Enhanced Tissue Penetration Research Articles

Recent advances of photoresponsive nanomaterials for diagnosis and treatment of acute kidney injury.

Non-invasive imaging in the near-infrared region (NIR) offers enhanced tissue penetration, reduced spontaneous fluorescence of biological tissues, and improved signal-to-noise ratio (SNR), rendering it more suitable for in vivo deep tissue imaging. In recent years, a plethora of NIR photoresponsive materials have been employed for disease diagnosis, particularly acute kidney injury (AKI). These encompass inorganic nonmetallic materials such as carbon (C), silicon (Si), phosphorus (P), and upconversion nanoparticles (UCNPs); precious metal nanoparticles like gold and silver; as well as small molecule and organic semiconductor polymer nanoparticles with near infrared responsiveness. These materials enable effective therapy triggered by NIR light and serve as valuable tools for monitoring AKI in living systems. The review provides a concise overview of the current state and pathological characteristics of AKI, followed by an exploration of the application of nanomaterials and photoresponsive nanomaterials in AKI. Finally, it presents the design challenges and prospects associated with NIR photoresponsive materials in AKI.

Aggregation-Induced Emission Luminogen Based Wearable Visible-Light Penetrator for Deep Photodynamic Therapy.

Photodynamic therapy (PDT) has emerged as a preferred nonsurgical treatment in clinical applications due to its capacity to selectively eradicate diseased tissues while minimizing damage to normal tissue. Nevertheless, its clinical efficacy is constrained by the limited penetration of visible light. Although near-infrared (NIR) lasers offer enhanced tissue penetration, the dearth of suitable photosensitizers and a pronounced imaging-treatment disparity pose challenges. Additionally, clinical implementation via optical fiber implantation carries infection risks and necessitates minimally invasive surgery, contradicting PDT's noninvasive advantage. In this study, we introduce a brilliant approach utilizing aggregation-induced emission luminogens (AIEgen) to develop a visible-light penetrator (VLP), coupled with wireless light emitting diodes (LEDs), enabling deep photodynamic therapy. We validate the therapeutic efficacy of this visible-light penetrator in tissues inaccessible to conventional PDT, demonstrating significant suppression of inflammatory diffusion in vivo using AIEgen TBPPM loaded within the VLP, which exhibits a transmittance of 86% in tissues with a thickness of 3 mm. This innovative visible-light penetrator effectively overcomes the substantial limitations of PDT in clinical settings and holds promise for advancing phototherapy.

Toward Upconversion (Yb-Er) and near-Infrared (Yb-Ho-Er, Nd-Yb) Thermometry with Sea Urchin Type GdPO4 Nanoarchitectures.

In recent years, optical temperature probes operating in the second near-infrared (BW-II) and third near-infrared (BW-III) biological windows have garnered significant attention in the scientific community. For biological applications these probes offer distinct advantages, including enhanced tissue penetration depth, minimal autofluorescence, and a remarkable improvement in imaging sensitivity and spatial resolution. Moving toward theranostic applications, there is a growing demand for the development of materials that integrate both BW-II and BW-III thermometry systems with drug delivery functionalities. In this study, we concentrate on the development of GdPO4 materials, utilizing both hard and sacrificial template routes to synthesize (hollow) GdPO4 porous sea urchin-like particles. We first investigated the development of a Boltzmann-type thermometer utilizing an Yb-Er upconversion system, designed to operate within the physiological temperature range. Our exploration extends to the potential of GdPO4 particles in near-infrared (NIR) thermometry, spanning the first, second, and third biological windows with systems like Yb-Ho-Er, Nd-Yb, and Ho-Yb, respectively. We further examined the temperature impact of the Yb-Ho-Er system on the NIR emission within a biologically relevant setting, using a phantom that replicates biological tissue. Furthermore, we illustrate the successful loading of these materials with doxorubicin (DOX·HCl), a model anticancer drug, showing these particles exhibit pH-dependent DOX release. This demonstrates the versatility of these materials as upconversion and NIR thermometers while simultaneously serving as an on-demand drug carrier. The investigation involves assessing their cytotoxicity on specific human cells (Normal Human Dermal Fibroblasts (NHDFs)), to determine their viability for potential use in biological applications. The study also investigates how effectively loading the particles with DOX enables targeted delivery to a cellular model of lymphoma (Jurkat E6-1), resulting in cell death. This comprehensive analysis highlights the promising potential of GdPO4 particles for medical applications.

