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Journal articles on the topic 'Hydroxyapatite targeting'

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Author: Grafiati
Published: 10 December 2022
Last updated: 28 January 2023

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1

Xiong, Hui, Shi Du, Ping Zhang, Zhijie Jiang, Jianping Zhou, and Jing Yao. "Primary tumor and pre-metastatic niches co-targeting “peptides-lego” hybrid hydroxyapatite nanoparticles for metastatic breast cancer treatment." Biomaterials Science 6, no. 10 (2018): 2591–604. http://dx.doi.org/10.1039/c8bm00706c.

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2

Lalatonne, Y., M. Monteil, H. Jouni, J. M. Serfaty, O. Sainte-Catherine, N. Lièvre, S. Kusmia, P. Weinmann, M. Lecouvey, and L. Motte. "Superparamagnetic Bifunctional Bisphosphonates Nanoparticles: A Potential MRI Contrast Agent for Osteoporosis Therapy and Diagnostic." Journal of Osteoporosis 2010 (2010): 1–7. http://dx.doi.org/10.4061/2010/747852.

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A bone targeting nanosystem is reported here which combined magnetic contrast agent for Magnetic Resonance Imaging (MRI) and a therapeutic agent (bisphosphonates) into one drug delivery system. This new targeting nanoplatform consists of superparamagneticγFe2O3nanoparticles conjugated to 1,5-dihydroxy-1,5,5-tris-phosphono-pentyl-phosphonic acid (di-HMBPs) molecules with a bisphosphonate function at the outer of the nanoparticle surface for bone targeting. The as-synthesized nanoparticles were evaluated as a specific MRI contrast agent by adsorption study onto hydroxyapatite and MRI measurment. The strong adsorption of the bisphosphonates nanoparticles to hydroxyapatite and their use as MRIT2∗contrast agent were demonstrated. Cellular tests performed on human osteosarcoma cells (MG63) show thatγFe2O3@di-HMBP hybrid nanomaterial has no citoxity effect in cell viability and may act as a diagnostic and therapeutic system.
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3

Lee, Kyung Kwan, Jae-Geun Lee, Chul Soon Park, Sun Hyeok Lee, Naren Raja, Hui-suk Yun, Jeong-Soo Lee, and Chang-Soo Lee. "Bone-targeting carbon dots: effect of nitrogen-doping on binding affinity." RSC Advances 9, no. 5 (2019): 2708–17. http://dx.doi.org/10.1039/c8ra09729a.

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4

Kim, Jong-Won, Kyung-Kwan Lee, Kyoung-Woo Park, Moonil Kim, and Chang-Soo Lee. "Genetically Modified Ferritin Nanoparticles with Bone-Targeting Peptides for Bone Imaging." International Journal of Molecular Sciences 22, no. 9 (May 3, 2021): 4854. http://dx.doi.org/10.3390/ijms22094854.

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Bone homeostasis plays a major role in supporting and protecting various organs as well as a body structure by maintaining the balance of activities of the osteoblasts and osteoclasts. Unbalanced differentiation and functions of these cells result in various skeletal diseases, such as osteoporosis, osteopetrosis, and Paget’s disease. Although various synthetic nanomaterials have been developed for bone imaging and therapy through the chemical conjugation, they are associated with serious drawbacks, including heterogeneity and random orientation, in turn resulting in low efficiency. Here, we report the synthesis of bone-targeting ferritin nanoparticles for bone imaging. Ferritin, which is a globular protein composed of 24 subunits, was employed as a carrier molecule. Bone-targeting peptides that have been reported to specifically bind to osteoblast and hydroxyapatite were genetically fused to the N-terminus of the heavy subunit of human ferritin in such a way that the peptides faced outwards. Ferritin nanoparticles with fused bone-targeting peptides were also conjugated with fluorescent dyes to assess their binding ability using osteoblast imaging and a hydroxyapatite binding assay; the results showed their specific binding with osteoblasts and hydroxyapatite. Using in vivo analysis, a specific fluorescent signal from the lower limb was observed, demonstrating a highly selective affinity of the modified nanoparticles for the bone tissue. These promising results indicate a specific binding ability of the nanoscale targeting system to the bone tissue, which might potentially be used for bone disease therapy in future clinical applications.
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5

Kupikowska-Stobba, Barbara, and Mirosław Kasprzak. "Fabrication of nanoparticles for bone regeneration: new insight into applications of nanoemulsion technology." Journal of Materials Chemistry B 9, no. 26 (2021): 5221–44. http://dx.doi.org/10.1039/d1tb00559f.

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This review discusses nanoemulsion technology as a tool for fabrication of nanoparticles for bone regeneration applications including hydroxyapatite nanoparticles, polymer nanoparticles for drug/biomolecule delivery and bone-targeting nanoparticles.
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6

Vaingankar, Sucheta M., Thomas A. Fitzpatrick, Kristen Johnson, James W. Goding, Michele Maurice, and Robert Terkeltaub. "Subcellular targeting and function of osteoblast nucleotide pyrophosphatase phosphodiesterase 1." American Journal of Physiology-Cell Physiology 286, no. 5 (May 2004): C1177—C1187. http://dx.doi.org/10.1152/ajpcell.00320.2003.

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The ectonucleoside pyrophosphatase phosphodiesterase 1 (NPP1/PC-1) is a member of the NPP enzyme family that is critical in regulating mineralization. In certain mineralizing sites of bone and cartilage, membrane-limited vesicles [matrix vesicles (MVs)] provide a sheltered internal environment for nucleation of calcium-containing crystals, including hydroxyapatite. MV formation occurs by budding of vesicles from the plasma membrane of mineralizing cells. The MVs are enriched in proteins that promote mineralization. Paradoxically, NPP1, the type II transmembrane protein that generates the potent hydroxyapatite crystal growth inhibitor inorganic pyrophosphate (PPi), is also enriched in MVs. Although osteoblasts express NPP1, NPP2, and NPP3, only NPP1 is enriched in MVs. Therefore, this study uses mineralizing human osteoblastic SaOS-2 cells, a panel of NPP1 mutants, and NPP1 chimeras with NPP3, which does not concentrate in MVs, to investigate how NPP1 preferentially targets to MVs. We demonstrated that a cytosolic dileucine motif (amino acids 49–50) was critical in localizing NPP1 to regions of the plasma membrane that budded off into MVs. Moreover, transposition of the NPP1 cytoplasmic dileucine motif and flanking region (AAASLLAP) to NPP3 conferred to NPP3 the ability to target to the plasma membrane and, subsequently, concentrate in MVs. Functionally, the cytosolic tail dileucine motif NPP1 mutants lost the ability to support MV PPi concentrations and to suppress calcification. The results identify a specific targeting motif in the NPP1 cytosolic tail that delivers PPi-generating NPP activity to osteoblast MVs for control of calcification.
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7

Albayati, Zaineb A. F., Manjula Sunkara, Suzannah M. Schmidt-Malan, Melissa J. Karau, Andrew J. Morris, James M. Steckelberg, Robin Patel, et al. "Novel Bone-Targeting Agent for Enhanced Delivery of Vancomycin to Bone." Antimicrobial Agents and Chemotherapy 60, no. 3 (December 14, 2015): 1865–68. http://dx.doi.org/10.1128/aac.01609-15.

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We examined the pharmacokinetic properties of vancomycin conjugated to a bone-targeting agent (BT) with high affinity for hydroxyapatite after systemic intravenous administration. The results confirm enhanced persistence of BT-vancomycin in plasma and enhanced accumulation in bone relative to vancomycin. This suggests that BT-vancomycin may be a potential carrier for the systemic targeted delivery of vancomycin in the treatment of bone infections, potentially reducing the reliance on surgical debridement to achieve the desired therapeutic outcome.
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8

Song, Jiaming, Naiyu Cui, Xuran Mao, Qixuan Huang, Eui-Seok Lee, and Hengbo Jiang. "Sorption Studies of Tetracycline Antibiotics on Hydroxyapatite (001) Surface—A First-Principles Insight." Materials 15, no. 3 (January 21, 2022): 797. http://dx.doi.org/10.3390/ma15030797.

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Owing to the limitations of traditional systemic drug delivery in the treatment of bone diseases with side effects on normal cells, the selection of materials with high affinities for bones, as targeting ligands to modify drug carriers, has become an important research topic. Tetracyclines (TCs) have an adsorption effect on hydroxyapatite (HAp). Thus, they can be used as bone-targeting ligands and combined with drug carriers. In this study, density functional theory is used to analyze the interaction mechanism of TC, oxytetracycline (OTC), chlortetracycline, and HAp. We calculate the electrostatic potential (ESP) and molecular orbitals to predict the possible binding sites of TCs on the HAp surface. The adsorption energy is used to compare the affinities of the three TCs to HAp. An independent gradient model analysis is performed to study the weak interaction between TCs and HAp. The coordination bond between TCs and the HAp surface is evaluated by conducting a charge density difference analysis. The results show that OTC has the highest affinity to HAp because the introduction of hydroxyl groups change the adsorption configuration of OTC. Thus, OTC adsorbed on HAp in a broken-line shape exposes more binding sites. This study provides a theoretical basis for TCs as bone-targeting ligands in treating bone diseases and in improving the safety of treatment by selecting different bone-targeting ligands.
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9

Soriano‐Souza, Carlos, Helder Valiense, Elena Mavropoulos, Victor Martinez‐Zelaya, Andrea Machado Costa, Adriana T. Alves, Mariana Longuinho, et al. "Doxycycline containing hydroxyapatite ceramic microspheres as a bone‐targeting drug delivery system." Journal of Biomedical Materials Research Part B: Applied Biomaterials 108, no. 4 (May 2020): 1351–62. http://dx.doi.org/10.1002/jbm.b.34484.

