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Advanced Drug Delivery Reviews (v.57, #7)

Editorial Board (pp. ii).

Targeted drug delivery for musculoskeletal diseases by Dong Wang; Scott C. Miller; Jindřich Kope�?ek (pp. 935-937).

Quest for the Holy Grail to cure arthritis and osteoporosis: Emphasis on bone drug delivery systems by Daniel G. Arkfeld; Elyse Rubenstein (pp. 939-944).

The number of new medications to treat and even prevent arthritis and osteoporosis has expanded dramatically in recent years. Where once there were only surgical options to treat such end-stage diseases, there are now treatments targeted at the early steps in musculoskeletal pathophysiology. The use of different modalities to maximize drug access to specific bone tissues has created a golden opportunity for mechanistic studies in drug delivery systems for treating osteoporosis and other musculoskeletal diseases. This theme issue provides a timely analysis of the challenges and accomplishments in delivering medicine to the target sites in the musculoskeletal system and also provides a preview of what may come in the future for musculoskeletal medicine. As the number of animal studies and clinical trials is on the rise, the possibility to prevent or even cure the aforementioned disorders has never been closer.

Keywords: Arthritis; Osteoporosis; Drug delivery; Bone; Musculoskeletal disorders

Skeletal function and structure: Implications for tissue-targeted therapeutics by Jill E. Shea; Scott C. Miller (pp. 945-957).

Osteoporosis, arthritis, and periodontal disease are common diseases of the skeleton, all of which could benefit from new therapeutic strategies, including targeted drug delivery. While bone is a rigid structure, it is not inert, with the cells of the skeleton being able to repair damage and respond to alterations in mechanical stimuli and various endocrine agents. Several important factors related to bone physiology that could influence the success of a pharmacological treatment include heterogeneity in bone remodeling activities throughout the skeleton, differences in blood supply and local vascularization, and the “blood–bone�? barrier. The structural qualities of bone, especially the presence of hydroxyapatite crystals in the bone mineral and the established binding of certain molecules to this mineral phase, including tetracyclines, bisphosphonates, and other chelators, provide unique opportunities to treat skeletal diseases using targeted drug delivery. Additional opportunities exist in targeting sites with contrasting bone surface activities, including surfaces that are inactive, forming new bone or being resorbed. The ultimate key to developing new bone-targeted therapies is to understand and exploit the physiological characteristics at the desired target sites.

Keywords: Bone physiology; Bone remodeling; Bone structure; Vascularity; Osteoporosis; Rheumatoid arthritis; Bone targeting

Mechanism of osteoclast mediated bone resorption—rationale for the design of new therapeutics by Kalervo V��n�nen (pp. 959-971).

Bone resorption is an important cellular function in the development and physiology of the skeleton. Pathophysiology of several skeletal diseases includes either increased (for instance osteoporosis, metastatic bone disease and Paget's disease of bone) or decreased (various syndromes of osteopetrosis) bone resorption rate. Thus there is a genuine need to regulate, especially inhibit, bone resorption rate in several diseases. Bone resorption can be inhibited by several strategies. One can prevent osteoclast formation, inhibit their action or induce premature cell death. All these strategies have been used in pharmacology to inhibit bone resorption and there are also physiological regulators for each of these three different phases of in osteoclast life.Many present resorption inhibitors inhibit osteoclast formation via osteoblastic cells since they are producing a number of factors that are essential for osteoclast differentiation. Best characterized of these factors are macrophage colony stimulating factor (M-CSF) and receptor activator of NF�B ligand (RANKL). For instance sex steroids, parathyroid hormone and some interleukins are known to exert their positive or negative effects on osteoclast differentiation via the RANK/RANKL/osteoprotegrin pathway. It is not yet clear enough how specific intervention to osteoclast formation is since also other cell lineages derived from hematopoetic precursors use similar signalling pathways.An effective inhibition of bone resorption can also be achieved by inhibiting osteoclast activity to resorb bone. Examples of this category of physiological and pharmacological inhibitors are calcitonin and aminobisphosphonates, respectively. Finally one can reduce bone resorption by shortening osteoclast lifespan with substances that induce apoptosis in osteoclasts. A good example of these substances is a first generation bisphosphonate, clodronate. Several new potential molecular targets have been revealed during recent years since many individual molecules in osteoclast differentiation, function and apoptosis have been identified and their physiological functions revealed. Thus we are expecting several new bone inhibitors to be developed in following years both for experimental studies and finally also for clinical use.

Keywords: Bone; Resorption; Osteoclast; Intracellular trafficking; Osteoporosis

The role of cathepsins in osteoporosis and arthritis: Rationale for the design of new therapeutics by Yoshiyuki Yasuda; Jadwiga Kaleta; Dieter Br�mme (pp. 973-993).

Human cysteine proteases of the papain family have been recognized as potential drug targets for musculoskeletal diseases. Most of the interest is focused on cathepsins S and K, which display selective expression in cells of the immune system and cells capable to efficiently degrade extracellular matrix proteins, in particular collagens. The predominant expression of cathepsin K in osteoclasts has rendered the enzyme into a major target for the development of novel anti-resorptive drugs in osteoporosis whereas cathepsin S appears to be an attractive drug target candidate for various inflammatory diseases including rheumatoid arthritis. Since rheumatoid arthritis is at the same time an inflammatory and joint destructive disorder, the combined inhibition of both cathepsins S and K should be beneficial. This review will outline the rationale and recent progress for targeting cathepsins in arthritis and osteoporosis.

