Bone-targeted Delivery Research Articles

Novel Treatment Option for Rheumatoid Arthritis through Bone‐Targeted Delivery of Novokinin

ObjectiveRheumatoid arthritis (RA) is an autoimmune inflammatory disorder affecting about 1‐2% of the world population. RA is known to be a major cause of disability which progresses eventually to systemic complexities with high chances of early morbidity. This complex dynamic situation of inflammation is orchestrated by multiple systems in the body, including the Renin‐Angiotensin System (RAS). Angiotensin II (Ang II), a main effector peptide in the RAS, predominantly binds to Angiotensin II Type (I) receptor (AT1R). When it overproduced can result in inflammation, vasoconstriction, and oxidative stress. Ang II also binds to Angiotensin II Type (II) receptor (AT2R), which provides functional antagonism to AT1R activation. Novokinin, a synthetic peptide, promotes beneficial effects through activation of AT2R, and can be considered a potential drug candidate for alternative therapy in RA if its plasma stability and half‐life could be improved. Here, we developed a novel bone‐targeting novokinin Conjugate (Novo Conj), which binds to the bone, utilizes it as a reservoir while protecting it from enzymatic and hydrolytic degradation. We hypothesized that this delivery approach would extend the peptide half‐life and provide sustained plasma levels to elicit anti‐inflammatory activity.MethodHealthy male, Sprague Dawley rats, were induced adjuvant arthritis (AA) by administering 0.2mL of 50mg/mL of Mycobacterium butyricum through the tail base injection. Arthritic rats were divided into three groups (n=5/group) and dosed with saline (Inflamed), novokinin of 400 µg/kg (Novokinin), or an equivalent dose of 400 µg/kg of novokinin (Novo Conj). A group of healthy rats (n=5) received saline and was taken as a healthy control (Control) group. After the emergence of arthritis (i.e., 10‐12 days after adjuvant arthritis induction), animals were dosed with assigned treatment every other day for two weeks. Animals were monitored three times a week for their body weight, paw, and joint diameters. At the end of the experiment, rats were euthanized, plasma/tissues were harvested and analyzed for plasma nitric oxide (NO) and the RAS components by western blot.ResultsThe induction of AA led to a significant reduction in percent body weight gain over time, increased paws and joints swelling, and elevated plasma NO levels. AA brought an imbalance in the RAS enzymatic inflammatory axis indicator, i.e., Angiotensin‐Converting Enzyme (ACE) and ACE2 causing a reduction in ACE2/ACE and AT2R/AT1R ratio. The treatment of arthritic rats by novokinin and Novo Conj restored their body weight gain, reduced paws and joints' swelling, lowered the plasma NO level, and reinstated the imbalanced ratios of enzymes and receptors. These observed anti‐inflammatory effects were significantly higher in the Novo Conj group.ConclusionThis result indicates that the novokinin and its bone‐targeted conjugate shows anti‐inflammatory effects through the RAS. The observed enhanced impacts could be attributed to improved stability and extension of the half‐life of novokinin through its conjugation and binding to the bone. Our novel bone‐targeting delivery of novokinin offers effective alternative therapy for managing RA signs and symptoms and could be further utilized for various RAS disorders.

Bone-targeted polymeric nanoparticles as alendronate carriers for potential osteoporosis treatment

Bone-targeted polymeric nanoparticles for alendronate delivery based on Poly (lactic-co-glycolic acid) conjugated chitosan (CS-PLGA) and alendronate conjugated PLGA (Alen-PLGA) are fabricated and their superior performances are evaluated. The nanoparticles exhibited sustained Alen release without obvious burst release and good cytocompatibility against MC3T3 cells. Alen-modified nanoparticles demonstrated a high affinity to hydroxyapatite, which is the main mineral component of bone, indicating their feasibility for bone-targeted delivery. In addition, unlike nanoparticles without Alen, Alen-modified nanoparticles were preferentially taken up by MC3T3 cells, compared to HDF cells, revealing their specific uptake for osteoblast-like cells. Thus, the Alen-modified nanoparticles can potentially be developed as bone-targeted carriers for osteoporosis treatment.