PoLambRimetry: a multispectral polarimetric atlas of lamb brain.

Mueller matrix imaging (MMI) is a comprehensive form of polarization imaging useful for assessing structural changes. However, there is limited literature on the polarimetric properties of brain specimens, especially with multispectral analysis. We aim to employ multispectral MMI for an exhaustive polarimetric analysis of brain structures, providing a reference dataset for future studies and enhancing the understanding of brain anatomy for clinicians and researchers. A multispectral wide-field MMI system was used to measure six fresh lamb brain specimens. Multiple decomposition methods (forward polar, symmetric, and differential) and polarization invariants (indices of polarimetric purity and anisotropy coefficients) have been calculated to obtain a complete polarimetric description of the samples. A total of 16 labels based on major brain structures, including grey matter (GM) and white matter (WM), were identified. -nearest neighbors classification was used to distinguish between GM and WM and validate the feasibility of MMI for WM identification. As the wavelength increases, both depolarization and retardance increase, suggesting enhanced tissue penetration into deeper layers. Moreover, utilizing multiple wavelengths allowed us to track dynamic shifts in the optical axis of retardance within the brain tissue, providing insights into morphological changes in WM beneath the cortical surface. The use of multispectral data for classification outperformed all results obtained with single-wavelength data and provided over 95% accuracy for the test dataset. The consistency of these observations highlights the potential of multispectral wide-field MMI as a non-invasive and effective technique for investigating the brain's architecture.

Synthesis and Evaluation of 99mTc(CO)3 Complexes with Ciprofloxacin Dithiocarbamate for Infection Imaging.

Background: The accurate diagnosis of bacterial infections remains a critical challenge in clinical practice. Traditional imaging modalities like computed tomography (CT) and magnetic resonance imaging (MRI) often fail to distinguish bacterial infections from sterile inflammation. Nuclear medicine, such as technetium-99m (99mTc) radiopharmaceuticals, offers a promising alternative due to its ideal characteristics. Methods: This study explores the development of [2 + 1] mixed-ligand 99mTc-labeled ciprofloxacin dithiocarbamate (Cip-DTC) complexes combined with various phosphine ligands, including triphenylphosphine (PPh3), tris(4-methoxyphenyl)phosphine (TMPP), methyl(diphenyl)phosphine (MePPh2), dimethylphenylphosphine (DMPP), and 1,3,5-triaza-7-phosphaadamantane (ADAP). The characterization of 99mTc-complexes was conducted using rhenium analogs as structural models to ensure similar coordination. Results: Stability studies demonstrated the high integrity (97-98%) of the complexes under various conditions, including cysteine and histidine challenges. Lipophilicity studies indicated that complexes with higher logD7.4 values (1.6-2.7) exhibited enhanced tissue penetration and prolonged circulation. Biodistribution studies in Swiss Albino mice with induced infections and aseptic inflammation revealed distinct patterns. Specifically, the complex fac-[99mTc(CO)3(Cip-DTC)(PPh3)] (2') showed high infected/normal muscle ratios (4.62 at 120 min), while the complex fac-[99mTc(CO)3(Cip-DTC)(TMPP)] (3') demonstrated delayed but effective targeting (infected/normal muscle ratio of 3.32 at 120 min). Conclusions: These findings highlight the potential of 99mTc-labeled complexes as effective radiopharmaceuticals for the differential diagnosis of bacterial infections, advancing nuclear medicine diagnostics. Future studies will focus on optimizing molecular weight, lipophilicity, and stability to further enhance the diagnostic specificity and clinical utility of these radiopharmaceuticals.