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10

Goswami, Moushmi, Pavni Rekhi, Mousumi Debnath, and Seeram Ramakrishna. "Microbial Polyhydroxyalkanoates Granules: An Approach Targeting Biopolymer for Medical Applications and Developing Bone Scaffolds." Molecules 26, no. 4 (February 6, 2021): 860. http://dx.doi.org/10.3390/molecules26040860.

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Microbial polyhydroxyalkanoates (PHA) are proteinaceous storage granules ranging from 100 nm to 500 nm. Bacillus sp. serve as unique bioplastic sources of short-chain length and medium-chain length PHA showcasing properties such as biodegradability, thermostability, and appreciable mechanical strength. The PHA can be enhanced by adding functional groups to make it a more industrially useful biomaterial. PHA blends with hydroxyapatite to form nanocomposites with desirable features of compressibility. The reinforced matrices result in nanocomposites that possess significantly improved mechanical and thermal properties both in solid and melt states along with enhanced gas barrier properties compared to conventional filler composites. These superior qualities extend the polymeric composites’ applications to aggressive environments where the neat polymers are likely to fail. This nanocomposite can be used in different industries as nanofillers, drug carriers for packaging essential hormones and microcapsules, etc. For fabricating a bone scaffold, electrospun nanofibrils made from biocomposite of hydroxyapatite and polyhydroxy butyrate, a form of PHA, can be incorporated with the targeted tissue. The other methods for making a polymer scaffold, includes gas foaming, lyophilization, sol–gel, and solvent casting method. In this review, PHA as a sustainable eco-friendly NextGen biomaterial from bacterial sources especially Bacillus cereus, and its application for fabricating bone scaffold using different strategies for bone regeneration have been discussed.
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11

Kargozar, Saeid, Sahar Mollazadeh, Farzad Kermani, Thomas J. Webster, Simin Nazarnezhad, Sepideh Hamzehlou, and Francesco Baino. "Hydroxyapatite Nanoparticles for Improved Cancer Theranostics." Journal of Functional Biomaterials 13, no. 3 (July 20, 2022): 100. http://dx.doi.org/10.3390/jfb13030100.

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Beyond their well-known applications in bone tissue engineering, hydroxyapatite nanoparticles (HAp NPs) have also been showing great promise for improved cancer therapy. The chemical structure of HAp NPs offers excellent possibilities for loading and delivering a broad range of anticancer drugs in a sustained, prolonged, and targeted manner and thus eliciting lower complications than conventional chemotherapeutic strategies. The incorporation of specific therapeutic elements into the basic composition of HAp NPs is another approach, alone or synergistically with drug release, to provide advanced anticancer effects such as the capability to inhibit the growth and metastasis of cancer cells through activating specific cell signaling pathways. HAp NPs can be easily converted to smart anticancer agents by applying different surface modification treatments to facilitate the targeting and killing of cancer cells without significant adverse effects on normal healthy cells. The applications in cancer diagnosis for magnetic and nuclear in vivo imaging are also promising as the detection of solid tumor cells is now achievable by utilizing superparamagnetic HAp NPs. The ongoing research emphasizes the use of HAp NPs in fabricating three-dimensional scaffolds for the treatment of cancerous tissues or organs, promoting the regeneration of healthy tissue after cancer detection and removal. This review provides a summary of HAp NP applications in cancer theranostics, highlighting the current limitations and the challenges ahead for this field to open new avenues for research.
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12

Ouyang, Liang, Wencai Huang, Gu He, and Li Guo. "Bone Targeting Prodrugs Based on Peptide Dendrimers, Synthesis and Hydroxyapatite Binding In Vitro." Letters in Organic Chemistry 6, no. 4 (June 1, 2009): 272–77. http://dx.doi.org/10.2174/157017809788489981.

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13

HENGST, V., C. OUSSOREN, T. KISSEL, and G. STORM. "Bone targeting potential of bisphosphonate-targeted liposomesPreparation, characterization and hydroxyapatite binding in vitro." International Journal of Pharmaceutics 331, no. 2 (March 1, 2007): 224–27. http://dx.doi.org/10.1016/j.ijpharm.2006.11.024.

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14

Vormbrock, Ingo, Gernot Kaber, Sonja Hartwig, Jürgen Eckel, Karsten Schrör, and Stefan Lehr. "Targeting phosphoprotein profiling by combination of hydroxyapatite-based phosphoprotein enrichment and SELDI-TOF MS." Archives of Physiology and Biochemistry 116, no. 4-5 (August 23, 2010): 181–87. http://dx.doi.org/10.3109/13813455.2010.506219.

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15

Sahu, Swetapadma, and Monalisa Mishra. "Hydroxyapatite nanoparticle causes sensory organ defects by targeting the retromer complex in Drosophila melanogaster." NanoImpact 19 (July 2020): 100237. http://dx.doi.org/10.1016/j.impact.2020.100237.

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16

Rotman, Stijn G., Thomas F. Moriarty, Benjamin Nottelet, Dirk W. Grijpma, David Eglin, and Olivier Guillaume. "Poly(Aspartic Acid) Functionalized Poly(ϵ-Caprolactone) Microspheres with Enhanced Hydroxyapatite Affinity as Bone Targeting Antibiotic Carriers." Pharmaceutics 12, no. 9 (September 17, 2020): 885. http://dx.doi.org/10.3390/pharmaceutics12090885.

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Bone infection is a feared complication for patients with surgically fixed bone fractures and local antibiotic delivery is important in prophylaxis and treatment of these infections. Recent studies indicated that Staphylococcus aureus can penetrate bone tissue through micron-sized canaliculi and evade systemic and currently available local antibiotic treatments. Targeting bacteria within the bone requires highly efficient delivery of antimicrobials to the infected bone tissue. In this work, a biodegradable microsphere carrier loaded with antibiotics and with specific affinity to bone mineral was developed. Two widely used antibiotics, i.e., Gentamicin-dioctyl sulfosuccinate (GM-AOT) and Ciprofloxacin (CF) were embedded in poly(ϵ-caprolactone) (PCL) microspheres fabricated by oil-in-water emulsion techniques with carboxylated poly(vinyl alcohol) (cPVA) as surfactant. The carboxylic acid groups present at the Poly(ϵ-caprolactone)/cPVA (PCL-cPVA) microsphere surface were functionalized with aspartic acid oligomers (ASP) granting bone targeting properties. We report on cPVA synthesis, microsphere formulation, and antibiotic loading of PCL/cPVA-ASP microspheres. Antibiotic loaded PCL/cPVA-ASP microspheres show sustained release of its antibiotic load and can inhibit bacterial growth in vitro for up to 6 days. PCL/cPVA-ASP microspheres show enhanced affinity to mineralized substrates compared to non-functionalized PCL/cPVA microspheres. These findings support further development of these bone targeting antibiotic carriers for potential treatment of persistent bone infections.
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17

Ganss, B., R. H. Kim, and J. Sodek. "Bone Sialoprotein." Critical Reviews in Oral Biology & Medicine 10, no. 1 (January 1999): 79–98. http://dx.doi.org/10.1177/10454411990100010401.

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The search for a protein nucleator of hydroxyapatite crystal formation has been a focus for the isolation and characterization of the major non-collagenous proteins in bone. Of the proteins characterized to date, bone sialoprotein (BSP) has emerged as the only bona fide candidate for nucleation. BSP is a highly glycosylated and sulphated phosphoprotein that is found almost exclusively in mineralized connective tissues. Characteristically, polyglutamic acid and arginine-glycine-aspartate (RGD) motifs with the ability to bind hydroxyapatite and cell-surface integrins, respectively, have been conserved in the protein sequence. Expression of the BSP gene, which is induced in newly formed osteoblasts, is up-regulated by hormones and cytokines that promote bone formation and down-regulated by factors that suppress bone formation. Thus, BSP has the biophysical and chemical properties of a nucleator, and its temporo-spatial expression coincides with de novo mineralization in bone and cementum. Moreover, BSP has been associated with mineral crystal formation in several pathologies, including breast carcinomas. However, the ability of BSP to mediate cell attachment and to signal through the RGD motif points to alternate functions for BSP which need further investigation. In combination, the hydroxyapatite-binding polyglutamic acid sequences and the RGD provide bi-functional entities through which BSP may mediate the targeting and attachment of normal and metastasizing cells to the bone surface.
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18

Jeon, Eunyi, and Jun-Hyeog Jang. "Protein Engineering of a Fibroblast Growth Factor 2 Protein for Targeting to Bone Mineral Hydroxyapatite." Protein & Peptide Letters 16, no. 6 (June 1, 2009): 664–67. http://dx.doi.org/10.2174/092986609788490267.

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19

Ansari, Legha, Mansooreh Derakhshi, Elnaz Bagheri, Nasser Shahtahmassebi, and Bizhan Malaekeh-Nikouei. "Folate conjugation improved uptake and targeting of porous hydroxyapatite nanoparticles containing epirubicin to cancer cells." Pharmaceutical Development and Technology 25, no. 5 (February 6, 2020): 601–9. http://dx.doi.org/10.1080/10837450.2020.1725045.