Remote-controllable bone-targeted delivery of estradiol for the treatment of ovariectomy-induced osteoporosis in rats

BackgroundOsteoporosis (OP) is a systemic skeletal disease marked by bone mass reduction and bone tissue destruction. Hormone replacement therapy is an effective treatment for post-menopausal OP, but estrogen has poor tissue selectivity and severe side effects.ResultsIn this study, we constructed a poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs)-based drug delivery system to co-load 17β estradiol (E2) and iron oxide (Fe3O4) together, modified with alendronate (AL) to achieve bone targeting and realize a magnetically remote-controllable drug release. The NPs were fabricated through the emulsion solvent diffusion method. The particle size was approximately 200 nm while the encapsulation efficiency of E2 was 58.34 ± 9.21%. The NPs were found to be spherical with a homogenous distribution of particle size. The NPs showed good stability, good biocompatibility, high encapsulation ability of E2 and excellent magnetic properties. The NPs could be effectively taken up by Raw 264.7 cells and were effective in enriching drugs in bone tissue. The co-loaded NPs exposed to an external magnetic field ameliorated OVX-induced bone loss through increased BV/TV, decreased Tb.N and Tb.Sp, improved bone strength, increased PINP and OC, and downregulated CTX and TRAP-5b. The haematological index and histopathological analyses displayed the NPs had less side effects on non-skeletal tissues.ConclusionsThis study presented a remote-controlled release system based on bone-targeted multifunctional NPs and a new potential approach to bone-targeted therapy of OP.Graphic abstract

Alendronate-Decorated Nanoparticles as Bone-Targeted Alendronate Carriers for Potential Osteoporosis Treatment.

Osteoporosis is a skeletal disorder characterized by a low bone mass and density. Alendronate (Alen), a second-generation bisphosphonate drug, was indicated as the first-line regimen for the treatment of osteoporosis. However, the use of Alen has been limited due to its low bioavailability and gastrointestinal side effects. Herein, Alen-decorated nanoparticles were prepared through ionic cross-linking between poly (lactic-co-glycolic acid), β-cyclodextrin-modified chitosan (PLGA-CS-CD), and Alen-modified alginate (ALG-Alen) for Alen loading and bone-targeted delivery. Alen was selected as a therapeutic drug and a bone-targeting ligand. The nanoparticles have negatively charged surfaces, and sustained release of Alen from the nanoparticles can be observed. Cytotoxicity detected using cell counting kit-8 (CCK-8) assay and lactate dehydrogenase release test on MC3T3 cells showed that the nanoparticles had good cytocompatibility. A hemolysis test showed that the hemolysis ratios of nanoparticles were <5%, indicating that the nanoparticles had no significant hemolysis effect. Moreover, the Alen-decorated nanoparticles exhibited enhanced binding affinity to the hydroxyapatite (HAp) disks compared with that of nanoparticles without Alen modification. Thus, the Alen-decorated nanoparticles might be developed as promising bone-targeted carriers for the treatment of osteoporosis.

Calcium-bisphosphonate Nanoparticle Platform as a Prolonged Nanodrug and Bone-Targeted Delivery System for Bone Diseases and Cancers.

Bone and bone-related diseases are the major cause of mobility hindrance and mortality in humans and there is no effective and safe treatment for most of them, especially, for bone and bone metastatic cancers. Bisphosphonates (BPs) are a group of small-molecule drugs for treating osteoporosis and bone cancers but have a very short half-life in circulation, requiring high doses and long-term repeat use that can cause severe side effects. Previous attempts of using nanoparticles to deliver BPs have issues of drug loading capacity and endosome escape/drug release. The present study reports the direct synthesis of BP nanoparticles by precipitating bone-favorable calcium ions and a third-generation BP, risedronate (Ca-RISNPs), to achieve high drug loading, endosomal release, and strong bone-targeting properties. The Ca-RISNPs are monodispersed with high stability at physiological pH but readily dissociate at endosomal pH conditions. They demonstrate strong penetration ability and uniform distribution in human bone and cartilage tissues and the superior drug and DNA (plasmid and oligo double strand DNA) delivery capacity in bone cells. These NPs also exhibit high specificity in killing tumor-associated macrophages (TAMs) and inhibit TAM-induced tumor cell migration. Collectively, our data indicate that this BP nanodrug platform has a great potential in managing bone-related diseases and cancers as a prolonged BP nanodrug and simultaneously as the bone-targeted drug delivery system.