Citrus aurantifolia-derived carbon quantum dots with red fluorescence emission for codelivery with curcumin as theranostic liposomes for lung cancer

BackgroundCarbon dots (CDs) derived from Citrus aurantifolia represent a promising platform for advanced cancer therapy and diagnostics (theranostics). These CDs are synthesized through a sustainable and cost-effective hydrothermal method, utilizing fruit juice as a green carbon source. Despite the potential, research on the synthesis of citrus-based CDs, especially regarding their red fluorescence emission, which is crucial for enhanced tissue penetration and biomedical efficacy, remains limited.ResultsIn this study, CDs were successfully synthesized from C. aurantifolia fruit, yielding nanoparticles below 5 nm in size (PDI 0.231 ± 0.04). Characterization revealed favorable optical properties, including excitation-dependent fluorescent behavior with prominent red emission under higher excitation wavelengths, a quantum yield of 8.17%, and stable photoluminescence. Chemical composition analysis using XPS, FTIR, and XRD confirmed the purity and structure of the CDs.To explore their biomedical application, CDs were co-loaded with curcumin into liposomes. The formulations had a mean size of 177.2 ± 3.6 nm (PDI 0.270 ± 0.012), demonstrated efficient drug entrapment (60.32 ± 2.24%), and exhibited rapid release kinetics, with 90.21 ± 2.16% of the drug release within 8 h. In vitro studies using A549 lung cancer cells demonstrated superior cellular uptake and cytotoxicity of Cur-CD-loaded liposomes compared to curcumin alone (Cur-Suspension), achieving IC50 values of 0.093 ± 0.011 µg/ml and 0.016 ± 0.006 µg/ml, respectively.ConclusionThis research underscores C. aurantifolia as a viable natural source for green CD synthesis. The obtained CDs with red fluorescence emission, optimized through reaction conditions and excitation wavelengths, hold promise for enhanced biological applications, particularly in the realm of lung cancer therapy. The findings advocate for further exploration and refinement of citrus-based CDs as versatile theranostic agents, capitalizing on their sustainable origins and potent biomedical properties. The combination of citrus-derived CDs with curcumin loaded into liposomal formulations represents a potent theranostic strategy for lung cancer treatment, leveraging the unique properties of CDs and their potential for targeted and effective therapy.Graphical abstract

Study protocol for Near-infrared molecular imaging for lung cancer detection and treatment during mini-invasive surgery (phase II Trial) - (the RECOGNISE study)

Introduction. To date, radical surgery remains the best curative option in patients with early-stage lung cancer. In patients with small lung lesions, video-assisted thoracic surgery (VATS) should be increasingly chosen as a fundamental alternative to thoracotomy as it is associated with less postoperative pain and better quality of life. This scenario necessarily increases the need for thoracic surgeons to implement new localization techniques. The conventional near-infrared (NIR) indocyanine green (ICG) method demonstrated a significant limitation in deep cancer recognition, principally due to its intrinsic low-depth tissue penetration. Similarly, the lymph-node sentinel approach conducted by the ICG method was demonstrated to be inefficient, mainly due to the non-specificity of the tracker and the irregular pathway of pulmonary lymph node drainage. Our study aims to evaluate the effectiveness of Cetuximab- IRDye800CW in marking lung nodules and mediastinal lymph nodes. Methods and analysis. This study is defined as an open-label, single-arm, single-stage phase II trial evaluating the effectiveness of Cetuximab-IRDye800CW in detecting tumors and lymph-node metastases in patients with lung cancer who are undergoing video-assisted thoracic surgery (VATS). Cetuximab is a monoclonal antibody that binds, inhibits, and degrade the EGFR. The IRDye® 800CW, an indocyanine-type NIR fluorophore, demonstrated enhanced tissue penetration compared to other NIR dyes. The combination with the clinical approved monoclonal antibody anti-epidermal growth factor EGFR Cetuximab (Cetuximab-IRDye800) has shown promising results as a specific tracker in different cancer types (i.e., brain, pancreas, head, and neck). The study’s primary outcome is focused on the proportion of patients with lung nodules detected during surgery using an NIR camera. The secondary outcomes include a broad spectrum of items, including the proportion of patients with detection of unexpected cancer localization during surgery by NIR camera and the proportion of patients with negative surgical margins, the evaluation of the time spawns between the insertion of the NIR camera and the visualization of the nodule and the possible morbidity of the drug assessed during and after the drug infusion. Ethics and dissemination. This trial has been approved by the Ethical Committee of Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino (Torino, Italy) and by the Italian Medicines Agency (AIFA). Findings will be written as methodology papers for conference presentations and published in peer-reviewed journals. The Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, the University of Torino, and the AIRC Public Engagement Divisions will help identify how best to publicize the findings.Trial registration EudraCT 202,100,645,430. ClinicalTrials.gov NCT06101394 (October 23, 2023).

