Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases.

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival. The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect. To improve the treatment efficacy, we developed Pluronic P123 (P123)-based polymeric micelles dually decorated with alendronate (ALN) and cancer-specific phage protein DMPGTVLP (DP-8) for targeted drug delivery to breast cancer bone metastases. Doxorubicin (DOX) was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity (3.44%). The DOX-loaded polymeric micelles were spherical, 123 nm in diameter on average, and exhibited a narrow size distribution. The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release. The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells. Rapid binding of the micelles to hydroxyapatite (HA) microparticles indicated their high affinity for bone. P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model. In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity. In conclusion, our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

Synthesis and preliminary anticancer evaluation of photo-responsive prodrugs of hydroxymethylene bisphosphonate alendronate.

The antitumoral activity of hydroxymethylene bisphosphonates (HMBP) such as alendronate or zoledronate is hampered by their exceptional bone-binding properties and their short plasmatic half-life which preclude their accumulation in non-skeletal tumors. In this context, the use of lipophilic prodrugs represents a simple and straightforward strategy to enhance the biodistribution of bisphosphonates in these tissues. We describe in this article the synthesis of light-responsive prodrugs of HMBP alendronate. These prodrugs include lipophilic photo-removable nitroveratryl groups which partially mask the highly polar alendronate HMBP scaffold. Photo-responsive prodrugs of alendronate are stable in physiological conditions and display reduced toxicity compared to alendronate against MDA-MB-231 cancer cells. However, the antiproliferative effect of these prodrugs is efficiently restored after cleavage of their nitroveratryl groups upon exposure to UV light. In addition, substitution of alendronate with such photo-responsive substituents drastically reduces its bone-binding properties, thereby potentially improving its biodistribution in soft tissues after i.v. administration. The development of such lipophilic photo-responsive prodrugs is a promising approach to fully exploit the anticancer effect of HMBPs on non-skeletal tumors.

Development of an injectable chitosan-based hydrogel containing nano-hydroxy-apatite and alendronate for MSC-based therapy.

BACKGROUND: The combination of cells and biomaterials has become a powerful approach to regenerative medicine in recent years. Understanding the in-vitro interactions between cells and biomaterials is crucial for the success of regenerative medicine. AIM: In this study, we developed an AD-pectin/chitosan/nano-crystalline cellulose scaffold with nano-hydroxy-apatite (n-HAP) and alendronate (ALN). The second step was to evaluate its effect on the immunomodulatory properties and biological behaviors of seeded adipose-derived mesenchymal stem cells (ADSCs) for bone tissue repair. MATERIAL AND METHOD: After preparing and evaluating the characterization tests of the new combined n-HAP scaffold, we established different culture conditions to evaluate ADSC growth on this scaffold with or without ALN. The main assays were MTT assay, RT-PCR, and ELISA. RESULTS: Our data regarding characterization tests (including SEM, TGA, FTIR, gelation time, swelling ratio, rheology and degradation tests) of ALN-loaded n-HAP scaffold showed the proper stability and good mechanical status of the scaffold. ADSC proliferation and viability increased in the presence of the scaffold compared with other conditions. Moreover, our data demonstrated increased gene expression and protein levels of anti-inflammatory TGF-ß, HGF, and IDO cytokines in the presence of the ALN-loaded n-HAP scaffold, indicating the increased immunosuppressive activity of ADSCs in vitro. CONCLUSION: This study demonstrates the promising abilities of the ALN-loaded n-HAP scaffold to increase the proliferation, viability, and immunomodulatory capacity of ADSCs, elucidating new aspects of cell-material interactions that can be used for bone tissue regeneration/repair, and paving the path of future research in developing new approaches for MSC- based therapy.

Study on a co-hybrid nano-hydroxyapatite with lignin derivatives and alendronate and the reinforce effect for poly(lactide-co-glycolide).