An MSC bone-homing compound, Rab001, increases bone mass and reduces the incidence of osteonecrosis in a glucocorticoid-induced osteonecrosis mouse model.

Currently, there are no effective medications to either prevent or slow the progression of atraumatic osteonecrosis (ON).The objective of this study is to determine the effects of bone-targeted delivery of mesenchymal stem cells on the prevalence of ON in a glucocorticoid (GC)-induced mouse model. Eight-week-old male BALB/c mice were randomized into groups that received placebo (PL), prednisolone (GC), or concurrent treatments with GC+mesenchymal stromal cells (MSCs), Rab001 or GC+Rab001 + MSCs. Human parathyroid hormone (hPTH) was used as a positive control for bone anabolism. Mice were killed after 30days, and quantitative measurements of bone mass, bone strength, prevalent ON at the distal femoral epiphysis (DFE) were performed. Angiogenesis was accessed by RNA-Seq, the circulating angiogenic markers, as well as by immunohistochemical staining. We have showed that a novel agent, Rab001 that can noncovalently bind to mesenchymal stem cells (MSC) and direct them to the bone, prevents the incidence of glucocorticoid-induced osteonecrosis in the mouse. In contrast, PTH, a bone anabolic treatment, preserves bone mass but sustains higher ON incidence than Rab001+/- MSC-treated mice. The results of these experiments reveal that glucocorticoids increase the prevalence of ON, and agents that prevent loss of bone vascularity appear to prevent the development of ON. This intervention might be useful in patients with early stages of atraumatic ON.

Bone-Targeted Drug Delivery Systems and Strategies for Treatment of Bone Metastasis.

Bone metastases can cause high morbidity and mortality, often developing as they advance, especially in patients with prostate and breast cancers. Most drugs are rarely distributed to the bone and are hence pharmacologically ineffective in treating bone metastases. The development of drug targeting technologies is required for the efficient treatment of bone metastases. To date, numerous bone-targeting ligands, including tetracyclines, bisphosphonates, aspartic acid, and aptamers have been developed and used for bone-targeted delivery of anti-tumor drugs, peptide/protein drugs, nucleic acid drugs, and diagnostic imaging agents. The conjugates of drugs with bone-targeting ligands were first developed in the field of bone drug targeting systems; macromolecular carriers and nanoparticles modified with these bone-targeting ligands have also been developed. Additionally, antibodies to prostate-specific membrane antigen (PSMA) and human epidermal growth factor receptor 2 (HER2) are used in active targeting bone metastatic prostate cancer and breast cancer, respectively. Some conjugates using antibodies to PSMA and HER2 were developed and used in clinical trials. In this review, recent challenges in the development of bone-targeted delivery systems and strategies for the treatment of bone metastasis have been summarized. Future development of novel drug formulations in order to optimize targeted drug delivery in the treatment of bone metastasis have also been discussed.

Nanocomposites drug delivery systems for the healing of bone fractures.

The skeletal system is fundamental for the structure and support of the body consisting of bones, cartilage, and connective tissues. Poor fracture healing is a chief clinical problem leading to disability, extended hospital stays and huge financial liability. Even though most fractures are cured using standard clinical methods, about 10% of fractures are delayed or non-union. Despite decades of progress, the bone-targeted delivery system is still restricted due to the distinctive anatomical bone features. Recently, various novel nanocomposite systems have been designed for the cell-specific targeting of bone, enhancing drug solubility, improving drug stability and inhibiting drug degradation so that it can reach its target site without being removed in the systemic circulation. Such targeting systems could consist of biological compounds i.e. bone marrow stem cells (BMSc), growth factors, RNAi, parathyroid hormone or synthetic compounds, i.e. bisphosphonates (BPs) and calcium phosphate cement. Hydrogels and nanoparticles are also being employed for fracture healing. In this review, we discussed the normal mechanism of bone healing and all the possible drug delivery systems being employed for the healing of the bone fracture.

