro and in normal tissues in mice with a half-life as short as 3.5 days. Biocompatibility of Ge NPs is confirmed in vivo by hematological, biochemical, and histological analyses. Strong optical absorption of Ge in the near-infrared spectral range enables photothermal treatment of engrafted tumors in vivo, following intravenous injection of Ge NPs. The photothermal therapy results in a 3.9-fold reduction of the EMT6/P adenocarcinoma tumor growth with significant prolongation of the mice survival. Excellent mass-extinction of Ge NPs (7.9 L g-1 cm-1 at 808 nm) enables photoacoustic imaging of bones and tumors, following intravenous and intratumoral administrations of the nanomaterial. As such, strongly absorbing near-infrared-light biodegradable Ge nanomaterial holds promise for advanced theranostics.

A modular design of low-background bioassays based on a high-affinity molecular pair barstar:barnase.

High-affinity molecular pairs provide a convenient and flexible modular base for the design of molecular probes and protein/antigen assays. Specificity and sensitivity performance indicators of a bioassay critically depend on the dissociation constant (K(D)) of the molecular pair, with avidin:biotin being the state-of-the-art molecular pair (K(D) ∼ 1 fM) used almost universally for applications in the fields of nanotechnology and proteomics. In this paper, we present an alternative high-affinity protein pair, barstar:barnase (K(D) ∼ 10 fM), which addresses several shortfalls of the avidin:biotin system, including non-negligible background due to the non-specific binding. A quantitative assessment of the non-specific binding carried out using a model assay revealed inherent irreproducibility of the [strept]avidin:biotin-based assays, attributed to the avidin binding to solid phases, endogenous biotin molecules and serum proteins. On the other hand, the model assays assembled via a barstar:barnase protein linker proved to be immune to such non-specific binding, showing good prospects for high-sensitivity rare biomolecular event nanoproteomic assays.

Effect of the nanodiamond host on a nitrogen-vacancy color-centre emission state.

Control over the quantum states of individual luminescent nitrogen-vacancy (NV) centres in nanodiamonds (NDs) is demonstrated by careful design of the crystal host: its size, surface functional groups, and interfacing substrate. By progressive etching of the ND host, the NV centres are induced to switch from latent, through continuous, to intermittent or "blinking" emission states. The blinking mechanism of the NV centre in NDs is elucidated and a qualitative model proposed to explain this phenomenon in terms of the centre electron(s) tunnelling to acceptor site(s). These measurements suggest that the substrate material and its proximity to the NV are responsible for the fluorescence intermittency.