Mechanism and design of organic afterglow luminescent probes for cancer theranostics

Organic afterglow luminescent probes (OALPs), characterized by their long-lasting luminescence after irradiation (by light, ultrasound, or X-rays) cessation, are pivotal tools in autofluorescence-free optical imaging. They exhibit ultra-low background noise interference, enhancing imaging sensitivity and ensuring clearer, more reliable imaging results. Moreover, they offer deeper tissue penetration compared to traditional optical imaging modalities, providing various information from deep tissues. Recently developed sonoafterglow and radioafterglow further enhance tissue penetration depth. This review outlines 2 design approaches for OALPs: coencapsulation and conjugation, which are derived from their luminescent mechanism. Guided by these strategies, researchers have designed 3 types of OALPs: near-infrared OALPs, responsive OALPs, and ratiometric OALPs. Additionally, we also provided examples of how OALPs are integrated with therapy and applied in the field of cancer theranostics. Finally, we discuss certain challenges encountered in the advancement of the next generation of OALPs, aiming to broaden their scope of applications.

Single-Domain Antibodies as Antibody-Drug Conjugates: From Promise to Practice-A Systematic Review.

Antibody-drug conjugates (ADCs) represent potent cancer therapies that deliver highly toxic drugs to tumor cells precisely, thus allowing for targeted treatment and significantly reducing off-target effects. Despite their effectiveness, ADCs can face limitations due to acquired resistance and potential side effects. This study focuses on advances in various ADC components to improve both the efficacy and safety of these agents, and includes the analysis of several novel ADC formats. This work assesses whether the unique features of VHHs-such as their small size, enhanced tissue penetration, stability, and cost-effectiveness-make them a viable alternative to conventional antibodies for ADCs and reviews their current status in ADC development. Following PRISMA guidelines, this study focused on VHHs as components of ADCs, examining advancements and prospects from 1 January 2014 to 30 June 2024. Searches were conducted in PubMed, Cochrane Library, ScienceDirect and LILACS using specific terms related to ADCs and single-domain antibodies. Retrieved articles were rigorously evaluated, excluding duplicates and non-qualifying studies. The selected peer-reviewed articles were analyzed for quality and synthesized to highlight advancements, methods, payloads, and future directions in ADC research. VHHs offer significant advantages for drug conjugation over conventional antibodies due to their smaller size and structure, which enhance tissue penetration and enable access to previously inaccessible epitopes. Their superior stability, solubility, and manufacturability facilitate cost-effective production and expand the range of targetable antigens. Additionally, some VHHs can naturally cross the blood-brain barrier or be easily modified to favor their penetration, making them promising for targeting brain tumors and metastases. Although no VHH-drug conjugates (nADC or nanoADC) are currently in the clinical arena, preclinical studies have explored various conjugation methods and linkers. While ADCs are transforming cancer treatment, their unique mechanisms and associated toxicities challenge traditional views on bioavailability and vary with different tumor types. Severe toxicities, often linked to compound instability, off-target effects, and nonspecific blood cell interactions, highlight the need for better understanding. Conversely, the rapid distribution, tumor penetration, and clearance of VHHs could be advantageous, potentially reducing toxicity by minimizing prolonged exposure. These attributes make single-domain antibodies strong candidates for the next generation of ADCs, potentially enhancing both efficacy and safety.