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20

Kataoka, Takuya, Shigeaki Abe, and Motohiro Tagaya. "Synthesis of Europium(III) Complex-Based Hydroxyapatite Nanocrystals for Biolabeling Applications." Key Engineering Materials 782 (October 2018): 41–46. http://dx.doi.org/10.4028/www.scientific.net/kem.782.41.

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We synthesized the inorganic/organic hybrid nanocrystal (EHA) by hydroxyapatite (HA) nanocrystal growth under the existence of tris(2,2,6,6-tetramethyl-3,5-heptanedionato)europium(III) (EuTH) complex. Then, folic acid derivative (FA-NHS: folate N-hydroxysuccinimidyl ester) as the targeting ligand for the HeLa cancer cells was immobilized on the EHA by the mediation of 3-aminopropyltriethoxysilane (APTES) and methyltriethoxysilane (MTES). When the FA-NHS molecular occupancy ratio on the EHA surface is around 3 to 5 %, the strong luminescence from the f-f transition of the Eu3+ ion and luminescence associated with energy transfer between the EuTH-FA monomer near 518 nm were observed. Moreover, the dispersibility in phosphate buffer saline was confirmed with immobilizing the positively-charged FA-NHS. The affinity and non-cytotoxicity between the nanocrystals and HeLa cancer cells were confirmed for 3 days. The red luminescence from the cells could be observed by fluorescence microscopy and the luminescence spectra.
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21

AbouAitah, Khaled, Agata Stefanek, Iman M. Higazy, Magdalena Janczewska, Anna Swiderska-Sroda, Agnieszka Chodara, Jacek Wojnarowicz, et al. "Effective Targeting of Colon Cancer Cells with Piperine Natural Anticancer Prodrug Using Functionalized Clusters of Hydroxyapatite Nanoparticles." Pharmaceutics 12, no. 1 (January 16, 2020): 70. http://dx.doi.org/10.3390/pharmaceutics12010070.

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Targeted drug delivery offers great opportunities for treating cancer. Here, we developed a novel anticancer targeted delivery system for piperine (Pip), an alkaloid prodrug derived from black pepper that exhibits anticancer effects. The tailored delivery system comprises aggregated hydroxyapatite nanoparticles (HAPs) functionalized with phosphonate groups (HAP-Ps). Pip was loaded into HAPs and HAP-Ps at pH 7.2 and 9.3 to obtain nanoformulations. The nanoformulations were characterized using several techniques and the release kinetics and anticancer effects investigated in vitro. The Pip loading capacity was >20%. Prolonged release was observed with kinetics dependent on pH, surface modification, and coating. The nanoformulations fully inhibited monolayer HCT116 colon cancer cells compared to Caco2 colon cancer and MCF7 breast cancer cells after 72 h, whereas free Pip had a weaker effect. The nanoformulations inhibited ~60% in HCT116 spheroids compared to free Pip. The Pip-loaded nanoparticles were also coated with gum Arabic and functionalized with folic acid as a targeting ligand. These functionalized nanoformulations had the lowest cytotoxicity towards normal WI-38 fibroblast cells. These preliminary findings suggest that the targeted delivery system comprising HAP aggregates loaded with Pip, coated with gum Arabic, and functionalized with folic acid are a potentially efficient agent against colon cancer.
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Nawrotek, Katarzyna, Mariusz Mąkiewicz, and Dawid Zawadzki. "Fabrication and Characterization of Polycaprolactone/Chitosan—Hydroxyapatite Hybrid Implants for Peripheral Nerve Regeneration." Polymers 13, no. 5 (March 3, 2021): 775. http://dx.doi.org/10.3390/polym13050775.

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Major efforts for the advancement of tubular-shaped implant fabrication focused recently on the development of 3D printing methods that can enable the fabrication of complete devices in a single printing process. However, the main limitation of these solutions is the use of non-biocompatible polymers. Therefore, a new technology for obtaining hybrid implants that employ polymer extrusion and electrophoretic deposition is applied. The fabricated structures are made of two layers: polycaprolactone skeleton and chitosan–hydroxyapatite electrodeposit. Both of them can be functionalized by incorporation of mechanical or biological cues that favor ingrowth, guidance, and correct targeting of axons. The electrodeposition process is conducted at different voltages in order to determine the influence of this process on the structural, chemical, and mechanical properties of implants. In addition, changes in mechanical properties of implants during their incubation in phosphate-buffered solution (pH 7.4) at 37 °C up to 28 days are examined. The presented technology, being low-cost and relatively simple, shall find a broad scope of applications in customized nerve tissue engineering.
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23

Alonso-de Castro, Silvia, Emmanuel Ruggiero, Aitor Lekuona Fernández, Unai Cossío, Zuriñe Baz, Dorleta Otaegui, Vanessa Gómez-Vallejo, Daniel Padro, Jordi Llop, and Luca Salassa. "Functionalizing NaGdF4:Yb,Er Upconverting Nanoparticles with Bone-Targeting Phosphonate Ligands: Imaging and In Vivo Biodistribution." Inorganics 7, no. 5 (April 30, 2019): 60. http://dx.doi.org/10.3390/inorganics7050060.

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Lanthanide-doped upconverting nanoparticles (UCNPs) transform near infrared light (NIR) into higher-energy UV and visible light by multiphotonic processes. Owing to such unique feature, UCNPs have found application in optical imaging and have been investigated for the NIR light activation of prodrugs, including transition metal complexes of interest in photochemotherapy. Besides, UCNPs also function as magnetic resonance imaging (MRI) contrast agents and positron emission tomography (PET) probes when labelled with radionuclides such as 18F. In this contribution, we report on a new series of phosphonate-functionalized NaGdF4:Yb,Er UCNPs that show affinity for hydroxyapatite (inorganic constituent of bones), and we discuss their potential as bone targeting multimodal (MRI/PET) imaging agents. In vivo biodistribution studies of 18F-labelled NaGdF4:Yb,Er UCNPs in rats indicate that surface functionalization with phosphonates favours the accumulation of nanoparticles in bones over time. PET results reveal leakage of 18F− for phosphonate-functionalized NaGdF4:Yb,Er and control nanomaterials. However, Gd was detected in the femur for phosphonate-capped UCNPs by ex vivo analysis using ICP-MS, corresponding to 6–7% of the injected dose.
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Ergun, Asli, Xiaojun Yu, Antonio Valdevit, Arthur Ritter, and Dilhan M. Kalyon. "Radially and Axially Graded Multizonal Bone Graft Substitutes Targeting Critical-Sized Bone Defects from Polycaprolactone/Hydroxyapatite/Tricalcium Phosphate." Tissue Engineering Part A 18, no. 23-24 (December 2012): 2426–36. http://dx.doi.org/10.1089/ten.tea.2011.0625.

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25

Rawat, Purnima, Iqbal Ahmad, Shindu C. Thomas, Shweta Pandey, Divya Vohora, Sarika Gupta, Farhan Jalees Ahmad, and Sushama Talegaonkar. "Revisiting bone targeting potential of novel hydroxyapatite based surface modified PLGA nanoparticles of risedronate: Pharmacokinetic and biochemical assessment." International Journal of Pharmaceutics 506, no. 1-2 (June 2016): 253–61. http://dx.doi.org/10.1016/j.ijpharm.2016.04.049.

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Safarova (Yantsen), Yuliya, Farkhad Olzhayev, Bauyrzhan Umbayev, Andrey Tsoy, Gonzalo Hortelano, Tursonjan Tokay, Hironobu Murata, Alan Russell, and Sholpan Askarova. "Mesenchymal Stem Cells Coated with Synthetic Bone-Targeting Polymers Enhance Osteoporotic Bone Fracture Regeneration." Bioengineering 7, no. 4 (October 12, 2020): 125. http://dx.doi.org/10.3390/bioengineering7040125.

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Osteoporosis is a progressive skeletal disease characterized by reduced bone density leading to bone fragility and an elevated risk of bone fractures. In osteoporotic conditions, decrease in bone density happens due to the augmented osteoclastic activity and the reduced number of osteoblast progenitor cells (mesenchymal stem cells, MSCs). We investigated a new method of cell therapy with membrane-engineered MSCs to restore the osteoblast progenitor pool and to inhibit osteoclastic activity in the fractured osteoporotic bones. The primary active sites of the polymer are the N-hydroxysuccinimide and bisphosphonate groups that allow the polymer to covalently bind to the MSCs’ plasma membrane, target hydroxyapatite molecules on the bone surface and inhibit osteolysis. The therapeutic utility of the membrane-engineered MSCs was investigated in female rats with induced estrogen-dependent osteoporosis and ulnar fractures. The analysis of the bone density dynamics showed a 27.4% and 21.5% increase in bone density at 4 and 24 weeks after the osteotomy of the ulna in animals that received four transplantations of polymer-modified MSCs. The results of the intravital observations were confirmed by the post-mortem analysis of histological slices of the fracture zones. Therefore, this combined approach that involves polymer and cell transplantation shows promise and warrants further bio-safety and clinical exploration.
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Luo, Dandan, Xiaochun Xu, M. Zubair Iqbal, Qingwei Zhao, Ruibo Zhao, Jabeen Farheen, Quan Zhang, Peiliang Zhang, and Xiangdong Kong. "siRNA-Loaded Hydroxyapatite Nanoparticles for KRAS Gene Silencing in Anti-Pancreatic Cancer Therapy." Pharmaceutics 13, no. 9 (September 8, 2021): 1428. http://dx.doi.org/10.3390/pharmaceutics13091428.