A novel co-hybrid nano-apatite (n-HA) by introducing lignin derivatives (LDs) and alendronate (ALE) was designed to reinforce poly(lactide-co-glycolide) (PLGA). The effect of different addition methods and contents of LDs, lignin derivatives sorts of lignosulfonate (LS), alkali lignin (AL) and carboxymethyl lignin (CML), and the addition order of ALE on the dispersion of hybrid n-HA, and reinforce effective for PLGA were investigated by FTIR, XRD, TEM, TGA, XPS, N2 adsorption/desorption, zeta potential, dispersion experiments, universal testing machine, SEM, DSC and POM. The results showed that the addition order could regulate the growth of n-HA crystal planes by binding with Ca2+, and co-hybrid HA by LDs and ALE possessed better dispersion owing to the synergistic effect. Moreover, 10 wt% LS-ALE-n-HA displayed the best reinforce effect, and the tensile strength of composite was 24.43 % higher than that of PLGA, even 15 wt% LS-ALE-n-HA was added, it still exhibited reinforce effect for PLGA. In vitro soaking in simulated body fluid (SBF) results indicated that LS-ALE-n-HA delayed tensile strength reduce of PLGA and promoted bone-like apatite deposition. The cell proliferation results demonstrated that the hybrid n-HA by the introduction of ALE endowed PLGA with better cell adhesion and proliferation.

Alendronate conjugate for targeted delivery to bone-forming prostate cancer.

Bone is the primary metastasis site for lethal prostate cancer, often resulting in poor prognosis, crippling pain, and diminished functioning that drastically reduce both quality of life and survivability Uniquely, prostate cancer bone metastasis induces aberrant bone overgrowth, due to an increase of osteoblasts induced by tumor-secreted bone morphogenetic protein 4 (BMP4). Conjugating drugs to substances that target the tumor-induced bone area within the metastatic tumor foci would be a promising strategy for drug delivery. To develop such a strategy, we conjugated a near infrared (NIR) fluorescent probe, the dye Cy5.5, to serve as a surrogate for drugs, with alendronate, which targets bone. Characterization, such as infrared spectroscopy, confirmed the synthesis of the Cy5.5-ALN conjugate. The maximum absorbance of free Cy5.5, which was at 675 nm, did not change upon conjugation. Alendronate targeted the bone component hydroxyapatite in a dose-dependent manner up to 2.5 µM, with a maximum of 85% of Cy5.5-ALN bound to hydroxyapatite, while free Cy5.5 alone had 6% binding. In in vitro cell binding studies, Cy5.5-ALN bound specifically with mineralized bone matrix of differentiated MC3T3-E1 cells or 2H11 endothelial cells that were induced to become osteoblasts through endothelial-to-osteoblast transition, the underlying mechanism of prostate-cancer-induced bone formation. Neither Cy5.5-ALN nor free Cy5.5 bound to undifferentiated MC3T3-E1 or 2H11 cells. Bone-targeting efficiency studies in non-tumor-bearing mice revealed accumulation over time in the spine, jaw, knees, and paws injected with Cy5.5-ALN, and quantification showed higher accumulation in femurs than in muscle at up to 28 days, while the free Cy5.5 dye was observed circulating without preferential accumulation and decreased over time. There was a linear relationship with fluorescence when the injected concentration of Cy5.5-ALN was between 0.313 and 1.25 nmol/27 g of mouse, as quantified in mouse femurs both in vivo and ex vivo. Ex vivo evaluation of bone-targeting efficiency in nude mice was 3 times higher for bone-forming C4-2b-BMP4 tumors compared to non-bone-forming C4-2b tumors (p-value <0.001). Fluorescence microscopy imaging of the tumors showed that Cy5.5-ALN co-localized with the bone matrix surrounding tumor-induced bone, but not with the viable tumor cells. Together, these results suggest that a drug-ALN conjugate is a promising approach for targeted delivery of drug to the tumor-induced bone area in the metastatic foci of prostate cancer.

Multifunctional Scaffold for Osteoporotic Pathophysiological Microenvironment Improvement and Vascularized Bone Defect Regeneration.

Osteoporosis is a degenerative bone disease resulting from bone homeostasis imbalance regulated by osteoblasts and osteoclasts. Treating osteoporotic bone defects tends to be more difficult due to suppressed osteogenic differentiation, hyperactive osteoclastogenesis, and impaired angiogenesis. Hence, a drug carrier system composed of gelatin-coated hollow mesoporous silica nanoparticles (HMSNs/GM) loaded with pro-osteogenic parathyroid (PTH) and anti-osteoclastogenic alendronate (ALN) is constructed and compounded into calcium magnesium phosphate cement (MCPC). The spatial-temporal release of ions and drugs, controllable degradation rate, and abundant pore structure of MCPC composites enhance osteoporotic bone regeneration in ovariectomized rats by accelerating vascularization, promoting osteogenic differentiation and mineralization, and inhibiting osteoclastogenesis and bone resorption. The MCPC/HMSNs@ALN-PTH/GM demonstrates a synergistic threefold effect on osteogenesis, osteoclastogenesis, and angiogenesis. It improves the osteoporotic pathophysiological microenvironment and promotes osteoporotic vascularized bone defect regeneration, holding huge potential for other functional biomaterials design and clinical management.