A bone-targeting delivery system carrying osteogenic phytomolecule icaritin prevents osteoporosis in mice

Targeting delivery system has been widely used in packaging drugs for medical therapies attributed to its high efficiency and efficacy. A Traditional Chinese Medicine (TCM) formula consisting of Herba Epimedii has previously been shown to effectively treat postmenopausal osteoporosis. We have subsequently found that icaritin, which was a flavonoid isolated from both Herba Epimedii and its serum metabolites after oral administration, inhibited the adipogenic capacity of bone mesenchymal stem cells (BMSCs) while promoted their osteogenesis. However, previous pharmacokinetic analyses have shown that icaritin had a short half-life in blood and only trace amounts of the molecule reach the bone tissue. To overcome this limitation, we developed a bone-targeting liposome containing an oligopeptide of eight aspartate residues (Asp8), which had previously been shown to specifically target the bone, encapsulating icaritin. In vivo, we found that the Asp8-icaritin-liposome enhanced bone formation in ovariectomized mice compared to an icaritin-liposome control lacking the Asp8 moiety. Through in vitro mechanistic studies we further found that icaritin inhibited adipogenesis through an Akt/GSK-3β/β-catenin signaling pathway. Taken together, our study shows that Asp8-liposome as a bone-targeting delivery system is effective to carry an osteogenic phytomolecule for facilitating and enhancing its therapeutic effects on the prevention of estrogen depletion-induced osteoporosis.

Bone-targeted delivery of simvastatin-loaded PEG-PLGA micelles conjugated with tetracycline for osteoporosis treatment.

This study aimed to investigate the improved therapeutic efficacy and pharmacokinetic profiles of simvastatin (SIM) with imparted bone targeting potential using tetracycline-mediated PEG-PLGA (TC-PEG-PLGA) micelles in osteoporotic rats. The SIM-loaded TC-PEG-PLGA (TC-PEG-PLGA/SIM) micelles were evaluated for particle size, morphology, stability, loading efficiency, cell viability, bone mineral binding ability in vitro, mineralization, pharmacokinetics, and pharmacodynamics. TC-PEG-PLGA conjugates were successfully and could self-assembly form micelles in aqueous medium with a 19.4μg/mL critical micelle concentration. Then, TC-PEG-PLGA/SIM micelles were prepared with solvent diffusion method, and the obtained micelles (56.21 ± 7.39nm average size; 81.8 ± 3.1% encapsulation efficiency; and 7.56 ± 0.27% drug loading) led to the prolonged release of SIM from micelles. Cellular uptake test indicated that TC had no effects on micellar internalization and micellar internalization was mainly involved with clathrin-mediated endocytic pathway. In vivo pharmacokinetic results indicated that TC-PEG-PLGA/SIM micelles exhibited a significantly prolonged time in systemic circulation and were preferentially accumulated in bone tissue. TC-PEG-PLGA/SIM micelles showed better therapeutic effects, as reflected by the improved bone mineral density, bone mineral content, and bone mechanical strength. Overall, these results suggested that TC-PEG-PLGA/SIM micelles provide several advantages, including prolonged systemic circulation, enhanced bone tissue distribution, and improved therapeutic outcomes in osteoporotic rats.

Bortezomib-catechol conjugated prodrug micelles: combining bone targeting and aryl boronate-based pH-responsive drug release for cancer bone-metastasis therapy.

The treatment of metastatic tumors is highly desirable in clinics, which has also increased the interest in the design of nanoscale drug delivery systems. Bone metastasis is one of the most common pathways in the metastasis of breast cancer, and it is also an important cause for tumor recurrence and death. The aryl boronate group, as an acid-labile linker, has been introduced into nano-assemblies in recent years. Especially, as a proteasome inhibitor anticancer drug with a boric acid group, bortezomib can facilitate the formation of pH-sensitive aryl boric acid ester linkage with the catecholic group. In this study, bortezomib-loaded micelles with bone targeting properties were constructed for the treatment of breast cancer bone metastasis. The mixed micelles employed alendronate (ALN) as the bone-targeting ligand and encapsulated bortezomib-catechol conjugates as the cargo. In vitro and in vivo studies showed that compared with free drugs or control micelles, these prodrug micelles (ALN-NP) exhibited many favorable properties such as reduced systemic toxicity and improved therapeutic effects. Therefore, ALN-NP is promising as a nanovehicle for bone-targeting delivery of chemotherapeutic drugs. Furthermore, this study offers a novel strategy combining bone targeting and aryl boronate-based pH-responsive drug release for anti-metastasis therapy.

