Hydrophobized Hydrogels: Construction Strategies,Properties, and Biomedical Applications

Hydrogels, as 3D networks containing huge amount of water, display similarity to soft tissues, and thus they are of wide interest in tissue engineering. Hydrogels, due to biocompatibility and porous structure, are valuable therapeutic platforms for hydrophilic drugs. Over the last decade, there has been a strong emphasis on the development of hydrogel platforms with the ability to increase the solubility of hydrophobic drugs. However, the pronounced discrepancy between the hydrophilic character of hydrogels and the hydrophobic nature of numerous pharmacologically active compounds is problematic. In recent years, different strategies are applied using special polymer constructs or composite materials exploiting the advanced scientific knowledge in the area of polymer and lipid-based nano- and microcarriers hydrophobization of the hydrogel turns out to be not only valuable in terms of achieving the ability to dissolve poorly soluble drugs in water, but also proves to be crucial in obtaining bioadhesion in wet conditions, but also, unexpected abnormal water swelling behavior, as well as in mechanical properties such as the dissipation mechanism and self-healable hydrogel properties. This review is mainly focused on recent advances in the usage of hydrophobized hydrogels in biomedical applications.     

A Novel Strategy for Visualizing,Tracing, and Measuring the Gastrointestinal Absorption of Silver Nanoparticles

The silver-based formulation has become one of the most widely used nanoagents for agrifood industry and clinical translation. However, the in vivo fate of silver nanoparticles (AgNPs) via oral exposure remains poorly understood. Here, a specific strategy is shown for tracking the gastrointestinal transformation, intestinal absorption, and organ distribution of particulate Ag after oral exposure by using the gold (Au)-Ag core−shell NPs (Au@AgNPs). Taking advantage of both plasmonic and elemental characteristics of Au@AgNPs, the transformation of particulate Ag in the gastrointestinal tract (GIT), and later on, intestinal absorption are visualized at the single-particle level. Furthermore, quantitative analysis reveals that the clearance rate of ingested particulate Ag from the blood and organs is much higher than that of ionic Ag, and at 6 h post-oral administration, the former only contributed 0.08%, 1.10%, and 0.64% of the total Ag in the liver, spleen, and kidneys. Finally, the transcellular and paracellular pathways are identified as two possible mechanisms responsible for the transepithelial transport of particulate Ag. This study opens an avenue toward the examination of oral bioavailability of NPs and may have important implications in exploring the oral delivery technologies of nanoagents.     

Biomaterials Functionalized with MSC Secreted Extracellular Vesicles and Soluble Factors for Tissue Regeneration

The therapeutic benefits of mesenchymal stromal cell (MSC) transplantation are attributed to their secreted factors, including extracellular vesicles (EVs) and soluble factors. The potential of employing the MSC secretome as an alternative acellular approach to cell therapy is being investigated in various tissue injury indications, but EVs administered via bolus injections are rapidly sequestered and cleared. However, biomaterials offer delivery platforms to enhance EV retention rates and healing efficacy. This review highlights the mechanisms underpinning the therapeutic effects of MSC‐EVs and soluble factors as effectors of immunomodulation and tissue regeneration, conferred primarily via their nucleic acid and protein contents. Discussed is how manipulating the cell culture microenvironment or genetic modification of MSCs can further augment the potency of their secretions. The most recent advances in the development of EV‐functionalized biomaterials that mediate enhanced angiogenesis and cell survival, while attenuating inflammation and fibrosis, are presented. Finally, some technical challenges to be considered for the clinical translation of biomaterials carrying MSC‐secreted bioactive cargo are discussed.     

Enzyme Prodrug Therapy Engineered into Biomaterials

In this work, enzyme‐prodrug therapy (EPT) is engineered into hydrogel biomaterials to achieve localized synthesis of the drugs and their delivery to the adhering cells. The use of EPT in the context of drug delivery mediated by biomaterials significantly empowers the latter in that the same hydrogel is used to successfully synthesize several drugs with dissimilar structures and therapeutic effects. The concentration of the synthesized drugs is conveniently controlled by the concentration of the administered prodrugs. Using prodrugs for two therapeutic agents allows their synthesis and delivery with independent control over the concentration and the time of administration of each of the drugs. Using these tools, sequential delivery of drugs for anti‐inflammatory and anti‐proliferative activity is accomplished whereby the synthesis of drugs is mediated by the same enzyme‐functionalized hydrogel. The use of EPT to perform combination therapy mediated by an implantable biomaterial is also reported. Taken together, these results contribute significantly to the development of flexible and highly powerful tools of substrate‐mediated drug delivery with applications in the design of therapeutic implants and tissue engineering.     