How Efficient are Alendronate-Nano/Biomaterial Combinations for Anti-Osteoporosis Therapy? An Evidence-Based Review of the Literature.

Osteoporosis is defined as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Because of the systemic nature of osteoporosis, the associated escalation in fracture risk affects virtually all skeletal sites. The problem is serious since it is estimated that more than 23 million men and women are at high risk of osteoporotic-like breakages in the European Union. Alendronate (ALN) is the most commonly prescribed oral nitrogen-containing bisphosphonate (BP) for the prevention and the therapy of osteoporosis. This is also one of the most intensely studied drugs in this field. However, ALN is characterized by restricted oral absorption and bioavailability and simultaneously its administration has serious side-effects (jaw osteonecrosis, irritation of the gastrointestinal system, nausea, musculoskeletal pain, and cardiovascular risks). Therefore, delivery systems enabling controlled release and local action of this drug are of great interest, being widely researched and presented in the literature. In this review, we discuss the current trends in the design of various types of alendronate carriers. Our paper is focused on the most recent developments in the field of nano/biomaterials-based systems for ALN delivery, including nano/microformulations, synthetic/natural polymeric and inorganic materials, hydrogel-based materials, scaffolds, coated-like structures, as well as organic-inorganic hybrids. Topics related to the treatment of complex bone diseases including osteoporosis have been covered in several more general reviews; however, the systems for this particular drug have not yet been discussed in detail.

Alendronate-Modified Nanoceria with Multiantioxidant Enzyme-Mimetic Activity for Reactive Oxygen Species/Reactive Nitrogen Species Scavenging from Cigarette Smoke.

Highly toxic radicals including reactive oxygen species (ROS) and reactive nitrogen species (RNS) in cigarette smoke play an important role in oxidative damage of the lungs, which cannot be efficiently scavenged by current filter techniques. Herein, a novel alendronate-coated nanoceria (CeAL) nanozyme is explored for cigarette filter modification for ROS/RNS scavenging. The CeAL nanozyme with an adjustable oxidation state and high thermal stability exhibits an excellent superoxide dismutase (SOD)-like activity, hydroxyl radical elimination capacity, catalase-mimicking activity, and nitric oxide radical scavenging ability. These synergistic antioxidant abilities make the CeAL nanozyme a lucrative additive for cigarette filters. The filter incorporated with the CeAL nanozyme can efficiently scavenge ROS/RNS in the hot smoke generated by burned commercial cigarettes, resulting in reduction of oxidative stress-induced pulmonary injury and acute inflammation of mice. The developed CeAL nanozyme opens up new opportunities for cigarette filter modification to decrease the toxicity of cigarette smoke and expands the application fields of nanoceria.

HAP-Multitag, a PET and Positive MRI Contrast Nanotracer for the Longitudinal Characterization of Vascular Calcifications in Atherosclerosis.

Vascular microcalcifications are associated with atherosclerosis plaque instability and, therefore, to increased mortality. Because of this key role, several imaging probes have been developed for their in vivo identification. Among them, [18F]FNa is the gold standard, showing a large uptake in the whole skeleton by positron emission tomography. Here, we push the field toward the combined anatomical and functional early characterization of atherosclerosis. For this, we have developed hydroxyapatite (HAP)-multitag, a bisphosphonate-functionalized 68Ga core-doped magnetic nanoparticle showing high affinity toward most common calcium salts present in microcalcifications, particularly HAP. We characterized this interaction in vitro and in vivo, showing a massive uptake in the atherosclerotic lesion identified by positron emission tomography (PET) and positive contrast magnetic resonance imaging (MRI). In addition, this accumulation was found to be dependent on the calcification progression, with a maximum uptake in the microcalcification stage. These results confirmed the ability of HAP-multitag to identify vascular calcifications by PET/(T1)MRI during the vulnerable stages of the plaque progression.

Tissue-Nonspecific Alkaline Phosphatase (TNAP) as the Enzyme Involved in the Degradation of Nucleotide Analogues in the Ligand Docking and Molecular Dynamics Approaches.

