'Magic bullets' for bone diseases: progress in rational design of bone-seeking medicinal agents.
An ideal therapeutic agent for bone diseases should act solely on bone tissue with no pharmacological activity at other anatomical sites. Current therapeutic agents, however, do not usually display a preferential affinity to bones and non-specifically distribute throughout the body after administration. Attempts to design bone-specific agents have relied on engineering a desired therapeutic agent with bone-seeking molecules so that the latter delivers the therapeutic agents specifically to bones. In this critical review, we summarize the latest attempts to engineer bone-seeking therapeutic agents based on formulating therapeutic agents with bisphosphonates, a class of compounds with high affinity to biological apatite. We first provide a relevant summary of the structure of bone mineral and bisphosphonates, highlighting the mode of interaction between these two entities. The use of bisphosphonates in the diagnosis of bone diseases is then presented, since this application helps us to understand the bone-carrier properties of bisphosphonates under physiological conditions. A summary of recent attempts to formulate bisphosphonates with traditional therapeutic agents to restrict their activities to bone tissues is then provided, with special emphasis on the structure-function relationships of the engineered compounds. Finally, attempts to use bisphosphonates to deliver macromolecular therapeutics (i.e., proteins) are summarized, based on recent data from the authors' lab. The collective research into bone-seeking medicinal agents is progressively laying the foundation for next-generation 'magic bullets' that display desirable activities at the disease sites with no undesirable activity on other organ systems. (164 references.).
Zhang
Sufeng
S
Department of Chemical & Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, Alberta, Canada T6G 2G6.
Gangal
Geeti
G
Uludağ
Hasan
H
D000900:Anti-Bacterial Agents / Q000737:chemistry; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D001847:Bone Diseases / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D004164:Diphosphonates / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D015195:Drug Design; D015394:Molecular Structure; D010778:Photochemotherapy; D011506:Proteins / Q000737:chemistry
D000900:Anti-Bacterial Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004337:Drug Carriers; D011506:Proteins