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Osteoarthritis is a prevalent and debilitating disease that involves pathological contributions from numerous joint tissues and cells. The joint is a challenging arena for drug ...delivery, since the joint has poor bioavailability for systemically administered drugs and experiences rapid clearance of therapeutics after intra-articular injection. Moreover, each tissue within the joint presents unique barriers to drug localization. In this review, the various applications of nanotechnology to overcome these drug delivery limitations are investigated. Nanomaterials have reliably shown improvements to retention profiles of drugs within the joint space relative to injected free drugs. Additionally, nanomaterials have been modified through active and passive targeting strategies to facilitate interactions with and localization within specific joint tissues such as cartilage and synovium. Last, the limitations of drawing cross-study comparisons, the implications of synovial fluid, and the potential importance of multi-modal therapeutic strategies are discussed. As emerging, cell-specific disease modifying osteoarthritis drugs continue to be developed, the need for targeted nanomaterial delivery will likely become critical for effective clinical translation of therapeutics for osteoarthritis.
Improving drug delivery to the joint is a pressing clinical need. Over 27 million Americans live with osteoarthritis, and this figure is continuously expanding. Numerous drugs have been investigated but have failed in clinical trials, likely related to poor bioavailability to target cells. This article comprehensively reviews the advances in nano-scale delivery vehicles designed to overcome the delivery barriers in the joint. This is the first review to analyze active and passive targeting strategies systematically for different target sites while also delineating between tissue homing and whole joint retention. By bringing together the lessons learned across numerous nano-scale platforms, researchers may be able to hone future nanomaterial designs, allowing emerging therapeutics to perform with clinically relevant efficacy and disease modifying potential.
A major hurdle limiting the ability to treat and cure osteoarthritis, a common and debilitating disease, is rapid joint clearance and limited cartilage targeting of intra-articular therapies. ...Nanoscale drug carriers have the potential to improve therapeutic targeting and retention in the joint after direct injection; however, there still lacks a fundamental understanding of how the physicochemical properties of nanoparticles (NPs) influence localization to the degenerating cartilage and how joint conditions such as disease state and synovial fluid impact NP biodistribution. The goal of this study was to assess how physicochemical properties of NPs influence their interactions with joint tissues and, ultimately, cartilage localization. Ex vivo models of joint tissues were used to study how poly(lactide-co-glycolide) (PLGA) and polystyrene (PS) NP size, charge, and surface chemistry influence cartilage retention under normal and disease-mimicking conditions. Of the particles investigated, PLGA NPs surface-modified with a quaternary ammonium cation had the greatest retention within cartilage explants; however, retention was diminished 2- to 2.9-fold in arthritic tissue and in the presence of synovial fluid. Interactions with synovial fluid induced changes to NP surface properties and colloidal stability in vitro. The impact of NP charge on “off-target” synoviocyte uptake was also dependent on synovial fluid interactions. The results suggest that the design of nanocarriers for targeted drug delivery within the joint cannot be based on a single parameter such as zeta potential or size, and that the fate of injected delivery systems will likely be influenced by the disease state of the joint and the presence of synovial fluid.
Natural killer (NK) cells, which are an exciting alternative cell source for cancer immunotherapies, must sense and respond to their physical environment to traffic to and eliminate cancer cells. ...Herein, we review the mechanisms by which NK cells receive mechanical signals and explore recent key findings regarding the impact of the physical characteristics of solid tumors on NK cell functions. Data suggest that different mechanical stresses present in solid tumors facilitate NK cell functions, especially infiltration and degranulation. Moreover, we review recent engineering advances that can be used to systemically study the role of mechanical forces on NK cell activity. Understanding the mechanisms by which NK cells interpret their environment presents potential targets to enhance NK cell immunotherapies for the treatment of solid tumors.
A challenge in cancer research is the lack of biomimetic models that incorporate cancer cells, blood vessels, lymphatic vessels, and immune cells. This challenge highlights the gap between an in vivo ...system and common in vitro assays, which do not recapitulate the tumor microenvironment. To bridge this gap, our lab has introduced the rat mesentery culture model, which provides a complex and physiologically relevant culture system that enables the real‐time tracking of multiple cell types during angiogenesis and lymphangiogenesis. The objective of this study was to demonstrate the feasibility of culturing transplanted tumor spheroids on rat mesenteric tissues for investigating cancer cell‐angiogenesis interactions. Two lung carcinoma cell lines, A549 and H1299, were labeled with DiI and suspended in a hanging drop culture system consisting of MEM + 10% FBS for 4 days to form fluorescent spheroids. These spheroids were then seeded onto excised rat mesentery tissues (approximately 20 spheroids per tissue). Tissues with transplanted spheroids were cultured for 3 days. To identify blood vessels during various culture timepoints, tissues were labeled with FITC‐conjugated lectin and imaged on Day 2 and Day 3. On Day 3, tissues were labeled for PECAM, NG2, and CD11b to identify endothelial cells, pericytes, and macrophages respectively. Labeling a subset of tissues for Calcien AM enabled the detection of live cells. Observations confirmed that tumor spheroids remained viable and intact during culture. The apparent increase in individual cells along the periphery of the spheroids suggests radial cell migration into the tissue. Spheroids were observed in the same regions of angiogenic microvascular networks characterized by increased sprouting and vessel density. Angiogenesis was also confirmed by comparing time‐lapse lectin labeling of vessels. For some spheroids, directed sprouting towards spheroids was also observed. The presence of lymphatic vessels (identified by PECAM labeling morphology), NG2+ pericytes, and CD11b+ macrophages confirmed a multi‐cellular environment. These results support the feasibility of co‐culturing tumor spheroids and rat mesenteric tissues as well as a new approach for exploring how cancer cells interact with a surrounding microvasculature and their local environment.