Amidoxime-based radio-microspheres for Internal Irradiation combined with a checkpoint-blocking nanobody boost antitumor immunity

Trans-arterial radioembolization (TARE) therapy confronts significant technical challenges in the preparation of metal nuclide-labeled microsphere carriers, the development of stable and efficient radionuclide labeling strategies, and the ability to treat multiple small lesions in solid tumors. In this study, we synthesized 177Lu-labeled amidoxime-based polyvinyl alcohol microspheres (177Lu-PVA-g-PAO-Ms) using in situ synthesis of trunk compounds with chem-induced grafting polymerization. The resulting 177Lu-PVA-g-PAO-Ms showed excellent stability in radiolabeling and demonstrated high accumulation and prolonged retention in various preclinical rodent models, as observed through SPECT/CT imaging. The cumulative radioactivity uptake in the tumor reached as high as 12.27 %ID/g. In a mouse subcutaneous metastatic tumor model, we observed a significant abscopal effect of radioimmunotherapy after administering a combination of 177Lu-PVA-g-PAO-Ms and an anti-PD-L1 nanobody. These findings highlight the ability of PVA-g-PAO-Ms to chelate radionuclides efficiently and securely. Furthermore, when combined with nanobodies with enhanced tissue penetration capabilities, these microspheres hold great potential as innovative carrier platforms, offering new therapeutic strategies for integrating TARE with systemic immunotherapy.

A near-infrared fluorescent probe for differentiating cancer cells from normal cells and early diagnosis of liver cirrhosis

BackgroundCirrhosis represents the terminal stage of liver disease progression and timely intervention in a diseased liver can enhance the likelihood of recovery. Viscosity, a crucial parameter of the cellular microenvironment, is intricately linked to the advancement of cirrhosis. However, viscosity monitoring still faces significant challenges in achieving non-invasive and rapid early diagnosis of cirrhosis. Near-infrared (NIR) fluorescence imaging has the advantages of high sensitivity, non-destructive detection, and ignoring background fluorescence interference, plays an important role in diagnosing and treating various biological diseases. Hence, monitoring cellular viscosity changes with NIR fluorescence probe holds great significance in the early diagnosis of cirrhosis. ResultsIn this study, the NIR fluorescence probe based on the intramolecular charge transfer (TICT) mechanism was developed for imaging applications in mouse model of liver cirrhosis. A molecular rotor-type viscosity-responsive probe was synthesized by linking dioxanthracene groups via carbon-carbon double bonds. The probe demonstrated remarkable sensitivity, high selectivity and photostability, with its responsiveness to viscosity largely unaffected by factors such as polarity, pH, and interfering ions. The probe could effectively detect various drug-induced changes in cellular viscosity, enabling the differentiation between normal cells and cancerous cells. Furthermore, the enhanced tissue penetration capabilities of probe facilitated its successful application in mouse model of liver cirrhosis, allowing for the assessment of liver disease severity based on fluorescence intensity and providing a powerful tool for early diagnosis of cirrhosis. SignificanceA NIR viscosity-sensitive fluorescent probe was specifically designed to effectively monitor alterations in cellular and organ viscosity, which could advance the understanding of the biological characteristics of cancer and provide theoretical support for the early diagnosis of cirrhosis. Overall, this probe held immense potential in monitoring viscosity-related conditions, expanding the range of biomedical tools available.

Genetic targeting of the mouse immunoglobulin locus to permit the expression of heavy-chain only antibodies against viral antigens

