Liver Fibrosis—From Mechanisms of Injury to Modulation of Disease

The Transregional Collaborative Research Center “Organ Fibrosis: From Mechanisms of Injury to Modulation of Disease” (referred to as SFB/TRR57) was funded for 13 years (2009–2021) by the German Research Council (DFG). This consortium was hosted by the Medical Schools of the RWTH Aachen University and Bonn University in Germany. The SFB/TRR57 implemented combined basic and clinical research to achieve detailed knowledge in three selected key questions: (i) What are the relevant mechanisms and signal pathways required for initiating organ fibrosis? (ii) Which immunological mechanisms and molecules contribute to organ fibrosis? and (iii) How can organ fibrosis be modulated, e.g., by interventional strategies including imaging and pharmacological approaches? In this review we will summarize the liver-related key findings of this consortium gained within the last 12 years on these three aspects of liver fibrogenesis. We will highlight the role of cell death and cell cycle pathways as well as nutritional and iron-related mechanisms for liver fibrosis initiation. Moreover, we will define and characterize the major immune cell compartments relevant for liver fibrogenesis, and finally point to potential signaling pathways and pharmacological targets that turned out to be suitable to develop novel approaches for improved therapy and diagnosis of liver fibrosis. In summary, this review will provide a comprehensive overview about the knowledge on liver fibrogenesis and its potential therapy gained by the SFB/TRR57 consortium within the last decade. The kidney-related research results obtained by the same consortium are highlighted in an article published back-to-back in Frontiers in Medicine.

A “Double-Locked” and Enzyme/pH-Activated Theranostic Agent for Accurate Tumor Imaging and Therapy

Theranostic agents for concurrent cancer therapy and diagnosis have begun attracting attention as a promising modality. However, accurate imaging and identification remains a great challenge for theranostic agents. Here, we designed and synthesized a novel theranostic agent H6M based on the “double-locked” strategy by introducing an electron-withdrawing nitro group into 1-position of a pH-responsive 3-amino-β-carboline and further covalently linking the hydroxamic acid group, a zinc-binding group (ZBG), to the 3-position of β-carboline to obtain histone deacetylase (HDAC) inhibitory effect for combined HDAC-targeted therapy. We found that H6M can be specifically reduced under overexpressed nitroreductase (NTR) to produce H6AQ, which emits bright fluorescence at low pH. Notably, H6M demonstrated a selective fluorescence imaging via successive reactions with NTR (first “key”) and pH (second “key”), and precisely identified tumor margins with a high S/N ratio to guide tumor resection. Finally, H6M exerted robust HDAC1/cancer cell inhibitory activities compared with a known HDAC inhibitor SAHA. Therefore, the NTR/pH-activated theranostic agent provided a novel tool for precise diagnosis and efficient tumor therapy.

Multifunctional Platinum(IV) and Cyanine Dye-based Polyprodrug for Trimodal Imaging-Guided Chemo-Phototherapy

Imaging-guided chemo-phototherapy based on a single nanoplatform has a great significance to improve the efficiency of cancer therapy and diagnosis. However, high drugs content, no burst release and real-time tracking...

A Nano Approach to Formulate Photosensitizers for Photodynamic Therapy

: Conventional treatment modalities for tumors face a variety of pitfalls including non-specific interactions leading to multiple adverse effects. These adverse effects are being overcome through innovations that are highly intense and selective delivery of therapeutic agents. More recently, Photodynamic therapy (PDT) has gained its value over conventional chemo- and radiotherapies due to the use of photosensitizers (PS) with an illuminating light source. Photosensitizers have crossed three generations with Photofrin being the first clinically approved PS for PDT. Even though these PS have proved to have cytotoxic effects against tumor cells, they suffer the selective distribution and concentration into the tumor sites that are deeply localized. To overcome these disadvantages, nanoformulations are currently being employed due to their unmatched physicochemical and surface properties. These nanoformulations include the encapsulation of PS acting as a nanocarrier for the PS or the functionalization of PS onto the surface of nanoparticles. The design of such nanoformulations involved in PDT is critical and valuable to consider. Along with PDT, several multifunctional approaches are being uplifted in the current trend where combined therapy and diagnosis are of importance. Furthermore, targeted, selective and specific delivery of the PS-loaded nanoformulations with receptor-mediated endocytosis is of interest to achieve better internalization into the tumor site. ROS generation with the interaction of PS augments cell death mechanisms exhibited due to PDT leading to the immunogenic response that further results an adaptive immune memory which prevents recurrence of tumor metastasis. Therefore, this review concentrates on the mechanisms of PDT, examples of nanocarriers and nanoparticles that are employed in PDT, combined therapies, and theranostics with PDT. A step forward, molecular mechanisms of nano-based PDT agents in killing tumor sites and design considerations for better PDT outcomes have been discussed.

