Deep Tissue Penetration Research Articles

Acute Invasive Pulmonary Aspergillosis: Clinical Presentation and Treatment.

Among all clinical manifestations of pulmonary aspergillosis, invasive pulmonary aspergillosis (IPA) is the most acute presentation. IPA is caused by Aspergillus hyphae invading the pulmonary tissue, causing either tracheobronchitis and/or bronchopneumonia. The degree of fungal invasion into the respiratory tissue can be seen as a spectrum, going from colonization to deep tissue penetration with angio-invasion, and largely depends on the host's immune status. Patients with prolonged, severe neutropenia and patients with graft-versus-host disease are at particularly high risk. However, IPA also occurs in other groups of immunocompromised and nonimmunocompromised patients, like solid organ transplant recipients or critically ill patients with severe viral disease. While a diagnosis of proven IPA is challenging and often warranted by safety and feasibility, physicians must rely on a combination of clinical, radiological, and mycological features to assess the likelihood for the presence of IPA. Triazoles are the first-choice regimen, and the choice of the drug should be made on an individual basis. Adjunctive therapy such as immunomodulatory treatment should also be taken into account. Despite an improving and evolving diagnostic and therapeutic armamentarium, the burden and mortality of IPA still remains high. This review aims to give a comprehensive and didactic overview of the current knowledge and best practices regarding the epidemiology, clinical presentation, diagnosis, and treatment of acute IPA.

Cathepsin B Responsive Peptide-Purpurin Conjugates Assembly-Initiated in Situ Self-Aggregation for Cancer Sonotheranostics.

Sonodynamic therapy (SDT) was hampered by the sonosensitizers with low bioavailability, tumor accumulation, and therapeutic efficiency. In situ responsive sonosensitizer self-assembly strategy may provide a promising route for cancer sonotheranositics. Herein, an intelligent sonotheranostic peptide-purpurin conjugate (P18-P) is developed that can self-assemble into supramolecular structures via self-aggregation triggered by rich enzyme cathepsin B (CTSB). After intravenous injection, the versatile probe could achieve deep tissue penetration because of the penetration sequence of P18-P. More importantly, CTSB-triggered self-assembly strongly prolonged retention time, amplified photoacoustic imaging signal for sensitive CTSB detection, and boosted reactive oxygen species for advanced SDT, evoking specific CTSB responsive sonotheranostics. This peptide-purpurin conjugate may serve as an efficient sonotheranostic platform for the early diagnosis of CTSB activity and effective cancer therapy.

An NIR-II Excitable AIE Small Molecule with Multimodal Phototheranostic Features for Orthotopic Breast Cancer Treatment.

One-for-all phototheranostics, referring to a single component simultaneously exhibiting multiple optical imaging and therapeutic modalities, has attracted significant attention due to its excellent performance in cancer treatment. Benefitting from the superiority in balancing the diverse competing energy dissipation pathways, aggregation-induced emission luminogens (AIEgens) are proven to be ideal templates for constructing one-for-all multimodal phototheranostic agents. However, to this knowledge, the all-round AIEgens that can be triggered by a second near-infrared (NIR-II, 1000-1700nm) light have not been reported. Given the deep tissue penetration and high maximum permissible exposure of the NIR-II excitation light, herein, this work reports for the first time an NIR-II laser excitable AIE small molecule (named BETT-2) with multimodal phototheranostic features by taking full use of the advantage of AIEgens in single molecule-facilitated versatility as well as synchronously maximizing the molecular donor-acceptor strength and conformational distortion. As formulated into nanoparticles (NPs), the high performance of BETT-2 NPs in NIR-II light-driven fluorescence-photoacoustic-photothermal trimodal imaging-guided photodynamic-photothermal synergistic therapy of orthotopic mouse breast tumors is fully demonstrated by the systematic in vitro and in vivo evaluations. This work offers valuable insights for developing NIR-II laser activatable one-for-all phototheranostic systems.

