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In this study, we utilized the bone-targeting moiety of dendritic oligopeptides consisting of three aspartic acid moieties (dAsp3) and amphiphilic polymers (poly(ethylene glycol)-block-poly(lactic-co-glycolic acid); PEG-PLGA) to create dAsp3-PEG-PLGA (APP) nanoparticles (NPs), which can carry SIM to treat OP. An in vivo imaging system showed that gold nanocluster (GNC)-PLGA\/APP NPs had a significantly higher accumulation rate in representative bone tissues. In vivo experiments comparing low-dose SIM treatment (0.25 mg\/kg per time, 2 times per week) showed that bone-targeting SIM\/APP NPs could increase the bone formation effect compared with non-bone-targeting SIM\/PP NPs in a local bone loss of hindlimb suspension (disuse) model, but did not demonstrate good bone formation in a postmenopausal (ovariectomized) model of systemic bone loss. The APP NPs could effectively target high mineral levels in bone tissue and were expected to reduce side effects in other organs affected by SIM. However, in vivo OP model testing showed that the same lower dose could not be used to treat different types of OP.<\/jats:p>","DOI":"10.3390\/ijms231810530","type":"journal-article","created":{"date-parts":[[2022,9,12]],"date-time":"2022-09-12T22:53:46Z","timestamp":1663023226000},"page":"10530","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Bone-Targeting Nanoparticles of a Dendritic (Aspartic acid)3-Functionalized PEG-PLGA Biopolymer Encapsulating Simvastatin for the Treatment of Osteoporosis in Rat Models"],"prefix":"10.3390","volume":"23","author":[{"given":"Che-Wei","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Regenerative Medicine and Cell Therapy Research Center, Office of Research and Development, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Yun","family":"Lee","sequence":"additional","affiliation":[{"name":"Regenerative Medicine and Cell Therapy Research Center, Office of Research and Development, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Ph.D. Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4191-2183","authenticated-orcid":false,"given":"Sung-Yen","family":"Lin","sequence":"additional","affiliation":[{"name":"Regenerative Medicine and Cell Therapy Research Center, Office of Research and Development, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Departments of Orthopaedics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Department of Orthopaedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Department of Orthopaedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung 80145, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2709-5604","authenticated-orcid":false,"given":"Lin","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, 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Rev. Pathol. Mech. Dis."},{"key":"ref_2","unstructured":"Marcus, R., Feldman, D., and Kelsey, J. (2001). Magnitude and Impact of Osteoporotic Fractures. Osteoporosis, Academic Press. [2nd ed.]."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/s41574-019-0220-8","article-title":"Fracture Prediction, Imaging and Screening in Osteoporosis","volume":"15","author":"Fuggle","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.jconrel.2011.10.001","article-title":"Bone Targeting for the Treatment of Osteoporosis","volume":"161","author":"Luhmann","year":"2012","journal-title":"J. Control. Release"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1007\/s11657-013-0136-1","article-title":"Osteoporosis in the European Union: Medical Management, Epidemiology and Economic Burden","volume":"8","author":"Hernlund","year":"2013","journal-title":"Arch. Osteoporos."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s40273-020-00965-9","article-title":"An Updated Systematic Review of Cost-Effectiveness Analyses of Drugs for Osteoporosis","volume":"39","author":"Li","year":"2021","journal-title":"Pharmacoeconomics"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"91","DOI":"10.19080\/OROAJ.2017.05.555673","article-title":"Overview of Osteoporosis","volume":"5","author":"Kumari","year":"2017","journal-title":"Orthop. Rheumatol. Open Access J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1002\/jbmr.5650110504","article-title":"Age-Related Changes in Osteogenic Stem Cells in Mice","volume":"11","author":"Bergman","year":"1996","journal-title":"J. Bone Miner. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/0002-9343(83)90860-4","article-title":"Evidence for Two Distinct Syndromes of Involutional Osteoporosis","volume":"75","author":"Riggs","year":"1983","journal-title":"Am. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S15","DOI":"10.1016\/S0020-1383(16)30004-3","article-title":"Main Differences in Osteoporotic Fracture Models: Which Should I Use?","volume":"47","author":"Simpson","year":"2016","journal-title":"Injury"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"293808","DOI":"10.4061\/2011\/293808","article-title":"A Review on Current Osteoporosis Research: With Special Focus on Disuse Bone Loss","volume":"2011","author":"Lau","year":"2011","journal-title":"J. Osteoporos."