Recent Advances in Nanomaterials for Therapy and Diagnosis of Cardiovascular Disease

Cardiovascular diseases (CVDs) are among the world’s widely affected disorders, including ischemia and stroke. Acute Myocardial ischemia (AMI) is a deadly disease caused by irreversible damage to the left ventricular heart tissues. The thromboembolic plaque stops the oxygen supply to the main blood vessels and ventricles. During chronic inflammation, myocardial infarction and free radicals damage stable myocardium, smooth muscles cell, and epithelial cells caused by outer membrane loss and ventricular wall smoothing and dilation. Specially constructed scaffolds made of biological and nanoparticles have been created to shield the left ventricle from further injury and recover ischemic endothelial cells. Preclinical experiments have demonstrated that scaffolds containing growth factors and cells will regenerate ischemic tissue into a stable pericardium in good working order. Various medicinal approaches that treat cardiovascular disease conditions at different stages are discussed in this review article, with biomaterials receiving special attention. This review further addresses the manipulation and manufacturing of biomedical implantable devices using nanomedicine methods and drug delivery principles. The use of graphene and exosomal nanovesicle in cardiovascular therapeutics recently progressed in research studies.

Nanomaterials: Synthesis and Applications in Theranostics

Nanomaterials are endowed with unique features and essential properties suitable for employing in the field of nanomedicine. The nanomaterials can be classified as 0D, 1D, 2D, and 3D based on their dimensions. The nanomaterials can be malleable and ductile and they can be drawn into wires and sheets. Examples of nanomaterials are quantum dots (0D), nanorods, nanowires (1D), nanosheets (2D), and nanocubes (3D). These nanomaterials can be synthesized using top-down and bottom-up approaches. The achievements of 0D and 1D nanomaterials are used to detect trace heavy metal (e.g., Pb2+) and have higher sensitivity with the order of five as compared to conventional sensors. The achievements of 2D and 3D nanomaterials are used as diagnostic and therapeutic agents with multifunctional ability in imaging systems such as PET, SPECT, etc. These imaging modalities can be used to track the drug in living tissues. This review comprises the state-of-the-art of the different dimensions of the nanomaterials employed in theranostics. The nanomaterials with different dimensions have unique physicochemical properties that can be utilized for therapy and diagnosis. The multifunctional ability of the nanomaterials can have a distinct advantage that is used in the field of theranostics. Different dimensions of the nanomaterials would have more scope in the field of nanomedicine.

Development of Polymer-Based Nanoformulations for Glioblastoma Brain Cancer Therapy and Diagnosis: An Update

Brain cancers, mainly high-grade gliomas/glioblastoma, are characterized by uncontrolled proliferation and recurrence with an extremely poor prognosis. Despite various conventional treatment strategies, viz., resection, chemotherapy, and radiotherapy, the outcomes are still inefficient against glioblastoma. The blood–brain barrier is one of the major issues that affect the effective delivery of drugs to the brain for glioblastoma therapy. Various studies have been undergone in order to find novel therapeutic strategies for effective glioblastoma treatment. The advent of nanodiagnostics, i.e., imaging combined with therapies termed as nanotheranostics, can improve the therapeutic efficacy by determining the extent of tumour distribution prior to surgery as well as the response to a treatment regimen after surgery. Polymer nanoparticles gain tremendous attention due to their versatile nature for modification that allows precise targeting, diagnosis, and drug delivery to the brain with minimal adverse side effects. This review addresses the advancements of polymer nanoparticles in drug delivery, diagnosis, and therapy against brain cancer. The mechanisms of drug delivery to the brain of these systems and their future directions are also briefly discussed.

Advancement and Strategies for the Development of Peptide-Drug Conjugates: Pharmacokinetic Modulation, Role and Clinical Evidence Against Cancer Management

: Currently, many new treatment strategies are being used for the management of cancer. Among them, chemotherapy based on peptides has been of great interest due to the unique features of peptides. This review discusses the role of peptide and peptides analogues in the treatment of cancer, with special emphasis on their pharmacokinetic modulation and research progress. Low molecular weight, targeted drug delivery, enhanced permeability, etc., of the peptide-linked drug conjugates, lead to an increase in the effectiveness of cancer therapy. Various peptides have recently been developed as drugs and vaccines with an altered pharmacokinetic parameter which has subsequently been assessed in different phases of the clinical study. Peptides have made a great impact in the area of cancer therapy and diagnosis. Targeted chemotherapy and drug delivery techniques using peptides are emerging as excellent tools in minimizing problems with conventional chemotherapy. It can be concluded that new advances in using peptides to treat different types of cancer have been shown by different clinical studies indicating that peptides could be used as an ideal therapeutic method in treating cancer due to the novel advantages of peptides. The development of identifying and synthesizing novel peptides could provide a promising choice to patients with cancer.