Stimuli‐Responsive Nanocarriers for Transcytosis‐Based Cancer Drug Delivery

Significant challenges persist in enhancing the delivery efficiency of tumor nanomedicines, predominantly due to the difficulty of successfully surpassing pathophysiological barriers. Enhancing tumor penetration of nanomedicines in such conditions represents a pivotal goal in advancing anticancer nanotherapeutics. Transcytosis emerges as a promising solution in this context, addressing the limitations of passive drug delivery. By harnessing diverse stimuli to induce transcytosis, nanocarriers can achieve precise drug delivery and deep tumor penetration, resulting in high therapeutic efficacy and reduced systemic exposure to the therapeutic compound. This review briefly examines various stimuli‐responsive nanosystems and offers an overview and outlook on the development of stimuli‐responsive nanocarriers for transcytosis‐based cancer drug delivery, aiming to provide informative insights for the design of nanomedicines capable of deep tissue penetration and enhanced therapeutic efficacy.

2, 1, 3‐Benzothiadiazole Derivative Small Molecule Fluorophores for NIR‐II Bioimaging

AbstractSecond near‐infrared (NIR‐II) bioimaging technology shows broad application prospects in the field of biomedical due to its significant superiority in deep tissue penetration and high signal‐to‐background ratio. Among them, organic small molecule fluorophores have received progressively more consideration due to their low biotoxicity, high biocompatibility, rapid clearance, and good modification properties. As the key acceptor core, 2, 1, 3‐benzothiadiazole (BTD) derivative plays an essential role in the construction of donor‐acceptor‐donor type NIR‐II fluorophores. This mini‐review summarizes the research development of NIR‐II small molecule fluorophores based on BTD derivatives in the field of bioimaging, focusing on molecular design and photophysical properties, and introduces a part of the applications in the biological field. Furthermore, the challenges of BTD‐based NIR‐II fluorophores in the future development and application are discussed .

A multifunctional protein pre-coated metal-organic framework for targeted delivery with deep tissue penetration.

Targeted drug delivery using metal-organic frameworks (MOFs) has shown significant progress. However, the tumor microenvironment (TME) impedes efficient MOF particle transfer into tumor cells. To tackle this issue, we pre-coated nano-sized MOF-808 particles with multifunctional proteins: glutathione S-transferase (GST)-affibody (Afb) and collagenase, aiming to navigate the TME more effectively. The surface of MOF-808 particles is coated with GST-Afb-a fusion protein of GST and human epidermal growth factor receptor 2 (HER2) Afb or epidermal growth factor receptor (EGFR) Afb which has target affinity. We also added collagenase enzymes capable of breaking down collagen in the extracellular matrix (ECM) through supramolecular conjugation, all without chemical modification. By stabilizing these proteins on the surface, GST-Afb mitigate biomolecule absorption, facilitating specific tumor cell targeting. Simultaneously, collagenase degrades the ECM in the TME, enabling deep tissue penetration of MOF particles. Our resulting system, termed collagenase-GST-Afb-MOF-808 (Col-Afb-M808), minimizes undesired interactions between MOF particles and external biological proteins. It not only induces cell death through Afb-mediated cell-specific targeting, but also showcases advanced cellular internalization in 3D multicellular spheroid cancer models, with effective deep tissue penetration. The therapeutic efficacy of Col-Afb-M808 was further assessed via in vivo imaging and evaluation of tumor inhibition following injection of IR-780 loaded Col-Afb-M808 in 4T1tumor-bearing nude mice. This study offers key insights into the regulation of the multifunctional protein-adhesive surface of MOF particles, paving the way for the designing even more effective targeted drug delivery systems with nano-sized MOF particles.

A rapid investigation of near-infrared (NIR) fluorescent switch-on probes for detection and in cellulo tracking of G-quadruplex and double-stranded DNA.