Keywords: Cathepsin K; Cathepsin S; Cysteine proteases; Osteoporosis; Arthritis; Cysteine protease inhibitors

Targeting of therapeutic agents to bone to treat metastatic cancer by Cedo M. Bagi (pp. 995-1010).

The three main organs affected by metastasis of all cancers include lungs, liver, and bone. Clinical confirmation of tumor spread to these organs is a negative prognostic sign that marks the stage when disease is rarely curable. Today, treatment of bone metastases is primarily palliative. The aims of treatment are to relieve pain, prevent development of pathologic fractures, improve mobility and function, and if possible, prolong survival. Significant improvements in our understanding of tumor biology along with early tumor detection has led to the discovery of few innovative approaches aimed to treat bone metastases. The most promising treatment modalities include combination of anti-cancer therapies (surgery, radiation therapy, citostatic therapy) with bone antiresorptive therapies (bisphosphonate) that specifically target osteoclasts, bone resorbing cells. The osteoclast, whose increased activity is induced by the tumor, is responsible for the deterioration of bone mass and structure along with the release of grow factors that feed back and support further tumor growth. The current pharmaceutical approach is to target bone metastases by developing drugs that specifically target tumor cells in bone in addition to bone stroma since skeletal metastases are more resistant to treatment, present the highest bulk of tumor mass in the body, serve as site for secondary spread of tumor cells, and are associated with significant morbidity. There is a real need for a more effective modified release of newer anti-cancer drugs such as gene therapy and immunotherapy by using established and novel delivery platforms that will improve therapy and reduce side effects as a result of more appropriate plasma profiles. Overall, however, developments regarding treatment of cancer metastases to bone are encouraging. The scope of future advancements is immense and includes innovative therapeutics and delivery systems aimed to improve skeletal affinity, selectivity, and efficacy of drugs.

Keywords: Bone metastases; Breast cancer; Prostate cancer; Treatment modalities

Designing proteins for bone targeting by Sébastien A. Gittens; Geeti Bansal; Ronald F. Zernicke; Hasan Uludağ (pp. 1011-1036).

Protein-based therapeutic agents intended for bone diseases should ideally exhibit a high affinity to bone tissue, so that their systemic administration will result in specific delivery to bone with minimal distribution to extra-skeletal sites. This was shown possible in the authors' lab by modifying a desired protein with bisphosphonates (BPs) that exhibit an exceptionally high affinity to the bone-mineral hydroxyapatite. In this review, we explore the potential applications of that concept by summarizing the bone diseases and candidate proteins that will benefit from the proposed bone delivery approach. A selective synopsis of BP synthesis is presented to highlight the synthesis of functional BPs suitable for covalent attachment to proteins. Finally, we present a summary of recent research results from the authors' laboratory emphasizing factors influencing bone affinity of the conjugates. We conclude with future research avenues that are considered critical for clinical entry of the BP-targeted therapeutic agents.

Keywords: Bone targeting; Drug delivery; Bisphosphonate synthesis; Disease-modifying proteinaceous drugs; Skeletal diseases

Synthetic biodegradable polymers as drug delivery systems for bone morphogenetic proteins by N. Saito; N. Murakami; J. Takahashi; H. Horiuchi; H. Ota; H. Kato; T. Okada; K. Nozaki; K. Takaoka (pp. 1037-1048).

Bone morphogenetic proteins (BMP) induce bone formation in vivo, and clinical application in repair of bone fractures and defects is expected. However, appropriate systems to deliver BMP for clinical use need to be developed. We synthesized a new synthetic biodegradable polymer, poly-d,l-lactic acid-para-dioxanone-polyethylene glycol block copolymer (PLA-DX-PEG), to serve as a biocompatible, biodegradable polymer for recombinant human (rh) BMP-2 delivery systems. In animal experiments, new bone was efficiently formed and a large bone defect was repaired using PLA-DX-PEG/rhBMP-2 composites. In addition, this new polymer could be used as an injectable delivery system for rhBMP-2. The rhBMP-2/PLA-DX-PEG composites also could be combined with other materials such as hydroxyapatite or titanium. This new synthetic polymer might be used for rhBMP-2 delivery in various clinical situations involving repair of bone, leading to great changes in orthopedic treatment.

Keywords: Bone formation; Bone repair; Fracture; Bone defect; Recombinant human bone morphogenetic protein-2; Tissue engineering

Bone-targeting macromolecular therapeutics by Dong Wang; Scott C. Miller; Pavla Kope�?ková; Jindřich Kope�?ek (pp. 1049-1076).

Musculoskeletal diseases such as osteoporosis are recognized as major public health problems worldwide. Many novel therapeutic agents have been identified for the treatment of these diseases. However, the majority of them are not specific to hard tissue, resulting significant toxicity. Bone-targeting drug delivery systems based on water-soluble polymers can specifically direct candidate drugs to bone thereby reducing side effects due to non-specific tissue interactions. Incorporation of a targeting moiety, a drug release mechanism, drug selection and optimization of the polymer carrier are all essential elements in the development of bone-targeting macromolecular therapeutics. Successful clinical application of this approach can significantly contribute to the development of treatments for many musculoskeletal diseases.

Keywords: Bone-targeting; Drug delivery; HPMA copolymer; Hydroxyapatite; Metalloproteinases (MMPs); Cathepsin K; Polyethylene glycol (PEG); Osteoporosis; Cancer bone metastasis; Rheumatoid arthritis

Guide to Authors (pp. 1077-1081).

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Advanced Drug Delivery Reviews (v.57, #7)