Multiple Protective Roles of Nanoliposome-Incorporated Baicalein against Alpha-Synuclein Aggregates

Nanoparticles are useful for increasing drug stability, solubility, and availability. The small molecule baicalein inhibits fibrillation, and detoxifies aggregates of α-synuclein (αSN) associated with Parkinson's disease (PD), but it suffers from instability, low solubility and consequent low availability. Here it is demonstrated that incorporation of baicalein into zwitterionic nanoliposomes (NLP-Ba) addresses these problems. NLP-Ba inhibits αSN fibril initiation, elongation, secondary nucleation, and also depolymerizes mature fibrils more effectively than free baicalein and prevents soluble αSN aggregates from seeding new fibrils. Importantly, NLP-Ba perturbs oligomers’ capacity to permeabilize the membrane. The interaction between NLP-Ba and αSN is confirmed by different biophysical techniques. This nanosystem crosses the blood-brain barrier in vitro and is effective against rotenone neurotoxicity in vivo. The effect of NLP-Ba on αSN fibrillation/cytotoxicity is attributed to a combination of free baicalein and empty NLPs. The results indicate a neuroprotective role for NLP-Ba in decreasing αSN pathogenicity in PD and highlight the use of nanoliposomes to mobilize poorly soluble hydrophobic drugs.     

Nano-Oncologicals: A Tortoise Trail Reaching New Avenues

Research efforts towards cancer therapeutics have resulted in the development of a variety of pharmacological molecules, including small synthetic molecules and biological drugs (RNA-based therapies and monoclonal antibodies—mAbs), intended to target tumor or immune-related cells, or their signaling mediators. The majority of them present important biopharmaceutical problems related to their difficulties for overcoming biological barriers and reach their targets. Nanotechnology has been, for more than 60 years, trying to solve these problems. As knowledge in drug discovery, molecular biology, and biomaterials advances, there has been significant progress in the adequate design of nanodelivery strategies that may significantly contribute to the exploitation of the new therapies. This review provides a critical overview of the current potential of nanotechnology to solve problems associated with the different categories of drugs. Starting with the general concept of passive and active targeting, it presents the distinct advantages that delivery technologies have shown to date for improving the therapeutic outcome of small drugs with cytotoxic activity, RNA- and mAb-based therapies. Moreover, it precisely describes the benefits of combining immunotherapies and nanotechnology. The most advanced technologies are put into perspective in relation to their translational pathway and the future avenues for nano-oncologicals.     

Layer‐by‐Layer Assembly of Functional Nanoparticles for Hepatocellular Carcinoma Therapy

Cancer treatments with conventional approaches often result in limited clinical outcomes due to inefficient therapeutic efficacy and cumulative toxicity against normal tissue. Recently, most research has focused on combined therapeutic studies by functional carriers. In this study, functional nanoparticles (FNPs) are assembled in a layer‐by‐layer fashion. FNPs are loaded with two drugs (10‐hydroxycamptothecin and apoptin plasmid) with dual hepatocellular carcinoma‐targeting ligands (lactobionic acid and biotin) on the surface. Cytotoxicity studies and acute toxicity experiments in BAL b/c mice show that blank FNPs demonstrate good biocompatibility. Flow cytometry analysis and cytotoxicity studies demonstrate that the dual‐targeting FNPs allow for better specificity and selectivity of the tumor mass. FNPs can escape from endosomal/lysosomal compartments effectively, as is demonstrated using the Cell Navigator lysosome staining kit. When the drugs are released into the cytosol, the nuclear localization signal can enhance the nuclear delivery of 10‐hydroxycamptothecin loaded carriers and apoptin plasmids, as is demonstrated by confocal laser scanning microscopy. In vivo experiments show the circulation time and tissue distribution of FNPs, which greatly improve the therapeutic efficacy of BAL b/c nude mice with subcutaneous tumors. Taken together, the results suggest that FNPs are a promising candidate for hepatocellular carcinoma therapy.     