A novel bone targeting delivery system carrying phytomolecule icaritin for prevention of steroid-associated osteonecrosis in rats

One of the effective strategies for prevention of steroid-associated osteonecrosis (SAON) is to inhibit bone resorption and fat formation and promote bone formation at osteonecrotic sensitive skeletal sites. We identified a novel phytomolecule that showed positive effects on osteogenesis, anti-bone resorption and anti-adipogenesis in vitro and also developed a bone-targeting delivery system (BTDS) for in vivo experimental study. The study investigated if our innovative synthesized BTDS carrying this phytomolecule would be able to effectively prevent SAON in a rat model. SAON was induced by combined injections of lipopolysaccharide and methylprednisolone. SAON rats were divided into four groups, one SAON untreated control group and three SAON treatment groups with different types of delivery systems (Asp8-liposome-icaritin, liposome-icaritin and Asp8-liposome) for two weeks. SAON lesions were identified and osteoclasts activity, osteogenesis and adipogenesis at these sites were evaluated by immunohistochemistry. Ex vitro study was also designed to evaluate the osteogenic and adipogenic potential of the isolated bone marrow stromal cells (BMSCs) via real-time PCR and histochemical staining. Our results showed that as a bone surface-specific BTDS, Asp8-liposome-icaritin effectively prevented steroids-treated rats from SAON with significantly decreased osteocytes apoptosis, down-regulated osteoclatsogenesis and up-regulated osteogenesis. However, both liposome-icaritin and Asp8-liposome treatment did not show significant efficacy for SAON prevention. In summary, this proof-concept-study showed for the first time that the innovative Asp8-liposome-icaritin BTDS was effective for prevention of SAON in terms of bone resorption prevention, adipogenesis suppression, and bone-formation enhancement.

Design, Synthesis, and Antimicrobial Evaluation of a Novel Bone-Targeting Bisphosphonate-Ciprofloxacin Conjugate for the Treatment of Osteomyelitis Biofilms.

Osteomyelitis is a major problem worldwide and is devastating due to the potential for limb-threatening sequelae and mortality. Osteomyelitis pathogens are bone-attached biofilms, making antibiotic delivery challenging. Here we describe a novel osteoadsorptive bisphosphonate-ciprofloxacin conjugate (BV600022), utilizing a "target and release" chemical strategy, which demonstrated a significantly enhanced therapeutic index versus ciprofloxacin for the treatment of osteomyelitis in vivo. In vitro antimicrobial susceptibility testing of the conjugate against common osteomyelitis pathogens revealed an effective bactericidal profile and sustained release of the parent antibiotic over time. Efficacy and safety were demonstrated in an animal model of periprosthetic osteomyelitis, where a single dose of 10 mg/kg (15.6 μmol/kg) conjugate reduced the bacterial load by 99% and demonstrated nearly an order of magnitude greater activity than the parent antibiotic ciprofloxacin (30 mg/kg, 90.6 μmol/kg) given in multiple doses. Conjugates incorporating a bisphosphonate and an antibiotic for bone-targeted delivery to treat osteomyelitis biofilm pathogens constitute a promising approach to providing high bone-antimicrobial potency while minimizing systemic exposure.

Nanoparticles for the treatment of osteoporosis

Osteoporosis is by far the most frequent metabolic disease affecting bone. Current clinical therapeutic treatments are not able to offer long-term solutions. Most of the clinically used anti-osteoporotic drugs are administered systemically, which might lead to side effects in non-skeletal tissues. Therefore, to solve these disadvantages, researchers have turned to nanotechnologies and nanomaterials to create innovative and alternative treatments. One of the innovative approaches to enhance osteoporosis therapy and prevent potential adverse effects is the development of bone-targeting drug delivery technologies. It minimizes the systemic toxicity and also improves the pharmacokinetic profile and therapeutic efficacy of chemical drugs. This paper reviews the current available bone targeting drug delivery systems, focusing on nanoparticles, proposed for osteoporosis treatment. Bone targeting delivery systems is still in its infancy, thus, challenges are ahead of us, including the stability and the toxicity issues. Newly developed biomaterials and technologies with potential for safer and more effective drug delivery, require multidisciplinary collaboration between scientists from many different areas, such as chemistry, biology, engineering, medicine, etc, in order to facilitate their clinical applications.