This review provides a comprehensive overview of the recent advancements in Near Infrared (NIR) fluorescence switch-on probes designed for the detection and in cellulo tracking of G-quadruplex and double-stranded DNA (dsDNA). G-quadruplexes, non-canonical DNA structures, play pivotal roles in regulating various biological processes, making them critical targets for therapeutic and diagnostic applications. The unique properties of NIR fluorescence probes, such as deep tissue penetration, minimal photodamage, and low autofluorescence background, offer significant advantages for bioimaging. We critically analyze the design strategies, photophysical properties, and binding mechanisms of various NIR fluorescence switch-on probes. Additionally, we discuss their efficacy and specificity in identifying G-quadruplexes and dsDNA within cellular environments. Key challenges and future directions for improving the sensitivity, selectivity, and biocompatibility of these probes are also highlighted. This review aims to underscore the potential of NIR fluorescence probes in advancing our understanding of DNA dynamics and their applications in biomedical research.

The application of ultrasound for skin and appendage regeneration: A comprehensive review

<p>Ultrasound, an exogenous physical stimulus, has important application prospects in the field of regenerative medicine, especially in skin regeneration, due to its safety, controllability, and deep penetration depth. This review examines the potential of ultrasound therapy in promoting skin regeneration by exploring its effects on skin cells, mechanisms of action in regeneration, and responsive materials. With its deep tissue penetration and excellent biocompatibility, ultrasound presents an attractive option for enhancing wound healing and skin regeneration. By discussing current challenges and future prospects, this review offers insights to guide the development of innovative ultrasound-based approaches for clinical wound treatment.</p>

Molecular engineering to design a bright near-infrared red photosensitizer: cellular bioimaging and phototherapy.

Near-infrared red (NIR) fluorescence imaging guide phototherapeutic therapy (PDT) has the advantages of deep tissue penetration, real-time monitoring of drug treatment and disease, little damage to normal tissue, low cytotoxicity and almost no side effects, and thus, it is attracting increasing research attention and is expected to show promising potential for clinical tumor treatment. The photosensitizer (PS), light source and oxygen are the three basic and important factors to construct PDT technology, and highly efficient PSs are still being passionately pursued because they determine the PDT efficiency. Ideal PSs should have properties such as good biocompatibility, deep tissue penetration, and highly efficient reactive oxygen species (ROS) generation despite the hypoxic environment. Therefore, pure organic type I PSs with NIR fluorescence have been receiving increasing attention due to their deep penetration and hypoxia resistance. However, reported NIR-active type I PSs usually require complex synthetic procedures, which presents a challenge for mass production. In this research work, based on the molecular design ideas of introducing the heavy atom effect and intramolecular charge transfer, we prepared three NIR-active type I PSs (TNZ, TNZBr, and TNZCHO) using a very simple method with one or two synthetic steps. Clear characterizations of photophysical properties, ROS performance tests, and fluorescent imaging of human umbilical vein endothelial (HUVE) cells and PDT treatment of HepG2 cells were carried out. The results revealed that the heavy atom and intramolecular charge transfer (ICT) effects could obviously enhance the ROS efficiency, and both PSs produce only type I ROS without any type II ROS (1O2) generation. The good NIR fluorescence brightness and type I ROS efficiency ensure satisfactory bioimaging and PDT outcomes. This research provides the possibility of preparing NIR-active type I PSs via mass production.

Defect-rich sonosensitizers based on CeO2 with Schottky heterojunctions for boosting sonodynamic/chemodynamic synergistic therapy.

Sonodynamic therapy (SDT) has been recognized as a promising treatment for cancer due to its advantages of superior specificity, non-invasiveness, and deep tissue penetration. However, the antitumor effect of SDT remains restricted by the limited generation of reactive oxygen species (ROS) due to the lack of highly efficient sonosensitizers. In this work, we developed the novel sonosensitizer Pt/CeO2-xSx by constructing oxygen defects through S doping and Pt loading in situ. Large amounts of oxygen defects have been obtained by S doping, endowing Pt/CeO2-xSx with the ability to suppress electron-hole recombination, further promoting ROS production. Moreover, the introduction of Pt nanoparticles can not only produce oxygen in situ for relieving hypoxia but also form a Schottky heterojunction with CeO2-xSx for further inhibiting electron-hole recombination. In addition, Pt/CeO2-xSx could effectively deplete overexpressed glutathione (GSH) via redox reactions, amplifying oxidative stress in the tumor microenvironment (TME). Combined with the excellent POD-mimetic activity, Pt/CeO2-xSx can achieve highly efficient synergistic therapy of SDT and chemodynamic therapy (CDT). All these findings demonstrated that Pt/CeO2-xSx has great potential for cancer therapy, and this work provides a promising direction for designing and constructing efficient sonosensitizers.