},{"key":"ref_12","first-page":"27","article-title":"Coding for Bone Diseases","volume":"23","author":"Howard","year":"2011","journal-title":"Record"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1007\/BF02347054","article-title":"3D Micro-Computed Tomography of Trabecular and Cortical Bone Architecture with Application to a Rat Model of Immobilisation Osteoporosis","volume":"38","author":"Laib","year":"2000","journal-title":"Med. Biol. Eng. Comput."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1001\/jama.285.6.785","article-title":"Osteoporosis Prevention, Diagnosis, and Therapy","volume":"285","author":"Klibanski","year":"2001","journal-title":"J. Am. Med. Assoc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"519","DOI":"10.2174\/138920007780866852","article-title":"Calcium Metabolism and Oxidative Stress in Bone Fractures: Role of Antioxidants","volume":"8","author":"Sheweita","year":"2007","journal-title":"Curr. Drug Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.bone.2005.07.029","article-title":"Strontium Ranelate: A Physiological Approach for Optimizing Bone Formation and Resorption","volume":"38","author":"Marie","year":"2006","journal-title":"Bone"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1210\/er.2004-0006","article-title":"Parathyroid Hormone and Teriparatide for the Treatment of Osteoporosis: A Review of the Evidence and Suggested Guidelines for Its Use","volume":"26","author":"Hodsman","year":"2005","journal-title":"Endocr. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1126\/science.286.5446.1946","article-title":"Stimulation of Bone Formation In Vitro and in Rodents by Statins","volume":"286","author":"Mundy","year":"1999","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1677\/JOE-07-0532","article-title":"Simvastatin Antagonizes Tumor Necrosis Factor-\u03b1 Inhibition of Bone Morphogenetic Proteins-2-Induced Osteoblast Differentiation by Regulating Smad Signaling and Ras\/Rho-Mitogen-Activated Protein Kinase Pathway","volume":"196","author":"Yamashita","year":"2008","journal-title":"J. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.jcis.2014.06.037","article-title":"Synthesis and Characterization of Cationic Polymeric Nanoparticles as Simvastatin Carriers for Enhancing the Osteogenesis of Bone Marrow Mesenchymal Stem Cells","volume":"432","author":"Wang","year":"2014","journal-title":"J. Colloid. Interface Sci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wang, C.-Z., Wang, Y.-H., Lin, C.-W., Lee, T.-C., Fu, Y.-C., Ho, M.-L., and Wang, C.-K. (2018). Combination of a Bioceramic Scaffold and Simvastatin Nanoparticles as a Synthetic Alternative to Autologous Bone Grafting. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19124099"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1902\/jop.2009.090429","article-title":"Clinical Effect of Subgingivally Delivered Simvastatin in the Treatment of Patients with Chronic Periodontitis: A Randomized Clinical Trial","volume":"81","author":"Pradeep","year":"2010","journal-title":"J. Periodontol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.jconrel.2015.07.022","article-title":"Potential Mechanisms and Applications of Statins on Osteogenesis: Current Modalities, Conflicts and Future Directions","volume":"215","author":"Oryan","year":"2015","journal-title":"J. Control. Release"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/S8756-3282(03)00034-6","article-title":"Effect of Simvastatin Treatment on Bone Mineral Density and Bone Turnover in Hypercholesterolemic Postmenopausal Women: A 1-Year Longitudinal Study","volume":"32","author":"Montagnani","year":"2003","journal-title":"Bone"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.yexmp.2008.12.004","article-title":"Nanoparticle-Based Targeted Drug Delivery","volume":"86","author":"Singh","year":"2009","journal-title":"Exp. Mol. Pathol."},{"key":"ref_26","first-page":"328","article-title":"A Review on Targeted Drug Delivery: Its Entire Focus on Advanced Therapeutics and Diagnostics","volume":"2","author":"Rani","year":"2014","journal-title":"Sch. J. App. Med. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4159","DOI":"10.1021\/mp400184v","article-title":"In Vitro and In Vivo Evaluation of Osteoporosis Therapeutic Peptide PTH 1-34 Loaded Pegylated Chitosan Nanoparticles","volume":"10","author":"Narayanan","year":"2013","journal-title":"Mol. Pharm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1166\/jbn.2013.1482","article-title":"Improvement in Bone Properties by Using Risedronate Adsorbed Hydroxyapatite Novel Nanoparticle Based Formulation in a Rat Model of Osteoporosis","volume":"9","author":"Sahana","year":"2013","journal-title":"J. Biomed. Nanotechnol."},{"key":"ref_29","first-page":"5671","article-title":"Tetracycline-Grafted PLGA Nanoparticles as Bone-Targeting Drug Delivery System","volume":"10","author":"Wang","year":"2015","journal-title":"Int. J. Nanomed."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"26699","DOI":"10.1039\/D0RA90074E","article-title":"Correction: A Novel Biocompatible, Simvastatin-Loaded, Bone-Targeting Lipid Nanocarrier for Treating Osteoporosis More Effectively","volume":"10","author":"Tao","year":"2020","journal-title":"RSC Adv."