Synthesis and Characterization of Bone Binding Antibiotic-1 (BBA-1), a Novel Antimicrobial for Orthopedic Applications.

Osteomyelitis and orthopedic infections are major clinical problems, limited by a lack of antibiotics specialized for such applications. In this paper, we describe the design and synthesis of a novel bone-binding antibiotic (BBA-1) and its subsequent structural and functional characterization. The synthesis of BBA-1 was the result of a two-step chemical conjugation of cationic selective antimicrobial-90 (CSA-90) and the bisphosphonate alendronate (ALN) via a heterobifunctional linker. This was analytically confirmed by HPLC, FT-IR, MS and NMR spectroscopy. BBA-1 showed rapid binding and high affinity to bone mineral in an in vitro hydroxyapatite binding assay. Kirby-Baur assays confirmed that BBA-1 shows a potent antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus comparable to CSA-90. Differentiation of cultured osteoblasts in media supplemented with BBA-1 led to increased alkaline phosphatase expression, which is consistent with the pro-osteogenic activity of CSA-90. Bisphosphonates, such as ALN, are inhibitors of protein prenylation, however, the amine conjugation of ALN to CSA-90 disrupted this activity in an in vitro protein prenylation assay. Overall, these findings support the antimicrobial, bone-binding, and pro-osteogenic activities of BBA-1. The compound and related agents have the potential to ensure lasting activity against osteomyelitis after systemic delivery.

Bisphosphonate-functionalized micelles for targeted delivery of curcumin to metastatic bone cancer.

Metastatic (secondary) bone cancer is one of the major causes of death in patients with advanced cancer. A lack of options for the targeted delivery of a desired therapeutic payload to multiple tumour modules located in the bone is still one of the foremost hurdles in the treatment/prevention of metastatic bone cancer. Curcumin has a proven anticancer potential with known challenges for application as a pharmaceutical agent. We have previously shown that micellar formulations could overcome some of these challenges and enhances its anti-cancer activity. In this study, we have developed a targeted drug delivery system using bisphosphonate (alendronate) conjugated Pluronic F127 micelles that could efficiently target, and specifically deliver curcumin to the osteolytic tumour microenvironment in the bone. Characterization of the formulation of curcumin-encapsulated alendronate-conjugated micelles demonstrated that the micelles have nanoscale size (∼27 nm) with a positive surface charge (+2.87 mV) and 4% drug loading. The alendronate-conjugated micelles showed significant bone-targeting potential. Rapid binding of the micelles to hydroxyapatite surface suggested that these nanoparticles are promising carriers for effective and targeted delivery of curcumin to osteolytic tumours in the bone.

The application of ceragenins to orthopedic surgery and medicine.

Osteomyelitis and infections associated with orthopedic implants represent a significant burden of disease worldwide. Ceragenins (CSAs) are a relatively new class of small-molecule antimicrobials that target a broad range of Gram-positive and Gram-negative bacteria as well as fungi, viruses, and parasites. This review sets the context of the need for new antimicrobial strategies by cataloging the common pathogens associated with orthopedic infection and highlighting the increasing challenges of managing antibiotic-resistant bacterial strains. It then comparatively describes the antimicrobial properties of CSAs with a focus on the CSA-13 family. More recently developed members of this family such as CSA-90 and CSA-131 may have a particular advantage in an orthopedic setting as they possess secondary pro-osteogenic properties. In this context, we consider several new preclinical studies that demonstrate the utility of CSAs in orthopedic models. Emerging evidence suggests that CSAs are effective against antibiotic-resistant Staphylococcus aureus strains and can prevent the formation of biofilms. There remains considerable scope for developing CSA-based treatments, either as coatings for orthopedic implants or as local or systemic antibiotics to prevent bone infection.