Nanoparticles with Precise Ratiometric Co‐Loading and Co‐Delivery of Gemcitabine Monophosphate and Cisplatin for Treatment of Bladder Cancer

Combination chemotherapy is a common practice in clinical management of malignancy. Synergistic therapeutic outcome is only achieved when tumor cells are exposed to cells in an optimal ratio. However, due to diverse physicochemical properties of drugs, no free drug cocktails or nanomaterials are capable of co‐loading and co‐delivering drugs at an optimal ratio. Herein, we develop a novel nano‐platform with precise ratiometric co‐loading and co‐delivery of two hydrophilic drugs for synergistic anti‐tumor effects. Based on previous work, we utilize a solvent displacement method to ratiometrically load dioleoyl phosphatidic acid (DOPA)‐gemcitabine monophosphate (GMP) and DOPA coated cisplatin‐precipitate nanocores into the same PLGA NP. These cores are designed to have similar hydrophobic surface properties. GMP and cisplatin are engineered into PLGA NP at an optimal synergistic ratio (5:1, mol:mol) with over 70% encapsulation efficiency and were ratiometrically taken up by tumor cells in vitro and in vivo. These PLGA NP exhibit synergistic anti‐cancer effects in a stroma‐rich bladder tumor model. A single injection of dual drugs in PLGA NP can significantly inhibit tumor growth. This nanomaterial‐system solves problems related to ratiometric co‐loading and co‐delivery of different hydrophilic moieties and provides possibilities for co‐loading hydrophilic drugs with hydrophobic drugs for combination therapy.     

Mesenchymal Stem Cell-Laden Composite β Cell Porous Microgel for Diabetes Treatment

Type 1 diabetes mellitus is a chronic metabolic condition characterized by the autoimmune damage of pancreatic β cells. As an alternative to continuous exogenous insulin administration of insulin, β cell transplantation is shown to provide an alternative approach for controlling hyperglycemia in diabetes. However, β cell transplantation faces significant challenges of low β cell proliferation and immunologic insults. Thus, novel approaches capable of promoting the islet microenvironment for sustainability is highly desired. This study develops mesenchymal stem cell (MSC)-laden composite β cell porous microgels (MGs) to address sustainability for the treatment of diabetes. The MGs are prepared via microfluidic droplet templates encapsulating both MSCs and β cells with porogen for creating a porous structure. In addition to offering a suitable microenvironment for nutrient delivery, the porous structure promoted β cell growth and insulin secretion. The outstanding anti-apoptotic and immunomodulatory roles of MSCs further provide a favorable environment for β cell survival and function. On this basis, the therapeutic performance of the MGs in reducing hyperglycemia and achieving sustained glycemic control in diabetic mice is demonstrated. Collectively, these results show that the novel MGs have great potential for the treatment of diabetes providing a promising platform for clinical β cell transplantation.     

Transformable Nanotheranostics Capable of Sensoring Nucleic Acid Drugs’ Spatiotemporal Behaviors

Nanotheranostics facilitates personalized treatment by providing imaging capabilities for nucleic acid drug vectors. However, available nanotheranostics are not yet capable of indicating the release behavior of nucleic acid drugs. Herein, four guidelines for the design of nanotheranostics are proposed. Under the guidance, transformable nanotheranostics are prepared that can sense the spatiotemporal behaviors of siRNA accumulation and release to facilitate personalized oncology treatment. The nanotheranostics sense the spatiotemporal accumulation behavior of siRNA in tumors through computerized tomography. Besides, the tumor cytoplasmic microenvironment mediates both siRNA release and nanotherapeutic agent transformation simultaneously. The transformation-activated magnetic resonance imaging (MRI) signals sense the spatiotemporal release behavior of siRNA. Moreover, the therapeutic effect of survivin-targeted siRNA can be diagnosed and confirmed by contrast-enhanced CT/MRI multi-modal imaging in real-time. The transformable nanotheranostics further promote personalized oncotherapy by nucleic acid drugs. These four guidelines are expected to direct the research and development of nucleic acid drug-based nanotheranostics. This study also provides a new perspective on real-time sensoring the spatiotemporal behaviors of nucleic acid drugs in vivo.     