Abstract Conventional antibodies are composed of two identical sets of heavy and light chains, forming a dimer. The CH1 domain of the antibody heavy chain is essential for the pairing of heavy and light chains. However, certain animals, such as camels and sharks, evolved to produce heavy-chain-only antibodies (HCAbs) by losing this crucial CH1 domain in some of their antibody heavy chain constant regions. These HCAbs boast unique physicochemical properties that confer significant advantages: their smaller size allows for improved access to target antigens, increased hydrophilicity, enhanced tissue penetration, and greater structural stability compared to standard antibodies. Our research has successfully established a mouse model that intrinsically produces HCAbs from the mouse's own immunoglobulin heavy chain locus. Our findings demonstrate that heavy-chain-only B cell receptors, once introduced, facilitate normal B cell development, promote germinal center formation, and enhance plasma cell differentiation relative to B cells producing conventional antibodies. These genetically modified mice were vaccinated with viral antigens, resulting in the production of HCAbs that specifically target the SARS-CoV-2 spike protein and the HIV-1 Env trimer. Through single-cell sequencing, we have identified unique nucleotide sequences of clonotypes; the HCAbs are being synthesized to assess their viral neutralization potential and antigen-binding affinity to highlight the efficacy of our model.

Modular design of bi- and multi-specific knob domain fusions.

The therapeutic potential of bispecific antibodies is becoming widely recognised, with over a hundred formats already described. For many applications, enhanced tissue penetration is sought, so bispecifics with low molecular weight may offer a route to enhanced potency. Here we report the design of bi- and tri-specific antibody-based constructs with molecular weights as low as 14.5 and 22 kDa respectively. Autonomous bovine ultra-long CDR H3 (knob domain peptide) modules have been engineered with artificial coiled-coil stalks derived from Sin Nombre orthohantavirus nucleocapsid protein and human Beclin-1, and joined in series to produce bi- and tri-specific antibody-based constructs with exceptionally low molecular weights. Knob domain peptides with coiled-coil stalks retain high, independent antigen binding affinity, exhibit exceptional levels of thermal stability, and can be readily joined head-to-tail yielding the smallest described multi-specific antibody format. The resulting constructs are able to bind simultaneously to all their targets with no interference. Compared to existing bispecific formats, the reduced molecular weight of the knob domain fusions may enable enhanced tissue penetration and facilitate binding to cryptic epitopes that are inaccessible to conventional antibodies. Furthermore, they can be easily produced at high yield as recombinant products and are free from the heavy-light chain mispairing issue. Taken together, our approach offers an efficient route to modular construction of minimalistic bi- and multi-specifics, thereby further broadening the therapeutic scope for knob domain peptides.

Fused Azulenyl Squaraine Derivatives Improve Phototheranostics in the Second Near‐Infrared Window by Concentrating Excited State Energy on Non‐Radiative Decay Pathways

AbstractThe second near‐infrared (NIR‐II) theranostics offer new opportunities for precise disease phototheranostic due to the enhanced tissue penetration and higher maximum permissible exposure of NIR‐II light. However, traditional regimens lacking effective NIR‐II absorption and uncontrollable excited‐state energy decay pathways often result in insufficient theranostic outcomes. Herein a phototheranostic nano‐agent (PS‐1 NPs) based on azulenyl squaraine derivatives with a strong NIR‐II absorption band centered at 1092 nm is reported, allowing almost all absorbed excitation energy to dissipate through non‐radiative decay pathways, leading to high photothermal conversion efficiency (90.98 %) and strong photoacoustic response. Both in vitro and in vivo photoacoustic/photothermal therapy results demonstrate enhanced deep tissue cancer theranostic performance of PS‐1 NPs. Even in the 5 mm deep‐seated tumor model, PS‐1 NPs demonstrated a satisfactory anti‐tumor effect in photoacoustic imaging‐guided photothermal therapy. Moreover, for the human extracted tooth root canal infection model, the synergistic outcomes of the photothermal effect of PS‐1 NPs and 0.5 % NaClO solution resulted in therapeutic efficacy comparable to the clinical gold standard irrigation agent 5.25 % NaClO, opening up possibilities for the expansion of NIR‐II theranostic agents in oral medicine.

Fused Azulenyl Squaraine Derivatives Improve Phototheranostics in the Second Near-Infrared Window by Concentrating Excited State Energy on Non-Radiative Decay Pathways.

