Telodendrimer functionalized hydrogel platform for sustained antibiotics release in infection control.

Wound infection commonly causes delayed healing, especially in the setting of chronic wounds. Local release of antibiotics is considered a viable approach to treat chronic wounds. We have developed a versatile telodendrimer (TD) platform for efficient loading of charged antibiotic molecules via a combination of multivalent and synergistic charge and hydrophobic interactions. The conjugation of TD in biocompatible hydrogel allows for topical application to provide sustained antibiotic release. Notably, a drug loading capacity as high as 20 % of the drug-to-resin dry weight ratio can be achieved. The payload content (PC) and release profile of the various antibiotics can be optimized by fine-tuning TD density and valency in hydrogel based on the charge and hydrophobic features of the drug, e.g., polymyxin B (PMB), gentamycin (GM), and daptomycin (Dap), for effective infection control. We have shown that hydrogel with moderately reduced TD density demonstrates a more favorable release profile than hydrogel with higher TD density. Antibiotics loaded in TD hydrogel have comparable antimicrobial potency and reduced cytotoxicity compared to the free antibiotics due to a prolonged, controlled drug release profile. In a mouse model of skin and soft tissue infection, the subcutaneous administration of PMB-loaded TD hydrogel effectively eliminated the bacterial burden. Overall, these results suggest that engineerable TD hydrogels have great potential as a topical treatment to control infection for wound healing. STATEMENT OF SIGNIFICANCE: Wound infection causes a significant delay in the wound healing process, which results in a significant financial and resource burden to the healthcare system. PEGA-telodendrimer (TD) resin hydrogel is an innovative and versatile platform that can be fine-tuned to efficiently encapsulate different antibiotics by altering charged and hydrophobic structural moieties. Additionally, this platform is advantageous as the TD density in the resin can also be fine-tuned to provide the desired antibiotic payload release profile. Sustained antibiotics release through optimization of TD density provides a prolonged therapeutic window and reduces burst release-induced cytotoxicity compared to conventional antibiotics application. Studies in a preclinical mouse model of bacteria-induced skin and soft tissue infection demonstrated promising therapeutic efficacy as evidenced by effective infection control and prolonged antibacterial efficacy of antibiotics-loaded PEGA-TD resin. In conclusion, the PEGA-TD resin platform provides a highly customizable approach for effective antibiotics release with significant potential for topical application to treat various bacterial wound infections to promote wound healing.

Unveiling cytokine charge disparity as a potential mechanism for immune regulation.

Cytokines are small signaling proteins that regulate the immune responses to infection and tissue damage. Surface charges of cytokines determine their in vivo fate in immune regulation, e.g., half-life and distribution. The overall negative charges in the extracellular microenvironment and the acidosis during inflammation and infection may differentially impact cytokines with different surface charges for fine-tuned immune regulation via controlling tissue residential properties. However, the trend and role of cytokine surface charges has yet to be elucidated in the literature. Interestingly, we have observed that most pro-inflammatory cytokines have a negative charge, while most anti-inflammatory cytokines and chemokines have a positive charge. In this review, we extensively examined the surface charges of all cytokines and chemokines, summarized the pharmacokinetics and tissue adhesion of major cytokines, and analyzed the link of surface charge with cytokine biodistribution, activation, and function in immune regulation. Additionally, we identified that the general trend of charge disparity between pro- and anti-inflammatory cytokines represents a unique opportunity to develop precise immune modulation approaches, which can be applied to many inflammation-associated diseases including solid tumors, chronic wounds, infection, and sepsis.

Functionalized core-shell nanogel scavenger for immune modulation therapy in sepsis.

Sepsis is a complex, life-threatening hyperinflammatory syndrome associated with organ failure and high mortality due to lack of effective treatment options. Here we report a core-shell hydrogel nanoparticle with the core functionalized with telodendrimer (TD) nanotrap (NT) to control hyperinflammation in sepsis. The combination of multi-valent charged and hydrophobic moieties in TD enables effective binding with biomolecules in NT. The higher crosslinking in the shell structure of nanogel excludes the abundant large serum proteins and allows for size-selectivity in scavenging the medium-sized septic molecules (10-30 kDa), e.g., lipopolysaccharides (LPS, a potent endotoxin in sepsis), thus reducing cytokine production. At the same time, the core-shell TD NT nanogel captures the over-flowing proinflammatory cytokines effectively both in vitro and in vivo from biological fluids to further control hyperinflammation. Intraperitoneal injection of core-shell TD NT nanogel effectively attenuates NF-κB activation and cytokine production in LPS-induced septic mouse models. These results indicate the potential applications of the injectable TD NT core-shell nanogel to attenuate local or systemic inflammation.