A Gene Therapy Technology‐Based Biomaterial for the Trigger‐Inducible Release of Biopharmaceuticals in Mice

Gene therapy scientists have developed expression systems for therapeutic transgenes within patients, which must be seamlessly integrated into the patient's physiology by developing sophisticated control mechanisms to titrate expression levels of the transgenes into the therapeutic window. However, despite these efforts, gene‐based medicine still faces security concerns related to the administration of the therapeutic transgene vector. Here, molecular tools developed for therapeutic transgene expression can readily be transferred to materials science to design a humanized drug depot that can be implanted into mice and enables the trigger‐inducible release of a therapeutic protein in response to a small‐molecule inducer. The drug depot is constructed by embedding the vascular endothelial growth factor (VEGF₁₂₁) as model therapeutic protein into a hydrogel consisting of linear polyacrylamide crosslinked with a homodimeric variant of the human FK‐binding protein 12 (F_M), originally developed for gene therapeutic applications, as well as with dimethylsuberimidate. Administrating increasing concentrations of the inducer molecule FK506 triggers the dissociation of F_M thereby loosening the hydrogel structure and releasing the VEGF₁₂₁ payload in a dose‐adjustable manner. Subcutaneous implantation of the drug depot into mice and subsequent administration of the inducer by injection or by oral intake triggers the release of VEGF₁₂₁ as monitored in the mouse serum. This study is the first demonstration of a stimuli‐responsive hydrogel that can be used in mammals to release a therapeutic protein on demand by the application of a small‐molecule stimulus. This trigger‐inducible release is a starting point for the further development of externally controlled drug depots for patient‐compliant administration of biopharmaceuticals.     

Rigorous mathematical modeling techniques for optimal delivery of macromolecules to the brain

Several treatment modalities for neurodegenerative diseases or tumors of the central nervous system involve invasive delivery of large molecular weight drugs to the brain. Despite the ample record of experimental studies, accurate drug targeting for the human brain remains a challenge. This paper proposes a systematic design method of administering drugs to specific locations in the human brain based on first principles transport in porous media. The proposed mathematical framework predicts achievable treatment volumes in target regions as a function of brain anatomy and infusion catheter position. A systematic procedure to determine the optimal infusion and catheter design parameters that maximize the penetration depth and volumes of distribution will be discussed. The computer simulations are validated with agarose gel phantom experiments and rat data. The rigorous computational approach will allow physicians and scientists to better plan the administration of therapeutic drugs to the central nervous system.      

Single Small Molecule-Assembled Mitochondria Targeting Nanofibers for Enhanced Photodynamic Cancer Therapy In Vivo

Photodynamic therapy (PDT) has emerged as an attractive alternative in cancer therapy, but its therapeutic effects are limited by the nonselective subcellular localization and poor intratumoral retention of small-molecule photosensitizes. Here a fiber-forming nanophotosensitizer (PQC NF) that is composed of mitochondria targeting small molecules of amphiphilicity is reported. Harnessing the specific mitochondria targeting, the light-activated PQC NFs produce approximately 110-fold higher amount of reactive oxygen species in cells than free photosensitizers and can dramatically induce mitochondrial disruption to trigger intense apoptosis, showing 20–50 times better in vitro anticancer potency than traditional photosensitizers. As fiber-shaped nanomaterials, PQC NFs also demonstrated a long-term retention in tumor sites, solving the challenge of rapid clearance of small-molecule photosensitizers from tumors. With these advantages, PQC NFs achieve a 100% complete cure rate in both subcutaneous and orthotopic oral cancer models with the administration of only a single dose. This type of single small molecule-assembled mitochondria targeting nanofibers offers an advantageous strategy to improve the in vivo therapeutic effects of conventional PDT.     

Advanced Functional Nanomaterials for Theranostics

Nanoscale materials have been explored extensively as agents for therapeutic and diagnostic (i.e., theranostic) applications. Research efforts have shifted from exploring new materials in vitro to designing materials that function in more relevant animal disease models, thereby increasing potential for clinical translation. Current interests include non‐invasive imaging of diseases, biomarkers, and targeted delivery of therapeutic drugs. Here, some general design considerations of advanced theranostic materials and challenges of their use, from both diagnostic and therapeutic perspectives, are discussed. Common classes of nanoscale biomaterials, including magnetic nanoparticles, quantum dots, upconversion nanoparticles, mesoporous silica nanoparticles, carbon‐based nanoparticles, and organic dye‐based nanoparticles, have demonstrated potential for both diagnosis and therapy. Variations such as size control and surface modifications can modulate biocompatibility and interactions with target tissues. The need for improved disease detection and enhanced chemotherapeutic treatments, together with realistic considerations for clinically translatable nanomaterials, will be key driving factors for theranostic agent research in the near future.     