Study of a new bone-targeting titanium implant-bone interface.

New strategies involving bone-targeting titanium (Ti) implant–bone interface are required to enhance bone regeneration and osseointegration for orthopedic and dental implants, especially in osteoporotic subjects. In this study, a new dual-controlled, local, bone-targeting delivery system was successfully constructed by loading tetracycline-grafted simvastatin (SV)-loaded polymeric micelles in titania nanotube (TNT) arrays, and a bone-targeting Ti implant–bone interface was also successfully constructed by implanting the delivery system in vivo. The biological effects were evaluated both in vitro and in vivo. The results showed that Ti surfaces with TNT–bone-targeting micelles could promote cytoskeletal spreading, early adhesion, alkaline phosphatase activity, and extracellular osteocalcin concentrations of rat osteoblasts, with concomitant enhanced protein expression of bone morphogenetic protein (BMP)-2. A single-wall bone-defect implant model was established in normal and ovariectomized rats as postmenopausal osteoporosis models. Microcomputed tomography imaging and BMP-2 expression in vivo demonstrated that the implant with a TNT-targeting micelle surface was able to promote bone regeneration and osseointegration in both animal models. Therefore, beneficial biological effects were demonstrated both in vitro and in vivo, which indicated that the bone-targeting effects of micelles greatly enhance the bioavailability of SV on the implant–bone interface, and the provision of SV-loaded targeting micelles alone exhibits the potential for extensive application in improving local bone regeneration and osseointegration, especially in osteoporotic subjects.

Advanced musculoskeletal imaging systems adopted for studying a novel bone-targeting delivery system carrying osteopromotive phytomolecule(s) developed for the prevention of oestrogen depletion-induced osteoporosis

Advanced musculoskeletal imaging systems adopted for studying a novel bone-targeting delivery system carrying osteopromotive phytomolecule(s) developed for the prevention of oestrogen depletion-induced osteoporosis

Bone-targeted delivery of nanodiamond-based drug carriers conjugated with alendronate for potential osteoporosis treatment

This paper describes the design of alendronate-conjugated nanodiamonds (Alen-NDs) and evaluation of their feasibility for bone-targeted delivery. Alen-NDs exhibited a high affinity to hydroxyapatite (HAp, the mineral component of bone) due to the presence of Alen. Unlike NDs (without Alen), Alen-NDs were preferentially taken up by MC3T3-E1 osteoblast-like cells, compared to NIH3T3 and HepG2 cells, suggesting their cellular specificity. In addition, NDs itself increased ALP activity of MC3T3-E1 cells, compared to control group (osteogenic medium) and Alen-NDs exhibited more enhanced ALP activity. In addition, an in vivo study revealed that Alen-NDs effectively accumulated in bone tissues after intravenous tail vein injection. These results confirm the superior properties of Alen-NDs with advantages of high HAp affinity, specific uptake for MC3T3-E1 cells, positive synergistic effect for ALP activity, and in vivo bone targeting ability. The Alen-NDs can potentially be employed for osteoporosis treatment by delivering both NDs and Alen to bone tissue.

Alendronate-decorated biodegradable polymeric micelles for potential bone-targeted delivery of vancomycin