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Pancreatic carcinoma (PC) is greatly induced by the KRAS gene mutation, but effective targeted delivery for gene therapy has not existed. Small interfering ribonucleic acid (siRNA) serves as an advanced therapeutic modality and holds great promise for cancer treatment. However, the development of a non-toxic and high-efficiency carrier system to accurately deliver siRNA into cells for siRNA-targeted gene silencing is still a prodigious challenge. Herein, polyethylenimine (PEI)-modified hydroxyapatite (HAp) nanoparticles (HAp-PEI) were fabricated. The siRNA of the KRAS gene (siKras) was loaded onto the surface of HAp-PEI via electrostatic interaction between siRNA and PEI to design the functionalized HAp-PEI nanoparticle (HAp-PEI/siKras). The HAp-PEI/siKras was internalized into the human PC cells PANC-1 to achieve the maximum transfection efficiency for active tumor targeting. HAp-PEI/siKras effectively knocked down the expression of the KRAS gene and downregulated the expression of the Kras protein in vitro. Furthermore, the treatment with HAp-PEI/siKras resulted in greater anti-PC cells’ (PANC-1, BXPC-3, and CFPAC-1) efficacy in vitro. Additionally, the HAp-PEI exhibited no obvious in vitro cytotoxicity in normal pancreatic HPDE6-C7 cells. These findings provided a promising alternative for the therapeutic route of siRNA-targeted gene engineering for anti-pancreatic cancer therapy.
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Ignjatović, Nenad, Sanja Vranješ Djurić, Žarko Mitić, Drina Janković, and Dragan Uskoković. "Investigating an organ-targeting platform based on hydroxyapatite nanoparticles using a novel in situ method of radioactive 125Iodine labeling." Materials Science and Engineering: C 43 (October 2014): 439–46. http://dx.doi.org/10.1016/j.msec.2014.07.046.

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Mabilleau, Guillaume, Benoit Gobron, Aleksandra Mieczkowska, Rodolphe Perrot, and Daniel Chappard. "Efficacy of targeting bone-specific GIP receptor in ovariectomy-induced bone loss." Journal of Endocrinology 239, no. 2 (November 2018): 215–27. http://dx.doi.org/10.1530/joe-18-0214.

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Glucose-dependent insulinotropic polypeptide (GIP) has been recognized in the last decade as an important contributor of bone remodelling and is necessary for optimal bone quality. However, GIP receptors are expressed in several tissues in the body and little is known about the direct vs indirect effects of GIP on bone remodelling and quality. The aims of the present study were to validate two new GIP analogues, called [d-Ala2]-GIP-Tag and [d-Ala2]-GIP1–30, which specifically target either bone or whole-body GIP receptors, respectively; and to ascertain the beneficial effects of GIP therapy on bone in a mouse model of ovariectomy-induced bone loss. Both GIP analogues exhibited similar binding capacities at the GIP receptor and intracellular responses as full-length GIP1–42. Furthermore, only [d-Ala2]-GIP-Tag, but not [d-Ala2]-GIP1–30, was undoubtedly found exclusively in the bone matrix and released at acidic pH. In ovariectomized animals, [d-Ala2]-GIP1–30 but not [d-Ala2]-GIP-Tag ameliorated bone stiffness at the same magnitude than alendronate treatment. Only [d-Ala2]-GIP1–30 treatment led to significant ameliorations in cortical microarchitecture. Although alendronate treatment increased the hardness of the bone matrix and the type B carbonate substitution in the hydroxyapatite crystals, none of the GIP analogues modified bone matrix composition. Interestingly, in ovariectomy-induced bone loss, [d-Ala2]-GIP-Tag failed to alter bone strength, microarchitecture and bone matrix composition. Overall, this study shows that the use of a GIP analogue that target whole-body GIP receptors might be useful to improve bone strength in ovariectomized animals.
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Howard Nielsen, Jeffery Jay, Stewart A. Low, and Philip S. Low. "3505 Fracture Targeted Parathyroid Hormone Agonist As An Effective Pharmaceutical For Bone Repair in Mouse and Canine Models." Journal of Clinical and Translational Science 3, s1 (March 2019): 105–6. http://dx.doi.org/10.1017/cts.2019.241.

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OBJECTIVES/SPECIFIC AIMS: The primary objective of this study was to evaluate the performance of a bone fracture targeted systemically administrable bone anabolic as a potential therapeutic for bone fracture repair. Currently all bone fracture repair therapeutic require local administration during surgery. However, the population that need the most assistance in repair bone fractures are not eligible for surgery. So, it was our goal to design an inject-able therapeutic to assist in bone fracture repair to reduce the invasiveness. The injectable nature of it allows for repair administration of the bone anabolic and for therapeutic effect throughout the entire bone fracture healing process. Targeting it to the bone fracture site reduces the toxicity and increases the efficacy. METHODS/STUDY POPULATION: METHODS To achieve the above objective, a bone mineral-(hydroxyapatite-) targeting oligopeptide was conjugated to the non-signaling end of an engineered parathyroid hormone related protein fragment 1-46 with substitutions at Glu22,25, Leu23,28,31, Aib29, Lys26,30 (ePTHrP). The negatively charged oligopeptide has been shown to target raw hydroxyapatite with remarkable specificity, while the attached PTHrP has been demonstrated to induce sustained and accelerated bone growth under control of endogenous morphogenic regulatory factors. The conjugate’s specificity arises from the fact that raw hydroxyapatite is only exposed whenever a bone is fractured, surgically cut, grafted, or induced to undergo accelerated remodeling. The hydroxyapatite-targeted conjugate can therefore be administered systemically (i.e. without invasive surgery or localized injection) and still accumulate on the exposed hydroxyapatite at the fracture site where it accelerates the healing process Murine in vivo experiments were conducted on female Swiss Webster mice (10 per group). Femoral fractures were induced with a 3-point bending device and stabilized. Mice were dosed with 3 nmol/kg/d of targeted-ePTHrP, non-conjugated (free) ePTHrP, or saline. Following a 4-week study, fracture callus densities were measured using microCT. Canine in vivo experiments were conducted on 1-year-old male beagles. Beagles underwent a 10 mm bilateral ulnar ostectomy. Two dogs in the treatment group and Three dogs in the control group were dosed daily with either targeted-ePTHrP 0.5nmol/kg/d or saline respectively. Dogs were x-rayed weekly for the first 6 weeks and then every other week thereafter. One tailed ANOVA followed by Dunnett’s post-hoc test was used to establish significance. All animal experiments were conducted as described in approved IACUC protocols. P<0.05 was considered significant. RESULTS/ANTICIPATED RESULTS: RESULTS SECTION: In the murine studies we observed a marked increase in fracture callus size and a 2-fold increase in bone deposition was observed in the targeted-ePTHrP group over the saline group (P<0.01). A significant doubling in bone density was also observed. Targeted-ePTHrP group fractured femurs were able to achieve their pre-fracture strength as early as 3 weeks compared to 9 weeks in the saline mice representing a 66% reduction in healing time. In the canine studies, we observe a significantly higher closure of the ostectomy gap than saline controls (P<0.05). In addition, no significant differences in weight are observed in the treatment vs. saline controls. No significant difference between the control group and treatment groups was found in a histological investigation of the organs. DISCUSSION/SIGNIFICANCE OF IMPACT: DISCUSSION: Although attempts have been made in developing a systemically administered fracture therapeutic for fracture repair, i.e. teriparatide, to date, no such anabolics have been approved for this use. In these studies there is evidence that anabolic activity was occurring at the fracture site, but at a level that did not meet FDA required end-points.2 It is plausible that if sufficient drug were to be delivered to a fracture site then improved fracture repair would be possible. In previous studies, we demonstrated fracture specific accumulation bone anabolics can be achieved by modifying the drug with acidic oligopeptides.3 Here, by modifying a safe, clinically proven, parathyroid hormone receptor agonist with an acidic oligopeptide we observe improved bone deposition and strength in mice. Furthermore, when administered to canine critical sized defect ostectomies, a more relevant and difficult model, we observe improved ostectomy closure. CLINICAL RELEVANCE:: The ability to accelerate bone fracture repair is a fundamental need that has not been addressed by conventional methods. By targeting bone anabolic agents to bone fractures, we can deliver sufficient concentrations of anabolic agent to the fracture site to accelerate healing, thus avoiding surgery and any ectopic bone growth associated with locally-applied bone anabolic agents.
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Lin, W. C., C. C. Chuang, C. Yao, and C. M. Tang. "Effect of Cobalt Precursors on Cobalt-Hydroxyapatite Used in Bone Regeneration and MRI." Journal of Dental Research 99, no. 3 (January 6, 2020): 277–84. http://dx.doi.org/10.1177/0022034519897006.