A novel NIR fluorescent probe for copper(ii) imaging in Parkinson's disease mouse brain.

Abnormal copper ion (Cu2+) levels are considered to be one of the pathological factors of Parkinson's disease (PD), but the internal relationship between Cu2+ and PD progression remains elusive. Visualizing Cu2+ in the brain will be pivotal for comprehending the underlying pathophysiological processes of PD. In this work, a near-infrared (NIR) fluorescent probe, DDAO-Cu, capable of detecting Cu2+ with exceptional sensitivity (about 1.8 nM of detection limit) and selectivity, rapid response (<3 min), and deep tissue penetration, was designed for quantification and visualization of the Cu2+ level. It could detect not only Cu2+ in cells but also the changes in the Cu2+ level in the rotenone-induced cell and zebrafish PD models. Moreover, DDAO-Cu can cross the blood-brain barrier to image Cu2+ in the brain of PD model mice. The imaging result showed a significant increase in Cu2+ levels in brain regions of PD model mice, including the cerebral cortex, hippocampus, and striatum. Meanwhile, Cu2+ levels in the substantia nigra region were significantly reduced in PD model mice. It revealed the nuanced relationship of Cu2+ levels in different brain regions in the disease and indicated the pathological complexity of PD. Overall, DDAO-Cu represents a novel and practical tool for investigating Cu2+-related physiological and pathological processes underlying Parkinson's disease.

Nanotechnology-enabled sonodynamic therapy against malignant tumors.

Sonodynamic therapy (SDT) is an emerging approach for malignant tumor treatment, offering high precision, deep tissue penetration, and minimal side effects. The rapid advancements in nanotechnology, particularly in cancer treatment, have enhanced the efficacy and targeting specificity of SDT. Combining sonodynamic therapy with nanotechnology offers a promising direction for future cancer treatments. In this review, we first systematically discussed the anti-tumor mechanism of SDT and then summarized the common nanotechnology-related sonosensitizers and their recent applications. Subsequently, nanotechnology-related therapies derived using the SDT mechanism were elaborated. Finally, the role of nanomaterials in SDT combined therapy was also introduced.

BODIPY-based photocages: rational design and their biomedical application.

Photocages, also known as photoactivated protective groups (PPGs), have been utilized to achieve controlled release of target molecules in a non-invasive and spatiotemporal manner. In the past decade, BODIPY fluorophores, a well-established class of fluorescent dyes, have emerged as a novel type of photoactivated protective group capable of efficiently releasing cargo species upon irradiation. This is due to their exceptional properties, including high molar absorption coefficients, resistance to photochemical and thermal degradation, multiple modification sites, favorable uncaging quantum yields, and highly adjustable spectral properties. Compared to traditional photocages that mainly absorb UV light, BODIPY-based photocages that absorb visible/near-infrared (Vis/NIR) light offer advantages such as deeper tissue penetration and reduced bio-autofluorescence, making them highly suitable for various biomedical applications. Consequently, different types of photoactivated protective groups based on the BODIPY skeleton have been established. This highlight provides a comprehensive overview of the strategies employed to construct BODIPY photocages by substituting leaving groups at different positions within the BODIPY fluorophore, including the meso-methyl position, boron position, 2,6-position, and 3,5-position. Furthermore, the application of these BODIPY photocages in biomedical fields, such as fluorescence imaging and controlled release of active species, is discussed.