Osteomyelitis is a bone infection disease which is caused by bacteria or other germs, and could cause serious impact on the health and working capacity of the patients. Alendronate (ALN) can chelate strongly with the calcium ion of hydroxyapatite (HA) which is commonly used to treat osteoporosis. Nanomedicine has attracted a lot of attention in that the nano-sized carrier can deliver drug molecules to specific site of interest with the aid of targeting moiety and achieve sustained release, resulting in improved therapeutic effect and reduced side effect. In this study, micelles self-assembled from poly(lactic acid-co-glycolic acid)-block-poly(ethylene glycol)-alendronate (PLGA-PEG-ALN) copolymer were prepared for bone-targeted delivery of vancomycin (Van). The chemical structure of PLGA-PEG-ALN was confirmed by proton nuclear magnetic resonance (1H-NMR) spectroscopy. The formation of the nanoparticles was characterized by dynamic light scattering, transmission electronic microscopy as well as the critical micelle concentration measurement. Release profiles from the micelles revealed that the conjugation of ALN to the surface of micelle did not pose adverse effect on the drug-loading capacity and release behaviors. The cytotoxicity of Van-loaded PLGA-PEG-ALN micelles as well as the blank micelles was evaluated via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay toward rat bone marrow stromal cells (rBMSCs) and human embryonic hepatocytes (L02 cells), and results showed that this Van-loaded micelle possesses appropriate cytotoxicity and is safe in the potential treatment of osteomyelitis. The in vitro affinity of PLGA-PEG-ALN micelles to the HA was also confirmed in vitro. The antibacterial effect of Van-loaded PLGA-PEG-ALN micelles was tested against Staphylococcus aureus (SA) which is the main pathogenic bacteria in osteomyelitis, and the results showed that the Van-loaded micelles can effectively inhibit the growth of SA. These results demonstrated that the PLGA-PEG-ALN micelles may be potentially used for the bone targeted delivery of Van.

Systemic drug delivery systems for bone tissue regeneration- a mini review.

Musculoskeletal metabolic diseases such as osteoporosis have become the major public health problems worldwide in our aging society. Pharmaceutical therapy is one of the approaches to prevent and treat related medical conditions. Most of the clinically used anti-osteoporotic drugs are administered systemically and have demonstrated some side effects in non-skeletal tissues. One of the innovative approaches to prevent potential adverse effects is the development of bone-targeting drug delivery technologies that not only minimizes the systemic toxicity but also improves the pharmacokinetic profile and therapeutic efficacy of chemical drugs. This paper reviews the currently available bone targeting drug delivery systems with emphasis as bone-targeting moieties, including the bonesurface- site-specific (bone formation dominant or bone resorption dominant) and cell-specific moieties. In addition, the connections of drug-bone-targeting moieties-carrier are also summarized, and the newly developed liposomes and nanoparticles are discussed for their potential use and main challenges in delivering therapeutic agents to bone tissue. As a rapid-developing biotechnology, systemic bonetargeting delivery system is promising but still in its infancy where challenges are ahead of us, including the stability and the toxicity issues, especially to fulfill the regulatory requirement to realize bench-to-bedside translation. Newly developed biomaterials and technologies with potential for safer and more effective drug delivery require multidisciplinary collaborations with preclinical and clinical scientists that are essential to facilitate their clinical applications.

Bi-directionally selective bone targeting delivery for anabolic and antiresorptive drugs: A novel combined therapy for osteoporosis?

Osteoporosis is a progressive systemic skeletal disease, in which the equilibrium of bone resorption and bone formation is disturbed. The drugs for osteoporosis can be divided into two categories according to their predominant effects: antiresorptive drugs and anabolic drugs. Antiresorptive drugs are designed to inhibit bone resorption and anabolic drugs are aiming to stimulate bone formation. On the other hand, most antiresorptive drugs usually decrease anabolic activities and reduce bone formation, while anabolic drugs can unintendedly increase bone resorption. Furthermore, both types of drugs show no preferential distribution in bone and can locate generally in the areas of both bone formation and bone resorption. Consequently, the non-specific interaction of these drugs with non-targeting area and cells can lead to a compromised efficacy. Combined therapies of antiresorptive and anabolic drugs do not necessarily yield superiority when compared to monotherapy. Here, basing on the targeting cells of these two kinds of drugs and the spatial distribution of osteoblasts and osteoclasts, we propose a novel drug delivery system of bi-directionally selective targeting in order to facilitate the efficacy of antiresorptive and anabolic drugs in combined therapy. In the system, an antiresorptive drug will be linked with a peptide of the eight repeating sequences of aspartate – (Asp)8 that can preferentially guide the drugs to bone resorption zone; while an anabolic drug linked with a peptide of six repeats of the sequence aspartate, serine, serine – (Asp–Ser–Ser)6 that can favorably guide the drugs to bone formation zone. The novel delivery system will improve the specific interaction between the drugs and their targeting cells. Furthermore, the system will reduce the non-specific interaction of the anabolic and antiresorptive drugs with their respective non-targeting cells, which will maximally reduce their side-effects. Therefore, we postulate that the new bone targeting drug delivery system will be a blessing for osteoporotic patients.