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In clinical dentistry practice, supplemental bone surgery or jawbone defect after tooth extraction must be assisted by a bone-filling material. Cobalt-substituted hydroxyapatite (COHA) effectively promotes bone cell growth, reduces the inflammatory response, and is an antibacterial agent. COHA can therefore be used as an alveolar bone-filling material or guided bone regeneration membrane. Meanwhile, COHA can be used in magnetic resonance imaging (MRI) with negative contrast agents and targeting materials without causing metal interference with the image. Hence, COHA has received increasing amounts of attention in recent years. However, the influence of different cobalt precursors on the synthesized COHA is still unknown. Therefore, COHA synthesized from 3 cobalt precursors (cobalt chloride, cobalt nitrate, and cobalt sulfate) was compared in this study. The results show that COHA synthesized by the precursor with the smallest anion radius, cobalt chloride, has a larger particle size (239 nm) and a higher cobalt ion substitution rate (15.6%). When the cobalt ion substitution rate increases, the MRI has a stronger contrast. Bioactivity data indicate that COHAC is more susceptible to degradation and therefore releases more cobalt ions to contribute to the differentiation of bone cells. Based on these studies, COHAC prepared with the cobalt chloride precursor has a higher cobalt ion substitution rate, faster degradation rate, better image contrast, and better bioactivity. It is therefore the preferred choice of bone-filling material for alveolar bone regeneration.
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Rill, Christoph, Zvonimir I. Kolar, Guido Kickelbick, Hubert Th Wolterbeek, and Joop A. Peters. "Kinetics and Thermodynamics of Adsorption on Hydroxyapatite of the [160Tb]Terbium Complexes of the Bone-Targeting Ligands DOTP and BPPED." Langmuir 25, no. 4 (February 17, 2009): 2294–301. http://dx.doi.org/10.1021/la803562e.

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Cai, Jin, Yanbing Duan, Jia Yu, Junqing Chen, Meng Chao, and Min Ji. "Bone-targeting glycol and NSAIDS ester prodrugs of rhein: Synthesis, hydroxyapatite affinity, stability, anti-inflammatory, ulcerogenicity index and pharmacokinetics studies." European Journal of Medicinal Chemistry 55 (September 2012): 409–19. http://dx.doi.org/10.1016/j.ejmech.2012.07.053.

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Struewing, Ian, Nathan Sienkiewicz, Chiqian Zhang, Nicholas Dugan, and Jingrang Lu. "Effective Early Treatment of Microcystis Exponential Growth and Microcystin Production with Hydrogen Peroxide and Hydroxyapatite." Toxins 15, no. 1 (December 20, 2022): 3. http://dx.doi.org/10.3390/toxins15010003.

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Mitigating cyanotoxin production is essential to protecting aquatic ecosystems and public health. However, current harmful cyanobacterial bloom (HCB) control strategies have significant shortcomings. Because predicting HCBs is difficult, current HCB control strategies are employed when heavy HCBs have already occurred. Our pilot study developed an effective HCB prediction approach that is employed before exponential cyanobacterial growth and massive cyanotoxin production can occur. We used a quantitative polymerase chain reaction (qPCR) assay targeting the toxin-encoding gene mcyA to signal the timing of treatment. When control measures were applied at an early growth stage or one week before the exponential growth of Microcystis aeruginosa (predicted by qPCR signals), both hydrogen peroxide (H2O2) and the adsorbent hydroxyapatite (HAP) effectively stopped M. aeruginosa growth and microcystin (MC) production. Treatment with either H2O2 (10 mg·L−1) or HAP (40 µm particles at 2.5 g·L−1) significantly reduced both mcyA gene copies and MC levels compared with the control in a dose-dependent manner. While both treatments reduced MC levels similarly, HAP showed a greater ability to reduce mcyA gene abundance. Under laboratory culture conditions, H2O2 and HAP also prevented MC production when applied at the early stages of the bloom when mcyA gene abundance was below 105 copies·mL−1.
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Varoni, Elena Maria, Michele Iafisco, Lia Rimondini, and Maria Prat. "Development of a Targeted Drug Delivery System: Monoclonal Antibodies Adsorption onto Bonelike Hydroxyapatite Nanocrystal Surface." Advanced Materials Research 409 (November 2011): 175–80. http://dx.doi.org/10.4028/www.scientific.net/amr.409.175.

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Together with cancer biomarker advance, nanotechnology could lead to a “personalized oncology”, where early tumour detection and diagnosis are more and more specific. A nanosized drug delivery system is mainly composed of three fundamental elements: i) a drug nanocarrier (1-100 nm), ii) an anti-cancer drug; iii) an active targeting molecule, recognizing a tumour associated marker expressed at the cell surface. In our study we used: i) hydroxyapatite nanocrystals (HA-NC), for its properties of large specific surface area, hydrophilicity and biodegradability with very low toxicity and ii) monoclonal antibodies (mAb), directed against CAR-3, a mucin tumour associated surface antigen, and against the Met/HGF-R, both of which are overexpressed on human carcinomas. In our study, nanosized HA-NC, poorly aggregating and biomimetic, were synthetised and characterized. After a preliminary isothermal adsorption of human polyclonal IgG, we functionalized HA-NC, coated or not with protein A (Prot A), with the two mAbs. IgG and Prot A isothermal adsorption curves were obtained; mAb absorption was achieved and prelimary Prot A coating appeared not to improve HA-NC loading capacity. IgG conformation onto HA-NC was investigated by means of Fourier Transformed InfraRed Spectroscopy, revealing a preferential binding with the constant antibody domain, and exposition of the variable domain, involved in antigen binding, on the biomaterial surface. These immunocomplexes are confirmed to be potentially used as targeted drug delivery system.
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Ningsih, Henni Setia, Liu-Gu Chen, Ren-Jei Chung, and Yu-Jen Chou. "An Investigation on Spray-Granulated, Macroporous, Bioactive Glass Microspheres for a Controlled Drug Delivery System." Materials 14, no. 11 (June 6, 2021): 3112. http://dx.doi.org/10.3390/ma14113112.

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Bioactive glass (BG) has been regarded as an excellent candidate for biomedical applications due to its superior properties of bioactivity, biocompatibility, osteoconductivity and biodegradability. Thus, in this study, we aimed to fabricate drug carriers that were capable of loading therapeutic antibiotics while promoting bone regeneration using macroporous BG microspheres, prepared by a spray drying method. Characterizations of particle morphology and specific surface area were carried out via scanning electron microscopy and nitrogen adsorption/desorption isotherm. Evaluations of in vitro bioactivity were performed based on Kokubo’s simulated body fluid to confirm the formation of the hydroxyapatite (HA) layer after immersion. In addition, the in vitro drug release behaviors were examined, using tetracycline as the therapeutic antibiotic in pH 7.4 and 5.0 environments. Finally, the results showed that BG microspheres of up to 33 μm could be mass-produced, targeting various therapeutic situations and their resulting bioactivities and drug release behaviors, and related properties were discussed.
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Reagan, Michaela R., Archana Swami, Pamela A. Basto, Yuji Mishima, Jinhe Liu, Siobhan Glavey, Grace B. O'Callaghan, et al. "Nanoparticle Design For Bone-Specific Chemotherapy and Microenvironmental Targeting In Multiple Myeloma." Blood 122, no. 21 (November 15, 2013): 881. http://dx.doi.org/10.1182/blood.v122.21.881.881.

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Abstract Introduction The bone marrow (BM) niche is known to exert a protective effect on lymphoid tumors, such as multiple myeloma (MM), where mesenchymal stem cell interactions with clonal plasma cells increase tumor proliferation and survival. However, certain cells within the BM milieu, such as mature osteoblasts and osteocytes, have demonstrated the potential to inhibit tumor growth; utilizing these cells presents a promising new anti-cancer approach. Hence, designing better methods of bone-specific delivery for both direct cancer cell treatment and indirect treatment through the modulation of bone cells may result in a potent, two-pronged anti-cancer strategy. Our work aimed to develop a novel system to target both MM and bone cells to induce greater osteogenesis and hamper tumor growth. Methods PEG–PLGA nanoparticles (NPs) coupled to alendronate (“bone-targeted”) or alone (“non-targeted”) were formulated and loaded with bortezomib (“BTZ-NPs”) or left empty (“BTZ-free”). NPs were characterized for their physiochemical properties, including size (using dynamic light scattering; surface charges (Zeta potential); and bone affinity (using hydroxyapatite binding). NPs were engineered with different formulation methods and those with the optimal physiochemical characteristics and drug encapsulation efficiency were used for further studies. BTZ release kinetics were analyzed using HPLC. Anti-MM effects were assessed in vitro using MTT, bioluminescence (BLI) and Annexin V/PI apoptosis flow cytometry analysis on MM1S cells. In vivo, efficacy was measured by mouse weight, BLI and survival after i.v. cancer cell injections in mice. Cellular uptake was assessed in vitro by flow cytometry and in vivo biodistribution was assessed using fluorescent whole body and fixed section imaging. Bone specificity was assessed in vitro by co-culture of bone-targeted and non-targeted NPs with bone chips or hydroxyapatite using fluorescence and TEM imaging. In an in vivo model of myeloma treatment, female Nod/SCID beige mice were injected i.v. with 4 × 106 Luc+/GFP+ MM1S cells and, at day 21, treated with a) BTZ, b) BTZ-bone-targeted NPs, c) BTZ-non-targeted NPs or d) BTZ-free bone-targeted NPs. Using an in vivo model of pre-treatment for cancer prevention, mice were pre-treated with i.p. injections of BTZ-bone-targeted NPs and appropriate controls thrice weekly for 3 weeks. They were then injected i.v. with Luc+/GFP+ 5TGM1 or MM1S cells and monitored for BLI and survival. Static and dynamic bone histomorphometry and μCT were used to assess effects of pre-treatment on bone formation and osteolysis prevention. Results Our biodegradable, NPs had uniform size distribution within the range of 100 to 200 nm based on the type of formulation, with a zeta potential of ±5mV. Bone- targeted NPs showed high affinity towards bone mineral in vitro and better skeletal accumulation in vivo compared to non-targeted NPs. NPs were easily up-taken by cells in vitro, and BTZ release kinetics showed a burst followed by a sustained-release pattern over 60 hrs. BTZ-NPs induced apoptosis in MM cells in vitro. Importantly, BTZ-bone-targeted-NP pre-treated mice showed significantly less tumor burden (BLI) and longer survival than free drug or drug-free bone-targeted NPs, thus demonstrating a tumor-inhibiting effect unique to the BTZ-bone-targeted-NPs. Pre-treatment with BTZ increased bone formation in tibias and femurs, as measured by μCT of bone volume/total volume, and trabecular thickness and number, suggesting that increased bone volume may inhibit MM. In a second mouse model, both BTZ-bone-targeted NPs and BTZ-free NPs were equally able to reduce tumor growth in vivo when given after tumor formation. Conclusion Bone-targeted nanoparticles hold great potential for clinical applications in delivering chemotherapies to bone marrow niches, reducing off-target effects, increasing local drug concentrations, and lengthening the therapeutic window. BTZ-bone-targeted NPs are able to slow tumor growth and increase survival in mice when used as a pre-treatment. This may result, at least in part, from BTZ-induced increased bone formation. These findings indicate that BTZ-bone-targeted NPs exert a chemopreventive effect in MM in vivo, thus suggesting their potential use in the clinical setting. Disclosures: Basto: BIND Therapeutics: Patent licensed by BIND, Patent licensed by BIND Patents & Royalties. Farokhzad:BIND Therapeutics: Employment, Equity Ownership; Selecta Biosciences: Employment, Equity Ownership. Ghobrial:Onyx: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees; BMS: Research Funding; Sanofi: Research Funding; Novartis: Membership on an entity’s Board of Directors or advisory committees.
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Yang, Tzu-Ruei, Ying-Hsuan Chen, Jasmina Wiemann, Beate Spiering, and P. Martin Sander. "Fossil eggshell cuticle elucidates dinosaur nesting ecology." PeerJ 6 (July 6, 2018): e5144. http://dx.doi.org/10.7717/peerj.5144.