Near-IR nanolignin sensitizers based on pyrene-conjugated chlorin and bacteriochlorin for ROS generation, DNA intercalation and bioimaging.

Near-infrared (NIR) fluorescent agents are extensively used for biomedical imaging due to their ability for deep tissue penetration. Tetrapyrrole-based photosensitizers are promising candidates in this regard. Further, the extended conjugation of such macromolecules with chromophores can enhance their fluorescence efficiency and DNA intercalation ability. Herein, pyrene-conjugated NIR photosensitizers, such as chlorin (PyChl) and bacteriochlorin (PyBac), were synthesized from the corresponding pyrene-porphyrin (PyP). The correlation between the theoretical and experimental optical properties (absorption and fluorescence spectroscopy results) was determined using the DFT/TD-DFT computational approach. Next, studies on the photophysical properties, reactive oxygen species (ROS) production, and DNA binding were conducted on these macrocycles to study the effect of pyrene conjugation on the pyrrolic ring. Furthermore, each photosensitizer was loaded into lignin nanoparticles (LNPs) using the solvent-antisolvent method to accomplish fluorescence-guided imaging. The developed near-IR chlorin- and bacteriochlorin-doped lignin nanocarriers (PyChl-LNCs and PyBac-LNCs) exhibited significant in vitro singlet oxygen generation upon red LED light exposure. Moreover, these macrocycle-loaded nanolignin sensitizers showed good fluorescence-guided bioimaging with fungal cells (Candida albicans). Further, the nanoprobes exhibited pH-dependent release profiles for biological applications. These nanolignin sensitizers demonstrated promising potential to be utilized in near-IR image-guided photodynamic therapy.

Targeting superficial cancers with gold nanoparticles: a review of current research.

Superficial cancers typically refer to cancers confined to the surface layers of tissue. Low-targeting therapies or side effects prompt exploration of novel therapeutic approaches. Gold nanoparticles (AuNPs), due to their unique optical properties, serve as effective photosensitizers, enabling tumor ablation through photothermal therapy (PTT). PTT induced by AuNPs can be achieved through light sources externally applied to the skin. Near-infrared radiation is the main light candidate due to its deep tissue penetration capability. This review explores recent advancements in AuNP-based PTT for superficial cancers, specifically breast, head and neck, thyroid, bladder and prostate cancers. Additionally, challenges and future directions in utilizing AuNPs for cancer treatment are discussed, emphasizing the importance of balancing efficacy with safety in clinical applications.

Light-responsive functional nanomaterials as pioneering therapeutics: a paradigm shift to combat age-related disorders.

Aging, marked by dysregulated cellular systems, gives rise to a spectrum of age-related disorders, including neurodegeneration, atherosclerosis, immunosenescence, and musculoskeletal issues. These conditions contribute significantly to the global disease burden, posing challenges to health span and economic resources. Current therapeutic approaches, although diverse in mechanism, often fall short in targeting the underlying cellular pathologies. They fail to address the issues compounded by altered pharmacokinetics in the elderly. Nanotechnology emerges as a transformative solution, offering tissue-specific targeted therapies through nanoparticles. Functional nanomaterials (FNMs) respond to internal or external stimuli, with light-responsive nanomaterials gaining prominence. Harnessing the benefits of deep tissue penetration and ease of manipulation particularly in the near-infrared spectrum, light-responsive FNMs present innovative strategies for age-related comorbidities. This review comprehensively summarizes the potential of light-responsive FNM-based approaches for targeting cellular environments in age-related disorders, and also emphasizes the advantages over traditional treatment modalities. Specifically, it focuses on the development of various classes of light-responsive functional nanomaterials including plasmonic nanomaterials, nanomaterials as carriers, upconversion nanomaterials, 2D nanomaterials, transition metal oxide and dichalcogenide nanomaterials and carbon-based nanomaterials against age related diseases. We foresee that such advanced developments in the field of nanotechnology could provide a new hope for clinical diagnosis and treatment of age-related disorders.

