SBIR-STTR Award

Infectious bone disease is a major cause of morbidity and mortality worldwide. Successful treatment often requires surgical intervention with longer-term antibiotic therapy. Bacterial biofilm pathogens are associated with most osseous infections and represent a major target of therapy. The biofilm pathogens associated with chronic bone infections bind to and colonize on bone surfaces. Bisphosphonates (BPs) are widely used antiresorptive medications that also bind to bone surfaces, and have therefore been utilized to treat lytic bone pathoses like osteoporosis, multiple myeloma, and metastatic bone disease. Consequently, we hypothesize that using a BP chemical moiety as a vector for the delivery of the antimicrobial agent, ciprofloxacin (CF) to bone surfaces (where biofilm pathogens reside), could represent a pharmacologically advantageous approach to the treatment of infectious bone disease in the jaw. Therefore, in this Phase I STTR project, we propose to develop a novel BP-ciprofloxacin conjugate (BP-CF) using a releasable linker chemistry strategy, for targeted bone delivery to effectively treat jawbone infections. To avoid any potential effects of BP therapy on bone remodelling or adverse events, we will utilize a pharmacologically inert BP that possesses strong bone affinity and will serve as a safe vector for the delivery and release of the antimicrobial agent. This will allow for the greatest translational/clinical potential in future development of this technology. The use of a non-pharmacologically active BP will also be helpful in delineating the source of activity in our proposed assays in order to directly study the effects of the antimicrobial agent with minimal confounders. This project will be carried out as a collaborative between BioVinc(r) LLC (Dr. Ebetino) and USC (Prof. Sedghizadeh). Dr. Ebetino and BioVinc's main focus is BP chemistry and biology as well as design and synthesis of bisphosphonate based drug delivery systems and imaging probes. Prof. Sedghizadeh and his collaborators will bring their expertise and capabilities in biofilm microbiology and in novel in vitro and in vivo models of osteolytic infections to this project. Prof. C. E. McKenna, Ph.D. (University of Southern California), an authority on bisphosphonate chemistry and "magic linker" technology key inventor, Prof. R. K. Boeckman (University of Rochester), an expert in synthetic organic chemistry and synthesis of bisphosphonate analogs, and Prof. M. N. Neely (Children's Hospital Los Angeles), an experienced clinician-scientist in the field of pharmacokinetics and infectious diseases, will also participate as consultants. Our transdisciplinary team is uniquely poised to develop and test the novel BP-CF compound for targeted therapeutics for infectious bone disease.

Public Health Relevance Statement:


Public Health Relevance:
The proposed research addresses an important and unmet medical need in the treatment of bone infectious diseases, e.g., jaw infections. In a partnership involving BioVinc, LLC and the Ostrow School of Dentistry at the University of Southern California, the novel bisphosphonate (BP)-ciprofloxacin prodrug conjugate will be synthesized and investigated for biofilm-mediated osteolytic infection treatment in an in vitro and in vivo animal model. The outcome of this study will be the generation of the novel BP-antimicrobial prodrug specifically targeting and delivering the antimicrobial agent to infected bone sites, with the goal of developing a highly potent and specific therapeutic treatment for preclinical research, and ultimately, clinical applications.

Project Terms:
Active Sites; Address; Adult; Adverse event; Affinity; analog; Animal Model; Antibiotic Therapy; Antibiotics; antimicrobial; antimicrobial drug; authority; bactericide; base; Binding (Molecular Function); Biochemical; Biological Assay; Biology; bisphosphonate; bone; Bone Diseases; Bone necrosis; Bone remodeling; Bone Surface; California; Carbamates; Characteristics; Chemicals; Chemistry; Chronic; Ciprofloxacin; Cleaved cell; Clinical; clinical application; Communicable Diseases; cytotoxicity; design; Development; Devices; Doctor of Philosophy; Drug Delivery Systems; Drug Kinetics; experience; Fluoroquinolones; Future; Generations; Goals; Hydroxyapatites; imaging probe; Implant; In Vitro; in vivo; in vivo Model; Infection; Infectious Bone Diseases; Jaw; Killings; Los Angeles; Lytic; Magic; Mediating; Medical; Methicillin; Methods; Microbial Biofilms; Microbiology; Minimum Inhibitory Concentration measurement; Modeling; Morbidity - disease rate; Mortality Vital Statistics; Multiple Myeloma; novel; Ofloxacin, (S)-Isomer; Operative Surgical Procedures; Organic Chemistry; Organic Synthesis; Osteolytic; Osteomyelitis; Osteoporosis; Outcome Study; Paget's Disease; pathogen; Pediatric Hospitals; Penetration; Periodontitis; Pharmaceutical Preparations; Phase; Physiological; pre-clinical research; Prodrugs; Pseudomonas aeruginosa; public health relevance; Research; Research Design; Resistance development; Safety; School Dentistry; Scientist; Site; Small Business Technology Transfer Research; Source; Staphylococcus aureus; success; Surface; System; targeted delivery; targeted treatment; Technology; technology development; Testing; Therapeutic; Toxic effect; Universities; vector