Oral Administration of Multistage Albumin Nanomedicine Depots (MANDs) for Targeted Efficient Alleviation of Chronic Inflammatory Diseases

Methotrexate (MTX) by oral taking has been employed as the first-line medication for various chronic inflammatory diseases treatment, such as Crohn's disease and rheumatoid arthritis (RA). However, the oral administration of MTX has very limited clinical benefits and will be discontinued due to the suboptimal response and severe adverse effects on intestinal mucosa. Herein, a multistage albumin nanomedicine depot (denoted as MAND) is formulated by encapsulating MTX-loaded human serum albumin nanoparticles (MTX@HSA NPs) into calcium alginate chitosan microcapsules using a gas-shearing technology. The MANDs can provide protection to MTX@HSA NPs with well-persisted biologic activity against gastric acid erosion and realize specific boost release of MTX@HSA NPs in the intestinal tract in response to the mild basic circumstance. The MTX@HSA NPs absorbed by intestine can selectively accumulate in inflammation lesion by exploiting the inflammation targeting ability of HSA. In the animal experiments, the MANDs show improved therapeutic efficacy for the treatment of both RA and colitis with minimized intestinal side effects in respect to the free MTX by oral administration. Therefore, this conceived oral MANDs can promote a more clinic popularity and enhanced benefits of MTX for the treatment of chronic inflammatory diseases.     

Nanomedicine-Boosting Tumor Immunogenicity for Enhanced Immunotherapy

Immunotherapy has revolutionized oncology remarkably and gained great improvements in cancer therapy. However, tumor immunotherapy still encounters serious challenges, especially certain tumors barely respond to immunotherapy. The lack of immunogenicity and subsequent insufficient antitumor immune activation is a pivotal reason. Here, a general introduction and the strengthening strategies of immunogenicity of a tumor for enhanced immunotherapy are reviewed. Specifically, nanotechnology nowadays is playing important roles in increasing the antitumor efficacy of various treatments, including immunotherapy. This review highlights how nanomedicines integrating one or more anticancer therapeutic methods (e.g., cancer vaccines, chemotherapy, phototherapy, and radiotherapy) to increase the tumor immunogenicity for rousing T cell related immune responses and achieving inspiring antitumor efficacy. Given the sophisticated immune evasion mechanisms, rational designed nanodrugs with combinational formulations are summarized to improve therapeutic efficacy in synergistic ways. Nanoplatforms taking advantage of the distinct features of tumor tissue or tumor cell with stimuli-responsiveness and targeting functions are introduced to accelerate tumor accumulation of drugs successfully and greatly promote therapeutic efficacy with low-dose administration and programmed drug release. Finally, the related challenges and personal perspectives of nanomedicines for tumor immunotherapy are concluded.     

Chasing the Bad News: An Analysis of 2005 Iraq and Afghanistan War Coverage on NBC and Fox News Channel

This study analyzes all stories aired on NBC Nightly News and Fox News Channel's Special Report With Brit Hume during 2005 about the U.S. wars in Iraq and Afghanistan, and compares that coverage with real‐world indicators to address an important question: Did the news media over‐report bad news from these conflicts, as claimed by the Bush administration and as one might expect given research into the press' negativity bias? This study finds that while both channels focused a fair amount on negative storylines, overall the news actually underplayed bad news from both countries. Fox News was much more sympathetic to the administration than NBC, suggesting that scholars should consider Fox as alternative, rather than mainstream, media.     