Oxidative stress is an important, but elusive, therapeutic target for osteoarthritis (OA). Antioxidant strategies that target oxidative stress through the elimination of reactive oxygen species (ROS) ...have been widely evaluated for OA but are limited by the physiological characteristics of the joint. Current hallmarks in antioxidant treatment strategies include poor bioavailability, poor stability, and poor retention in the joint. For example, oral intake of exogenous antioxidants has limited access to the joint space, and intra-articular injections require frequent dosing to provide therapeutic effects. Advancements in ROS-scavenging nanomaterials, also known as nanozymes, leverage bioactive material properties to improve delivery and retention. Material properties of nanozymes can be tuned to overcome physiological barriers in the knee. However, the clinical application of these nanozymes is still limited, and studies to understand their utility in treating OA are still in their infancy. The objective of this review is to evaluate current antioxidant treatment strategies and the development of nanozymes as a potential alternative to conventional small molecules and enzymes.
Tumors are complex tissues that consist of stromal cells, such as fibroblasts, immune cells and mesenchymal stem cells, as well as non-cellular components, in addition to neoplastic cells. ...Increasingly, there is evidence to suggest that these non-neoplastic cell components support cancer initiation, progression and metastasis and that their ablation or reprogramming can inhibit tumor growth. Our understanding of the activities of different parts of the tumor stroma in advancing cancer has been improved by the use of scaffold and matrix-based 3D systems originally developed for regenerative medicine. Additionally, drug delivery systems made from synthetic and natural biomaterials deliver drugs to kill stromal cells or reprogram the microenvironment for tumor inhibition. In this article, we review the impact of 3D tumor models in increasing our understanding of tumorigenesis. We also discuss how different drug delivery systems aid in the reprogramming of tumor stroma for cancer treatment.
The field of tissue engineering promises to deliver biological substitutes to repair or replace tissues in the body that have been injured or diseased. The clinical demand for musculoskeletal tissues ...is particularly high, especially for cartilage and bone defects. Although they are generally considered biologically simple structures, musculoskeletal tissues consist of highly organized three-dimensional networks of cells and matrix, giving rise to tissue structures with remarkable mechanical properties. Although the field of cartilage and bone tissue engineering has progressed significantly in recent years, the development of structurally ordered tissues has not been accomplished. More strategies are needed to ensure that the appropriate cell and matrix organization is being achieved in the engineered tissues. This review emphasizes how different cell types and scaffold designs can be used to modulate tissue properties and engineer more complex tissue structures, with emphasis on cartilage and bone tissues.
Bone metastases are common complications of solid tumors, particularly those of the prostate, breast, and lungs. Bone metastases can lead to painful and devastating skeletal-related events (SREs), ...such as pathological fractures and nerve compressions. Despite advances in treatment for cancers in general, options for bone metastases remain inadequate and generally palliative. Anticancer drugs (chemotherapy and radiopharmaceuticals) do not achieve therapeutic concentrations in the bone and are associated with dose-limiting side effects to healthy tissues. Nanomedicines, with their tunable characteristics, have the potential to improve drug targeting to bone metastases while decreasing side effects for their effective treatment. In this review, we present the current state of the art for nanomedicines to treat bone metastases. We also discuss new treatment modalities enhanced by nanomedicine and their effects on SREs and disease progression.
We investigated the biological response of chondrocytes isolated from different zones of articular cartilage and their cellular behaviors in poly (ethylene glycol)-based (PEG) hydrogels containing ...exogenous type I collagen, hyaluronic acid (HA), or chondroitin sulfate (CS). The cellular morphology was strongly dependent on the extracellular matrix component of hydrogels. Additionally, the exogenous extracellular microenvironment affected matrix production and cartilage specific gene expression of chondrocytes from different zones. CS-based hydrogels showed the strongest response in terms of gene expression and matrix accumulation for both superficial and deep zone chondrocytes, but HA and type I collagen-based hydrogels demonstrated zonal-dependent cellular responses.
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