Porous Silicon Nanoparticle-Based Delivery of Therapeutic Antibodies for Diabetic Wound Repair
Abstract
We will investigate the therapeutic potential of porous silicon nanoparticles as a vehicle to deliver therapeutic antibodies to chronic diabetic wounds, listed as a FY20 PRMRP Topic Area. The research addresses the Area of Encouragement related to interventions to address impaired diabetic wound healing, but is also well placed to mitigate the progression of pressure ulcers to advanced stages. Research Idea/Rationale: Non-healing foot ulcers are a major health concern for diabetics. Foot ulceration occurs in approximately 25% of all adults with diabetes mellitus. Surgical treatment of diabetic foot ulcers (DFUs), one of the most commonly occurring types of chronic wounds, remains difficult and often insufficient, leading to high morbidity. Impaired chronic wound healing results from a complex variety of factors, which slow the body’s capacity to close open sores, thereby enhancing opportunistic and persistent infections. Pharmaceutical drugs aim to improve diabetic wounds healing by facilitating the transition from chronic non-healing to successfully closed wounds. However, treatment options remain severely limited, especially as the administered drug is often compromised by the hostile environment inherent to most chronic wounds. Thus, there is an urgent need to develop innovative drug carriers/vehicles to deliver promising therapeutic agents for improved healing of DFUs. We have developed porous silicon (pSi) nanomaterials for applications in drug delivery. pSi is a biodegradable, high surface area material that has already demonstrated its safety and potential in drug delivery applications. This material has been optimized as for therapeutic agent delivery to wounds, overcoming many of the hurdles/limitations impeding pharmacological agent development in the wound healing field, especially relating to the protease-mediated degradation associated with chronic and bacterially infected wounds. These include: (1) it retains the stability/functionality of loaded antibodies, (2) it protects antibodies from protease-mediated degradation, (3) the rate of release can be finely controlled based on pH and/or temperature, and (4) it can be loaded with a high concentration of payload using a simple method that is upscalable. Therapeutic anti-Flightless I (Flii) antibodies improve wound healing and are an ideal candidate for delivery to DFUs by pSi. The protein, Flii, is dramatically elevated post-wounding, including in wound fluid isolated from DFUs, and contributes to poor healing outcomes. However, as demonstrated in a number of studies by us, when the action of Flii is impeded, wound healing is accelerated. Based on these findings, Partnering Principal Investigator (PI) Cowin developed a drug to inhibit Flii, anti-Flii monoclonal antibody (FnAb), which was then tested in wounds and displayed promising wound healing outcomes. Critically, FnAb was not as effective at treating diabetic wounds compared to normally healing wounds due to its hostile wound environment. This suggested the effectiveness of FnAb, as with other therapeutic antibodies designed to treat DFUs, could be greatly improved by packaging them into a suitable nanocarrier that is able to protect the payload from proteases, while also facilitating slow release of FnAb. In preliminary experiments, pSi NPs were demonstrated to be effective drug delivery agents, could be loaded with FnAb at high capacity, displayed controlled release, and protected FnAb from proteases. Providing proof of concept, in type 1 diabetic mice, FnAb-pSi NPs displayed improved healing, and critically, was significantly more effective than “naked” FnAb. The use of pSi NPs as a delivery vehicle therefore enhances FnAb delivery and functionality in diabetic wounds. Hypothesis: pSi NPs will provide protection to FnAbs from proteases known to reside in wounds such as DFUs, and also allow for their controlled and effective release to promote healing at the critical stages of wound repair,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110495
Entities
People
- Allison Cowin
Organizations
- United States Army
- University of South Australia