Pulmonary Delivery of Ceftazidime for the Treatment of Melioidosis in a Murine Model.

Burkholderia pseudomallei, the etiological agent responsible for melioidosis, exhibits a great public health toll in its endemic regions. The elevation of B. pseudomallei to a Tier I select agent underscores the urgent need for effective therapeutics and preventatives. The current treatment regimen for melioidosis is suboptimal, requiring an intensive phase of intravenous antibiotic followed by months of oral antibiotics. Inhaled antibiotics are a promising avenue to pursue for pulmonary diseases, including melioidosis, since this mode of delivery mimics the likely exposure route and can provide high drug doses directly to the infected tissue. Ceftazidime was delivered via a nose-only system to BALB/c mice challenged with B. pseudomallei. Mice treated with nebulized ceftazidime became symptomatic but survived until study end, which was comparable to those treated intraperitoneally. Upon necropsy, bacteria remained within the spleens of the majority of the experimental animals. The effectiveness of nebulized ceftazidime warrants additional studies to improve the treatment regimen and to test as a prophylactic therapy against B. pseudomallei.

Formulation and Characterization of Nanocluster Ceftazidime for the Treatment of Acute Pulmonary Melioidosis.

Melioidosis is an infectious disease caused by Burkholderia pseudomallei. The disease is responsible for a high proportion of human pneumonia and fatal bacteremia in the endemic areas of the world and is highly resistant to most commonly available antibiotics. Studies have shown that prophylactic antibiotic treatment, when administered 24 h following bacterial challenge, can prevent infection in a murine model. Prophylactic treatment against this disease using a pulmonary antibiotic formulation has not previously been examined, but may reduce the number of treatments required, allow for the delivery of higher doses, eliminate the need for intravenous administration, and help to minimize systemic side effects. Ceftazidime was formulated as a dry powder aerosol suitable for pulmonary delivery using previously developed NanoCluster dry powder technology. Pharmacokinetics of aerosolized ceftazidime was analyzed in a mouse model. This study demonstrates that ceftazidime can be formulated using NanoCluster technology as a dry powder aerosol suitable for pulmonary delivery to humans. We have also demonstrated the retention of nebulized ceftazidime in mouse lungs for up to 6 h after exposure. The results indicate that this treatment may be useful as a prophylactic treatment against melioidosis. Future work will examine the efficacy of this treatment against B. pseudomallei aerosol challenge.

Fluorinated copolymer nanoparticles for multimodal imaging applications.

Nanomaterials have emerged as valuable tools in biomedical imaging techniques. Here, the synthesis and characterization of a novel fluorinated nanoparticle with potential applications as an MRI contrast agent is reported. Particles were synthesized using a free radical polymerization technique. Secondary ion mass spectrometry analysis showed that the particles' surface contained fluorinated groups and nitrogen-containing groups. Solid-state NMR spectroscopy suggested the presence of two distinct fluorine resonances, which conforms to the structure of the fluorinated monomer. Ongoing studies aim to evaluate the performance of the nanoparticles as MRI contrast agents both in vitro and in vivo.

Therapeutic Particles and Biomaterials Technology Laboratory at the University of Kansas.

Novel technologies to enhance therapeutic delivery and biomaterial performance are fundamental to the development of improved products with fewer unwanted side effects. The Therapeutic Particles and Biomaterials Technology Laboratory at The University of Kansas (KS, USA) works at the interface of medicine and engineering to develop novel materials that enhance therapeutic delivery in a variety of biomedical applications. Research areas include aerosol drug delivery, targeted nanoparticles for drug and contrast agent delivery, biomaterials for tissue engineering and polymer therapeutics. The lab works with industry, academia and law firms through a variety of mechanisms such as fee-for-service, contract research and collaboration. Ultimately, the group aims to develop materials and drug delivery platforms that are fundamentally unique yet simple solutions to improve human health.

Nanoparticle formulations in pulmonary drug delivery.

The advent of nanotechnology has reignited interest in the lungs as a major route of drug delivery for both systemic and local treatments. The large surface area of the lungs and the minimal barriers impeding access to the lung periphery make this organ a suitable portal for a variety of therapeutic interventions. Nanoparticles provide new formulation options for both dispersed liquid droplet dosage forms such as metered dose inhalers and nebulizers, and dry powder formulations. Nanoparticle formulations have many advantages over traditional dosage forms, such as enhanced dissolution properties and the potential for intracellular drug delivery. Specifically, pure drug nanoparticles, polymeric nanoparticles, polyelectrolyte complexes, and drug-loaded liposomes offer some encouraging results for delivering drugs to and through the lungs. Methods are also being investigated to produce nanoparticles with properties suitable for improving access to the peripheral lung. Traditional techniques such as spray drying and grinding, and more recent advances in supercritical fluid extraction, precipitation, and solvent extraction have been employed to produce nanoparticle formulations for pulmonary delivery. Here, the benefits of nanoparticle formulations and current progress are compared in light of the practical encumbrances of producing formulations, and possible toxicological effects of these materials.

Pure insulin nanoparticle agglomerates for pulmonary delivery.

Diabetes is a set of diseases characterized by defects in insulin utilization, either through autoimmune destruction of insulin-producing cells (Type I) or insulin resistance (Type II). Treatment options can include regular injections of insulin, which can be painful and inconvenient, often leading to low patient compliance. To overcome this problem, novel formulations of insulin are being investigated, such as inhaled aerosols. Sufficient deposition of powder in the peripheral lung to maximize systemic absorption requires precise control over particle size and density, with particles between 1 and 5 microm in aerodynamic diameter being within the respirable range. Insulin nanoparticles were produced by titrating insulin dissolved at low pH up to the pI of the native protein, and were then further processed into microparticles using solvent displacement. Particle size, crystallinity, dissolution properties, structural stability, and bulk powder density were characterized. We have demonstrated that pure drug insulin microparticles can be produced from nanosuspensions with minimal processing steps without excipients, and with suitable properties for deposition in the peripheral lung.

A comparison of human umbilical cord matrix stem cells and temporomandibular joint condylar chondrocytes for tissue engineering temporomandibular joint condylar cartilage.

The temporomandibular joint (TMJ) presents many problems in modern musculoskeletal medicine. Patients who suffer from TMJ disorders often experience a major loss in quality of life due to the debilitating effects that TMJ disorders can have on everyday activities. Cartilage tissue engineering can lead to replacement tissues that could be used to treat TMJ disorders. In this study, a spinner flask was used for a period of 6 days to seed polyglycolic acid (PGA) scaffolds with either TMJ condylar chondrocytes or mesenchymal-like stem cells derived from human umbilical cord matrix (HUCM). Samples were then statically cultured for 4 weeks either in growth medium containing chondrogenic factors or in control medium. Immunohistochemical staining of HUCM constructs after 4 weeks revealed a strong presence of collagen I and minute amounts of collagen II, whereas TMJ constructs revealed little collagen I and no collagen II. The HUCM constructs were shown to contain more GAGs than the TMJ constructs quantitatively at week 0 and histologically at week 4. Moreover, the cellularity of HUCM constructs was 55% higher at week 0 and nearly twice as high after 4 weeks, despite being seeded at the same density. The increased level of biosynthesis and higher cellularity of HUCM constructs clearly demonstrates that the HUCM stem cells outperformed the TMJ condylar cartilage cells under the prescribed conditions. HUCM stem cells may therefore be an attractive alternative to condylar cartilage cells for TMJ tissue engineering applications. Further, given the availability and ease of obtaining HUCM stem cells, these findings may have far-reaching implications, leading to novel developments in both craniofacial and orthopaedic tissue replacement therapies.