Tissue-nonspecific alkaline phosphatase (TNAP) is known to be involved in the degradation of extracellular ATP via the hydrolysis of pyrophosphate (PPi). We investigated, using three different computational methods, namely molecular docking, thermodynamic integration (TI) and conventional molecular dynamics (MD), whether TNAP may also be involved in the utilization of ß,γ-modified ATP analogues. For that, we analyzed the interaction of bisphosphonates with this enzyme and evaluated the obtained structures using in silico studies. Complexes formed between pyrophosphate, hypophosphate, imidodiphosphate, methylenediphosphonic acid monothiopyrophosphate, alendronate, pamidronate and zoledronate with TNAP were generated and analyzed based on ligand docking, molecular dynamics and thermodynamic integration. The obtained results indicate that all selected ligands show high affinity toward this enzyme. The forming complexes are stabilized through hydrogen bonds, electrostatic interactions and van der Waals forces. Short- and middle-term molecular dynamics simulations yielded very similar affinity results and confirmed the stability of the protein and its complexes. The results suggest that certain effectors may have a significant impact on the enzyme, changing its properties.

Microsphere embedded hydrogel construct - binary delivery of alendronate and BMP-2 for superior bone regeneration.

Biomimetic delivery of osteoinductive growth factors via an osteoconductive matrix is an interesting approach for stimulating bone regeneration. In this context, the bone extracellular matrix (ECM) has been explored as an optimal delivery system, since it releases growth factors in a spatiotemporal manner from the matrix. However, a bone ECM hydrogel alone is weak, unstable, and prone to microbial contamination and also has been reported to have significantly reduced bone morphogenic protein-2 (BMP-2) post decellularization. In the present work, a microsphere embedded osteoinductive decellularized bone ECM/oleoyl chitosan based hydrogel construct (BOC) was developed as a matrix allowing dual delivery of an anti-resorptive drug (alendronate, ALN, via the microspheres) and BMP-2 (via the hydrogel) for a focal tibial defect in a rabbit model. The synthesized gelatin microspheres (GMs) were spherical in shape with diameter ∼32 µm as assessed by SEM analysis. The BOC construct showed sustained release of ALN and BMP-2 under the studied conditions. Interestingly, amniotic membrane-derived stem cells (HAMSCs) cultivated on the hydrogel construct demonstrated excellent biocompatibility, cell viability, and active proliferation potential. Additionally, cell differentiation on the constructs showed an elevated expression of osteogenic genes in an RT-PCR study along with enhanced mineralized matrix deposition as demonstrated by alkaline phosphatase (ALP) assay and alizarin red assay. The hydrogel construct was witnessed to have improved neo-vascularization potential in a chick chorioalantoic membrane (CAM) assay. Also, histological and computed tomographic findings evidenced enhanced bone regeneration in the group treated with the BOC/ALN/BMP hydrogel construct in a rabbit tibial defect model. To conclude, the developed multifunctional hydrogel construct acts as an osteoinductive and osteoconductive platform facilitating controlled delivery of ALN and BMP-2, essential for stimulating bone tissue regeneration.

Understanding the Protective Effect of Phytate in Bone Decalcification Related-Diseases.

Myo-inositol hexaphosphate (phytate; IP6) is a natural compound that is abundant in cereals, legumes, and nuts, and it can bind to crystal surfaces and disturb crystal development, acting as crystallization inhibitor. The adsorption of such inhibitors to crystal faces can also inhibit crystal dissolution. The binding of phytate to metal cofactors suggests that it could be used for treatment of osteoporosis. Our in-vitro study showed that phytate inhibits dissolution of hydroxyapatite (HAP). The effect of phytate was similar to that of alendronate and greater than that of etidronate. This led us to perform a cross-sectional study to investigate the impact of consumption of IP6 on bone mineral density (BMD) in post-menopausal women. Our data indicate that BMD and t-score of lumbar spine increased with increasing phytate consumption, and a phytate consumption higher than 307 mg/day was associated with a normal BMD (t-score > -1). These data suggest that phytate may have a protective effect in bone decalcification by adsorbing on the surfaces of HAP, and a daily consumption of phytate-rich foods (at least one serving/day of legumes or nuts) may help to prevent or minimize bone-loss disorders, such as osteoporosis. However, further studies are needed to gain a better understanding about the mechanism of inhibition of phytate in bone-related diseases (see graphical abstract).

Effect of drugs on bone mineral density in postmenopausal osteoporosis: a Bayesian network meta-analysis.