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The cuticle layer consisting mainly of lipids and hydroxyapatite (HAp) atop the mineralized avian eggshell is a protective structure that prevents the egg from dehydration and microbial invasions. Previous ornithological studies have revealed that the cuticle layer is also involved in modulating the reflectance of eggshells in addition to pigments (protoporphyrin and biliverdin). Thus, the cuticle layer represents a crucial trait that delivers ecological signals. While present in most modern birds, direct evidence for cuticle preservation in stem birds and non-avian dinosaurs is yet missing. Here we present the first direct and chemical evidence for the preservation of the cuticle layer on dinosaur eggshells. We analyze several theropod eggshells from various localities, including oviraptorid Macroolithus yaotunensis eggshells from the Late Cretaceous deposits of Henan, Jiangxi, and Guangdong in China and alvarezsaurid Triprismatoolithus eggshell from the Two Medicine Formation of Montana, United States, with the scanning electron microscope (SEM), electron probe micro-analysis (EPMA), and Raman spectroscopy (RS). The elemental analysis with EPMA shows high concentration of phosphorus at the boundary between the eggshell and sediment, representing the hydroxyapatitic cuticle layer (HAp). Depletion of phosphorus in sediment excludes the allochthonous origin of the phosphorus in these eggshells. The chemometric analysis of Raman spectra collected from fossil and extant eggs provides further supportive evidence for the cuticle preservation in oviraptorid and probable alvarezsaurid eggshells. In accordance with our previous discovery of pigments preserved in Cretaceous oviraptorid dinosaur eggshells, we validate the cuticle preservation on dinosaur eggshells through deep time and offer a yet unexplored resource for chemical studies targeting the evolution of dinosaur nesting ecology. Our study also suggests that the cuticle structure can be traced far back to maniraptoran dinosaurs and enhance their reproductive success in a warm and mesic habitat such as Montana and southern China during the Late Cretaceous.
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Ignjatović, Nenad L., Marija Sakač, Ivana Kuzminac, Vesna Kojić, Smilja Marković, Dana Vasiljević-Radović, Victoria M. Wu, Vuk Uskoković, and Dragan P. Uskoković. "Chitosan oligosaccharide lactate coated hydroxyapatite nanoparticles as a vehicle for the delivery of steroid drugs and the targeting of breast cancer cells." Journal of Materials Chemistry B 6, no. 43 (2018): 6957–68. http://dx.doi.org/10.1039/c8tb01995a.

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40

Zeng, Shuli, Ronghui Zhou, Xiaoke Zheng, Lan Wu, and Xiandeng Hou. "Mono-dispersed Ba 2+ -doped Nano-hydroxyapatite conjugated with near-infrared Cu-doped CdS quantum dots for CT/fluorescence bimodal targeting cell imaging." Microchemical Journal 134 (September 2017): 41–48. http://dx.doi.org/10.1016/j.microc.2017.05.003.

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41

Budiatin, Aniek Setiya, Maria Apriliani Gani, Chrismawan Ardianto, Samirah, Sahrati Yudiaprijah Daeng Pattah, Fitroh Mubarokah, and Junaidi Khotib. "The impact of glutaraldehyde on the characteristics of bovine hydroxyapatite-gelatin based bone scaffold as gentamicin delivery system." Journal of Basic and Clinical Physiology and Pharmacology 32, no. 4 (June 25, 2021): 687–91. http://dx.doi.org/10.1515/jbcpp-2020-0405.

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Abstract Objectives Biomaterials are widely used as drug delivery systems targeting bone tissue, such as to treat bone infectious disease. However, the addition of drugs to biomaterials weakens their mechanical properties. Crosslinkers are compounds that improve the mechanical properties of biomaterials. This study aims to determine the effect of glutaraldehyde (GTA) as a crosslinker on the characteristics of bovine hydroxyapatite-gelatin-based bone scaffold with gentamicin as antibiotics (BHA-GEL-GEN-GTA). Methods BHA-GEL-GEN-GTA scaffold with GTA solid content ranging from 0.1 to 1.4 wt% was made by direct compression. The compressive strength test was carried out using autograph. Scaffold degradation test was carried out by dissolving the scaffolds in PBS. Scaffold toxicity was performed by MTT assay using BHK-21 fibroblast cells. Results There was a significant difference in the scaffolds’ compressive strength due to differences in GTA volume. Scaffold crosslinked using GTA with solid content 0.1 and 0.2 wt% in 2 mL solution had higher compressive strength than those in 1 mL solution. Furthermore, GTA with solid content 0.6, 1, 1.2, and 1.4 wt% showed higher compressive strength than those without GTA. Degradation test results showed that GTA increased the percentage of weight loss and swelling of the scaffold. The scaffold exhibited a nontoxic profile in MTT assay. Conclusions GTA with optimum solid content shows great compressive strength, stable swelling profile with low percentage of scaffold’s weight loss, and is considered as nontoxic.
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Nguyen, Phuong T. M., Bac H. Vo, Nhung T. Tran, and Quyen D. Van. "Anti-biofilm activity of α-mangostin isolated from Garcinia mangostana L." Zeitschrift für Naturforschung C 70, no. 11-12 (November 1, 2015): 313–18. http://dx.doi.org/10.1515/znc-2015-0187.

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Abstract This study was carried out to further examine the anti-biofilm activity of α-mangostin (αMG) isolated from Garcinia mangostana L. grown in Vietnam, against a strongly biofilm producing Streptococcus mutans, a major causative agent of dental caries. The obtained data indicated that topical applications (twice-daily, 60 s exposure each) of 150 μM αMG during biofilm formation on the surfaces of hydroxyapatite disks (sHA) by S. mutans UA159 resulted in 30.7% reduction in biofilm accumulation after 68 h of growth. The treatment did not affect the viability of S. mutans cells in the biofilms. The surface activities of two key enzymes responsible for biofilm formation, i.e. the glycosyltransferases GtfB and GtfC, were reduced by 20 and 35%, respectively (vs. vehicle control, P < 0.05). Interestingly, αMG specifically targeted S. mutans in mixed biofilms, resulting in the decrease of the S. mutans population and total biofilm biomass. αMG was also found to accumulate within the biofilm of S. mutans up to 4.5 μg/biofilm, equal to a concentration of >10 μM/biofilm. In conclusion, this study confirmed anti-biofilm activity of αMG against S. mutans. A brief exposure to αMG may suppress biofilm formation by targeting key enzymes imvolved in biofilm formation.
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Tavares, Francisco J. T. M., Paula I. P. Soares, Jorge Carvalho Silva, and João Paulo Borges. "Preparation and In Vitro Characterization of Magnetic CS/PVA/HA/pSPIONs Scaffolds for Magnetic Hyperthermia and Bone Regeneration." International Journal of Molecular Sciences 24, no. 2 (January 6, 2023): 1128. http://dx.doi.org/10.3390/ijms24021128.

