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This study introduces a biocompatible, stimuli-responsive theranostic system with ultrasmall iron oxide nanoparticles (USPIONs) encapsulated within the hyaluronic acid-b-poly(lactic acid) (HA–PLA) polymersome membrane and a model protein in the core. 

Aims: Stimuli-responsive polymersomes are promising tools for protein-based therapies, but require deeper understanding and optimization of their pathology-responsive behavior. Materials & methods: Hyaluronic acid (HA)–poly(b-lactic acid) (PLA) polymersomes self-assembled from block copolymers of varying molecular weights of HA were compared for their physical properties, degradation and intracellular behavior. Results: Major results showed increasing enzyme-responsivity associated with decreasing molecular weight. The major formulation differences were as follows: the HA(5 kDa)–PLA formulation exhibited the most pronounced release of encapsulated proteins, while the HA(7 kDa)–PLA formulation showed the most different release behavior from neutral. Conclusion: We have discovered design rules for HA–PLA polymersomes for protein delivery, with lower molecular weight leading to higher encapsulation efficiency, greater release and greater intracellular uptake. 

Oxygen therapeutics has a range of applications in transfusion medicine and disease treatment. Synthetic molecules and all‐natural or semisynthetic hemoglobin‐based oxygen carriers (HBOCs) have seen success as potential circulating oxygen carriers. However, many early HBOC products stalled in development due to side effects from excess hemoglobin in the blood stream and hemoglobin entering the tissue. To overcome these issues, research has focused on increasing the molecular diameter of hemoglobin by polymerizing hemoglobin molecules or encapsulating hemoglobin in liposomal carriers. This work leverages the properties of silk fibroin, a cytocompatible and nonthrombogenic biopolymer, known to entrap protein‐based cargo, to engineer a fully protein‐based oxygen carrier. Herein, an all‐aqueous solvent evaporation technique is used to form silk particles via phase separation from a bulk polyvinyl alcohol phase. Particle size is tuned, and particles are formed with and without hemoglobin. The encapsulation efficiency and ferrous state of hemoglobin are analyzed, resulting in 60% encapsulation efficiency and a maximum of 20% ferric hemoglobin, yielding 100 μg mL⁻¹active hemoglobin in certain silk fibroin‐HBOCs formulations. The system does not elicit a strong inflammation response in vitro, demonstrating the potential for this particle system to serve as an injectable HBOC. 

The fields of drug and gene delivery have been revolutionized by the discovery and characterization of polymer-based materials. Polymeric nanomaterials have emerged as a strategy for targeted delivery because of features such as their impressive biocompatibility and improved availability. Use of naturally derived polymers in these nanomaterials is advantageous due to their biodegradability and bioresorption. Natural biopolymer-based particles composed of silk fibroins and other silk fiber-inspired proteins have been the focus of research in drug delivery systems due to their simple synthesis, tunable characteristics, and ability to respond to stimuli. Several silk and silk-inspired polymers contain a high proportion of reactive side groups, allowing for functionalization and addition of targeting moieties. In this review, we discuss the main classes of silk and silk-inspired polymers that are being used in the creation of nanomaterials. We also focus on the fabrication techniques used in generating a tunable design space of silk-based polymeric nanomaterials and detail how that translates into use for drug delivery to several distinct microenvironments.