Dental implants are a central part of modern dental practice with the overall market for replacement and reconstruction of teeth expected to reach over $4 billion in the next several years. It is estimated that over 30 million people in the United States are missing all of the teeth in one or both of their jaws leading to lower quality of life. Most of these implants will be successful for long-term reconstruction, however, some fail early after implantations and some (up to 30%) eventually succumb to peri-implantitis which is usually caused by a bacterial biofilm infection. To counter peri-implantitis, current practice includes local and/or systemic antibiotic treatment and surgical removal of the infected bone area around the implant. Following surgical debridement of the infected bone, bone grafting with natural or substitute bone graft material is often performed. However, clinical experience has demonstrated that the current treatments including systemic and/or local antibiotic therapy, surgery, and combinations of these do not universally result in cure. BioVinc is a company founded to be a leader in bone related diseases and has recently demonstrated in the Phase I project, the feasibility of treating peri-implantitis with systemic delivery of a bisphosphonate-antibiotic (ciprofloxacin) conjugate. In this Phase II STTR proposal we will move the BioVinc peri-implantitis solution toward commercial use by combining the conjugate compound with a bone graft substitute material for use in this indication. The BioVinc solution will allow sustained local release of the antibiotic directly into the bone specifically at the area where surgical cleaning and graft placement was carried out, thus allowing high therapeutic concentrations of antibiotic to be achieved at the disease sites without the potential for systemic toxicities associated with these agents. Our plan is to seek approval of this combination as a class III device and thus have a streamlined regulatory pathway. Successful completion of the proposed work will allow us to commercialize our innovative conjugate/bone graft material, marking a significant advance in the treatment of peri-implantitis disease.

Public Health Relevance Statement:
PROJECT NARRATIVE The number of dental implants has increased to over 500,000 per year due to the much improved outcomes of implants over other treatments. However, an estimated 25% of these dental implants become infected with a bacterial biofilm, leading to peri-implantitis with chance of implant failure, and in some cases serious infections. Here we outline a treatment strategy for the unmet need of peri-implantitis antimicrobial therapy, which would be of significant value to the public health.

Project Terms:
Adverse effects; Affinity; analog; Animal Model; Anti-Infective Agents; Antibiotic Therapy; Antibiotics; antimicrobial; Area; bactericide; Biodistribution; Biological Availability; Biological Preservation; bisphosphonate; bone; Bone necrosis; Bone Substitutes; Bone Tissue; Bone Transplantation; Calcium; Canis familiaris; Carbamates; Cattle; Chemicals; Ciprofloxacin; Clinical; commercialization; Consultations; Data; Debridement; Dental; Dental General Practice; Dental Implants; Dentistry; design; Devices; Disease; Dose; Drug Combinations; Drug Kinetics; Excision; experience; Failure; Fluoroquinolones; Generations; Goals; Grant; Growth; Hydroxyapatites; Implant; implantation; improved; improved outcome; In Vitro; in vivo; Infection; Infectious Bone Diseases; innovation; intraperitoneal; Jaw; Kinetics; Lead; Letters; Link; long bone; Mediating; Medical Device; Medicine; microbial; Microbial Biofilms; Modeling; Modernization; next generation; novel; Operative Surgical Procedures; Organism; Osteolytic; Osteomyelitis; Parents; Particle Size; pathogen; Penetration; peri-implantitis; Periodontitis; Pharmaceutical Preparations; Pharmacodynamics; Phase; phase 1 study; Phenylcarbamates; Product Approvals; Public Health; Quality of life; Rattus; reconstruction; Regulatory Pathway; Resolution; Safety; Scheme; Sinus; Site; Small Business Technology Transfer Research; Surface; System; systemic toxicity; targeted treatment; Testing; Therapeutic; Therapeutic Index; Time; Tooth structure; Toxicology; Transplanted tissue; Treatment Efficacy; treatment strategy; United States; Work