A hepatocellular carcinoma model with and without parenchymal liver damage that integrates technical and pathophysiological advantages for therapy testing.

Hepatocellular Carcinoma (HCC) is the most common form of primary liver cancer, with cirrhosis being its strongest risk factor. Interestingly, an increasing number of HCC cases is also observed without cirrhosis. We developed an HCC model via intrasplenic injection of highly tumorigenic HCC cells, which, due to cellular tropism, invade the liver and allow for a controllable disease progression.

Liposomal Nω-hydroxy-l-norarginine, a proof-of-concept: Arginase inhibitors can be incorporated in liposomes while retaining their therapeutic activity ex vivo.

Cancer immunotherapy has evolved significantly over the last decade, with therapeutics targeting the adaptive immune system showing exciting effects in clinics. Yet, the modulation of the innate immune system, particularly the tumor-associated innate immune cells which are an integral part of immune responses in cancer, remains less understood. The arginase 1 (Arg1) pathway is a pivotal metabolic pathway that tumor-associated innate immune cells exploit to create an immunosuppressive tumor microenvironment, leading to the evasion of immune surveillance.

Nanoparticle Delivery to Tumours: From EPR and ATR Mechanisms to Clinical Impact.

New insights into active versus passive nanoparticle tumour entry and exit mechanisms are enriching the understanding of tumour-targeted drug delivery. Here, we align the principles of the enhanced permeability and retention (EPR) and active transport and retention (ATR), and outline how their mechanistic features may be employed to improve the performance and clinical impact of cancer nanomedicines.

Nanomaterial-based contrast agents.

Medical imaging, which empowers the detection of physiological and pathological processes within living subjects, has a vital role in both preclinical and clinical diagnostics. Contrast agents are often needed to accompany anatomical data with functional information or to provide phenotyping of the disease in question. Many newly emerging contrast agents are based on nanomaterials as their high payloads, unique physicochemical properties, improved sensitivity and multimodality capacity are highly desired for many advanced forms of bioimaging techniques and applications.

Engineering Mesoscopic 3D Tumor Models with a Self-Organizing Vascularized Matrix.

Advanced in vitro systems such as multicellular spheroids and lab-on-a-chip devices have been developed, but often fall short in reproducing the tissue scale and self-organization of human diseases. A bioprinted artificial tumor model is introduced with endothelial and stromal cells self-organizing into perfusable and functional vascular structures. This model uses 3D hydrogel matrices to embed multicellular tumor spheroids, allowing them to grow to mesoscopic scales and to interact with endothelial cells.

Repurposing Tamoxifen for Tumor Microenvironment Priming and Enhanced Tumor-Targeted Drug Delivery.

The dense stromal matrix in fibrotic tumors hinders tumor-targeted drug delivery. Tamoxifen (TMX), an estrogen receptor modulator that is clinically used for the treatment of breast cancer, has been shown to reprogram the tumor microenvironment (TME) and to alleviate desmoplasia. We here investigated if TMX, administered in free and nano-formulated form, can be repurposed as a TME remodeling agent to improve tumor accumulation of nano-formulations in pancreatic ductal adenocarcinoma and triple-negative breast cancer mouse models, evaluated using clinical-stage Cy7-labeled core-crosslinked polymeric micelles (CCPM).

Transformative Materials for Interfacial Drug Delivery.

Drug delivery systems (DDS) are designed to temporally and spatially control drug availability and activity. They assist in improving the balance between on-target therapeutic efficacy and off-target toxic side effects. DDS aid in overcoming biological barriers encountered by drug molecules upon applying them via various routes of administration.

Intravital microscopy for real-time monitoring of drug delivery and nanobiological processes.

Intravital microscopy (IVM) expands our understanding of cellular and molecular processes, with applications ranging from fundamental biology to (patho)physiology and immunology, as well as from drug delivery to drug processing and drug efficacy testing. In this review, we highlight modalities, methods and model organisms that make up today's IVM landscape, and we present how IVM - via its high spatiotemporal resolution - enables analysis of metabolites, small molecules, nanoparticles, immune cells, and the (tumor) tissue microenvironment. We furthermore present examples of how IVM facilitates the elucidation of nanomedicine kinetics and targeting mechanisms, as well as of biological processes such as immune cell death, host-pathogen interactions, metabolic states, and disease progression.

Profiling target engagement and cellular uptake of cRGD-decorated clinical-stage core-crosslinked polymeric micelles.

Polymeric micelles are increasingly explored for tumor-targeted drug delivery. CriPec® technology enables the generation of core-crosslinked polymeric micelles (CCPMs) based on thermosensitive (mPEG-b-pHPMAmLac) block copolymers, with high drug loading capacity, tailorable size, and controlled drug release kinetics. In this study, we decorated clinical-stage CCPM with the αβ integrin-targeted cyclic arginine-glycine-aspartic acid (cRGD) peptide, which is one of the most well-known active targeting ligands evaluated preclinically and clinically.