The second near-infrared (NIR-II) theranostics offer new opportunities for precise disease phototheranostic due to the enhanced tissue penetration and higher maximum permissible exposure of NIR-II light. However, traditional regimens lacking effective NIR-II absorption and uncontrollable excited-state energy decay pathways often result in insufficient theranostic outcomes. Herein a phototheranostic nano-agent (PS-1 NPs) based on azulenyl squaraine derivatives with a strong NIR-II absorption band centered at 1092 nm is reported, allowing almost all absorbed excitation energy to dissipate through non-radiative decay pathways, leading to high photothermal conversion efficiency (90.98 %) and strong photoacoustic response. Both in vitro and in vivo photoacoustic/photothermal therapy results demonstrate enhanced deep tissue cancer theranostic performance of PS-1 NPs. Even in the 5 mm deep-seated tumor model, PS-1 NPs demonstrated a satisfactory anti-tumor effect in photoacoustic imaging-guided photothermal therapy. Moreover, for the human extracted tooth root canal infection model, the synergistic outcomes of the photothermal effect of PS-1 NPs and 0.5 % NaClO solution resulted in therapeutic efficacy comparable to the clinical gold standard irrigation agent 5.25 % NaClO, opening up possibilities for the expansion of NIR-II theranostic agents in oral medicine.

Abstract 485: Cancer killing effect of ultrasound-responsive mechanophore nanoparticles

Abstract Radiotherapy, a mainstay in cancer treatment, often inadvertently damages healthy tissues while targeting malignancies with free radicals. As an alternative, Photodynamic Therapy (PDT) employs non-ionizing photons to generate reactive oxygen species (ROS) in tumors, offering precise targeting with minimal long-term effects. However, its efficacy is constrained to superficial tumors due to the limited penetration of light. Sonodynamic Therapy (SDT), an evolution of PDT, uses ultrasound to enhance tissue penetration while maintaining its non-invasive nature. Initial SDT studies suggest that ultrasound can activate PDT's photosensitizers to produce ROS, offering a potential pathway for tumor eradication. Nevertheless, the principal mechanisms of ROS generation in SDT, namely pyrolysis and sonoluminescence, raise concerns about potential tissue injury. In our research, we introduce an innovative approach employing mechanophores into nanoparticles. Mechanophores, molecular units within polymers sensitive to mechanical stress, undergo transformations under such conditions, including the release of small molecules or free radicals. We have developed injectable nano-sized mechanophore nanoparticles, designed to respond to high-frequency ultrasound (>100 kHz) more efficiently and with reduced energy requirements. This study focuses on nano-engineering the echogenicity of these mechanophore nanoparticles to enhance ROS generation. When agitated with focused ultrasound (FUS), these nanoparticles successfully induced ROS, leading to significant cell death, a result not observed with FUS alone in the absence of nanoparticles. In vivo experiments using mouse orthotopic cancer models demonstrated these nanoparticles' ability to inhibit tumor growth effectively. Under biocompatible ultrasound conditions, the nanoparticles cause effective cancer cell eradication with minimal impact on surrounding healthy tissues. Our findings not only introduce a novel approach to cancer treatment but also pave the way for broader applications of mechanophore nanoparticles in biomedicine. This study underscores the potential of ultrasound-activatable mechanophore nanoparticles as a versatile, effective, and safe option for cancer therapy. Citation Format: Jian Wang, Shensheng Zhao, Junxi Yi, Yunyan Sun, Megha Agrawal, King Li, Jeffrey S. Moore, Michael Oelze, Yun-Sheng Chen. Cancer killing effect of ultrasound-responsive mechanophore nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 485.

