Osteoarthritis is a debilitating joint disease affecting nearly 30 million people for which there are no disease-modifying therapies. Several drugs that have failed clinical trials have shown inefficient and inadequate delivery to target cells. Anabolic growth factors are one class of such drugs that could be disease-modifying if delivered directly to chondrocytes, which reside deep within dense, anionic cartilage tissue. To overcome this biological barrier, we conjugated a growth factor to a cationic nanocarrier for targeted delivery to chondrocytes and retention within joint cartilage after direct intra-articular injection. The nanocarrier uses reversible electrostatic interactions with anionic cartilage tissue to improve tissue binding, penetration, and residence time. Amine terminal polyamidoamine (PAMAM) dendrimers were end functionalized with variable molar ratios of poly(ethylene glycol) (PEG) to control surface charge. From this small family of variably PEGylated dendrimers, an optimal formulation showing 70% uptake into cartilage tissue and 100% cell viability was selected. When conjugated to insulin-like growth factor 1 (IGF-1), the dendrimer penetrated bovine cartilage of human thickness within 2 days and enhanced therapeutic IGF-1 joint residence time in rat knees by 10-fold for up to 30 days. In a surgical model of rat osteoarthritis, a single injection of dendrimer–IGF-1 rescued cartilage and bone more effectively than free IGF-1. Dendrimer–IGF-1 reduced width of cartilage degeneration by 60% and volumetric osteophyte burden by 80% relative to untreated rats at 4 weeks after surgery. These results suggest that PEGylated PAMAM dendrimer nanocarriers could improve pharmacokinetics and efficacy of disease-modifying osteoarthritis drugs in the clinic.

Polyelectrolyte multilayer (PEM) coatings, constructed on the surfaces of tissue engineering scaffolds using layer‐by‐layer assembly (LbL), promote sustained release of therapeutic molecules and have enabled regeneration of large‐scale, pre‐clinical bone defects. However, these systems primarily rely on non‐specific hydrolysis of PEM components to foster drug release, and their pre‐determined drug delivery schedules potentially limit future translation into innately heterogeneous patient populations. To trigger therapeutic delivery directly in response to local environmental stimuli, an LbL‐compatible polycation solely degraded by cell‐generated reactive oxygen species (ROS) was synthesized. These thioketal‐based polymers were selectively cleaved by physiologic doses of ROS, stably incorporated into PEM films alongside growth factors, and facilitated tunable release of therapeutic bone morphogenetic protein‐2 (BMP‐2) upon oxidation. These coatings' sensitivity to oxidation was also dependent on the polyanions used in film construction, providing a simple method for enhancing ROS‐mediated protein delivery in vitro. Correspondingly, when implanted in critically‐sized rat calvarial defects, the most sensitive ROS‐responsive coatings generated a 50% increase in bone regeneration compared with less sensitive formulations and demonstrated a nearly threefold extension in BMP‐2 delivery half‐life over conventional hydrolytically‐sensitive coatings. These combined results highlight the potential of environmentally‐responsive PEM coatings as tunable drug delivery systems for regenerative medicine.

Contrast agents have long helped researchers and physicians alike delineate boundaries, but new diagnostic information is always sought after. A new field of molecularly targeted CT agents hopes to fill this void and supply physicians with prognostic information to find better treatments for patients. Borrowing from drug delivery and design, nanoparticles and similar platforms are being explored to help visualize complex biologic processes with never before seen resolution and fidelity. We discuss the development of this field and feasibility of translating some of these prospects to the clinic. Advances in chemistry, molecular biology, and engineering have molded this field emphasizing the early detection and treatment of diseases at the molecular and cellular level. Myriads of nanomedicine platforms have been proposed and developed and tested in laboratories and in preclinical models. However, very few have been translated to clinical trials. It is therefore a critical issue to recognize the factors affecting their eventual application in human. Better understanding of biological and biophysical obstacles encountered by these agents is necessary. Toward this aim, we critically review our present understanding of the biological obstacles encountered by the nano-agents, which we hope will motivate more studies to tune these technologies for future translational and clinical applications.