BACKGROUND: Osteoporosis affects mostly postmenopausal women, leading to deterioration of the microarchitectural bone structure and low bone mass, with an increased fracture risk with associated disability, morbidity and mortality. This Bayesian network meta-analysis compared the effects of current anti-osteoporosis drugs on bone mineral density. METHODS: The present systematic review and network meta-analysis follows the PRISMA extension statement to report systematic reviews incorporating network meta-analyses of health care interventions. The literature search was performed in June 2021. All randomised clinical trials that have investigated the effects of two or more drug treatments on BMD for postmenopausal osteoporosis were accessed. The network comparisons were performed through the STATA Software/MP routine for Bayesian hierarchical random-effects model analysis. The inverse variance method with standardised mean difference (SMD) was used for analysis. RESULTS: Data from 64 RCTs involving 82,732 patients were retrieved. The mean follow-up was 29.7 ± 19.6 months. Denosumab resulted in a higher spine BMD (SMD -0.220; SE 3.379), followed by pamidronate (SMD -5.662; SE 2.635) and zoledronate (SMD -10.701; SE 2.871). Denosumab resulted in a higher hip BMD (SMD -0.256; SE 3.184), followed by alendronate (SMD -17.032; SE 3.191) and ibandronate (SMD -17.250; SE 2.264). Denosumab resulted in a higher femur BMD (SMD 0.097; SE 2.091), followed by alendronate (SMD -16.030; SE 1.702) and ibandronate (SMD -17.000; SE 1.679). CONCLUSION: Denosumab results in higher spine BMD in selected women with postmenopausal osteoporosis. Denosumab had the highest influence on hip and femur BMD. LEVEL OF EVIDENCE: Level I, Bayesian network meta-analysis of RCTs.

Fabrication of Membrane Sensitive Electrodes for the Validated Electrochemical Quantification of Anti-Osteoporotic Drug Residues in Pharmaceutical Industrial Wastewater.

Accurate and precise application of ion-selective electrodes (ISEs) in the quantification of environmental pollutants is a strenuous task. In this work, the electrochemical response of alendronate sodium trihydrate (ALN) was evaluated by the fabrication of two sensitive and delicate membrane electrodes, viz. polyvinyl chloride (PVC) and glassy carbon (GC) electrodes. A linear response was obtained at concentrations from 1 × 10-5 to 1 × 10-2 M for both electrodes. A Nernstian slope of 29 mV/decade over a pH range of 8-11 for the PVC and GC membrane electrodes was obtained. All assay settings were carefully adjusted to obtain the best electrochemical response. The proposed technique was effectively applied for the quantification of ALN in pure form and wastewater samples, acquired from manufacturing industries. The proposed electrodes were effectively used for the determination of ALN in real wastewater samples without any prior treatment. The current findings guarantee the applicability of the fabricated ISEs for the environmental monitoring of ALN.

Bone-adhesive barrier membranes based on alendronate-functionalized poly(2-oxazoline)s.

To create a novel generation of barrier membranes with bone-adhesive properties, three-component membranes were successfully developed using a solvent-free approach by combining an occlusive polyester backing layer with a bone-adhesive fibrous gelatin carrier impregnated with calcium-binding alendronate-functionalized poly(2-oxazoline)s (POx-Ale). The mechanical properties of these novel membranes were similar to other commercially available barrier membranes. In contrast, the adhesion of our membranes towards bone was by far superior (i.e. 62-fold) compared to conventional commercially available Bio-Gide® membranes. Moreover, alendronate-functionalized membranes retained their bone-adhesive properties under wet conditions in phosphate-buffered saline (PBS) solutions with and without collagenase. Finally, the in vitro degradation of the membranes was studied by monitoring their weight loss upon immersion in PBS solutions with and without collagenase. The membranes degraded in a sustained manner, which was accelerated by the presence of collagenase due to enzymatic degradation of the carrier. In conclusion, our results show that surface functionalization of barrier membranes with alendronate moieties renders them adhesive to bone. As such, the biomaterials design strategy presented herein opens up new avenues of research on bone-adhesive membranes for guided bone regeneration.

Exploiting the anticancer effects of a nitrogen bisphosphonate nanomedicine for glioblastoma multiforme.