Development of nanobodies specific to clumping factors A of Staphylococcus aureus by yeast surface display

The Staphylococcus aureus clumping factor A (ClfA) is a fibrinogen (Fg) binding protein that plays an important role in the clumping of S. aureus in blood plasma. The current anti-infective approaches targeting ClfA are mainly based on monoclonal antibodies but showed less impressive efficacy for clinical applications. Nanobodies offer advantages in enhanced tissue penetration and a propensity to bind small epitopes. However, there is no report on generating specific nanobodies for ClfA. Here, we constructed a synthetic nanobody library based on yeast surface display to isolate nanobodies against the Fg binding domain ClfA221–550. We firstly obtained a primary nanobody directed to ClfA221–550, and then employed error-prone mutagenesis to enhance its binding affinity. Finally, 18 variants were isolated with high affinities (EC50, 1.1 ± 0.1 nM to 4.8 ± 0.3 nM), in which CNb1 presented the highest inhibition efficiency in the adhesion of S. aureus to fibrinogen. Moreover, structural simulation analysis indicated that the epitope for CNb1 partially overlapped with the binding sites for fibrinogen, thus inhibiting ClfA binding to Fg. Overall, these results indicated that the specific nanobodies generated here could prevent the adhesion of S. aureus to fibrinogen, suggesting their potential capacities in the control of S. aureus infections.

Recent Advances in Organometallic NIR Iridium(III) Complexes for Detection and Therapy.

Iridium(III) complexes are emerging as a promising tool in the area of detection and therapy due to their prominent photophysical properties, including higher photostability, tunable phosphorescence emission, long-lasting phosphorescence, and high quantum yields. In recent years, much effort has been devoted to develop novel near-infrared (NIR) iridium(III) complexes to improve signal-to-noise ratio and enhance tissue penetration. In this review, we summarize different classes of organometallic NIR iridium(III) complexes for detection and therapy, including cyclometalated ligand-enabled NIR iridium(III) complexes and NIR-dye-conjugated iridium(III) complexes. Moreover, the prospects and challenges for organometallic NIR iridium(III) complexes for targeted detection and therapy are discussed.

Lipid-based nanocarriers: an attractive approach for rheumatoid arthritis management.

Lipid nanoparticles (LNPs) have emerged as transformative tools in modern drug delivery, offering unparalleled potential in enhancing the efficacy and safety of various therapeutics. In the context of rheumatoid arthritis (RA), a disabling autoimmune disorder characterized by chronic inflammation, joint damage, and limited patient mobility, LNPs hold significant promise for revolutionizing treatment strategies. LNPs offer several advantages over traditional drug delivery systems, including improved pharmacokinetics, enhanced tissue penetration, and reduced systemic toxicity. This article concisely summarizes the pathogenesis of RA, its associated risk factors, and therapeutic techniques and their challenges. Additionally, it highlights the noteworthy advancements made in managing RA through LNPs, including liposomes, niosomes, bilosomes, cubosomes, spanlastics, ethosomes, solid lipid nanoparticles, lipid micelles, lipid nanocapsules, nanostructured lipid carriers, etc. It also delves into the specific functional attributes of these nanocarrier systems, focusing on their role in treating and monitoring RA.

Penetration enhancers strengthen tough hydrogel bioadhesion and modulate locoregional drug delivery.

The human body possesses natural barriers, such as skin and mucosa, which limit the effective delivery of therapeutics and integration of medical devices to target tissues. Various strategies have been deployed to breach these barriers mechanically, chemically, or electronically. The development of various penetration enhancers (PEs) offers a promising solution due to their ability to increase tissue permeability using readily available reagents. However, existing PE-mediated delivery methods often rely on weak gel or liquid drug formulations, which are not ideal for sustained local delivery. Hydrogel adhesives that can seamlessly interface biological tissues with controlled drug delivery could potentially resolve these issues. Here, we demonstrate that tough adhesion between drug-laden hydrogels and biological tissue (e.g. skin and tumours) can lead to effective local delivery of drugs deep into targeted tissues by leveraging the enhanced tissue penetration mediated by PEs. The drug release profile of the hydrogel adhesives can be fine-tuned by further engineering the nanocomposite hydrogel matrix to elute chemotherapeutics from 2 weeks to 2 months. Using a 3D tumour spheroid model, we demonstrated that PEs increased the cancer-killing effectiveness of doxorubicin by facilitating its delivery into tumour microtissues. Therefore, the proposed tough bioadhesion and drug delivery strategy modulated by PEs holds promise as a platform technique to develop next-generation wearable and implantable devices for cancer management and regenerative medicine.