Tumor Acidity and Near-Infrared Light Responsive Dual Drug Delivery Polydopamine-Based Nanoparticles for Chemo-Photothermal Therapy

Photothermal therapy (PTT) combined with chemotherapy, a promising strategy for breast cancer treatment, has a high potential to control drug release, reduce multidrug resistance, and improve therapeutic efficacy. The challenge is how to realize tumor ablation in deeper tissue and NIR-controlled drug delivery. Herein, tumor acidity and near-infrared light (NIR) responsive folic acid (FA) functionalized polydopamine (DPA) nanoparticles (NPs) are developed for doxorubicin (DOX) and epigallocatechin-3-gallate (EGCG) dual delivery. With the assistance of NIR, the cellular uptake of DOX-EGCG/DPA-FA NPs is about three- to sixfold higher when compared with the free DOX group and the control group without NIR irradiation. Moreover, biodistribution study in vivo indicates that DPA-FA NPs can enhance tumoral accumulation, penetration, retention of drugs, and display a ≈ 4- and 19-fold higher intra-tumoral distribution than that of the DPA NPs and free drug groups at 24 h postinjection. Furthermore, 60% of breast cancer-bearing mice survive over 70 days in the DOX-EGCG/DPA-FA NPs group. Additionally, DOX-EGCG/DPA-FA NPs can effectively boost therapeutic efficacy by inducing significant suppression of tumor growth and angiogenesis, and enhancement of apoptosis and necrosis of breast cancer cells. Taken together, DOX-EGCG/DPA-FA NPs may have potential applications as a useful nanoscale vector for enhanced cancer therapy.     

Magnetically Guidable Proteinaceous Adhesive Microbots for Targeted Locoregional Therapeutics Delivery in the Highly Dynamic Environment of the Esophagus

The esophagus is a tubular-shaped muscular organ where swallowed fluids and muscular contractions constitute a highly dynamic environment. The turbulent, coordinated processes that occur through the oropharyngeal conduit can often compromise targeted administration of therapeutic drugs to a lesion, significantly reducing therapeutic efficacy. Here, magnetically guidable drug vehicles capable of strongly adhering to target sites using a bioengineered mussel adhesive protein (MAP) to achieve localized delivery of therapeutic drugs against the hydrodynamic physiological conditions are proposed. A suite of highly uniform microparticles embedded with iron oxide (IO) nanoparticles (MAP@IO MPs) is microfluidically fabricated using the genipin-mediated covalent cross-linking of bioengineered MAP. The MAP@IO MPs are successfully targeted to a specific region and prolongedly retained in the tubular-structured passageway. In particular, orally administered MAP@IO MPs are effectively captured in the esophagus in vivo in a magnetically guidable manner. Moreover, doxorubicin (DOX)-loaded MAP@IO MPs exhibit a sustainable DOX release profile, effective anticancer therapeutic activity, and excellent biocompatibility. Thus, the magnetically guidable locomotion and robust underwater adhesive properties of the proteinaceous soft microbots can provide an intelligent modular approach for targeted locoregional therapeutics delivery to a specific lesion site in dynamic fluid-associated tubular organs such as the esophagus.     

Platelet Membrane Fragment Self-Assembled Oral Hydrogel Microspheres for Restoring Intestinal Microvascular Injury

Non-invasive management of intestinal microvascular injury with hemorrhage under constant biochemical-mechanical encroachment of luminal contents is a major clinical challenge. Herein, an oral hydrogel microsphere is designed, encapsulating the platelet membrane fragment self-assembled nanohydrogel fabricated by double-crosslinking of methacrylated hyaluronic acid and Rebamipide-loaded dendrimer (Rng@PMS), for self-localization of hemorrhagic focus and intensive management of intestinal microvascular injury via suppression of inflammation-mediated tissue injury and reintegration of the damaged mucosal barrier. The results indicate that Rng@PMS effectively adheres to exposed collagen on injured microvasculature and attaches to over 90% of activated macrophages within 10 min, endowing Rng@PMS with a significantly prolonged enteral dwell time (over 24 hours). Importantly, Rng@PMS generated from alginate is designed for oral colon-targeted delivery to avoid the erosion of gastrointestinal contaminants. In vivo study reveals oral administration of microspheres in murine hematochezia model upregulates the intestinal barrier proteins zonula occludens-1, Occludin, and muc2, and inhibits infiltration of neutrophils, dendritic cells, and macrophages in hemorrhagic foci, thereby reducing the hematochezia score from 4 to 0.8, and the pathology score from 5.3 to 0.5. Oral microspheres for in situ management of intestinal microvascular injury may be applicable more broadly to noninvasively treat diseases with symptoms of mucosal hemorrhage.