Intracellular delivery and deep tissue penetration of nucleoside triphosphates using photocleavable covalently bound dendritic polycations.

Nucleoside triphosphates (NTPs) are essential in various biological processes. Cellular or even organismal controlled delivery of NTPs would be highly desirable, yet in cellulo and in vivo applications are hampered owing to their negative charge leading to cell impermeability. NTP transporters or NTP prodrugs have been developed, but a spatial and temporal control of the release of the investigated molecules remains challenging with these strategies. Herein, we describe a general approach to enable intracellular delivery of NTPs using covalently bound dendritic polycations, which are derived from PAMAM dendrons and their guanidinium derivatives. By design, these modifications are fully removable through attachment on a photocage, ready to deliver the native NTP upon irradiation enabling spatiotemporal control over nucleotide release. We study the intracellular distribution of the compounds depending on the linker and dendron generation as well as side chain modifications. Importantly, as the polycation is bound covalently, these molecules can also penetrate deeply into the tissue of living organisms, such as zebrafish.

Sound Out the Deep Clarity: Super-resolution Photoacoustic Imaging at Depths.

Photoacoustic imaging (PAI), also known as optoacoustic imaging, is a hybrid imaging modality that combines the rich contrast of optical imaging with the deep penetration of ultrasound imaging. Over the past decade, PAI has been increasingly utilized in biomedical studies, providing high-resolution high-contrast images of endogenous and exogenous chromophores in various fundamental and clinical research. However, PAI faces challenges in achieving high imaging resolution and deep tissue penetration simultaneously, limited by the optical and acoustic interactions with tissues. Overcoming these limitations is crucial for maximizing the potential of PAI for biomedical applications. Recent advances in super-resolution PAI have opened new possibilities for achieving high imaging resolution at greater depths. This review provides a comprehensive summary of these promising strategies, highlights their representative applications, envisions the potential future directions, and discusses the broader impact on biomedical imaging.

Sorafenib and tetrakis (4-carboxyphenyl) porphyrin assembled nanoparticles for synergistic targeted chemotherapy and sonodynamic therapy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is characterized by a high degree of malignancy and mortality. Sorafenib (SOR), a multi-kinase inhibitor, is clinically used in the treatment of HCC. However, SOR suffers from serious side effects and drug resistance. The development of novel therapeutic strategies for HCC therapy is urgently needed. Sonodynamic therapy (SDT) has unique advantages in treating deep tumors due to the merits of deep tissue penetration, low side effects, and the absence of drug resistance. Here, we developed multifunctional nanoparticles (NPs) termed SOR-TCPP@PEG-FA by assembling SOR, tetrakis (4-carboxyphenyl) porphyrin (TCPP), and folic acid (FA)-modified DSPE-PEG. The FA group enhances the tumor targeting capability of these NPs, while TCPP generates ROS under ultrasound (US) irradiation, which are toxic to tumor cells, and SOR with chemotherapeutic effects is released, thus realizing the synergistic SDT and chemotherapy of tumors.

Review of NIR-responsive ''Smart'' carriers for photothermal chemotherapy.

This review focuses on the versatile applications of near-infrared (NIR)-responsive smart carriers in biomedical applications, particularly drug delivery and photothermal chemotherapy. These carriers demonstrate multi-responsive theranostics capabilities, including pH-dependent drug release, targeted delivery of chemotherapeutics, heat-mediated drug release, and photothermal tumor damage. Biological samples are transparent to NIR light with a suitable wavelength, and therefore, NIR light is advantageous for deep-tissue penetration. It also generates sufficient heat in tissue samples, which is beneficial for on-demand NIR-responsive drug delivery in vivo systems. The development of biocompatible materials with sufficient NIR light absorption properties and drug-carrying functionality has shown tremendous growth in the last five years. Thus, this review offers insights into the current research development of NIR-responsive materials with therapeutic potential and prospects aimed at overcoming challenges to improve the therapeutic efficacy and safety in the dynamic field of NIR-responsive drug delivery.