Glioblastoma multiforme (GBM) is an incurable aggressive brain cancer in which current treatment strategies have demonstrated limited survival benefit. In recent years, nitrogen-containing bisphosphonates (N-BPs) have demonstrated direct anticancer effects in a number of tumour types including GBM. In this study, a nano-formulation with the RALA peptide was used to complex the N-BP, alendronate (ALN) into nanoparticles (NPs) < 200 nm for optimal endocytic uptake. Fluorescently labelled AlexaFluor®647 Risedronate was used as a fluorescent analogue to visualise the intracellular delivery of N-BPs in both LN229 and T98G GBM cells. RALA NPs were effectively taken up by GBM where a dose-dependent response was evidenced with potentiation factors of 14.96 and 13.4 relative to ALN alone after 72 h in LN229 and T98G cells, respectively. Furthermore, RALA/ALN NPs at the IC50, significantly decreased colony formation, induced apoptosis and slowed spheroid growth in vitro. In addition, H-Ras membrane localisation was significantly reduced in the RALA/ALN groups compared to ALN or controls, indicative of prenylation inhibition. The RALA/ALN NPs were lyophilised to enhance stability without compromising the physiochemical properties necessary for functionality, highlighting the suitability of the NPs for scale-up and in vivo application. Collectively, these data show the significant potential of RALA/ALN NPs as novel therapeutics in the treatment of GBM.

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.

Formation of phosphonate coatings for improved chemical stability of upconverting nanoparticles under physiological conditions.

Upconverting nanoparticles (UCNPs) are being extensively investigated for applications in bioimaging because of their ability to emit ultraviolet, visible, and near-infrared light. NaYF4 is one of the most suitable host matrices for producing high-intensity upconversion fluorescence; however, UCNPs based on NaYF4 are not chemically stable in aqueous media. To prevent dissolution, their surfaces should be modified. We studied the formation of protective phosphonate coatings made of ethylenediamine(tetramethylenephosphonic acid), alendronic acid, and poly(ethylene glycol)-neridronate on cubic NaYF4 nanoparticles and hexagonal Yb3+,Er3+-doped upconverting NaYF4 nanoparticles (ß-UCNPs). The effects of synthesis temperature and ultrasonic agitation on the quality of the coatings were studied. The formation of the coatings was investigated by transmission electron microscopy, zeta-potential measurements, and infrared spectroscopy. The quality of the phosphonate coatings was examined with respect to preventing the dissolution of the NPs in phosphate-buffered saline (PBS). The dissolution tests were carried out under physiological conditions (37 °C and pH 7.4) for 3 days and were followed by measurements of the dissolved fluoride with an ion-selective electrode. We found that the protection of the phosphonate coatings can be significantly increased by synthesizing them at 80 °C. At the same time, the coatings obtained at this temperature suppressed the surface quenching of the upconversion fluorescence in ß-UCNPs.

Acidity constant and DFT-based modelling of pH-responsive alendronate loading and releasing on propylamine-modified silica surface.

A computational methodology that couples the acidity (Ka) and density functional theory (DFT) calculations has been developed to explain the pH-dependent drug loading on and releasing from mesoporous silica nanoparticles. The model has been validated by investigating the pH-dependent loading and releasing of a bisphosphonate drug molecule, alendronate, on a propylamine-modified quartz surface (101), a model for functionalized mesoporous silica nanoparticles. The pH-dependent interacting molecular species are the neutral and anionic forms of the drug molecule, silanol group of quartz surface and the functional group in the case of functionalized quartz surface. The interaction energies of all the molecular species of alendronate with silica surface are calculated by using the DFT-based CASTEP method. Five molecular states of alendronate (D0, D-, D2-, D3- and D4-), two for silica surface (S0 and S-) and two for propylamine (P+ and P0) are considered. Ten possible combinations of interactions of alendronate with silica surface and twenty for alendronate and propylamine-functionalized silica surfaces are calculated. The relative probability of interaction of a particular pair of drug and surface combination at a particular pH is weighed by the product of their fractions, the latter is calculated by using the Handerson-Hasselbach equation. The total interaction energies at a particular pH are calculated by summing the possible individual interaction energies. The variation of total interaction energy with pH shows that the functional group of propylamine lowers the interaction energy at lower pH values (1-5), thus favouring adsorption or loading of the drug and increases the interaction energy at higher pH values (pH > 8) and thus favours desorption or release of the drug. This is in agreement with experimental results where it is shown that propylamine-functionalized mesoporous silica nanoparticles load alendronate in the pH range of 1-5 and release at pH = 8. This method can be used to predict the pH-dependent drug loading and releasing of a particular combination of drug and on a particular drug delivery system.

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), ß-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.