Systematically evaluating DOTATATE and FDG as PET immuno-imaging tracers of cardiovascular inflammation.

In recent years, cardiovascular immuno-imaging by positron emission tomography (PET) has undergone tremendous progress in preclinical settings. Clinically, two approved PET tracers hold great potential for inflammation imaging in cardiovascular patients, namely FDG and DOTATATE. While the former is a widely applied metabolic tracer, DOTATATE is a relatively new PET tracer targeting the somatostatin receptor 2 (SST2).

Progression of Myeloproliferative Neoplasms (MPN): Diagnostic and Therapeutic Perspectives.

Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) are a heterogeneous group of hematologic malignancies, including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), as well as post-PV-MF and post-ET-MF. Progression to more symptomatic disease, such as overt MF or acute leukemia, represents one of the major causes of morbidity and mortality. There are clinically evident but also subclinical types of MPN progression.

Extracellular vesicles as a drug delivery system: A systematic review of preclinical studies.

During the past decades, extracellular vesicles (EVs) have emerged as an attractive drug delivery system. Here, we assess their pre-clinical applications, in the form of a systematic review. For each study published in the past decade, disease models, animal species, EV donor cell types, active pharmaceutical ingredients (APIs), EV surface modifications, API loading methods, EV size and charge, estimation of EV purity, presence of biodistribution studies and administration routes were quantitatively analyzed in a defined and reproducible way.

A paradigm shift in cancer nanomedicine: from traditional tumor targeting to leveraging the immune system.

Twenty-five years after the approval of the first anticancer nanodrug, we have to start re(de)fining tumor-targeted drug delivery alongside advances in immuno-oncology. Given that cancer is characterized by an immunological imbalance that goes beyond the primary tumor, we should focus on targeting, engaging, and modulating cancer-associated immune cells in the tumor microenvironment (TME), circulation, and immune cell-enriched tissues. When designed and applied rationally, nanomedicines will assist in restoring the immunological equilibrium at the whole-body level, which holds potential not only for cancer therapy, but also for the treatment of a range of other disorders.

Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition.

Trained immunity, a functional state of myeloid cells, has been proposed as a compelling immune-oncological target. Its efficient induction requires direct engagement of myeloid progenitors in the bone marrow. For this purpose, we developed a bone marrow-avid nanobiologic platform designed specifically to induce trained immunity.

Imaging Cardiovascular and Lung Macrophages With the Positron Emission Tomography Sensor Cu-Macrin in Mice, Rabbits, and Pigs.

Background: Macrophages, innate immune cells that reside in all organs, defend the host against infection and injury. In the heart and vasculature, inflammatory macrophages also enhance tissue damage and propel cardiovascular diseases.

Methods: We here use in vivo positron emission tomography (PET) imaging, flow cytometry, and confocal microscopy to evaluate quantitative noninvasive assessment of cardiac, arterial, and pulmonary macrophages using the nanotracer Cu-Macrin-a 20-nm spherical dextran nanoparticle assembled from nontoxic polyglucose.

Optical imaging of the whole-body to cellular biodistribution of clinical-stage PEG-b-pHPMA-based core-crosslinked polymeric micelles.

Core-crosslinked polymeric micelles (CCPM) based on PEG-b-pHPMA-lactate are clinically evaluated for the treatment of cancer. We macroscopically and microscopically investigated the biodistribution and target site accumulation of CCPM. To this end, fluorophore-labeled CCPM were intravenously injected in mice bearing 4T1 triple-negative breast cancer (TNBC) tumors, and their localization at the whole-body, tissue and cellular level was analyzed using multimodal and multiscale optical imaging.

Cancer nanomedicine meets immunotherapy: opportunities and challenges.

Cancer nanomedicines have shown promise in combination immunotherapy, thus far mostly preclinically but also already in clinical trials. Combining nanomedicines with immunotherapy aims to reinforce the cancer-immunity cycle, via potentiating key steps in the immune reaction cascade, namely antigen release, antigen processing, antigen presentation, and immune cell-mediated killing. Combination nano-immunotherapy can be realized via three targeting strategies, i.

In vitro and in vivo evaluation of organic solvent-free injectable melatonin nanoformulations.

Melatonin is a neurohormone with potenial therapeutic effects in many diseases including neonatal hypoxic-ischemic (HI) brain injury. Due to limited solubility in water there is currently no clinically available melatonin formulation for parenteral use. Clinical use of melatonin has thus relied on oral administration, which in many cases is hampered by low and variable bioavailability.

Tumor Targeting by αβ-Integrin-Specific Lipid Nanoparticles Occurs Phagocyte Hitchhiking.

Although the first nanomedicine was clinically approved more than two decades ago, nanoparticles' (NP) behavior is complex and the immune system's role in their application remains elusive. At present, only passive-targeting nanoformulations have been clinically approved, while more complicated active-targeting strategies typically fail to advance from the early clinical phase stage. This absence of clinical translation is, among others, due to the very limited understanding for targeting mechanisms.