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Conventional bone cancer treatment often results in unwanted side effects, critical-sized bone defects, and inefficient cancer-cell targeting. Therefore, new approaches are necessary to better address bone cancer treatment and patient’s recovery. One solution may reside in the combination of bone regeneration scaffolds with magnetic hyperthermia. By incorporating pristine superparamagnetic iron oxide nanoparticles (pSPIONs) into additively manufactured scaffolds we created magnetic structures for magnetic hyperthermia and bone regeneration. For this, hydroxyapatite (HA) particles were integrated in a polymeric matrix composed of chitosan (CS) and poly (vinyl alcohol) (PVA). Once optimized, pSPIONs were added to the CS/PVA/HA paste at three different concentrations (1.92, 3.77, and 5.54 wt.%), and subsequently additively manufactured to form a scaffold. Results indicate that scaffolds containing 3.77 and 5.54 wt.% of pSPIONs, attained temperature increases of 6.6 and 7.5 °C in magnetic hyperthermia testing, respectively. In vitro studies using human osteosarcoma Saos-2 cells indicated that pSPIONs incorporation significantly stimulated cell adhesion, proliferation and alkaline phosphatase (ALP) expression when compared to CS/PVA/HA scaffolds. Thus, these results support that CS/PVA/HA/pSPIONs scaffolds with pSPIONs concentrations above or equal to 3.77 wt.% have the potential to be used for magnetic hyperthermia and bone regeneration.
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Thode, Trason, Jaime Fornetti, Ryan Rodriguez del Villar, Alexis Weston, Serina Ng, Srikanta Dana, Raffaella Soldi, et al. "Abstract 3948: Development of bone-targeted Ron inhibitors to treat osseous metastases from breast cancers." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3948. http://dx.doi.org/10.1158/1538-7445.am2022-3948.

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Abstract Purpose: About 500,000 people each year worldwide die from metastatic breast cancer. More than 70% of these metastatic breast cancer patients have bone metastases and median survival time from diagnosis of bone metastasis is only 2-3 years. As breast cancer bone metastases are primarily osteolytic, patients suffer from significant morbidities, including severe pain, pathological fractures, nerve compression, and hypercalcemia. Previously, it was shown that RON receptor tyrosine kinase mediates breast cancer outgrowth at metastatic sites, promotes osteolytic bone destruction, and induces systemic immune suppression. We hypothesized that inhibition of RON in specialized resident macrophages and/or osteoclasts will eliminate metastasis through dual effects of blocking osteolysis and enhancing anti-tumor immunity. In this study, we have developed several bis(phosphonate) or phosphate conjugates of BMS-777607 and LY2801653, and report their accumulation in the bone microenvironment along with effects on osteolysis and tumor burden. Methods: We have utilized novel synthetic schemes for synthesis of the drug conjugates. In vitro kinase assays were performed using ADP-Glo RON kinase assay kit (Promega). Hydroxyapatite binding assay was used to determine binding of drug conjugates to the bone mineral. Changes in phosphorylation of RON was demonstrated by Western blotting. Plasma pharmacokinetics and bone accumulation of lead drug conjugates in mice was assessed by mass-spectrometry. An intratibial bone metastasis model in which MSP-expressing MMTV-PyMT tumor cells are injected into the tibia of mice was used to assess the effect of treatment with lead drug conjugates. Results: Seven novel drug conjugates were synthesized and inhibited RON kinase activity with an IC50 of 0.060-2.4 µM. Three drug conjugates demonstrated better hydroxyapatite binding when compared with BMS-777607. In agreement with the in vitro kinase activity, a variable decrease in the phosphorylation of RON was observed in cells treated with the drug conjugates. ZB-28, a monophosphonate derivative of BMS-777607, showed higher accumulation in the bone when compared with BMS-777607 but failed to block tumor-mediated bone osteolysis in an intratibial bone metastasis mouse model. Currently, a cleavable phosphate conjugate of BMS-777607 (ZB-32) is undergoing testing in the same mouse model. We have confirmed that ZB-32 and its hydrolyzed product ZB-33 accumulate in the bone to a significantly higher level than BMS-777607. These results along with preliminary ADME will be presented. Conclusion: Targeting RON kinase in the bone microenvironment is a promising approach to alleviate morbidities observed in breast cancer patients with bone metastases. We present novel bone-targeting conjugates of BMS-777607 and highlight the potential for clinical development. Citation Format: Trason Thode, Jaime Fornetti, Ryan Rodriguez del Villar, Alexis Weston, Serina Ng, Srikanta Dana, Raffaella Soldi, Mohan Kaadige, Hariprasad Vankayalapati, Srinivas Kasibhatla, Alana Welm, Sunil Sharma. Development of bone-targeted Ron inhibitors to treat osseous metastases from breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3948.
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45

Burgess, K., R. Winpenny, A. Saiani, A. Herrick, and R. Watson. "POS0478 TOPICAL CALCIUM CHELATORS FOR TARGETING CUTANEOUS CALCIFICATION: PRECLINICAL EVIDENCE OF EFFICACY." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 493.2–494. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2313.

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BackgroundCutis calcinosis, defined as sub-epidermal deposition of calcium salts, is a painful, disabling, disfiguring, problem in 20-40% of patients with systemic sclerosis. Its pathogenesis remains poorly understood and currently there is no effective disease-modifying pharmacotherapy. One potential strategy is topical application of calcium chelating agents, able to penetrate the epidermal barrier and dissolve subcutaneous calcinotic deposits in situ. To date, the only compound reported for this application has been sodium thiosulfate (STS), with often-contradictory results.ObjectivesTo test the hypothesis, in pre-clinical studies, that polycarboxylic acids can induce calcium dissolution without skin toxicity, with the long-term aim of developing an effective topical treatment for cutis calcinosis.MethodsWe compared the metal ion-chelating agents citric acid (CA) and ethylenediaminetetraacetic acid (EDTA) - polycarboxylic acids with well-characterised chelation profiles – to STS for their ability to chelate calcium, without inducing cytotoxicity or inflammation (pro-inflammatory cytokine expression and release), using in vitro 2D (keratinocyte [HaCaT]; fibroblast ([HCA2]) and recombinant human epidermal (RHE) models. The resultant data was subsequently used to predict therapeutic concentrations for assessment in a validated skin irritation model (SkinEthicTM; Episkin SA) and to assay maximal percutaneous absorption. At relative dermal concentrations, the dissolution performance of each chelator was further assessed using two different models of calcinosis: 1) pharmaceutical dissolution of a hydroxyapatite (HAp) tablet (1) and; 2) dissolution of a calcified extracellular matrix laid down by mineralising SaOS2 in vitro monolayer culture (2).ResultsIncubation with CA, EDTA and STS induced cytotoxicity in both in vitro cell lines studied at concentrations of >10 mM; only EDTA (10 mM) resulted in inflammatory cytokine release (IL8) from cells at these higher concentrations (cf positive control, Lipopolysaccharide 10 mg/mL). When applied topically to RHE models as near-saturated solutions, none of the chelators were categorised as skin irritants. Due to differences in their relative aqueous solubility, higher concentrations of CA (1600 mM) and STS (1200 mM) could be delivered through the RHE model than EDTA (200 mM). Using a simple linear regression model, the rate of compound absorption was: CA, 0.43 ± 0.05; STS, 0.26 ± 0.03 and; EDTA, 0.05 ± 0.01 g/L/hr. At each time-point, the cumulative concentration of compound in the receptor media was CA > STS > EDTA. Incubation with chelators had no effect on the integrity of the RHE by standard histology. Based on the rate of percutaneous absorption, the dissolution performance of each chelator was tested at relative dermal concentrations for phosphate dissolution (nmoles) of HAp (CA, 9.61 ±0.97; EDTA, 5.38 ± 0.28; 3.78 ± 0.58) and in the calcified in vitro model (Figure 1; CA, 3285 ± 105, STS, 947 ± 95, EDTA, 1174 ± 89), showing the superiority of CA in both model systems.Figure 1.Dissolution of a calcified extracellular matrix by citric acidConclusionOverall, this study highlights the promise of polycarboxylic acids, particularly CA, to target subcutaneous calcification, which are neither toxic nor inflammatory to the skin. Specifically, we have identified CA as a potentially more efficacious alternative to STS for the topical treatment of cutis calcinosis.References[1]Fei F, Gallas A, Chang YC, Rao Y, Hunter AC, Winpenny REP, Herrick AL, Lockyer NP, Blanford CF. 2017. Quartz crystal microbalance assay of clinical calcinosis samples and their synthetic models differentiates the efficacy of chelation-based treatments. ACS Appl Mater Interfaces, 9(33):27544-27552[2]Wang QG, Wimpenny I, Dey RE, Zhong X, Youle PJ, Downes S, Watts DC, Budd PM, Hoyland JA, Gough JE. 2018. The unique calcium chelation property of poly(vinyl phosphonic acid-co-acrylic acid) and effects on osteogenesis in vitro. J Biomed Mater Res Part A 2018:106A:168–179Disclosure of InterestsKyle Burgess: None declared, Richard Winpenny: None declared, Alberto Saiani: None declared, Ariane Herrick Speakers bureau: Janssen, Consultant of: Arena, Boehringer-Ingelheim, Camurus, CSL-Behring, Gesynta, Grant/research support from: Gesynta, Rachel Watson Consultant of: NAOS, AbbVie, Grant/research support from: Walgreens Alliance Boots.
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46

Koblenzer, Maximilian, Marek Weiler, Athanassios Fragoulis, Stephan Rütten, Thomas Pufe, and Holger Jahr. "Physiological Mineralization during In Vitro Osteogenesis in a Biomimetic Spheroid Culture Model." Cells 11, no. 17 (August 30, 2022): 2702. http://dx.doi.org/10.3390/cells11172702.