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1007\/s00223-009-9312-0","article-title":"Specific Binding and Mineralization of Calcified Surfaces by Small Peptides","volume":"86","author":"Yarbrough","year":"2010","journal-title":"Calcif. Tissue Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1021\/bm070121s","article-title":"Synthesis and In Vitro Hydroxyapatite Binding of Peptides Conjugated to Calcium-Binding Moieties","volume":"8","author":"Murphy","year":"2007","journal-title":"Biomacromolecules"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"131140","DOI":"10.1016\/j.matlet.2021.131140","article-title":"Porous BMP-2 Immobilized PLGA\/Glycol Chitosan Scaffold with Enhanced Hydrophilicity, Mineralization and Osteogenesis","volume":"308","author":"Amirian","year":"2022","journal-title":"Mater. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1177\/0885328217741757","article-title":"A Novel Hybrid Multichannel Biphasic Calcium Phosphate Granule-Based Composite Scaffold for Cartilage Tissue Regeneration","volume":"32","author":"Jung","year":"2018","journal-title":"J. Biomater. Appl."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4583","DOI":"10.1016\/j.actbio.2014.07.015","article-title":"Aspartic Acid-Based Modified PLGA-PEG Nanoparticles for Bone Targeting: In Vitro and in vivo Evaluation","volume":"10","author":"Fu","year":"2014","journal-title":"Acta Biomater."},{"key":"ref_36","first-page":"3895","article-title":"Local Delivery of Controlled-Release Simvastatin\/PLGA\/HAp Microspheres Enhances Bone Repair","volume":"8","author":"Tai","year":"2013","journal-title":"Int. J. Nanomed."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1177\/0883911517720813","article-title":"Evaluations of Clinical-Grade Bone Substitute-Combined Simvastatin Carriers to Enhance Bone Growth: In Vitro and In Vivo Analyses","volume":"33","author":"Lee","year":"2018","journal-title":"J. Bioact. Compat. Polym."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4398","DOI":"10.1039\/C6AY01036A","article-title":"Highly Sensitive and Selective Detection of Trinitrotoluene Using Cysteine-Capped Gold Nanoparticles","volume":"8","author":"Devi","year":"2016","journal-title":"Anal. Methods"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3177","DOI":"10.1021\/bm700697a","article-title":"Polyamine Analogues Bind Human Serum Albumin","volume":"8","author":"Beauchemin","year":"2007","journal-title":"Biomacromolecules"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"20180364","DOI":"10.1098\/rsif.2018.0364","article-title":"An Analytical Approach for Quantifying the Influence of Nanoparticle Polydispersity on Cellular Delivered Dose","volume":"15","author":"Johnston","year":"2018","journal-title":"J. R. Soc. Interface"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.ijpharm.2005.10.010","article-title":"Opsonization, Biodistribution, and Pharmacokinetics of Polymeric Nanoparticles","volume":"307","author":"Owens","year":"2006","journal-title":"Int. J. Pharm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1038\/nbt.3330","article-title":"Principles of Nanoparticle Design for Overcoming Biological Barriers to Drug Delivery","volume":"33","author":"Blanco","year":"2015","journal-title":"Nat. Biotechnol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1038\/nbt1340","article-title":"Renal Clearance of Quantum Dots","volume":"25","author":"Choi","year":"2007","journal-title":"Nat. Biotechnol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1002\/jemt.20408","article-title":"Contribution of High-Resolution Correlative Imaging Techniques in the Study of the Liver Sieve in Three-Dimensions","volume":"70","author":"Braet","year":"2007","journal-title":"Microsc. Res. Tech."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1182\/blood.V41.4.529.529","article-title":"The Role of the Sinus Wall in the Passage of Erythrocytes through the Spleen","volume":"41","author":"Chen","year":"1973","journal-title":"Blood"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1021\/mp800051m","article-title":"Factors Affecting the Clearance and Biodistribution of Polymeric Nanoparticles","volume":"5","author":"Alexis","year":"2008","journal-title":"Mol. Pharm."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0168-3659(01)00451-5","article-title":"Long-Circulating Poly(Ethylene Glycol)-Poly(D,L-Lactide) Block Copolymer Micelles with Modulated Surface Charge","volume":"77","author":"Yamamoto","year":"2001","journal-title":"J. Control. Release"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2636","DOI":"10.1039\/C9TB02860A","article-title":"Nanoparticles with Surface Features of Dendritic Oligopeptides as Potential Oral Drug Delivery Systems","volume":"8","author":"Bai","year":"2020","journal-title":"J. Mater. Chem. B Mater. Biol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1166\/jbn.2016.2259","article-title":"Cellular Internalization Mechanisms of Polyanhydride Particles: Implications for Rational Design of Drug Delivery Vehicles","volume":"12","author":"Phanse","year":"2016","journal-title":"J. Biomed. Nanotechnol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"539","DOI":"10.2217\/17460751.1.4.539","article-title":"Osteogenic Differentiation of Human Marrow-Derived Mesenchymal Stem Cells","volume":"1","author":"Marie","year":"2006","journal-title":"Regen. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"7260","DOI":"10.1038\/s41598-018-36109-5","article-title":"Aspartic and Glutamic Acid Templated Peptides Conjugation on Plasma Modified Nanofibers for Osteogenic Differentiation of Human Mesenchymal Stem Cells: A Comparative Study","volume":"8","author":"Onak","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3084","DOI":"10.1021\/cg800252f","article-title":"Bioinspired Synthesis of Mineralized Collagen Fibrils","volume":"8","author":"Deshpande","year":"2008","journal-title":"Cryst. Growth Des."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"763","DOI":"10.4155\/tde-2017-0057","article-title":"Challenges in Realizing Selectivity for Nanoparticle Biodistribution and Clearance: Lessons from Gold Nanoparticles","volume":"8","author":"Haute","year":"2017","journal-title":"Ther. Deliv."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1111\/1440-1681.12577","article-title":"Role of Simvastatin on Fracture Healing and Osteoporosis: A Systematic Review on in vivo Investigations","volume":"43","author":"Moshiri","year":"2016","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_55","first-page":"277","article-title":"Simvastatin Did Not Prevent nor Restore Ovariectomy-Induced Bone Loss in Adult Rats","volume":"6","author":"Yao","year":"2006","journal-title":"J. Musculoskelet. Neuronal Interact."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1111\/j.1365-2362.2009.02092.x","article-title":"Simvastatin Increases Osteoblasts and Osteogenic Proteins in Ovariectomized Rats","volume":"39","author":"Ho","year":"2009","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1007\/s00774-010-0231-y","article-title":"Simvastatin Induces Estrogen Receptor-Alpha Expression in Bone, Restores Bone Loss, and Decreases ER\u03b1 Expression and Uterine Wet Weight in Ovariectomized Rats","volume":"29","author":"Li","year":"2011","journal-title":"J. Bone Miner. Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1","DOI":"10.14312\/2398-0281.2016-1","article-title":"Disuse Osteoporosis: A Better Understanding of Pathophysiology May Lead to Potential Therapies","volume":"1","author":"Milsom","year":"2016","journal-title":"J. Diabetol. Endocrinol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.jbspin.2011.04.007","article-title":"Pathophysiology of Bone Loss in Disuse Osteoporosis","volume":"78","author":"Alexandre","year":"2011","journal-title":"Jt. Bone Spine"},{"key":"ref_60","first-page":"63","article-title":"Skeletal Response to Simulated Weightlessness: A Comparison of Suspension Techniques","volume":"58","author":"Wronski","year":"1987","journal-title":"Aviat. Space Environ. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1016\/j.micron.2007.09.006","article-title":"Effects of Risedronate in a Rat Model of Osteopenia Due to Orchidectomy and Disuse: Densitometric, Histomorphometric and Microtomographic Studies","volume":"39","author":"Libouban","year":"2008","journal-title":"Micron"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.1002\/smll.201100746","article-title":"One-Pot Synthesis of near-Infrared Fluorescent Gold Clusters for Cellular Fluorescence Lifetime Imaging","volume":"7","author":"Shang","year":"2011","journal-title":"Small"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1016\/0378-5173(89)90281-0","article-title":"Nanocapsule Formation by Interfacial Polymer Deposition Following Solvent Displacement","volume":"55","author":"Fessi","year":"1989","journal-title":"Int. J. Pharm."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1021\/mp400685v","article-title":"Mechanism Study of Cellular Uptake and Tight Junction Opening Mediated by Goblet Cell-Specific Trimethyl Chitosan Nanoparticles","volume":"11","author":"Zhang","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1152\/japplphysiol.00969.2001","article-title":"Hindlimb Unloading Rodent Model: Technical Aspects","volume":"92","author":"Globus","year":"2002","journal-title":"J. Appl. Physiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2308","DOI":"10.1002\/pen.23606","article-title":"Influence of magnetic field on the dissolution profile of cotrimoxazole inserted into poly(lactic acid-co-glycolic acid) and maghemite nanocomposites","volume":"53","author":"Pereira","year":"2013","journal-title":"Polym. Eng. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/18\/10530\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:29:25Z","timestamp":1760142565000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/18\/10530"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,11]]},"references-count":66,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["ijms231810530"],"URL":"https:\/\/doi.org\/10.3390\/ijms231810530","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,11]]}}}