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Bone health-targeting drug development strategies still largely rely on inferior 2D in vitro screenings. We aimed at developing a scaffold-free progenitor cell-based 3D biomineralization model for more physiological high-throughput screenings. MC3T3-E1 pre-osteoblasts were cultured in α-MEM with 10% FCS, at 37 °C and 5% CO2 for up to 28 days, in non-adherent V-shaped plates to form uniformly sized 3D spheroids. Osteogenic differentiation was induced by 10 mM β-glycerophosphate and 50 µg/mL ascorbic acid. Mineralization stages were assessed through studying expression of marker genes, alkaline phosphatase activity, and calcium deposition by histochemistry. Mineralization quality was evaluated by Fourier transformed infrared (FTIR) and scanning electron microscopic (SEM) analyses and quantified by micro-CT analyses. Expression profiles of selected early- and late-stage osteoblast differentiation markers indicated a well-developed 3D biomineralization process with strongly upregulated Col1a1, Bglap and Alpl mRNA levels and type I collagen- and osteocalcin-positive immunohistochemistry (IHC). A dynamic biomineralization process with increasing mineral densities was observed during the second half of the culture period. SEM–Energy-Dispersive X-ray analyses (EDX) and FTIR ultimately confirmed a native bone-like hydroxyapatite mineral deposition ex vivo. We thus established a robust and versatile biomimetic, and high-throughput compatible, cost-efficient spheroid culture model with a native bone-like mineralization for improved pharmacological ex vivo screenings.
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47

Falsetta, Megan L., Marlise I. Klein, José A. Lemos, Bruno B. Silva, Senyo Agidi, Kathy K. Scott-Anne, and Hyun Koo. "Novel Antibiofilm Chemotherapy Targets Exopolysaccharide Synthesis and Stress Tolerance in Streptococcus mutans To Modulate Virulence ExpressionIn Vivo." Antimicrobial Agents and Chemotherapy 56, no. 12 (September 17, 2012): 6201–11. http://dx.doi.org/10.1128/aac.01381-12.

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ABSTRACTFluoride is the mainstay of dental caries prevention, and yet current applications offer incomplete protection and may not effectively address the infectious character of the disease. Therefore, we evaluated the effectiveness of a novel combination therapy (CT; 2 mM myricetin, 4 mMtt-farnesol, 250 ppm of fluoride) that supplements fluoride with naturally occurring, food-derived, antibiofilm compounds. Treatment regimens simulating those experienced clinically (twice daily for ≤60 s) were used bothin vitroover a saliva-coated hydroxyapatite biofilm model andin vivowith a rodent model of dental caries. The effectiveness of CT was evaluated based on the incidence and severity of carious lesions (compared to fluoride or vehicle control). We found that CT was superior to fluoride (positive control,P< 0.05); topical applications dramatically reduced caries development in Sprague-Dawley rats, all without altering theStreptococcus mutansor total populations within the plaque. We subsequently identified the underlying mechanisms through which applications of CT modulate biofilm virulence. CT targets expression of keyStreptococcus mutansgenes during biofilm formationin vitroandin vivo. These are associated with exopolysaccharide matrix synthesis (gtfB) and the ability to tolerate exogenous stress (e.g.,sloA), which are essential for cariogenic biofilm assembly. We also identified a unique gene (SMU.940) that was severely repressed and may represent a potentially novel target; its inactivation disrupted exopolysaccharide accumulation and matrix development. Altogether, CT may be clinically more effective than current anticaries modalities, targeting expression of bacterial virulence associated with pathogenesis of the disease. These observations may have relevance for development of enhanced therapies against other biofilm-dependent infections.
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48

ŠIMKOVIČ, Martin, Gregory D. DEGALA, Sandra S. EATON, and Frank E. FRERMAN. "Expression of human electron transfer flavoprotein-ubiquinone oxidoreductase from a baculovirus vector: kinetic and spectral characterization of the human protein." Biochemical Journal 364, no. 3 (June 15, 2002): 659–67. http://dx.doi.org/10.1042/bj20020042.

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Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) is an iron—sulphur flavoprotein and a component of an electron-transfer system that links 10 different mitochondrial flavoprotein dehydrogenases to the mitochondrial bc1 complex via electron transfer flavoprotein (ETF) and ubiquinone. ETF-QO is an integral membrane protein, and the primary sequences of human and porcine ETF-QO were deduced from the sequences of the cloned cDNAs. We have expressed human ETF-QO in Sf9 insect cells using a baculovirus vector. The cDNA encoding the entire protein, including the mitochondrial targeting sequence, was present in the vector. We isolated a membrane-bound form of the enzyme that has a molecular mass identical with that of the mature porcine protein as determined by SDS/PAGE and has an N-terminal sequence that is identical with that predicted for the mature holoenzyme. These data suggest that the heterologously expressed ETF-QO is targeted to mitochondria and processed to the mature, catalytically active form. The detergent-solubilized protein was purified by ion-exchange and hydroxyapatite chromatography. Absorption and EPR spectroscopy and redox titrations are consistent with the presence of flavin and iron—sulphur centres that are very similar to those in the equivalent porcine and bovine proteins. Additionally, the redox potentials of the two prosthetic groups appear similar to those of the other eukaryotic ETF-QO proteins. The steady-state kinetic constants of human ETF-QO were determined with ubiquinone homologues, a ubiquinone analogue, and with human wild-type ETF and a Paracoccus—human chimaeric ETF as varied substrates. The results demonstrate that this expression system provides sufficient amounts of human ETF-QO to enable crystallization and mechanistic investigations of the iron—sulphur flavoprotein.
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Yang, Lei, Yumin Hu, Yuanfen Liu, Yanyan Liu, Si Miao, Zhen Li, Bohui Xu, and Yan Shen. "Preparation and in vitro evaluation of doxorubicin loaded alendronate modified hollow gold nanoparticles for bone-targeted chemo-photothermal therapy." Materials Express 10, no. 11 (November 1, 2020): 1950–59. http://dx.doi.org/10.1166/mex.2020.1862.

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The treatment of malignant bone tumors (including primary bone tumors and metastatic bone tumors) has always been a clinical challenge. The purpose of this study is to design a bone-targeted nano-carrier with photothermal effect to achieve chemo-photothermal therapy (CPT), which allows the minimal use of photothermal agents and chemical drugs to target bone tumors. Alendronate modified hollow gold nanoparticles (HGNPs- ALN) were synthesized using mercapto polyethylene glycol carboxyl (SH-PEG2000-COOH) as the connecting arm, fourier transform infrared spectroscopy (FTIR) and transmission electron microscopy (TEM) data show that HGNPs-ALN with a particle size of about 80 nm has been successfully synthesized. The hydroxyapatite affinity experiment in vitro indicated that HGNPs-ALN exhibited a high affinity to bone. In addition, the temperature of HGNPs-ALN under near-infrared laser irradiation can rise to 53 °C, which can achieve effective photothermal therapy for bone tumors. Bone-targeted hollow gold nanoparticles (DOX@HGNPs-ALN) loaded with doxorubicin hydrochloride (DOX) were synthesized by one-pot method. By comparing the stability and drug loading of HGNPs-ALN, it was concluded that the optimal mass ratio of HGNPs-ALN (calculated by the amount of gold) to DOX was about 1:2. HGNPs-ALN and DOX@HGNPs-ALN both have good photothermal stability and photothermal transformation properties, and confirmed the safety of HGNPs on human osteosarcoma cells. MTT experiments showed that DOX@HGNPs-ALN had the strongest killing effect on MG-63 osteosarcoma cells under laser irradiation (the killing rate is about 65%). According to these results, it can be considered that DOX@HGNPs-ALN has the potential of CPT synergistic targeting therapy for bone tumors.
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AlMuraikhi, Nihal, Dalia Ali, Radhakrishnan Vishnubalaji, Muthurangan Manikandan, Muhammad Atteya, Abdulaziz Siyal, Musaad Alfayez, Abdullah Aldahmash, Moustapha Kassem, and Nehad M. Alajez. "Notch Signaling Inhibition by LY411575 Attenuates Osteoblast Differentiation and Decreased Ectopic Bone Formation Capacity of Human Skeletal (Mesenchymal) Stem Cells." Stem Cells International 2019 (August 22, 2019): 1–12. http://dx.doi.org/10.1155/2019/3041262.

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Background. Chemical biology approaches using small molecule inhibitors targeting specific signaling pathways are useful tools to dissect the molecular mechanisms governing stem cell differentiation and for their possible use in therapeutic interventions. Methods. Stem cell signaling small molecule library functional screen was performed employing human bone marrow skeletal (mesenchymal) stem cells (hBMSCs). Alkaline phosphatase (ALP) activity and formation of mineralized matrix visualized by Alizarin red staining were employed as markers for osteoblastic differentiation. Global gene expression profiling was conducted using the Agilent microarray platform, and data normalization and bioinformatics were performed using GeneSpring software. Pathway analyses were conducted using the Ingenuity Pathway Analysis (IPA) tool. In vivo ectopic bone formation was performed using hBMSC mixed with hydroxyapatite–tricalcium phosphate granules that were implanted subcutaneously in 8-week-old female nude mice. Hematoxylin and eosin staining and Sirius red staining were performed to identify bone formation in vivo. Results. Among the tested molecules, LY411575, a potent γ-secretase and Notch signaling inhibitor, exhibited significant inhibitory effects on osteoblastic differentiation of hBMSCs manifested by reduced ALP activity, mineralized matrix formation, and decreased osteoblast-specific gene expression as well as in vivo ectopic bone formation. Global gene expression profiling of LY411575-treated cells revealed changes in multiple signaling pathways, including focal adhesion, insulin, TGFβ, IL6, and Notch signaling, and decreased the expression of genes associated with functional categories of tissue development. Among the affected signaling networks were TGFβ1, SPP1, and ERK regulatory networks. Conclusions. We identified γ-secretase inhibitor (LY411575) as a potent regulator of osteoblastic differentiation of hBMSC that may be useful as a therapeutic option for treating conditions associated with ectopic bone formation.
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