{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T05:59:39Z","timestamp":1788587979629,"version":"build-2803163510"},"reference-count":110,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,4,15]],"date-time":"2022-04-15T00:00:00Z","timestamp":1649980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>A biocompatible, biodegradable and FDA-approved polymer [Poly lactic-co-glycolic acid (PLGA)] was used to prepare the nanoparticles (NPs) to observe the effect of solvents, stabilizers and their concentrations on the physical properties of the PLGA-NPs, following the encapsulation and in vitro release of Indomethacin (IND). PLGA-NPs were prepared by the single-emulsion solvent evaporation technique using dichloromethane (DCM)\/chloroform as the organic phase with Polyvinyl-alcohol (PVA)\/Polyvinylpyrrolidone (PVP) as stabilizers to encapsulate IND. The effects of different proportions of PVA\/PVP with DCM\/chloroform on the physiochemical properties (particle size, the polydispersity index, the zeta potential by Malvern Zetasizer and morphology by SEM) of the NPs were investigated. DSC was used to check the physical state, the possible complexation of PLGA with stabilizer(s) and the crystallinity of the encapsulated drug. Stabilizers at all concentrations produced spherical, regular-shaped, smooth-surfaced discrete NPs. Average size of 273.2\u2013563.9 nm was obtained when PVA (stabilizer) with DCM, whereas it ranged from 317.6 to 588.1 nm with chloroform. The particle size was 273.2\u2013563.9 nm when PVP was the stabilizer with DCM, while it was 381.4\u2013466.6 nm with chloroform. The zeta potentials of PVA-stabilized NPs were low and negative (\u22120.62 mV) while they were comparatively higher and positive for PVP-stabilized NPs (+17.73 mV). Finally, drug-loaded optimal NPs were composed of PLGA (40 mg) and IND (4 mg) in 1 mL DCM\/chloroform with PVA\/PVP (1\u20133%), which resulted in sufficient encapsulation (54.94\u201374.86%) and drug loading (4.99\u20136.81%). No endothermic peak of PVA\/PVP appeared in the optimized formulation, which indicated the amorphous state of IND in the core of the PLGA-NPs. The in vitro release study indicated a sustained release of IND (32.83\u201352.16%) from the PLGA-NPs till 72 h and primarily followed the Higuchi matrix release kinetics followed by Korsmeyer\u2013Peppas models. The cell proliferation assay clearly established that the organic solvents used to prepare PLGA-NPs had evaporated. The PLGA-NPs did not show any particular toxicity in the HepG2 cells within the dose range of IND (250\u2013500 \u00b5g\/mL) and at an equivalent concentration of PLGA-NPs (3571.4\u20137142.7 \u00b5g\/mL). The cytotoxicity of the hepatotoxic drug (IND) was reduced by its encapsulation into PLGA-NPs. The outcomes of this investigation could be implemented to prepare PLGA-NPs of acceptable properties for the encapsulation of low\/high molecular weight drugs. It would be useful for further in vitro and in vivo applications to use this delivery system.<\/jats:p>","DOI":"10.3390\/pharmaceutics14040870","type":"journal-article","created":{"date-parts":[[2022,4,19]],"date-time":"2022-04-19T02:39:31Z","timestamp":1650335971000},"page":"870","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Effect of Solvents, Stabilizers and the Concentration of Stabilizers on the Physical Properties of Poly(d,l-lactide-co-glycolide) Nanoparticles: Encapsulation, In Vitro Release of Indomethacin and Cytotoxicity against HepG2-Cell"],"prefix":"10.3390","volume":"14","author":[{"given":"Musaed","family":"Alkholief","sequence":"first","affiliation":[{"name":"Nanobiotechnology Unit, Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5713-8858","authenticated-orcid":false,"given":"Mohd Abul","family":"Kalam","sequence":"additional","affiliation":[{"name":"Nanobiotechnology Unit, Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5227-3954","authenticated-orcid":false,"given":"Md Khalid","family":"Anwer","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8950-6571","authenticated-orcid":false,"given":"Aws","family":"Alshamsan","sequence":"additional","affiliation":[{"name":"Nanobiotechnology Unit, Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s12951-018-0392-8","article-title":"Nano based drug delivery systems: Recent developmentsi and future prospects","volume":"16","author":"Patra","year":"2018","journal-title":"J. Nanobiotechnol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s40824-020-00190-7","article-title":"Recent advances in polymeric drug delivery systems","volume":"24","author":"Sung","year":"2020","journal-title":"Biomater. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6236","DOI":"10.3390\/md12126236","article-title":"Design of Chitosan and Its Water Soluble Derivatives-Based Drug Carriers with Polyelectrolyte Complexes","volume":"12","author":"Wu","year":"2014","journal-title":"Mar. Drugs"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"510","DOI":"10.4236\/jbnb.2011.225062","article-title":"Recent Advances in Drug Delivery Systems","volume":"2","author":"Martinho","year":"2011","journal-title":"J. Biomater. Nanobiotechnol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"877","DOI":"10.2147\/IJN.S18905","article-title":"Polylactide-co-glycolide nanoparticles for controlled delivery of anticancer agents","volume":"6","author":"Dinarvand","year":"2011","journal-title":"Int. J. Nanomed."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1163\/156856206775997322","article-title":"Synthesis and characterization of PLGA nanoparticles","volume":"17","author":"Astete","year":"2006","journal-title":"J. Biomater. Sci. Polym. Ed."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1016\/S0142-9612(00)00115-0","article-title":"The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices","volume":"21","author":"Jain","year":"2000","journal-title":"Biomaterials"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.3390\/polym3031377","article-title":"Poly lactic-co-glycolic acid (PLGA) As biodegradable controlled drug delivery carrier","volume":"3","author":"Makadia","year":"2011","journal-title":"Polymers"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"367","DOI":"10.2174\/156720112801323053","article-title":"Polymers and drug delivery systems","volume":"9","author":"Albericio","year":"2012","journal-title":"Curr. Drug Deliv."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1002\/jbm.b.34544","article-title":"Dual growth factor delivery using PLGA nanoparticles in silk fibroin\/PEGDMA hydrogels for articular cartilage tissue engineering","volume":"108","author":"Keskin","year":"2020","journal-title":"J. Biomed. Mater. Res. Part B Appl. Biomater."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5000","DOI":"10.1021\/acs.molpharmaceut.9b00860","article-title":"Rational Design of PLGA Nanoparticle Vaccine Delivery Systems To Improve Immune Responses","volume":"16","author":"Gu","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1186\/1556-276X-6-447","article-title":"PLGA-based gene delivering nanoparticle enhance suppression effect of miRNA in HePG2 cells","volume":"6","author":"Liang","year":"2011","journal-title":"Nanoscale Res. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"728","DOI":"10.2174\/0929867324666161205130416","article-title":"Current Strategies in the Modification of PLGA-based Gene Delivery System","volume":"24","author":"Ramezani","year":"2017","journal-title":"Curr. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1186\/s13046-015-0231-9","article-title":"Functional characterization of biodegradable nanoparticles as antigen delivery system","volume":"34","author":"Petrizzo","year":"2015","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.ejps.2004.04.003","article-title":"Cystatin incorporated in poly(lactide-co-glycolide) nanoparticles: Development and fundamental studies on preservation of its activity","volume":"22","author":"Cegnar","year":"2004","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1080\/10837450.2016.1240184","article-title":"PLGA nanoparticles for intravitreal peptide delivery: Statistical optimization, characterization and toxicity evaluation","volume":"23","author":"Bisht","year":"2018","journal-title":"Pharm. Dev. Technol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.jconrel.2007.09.013","article-title":"Nano\/micro technologies for delivering macromolecular therapeutics using poly(d,l-lactide-co-glycolide) and its derivatives","volume":"125","author":"Mundargi","year":"2008","journal-title":"J. Control. Release"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/S0169-409X(97)00048-3","article-title":"Biodegradation and biocompatibility of PLA and PLGA microspheres","volume":"28","author":"Anderson","year":"1997","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.jconrel.2004.10.015","article-title":"Microencapsulation by solvent extraction\/evaporation: Reviewing the state of the art of microsphere preparation process technology","volume":"102","author":"Freitas","year":"2005","journal-title":"J. Control. Release"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1701035","DOI":"10.1002\/adhm.201701035","article-title":"Functionalizing PLGA and PLGA Derivatives for Drug Delivery and Tissue Regeneration Applications","volume":"7","author":"Martins","year":"2018","journal-title":"Adv. Health Mater."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1615\/CritRevTherDrugCarrierSyst.v21.i5.20","article-title":"PLGA Nanoparticles in Drug Delivery: The State of the Art","volume":"21","author":"Bala","year":"2004","journal-title":"Crit. Rev. Ther. Drug Carr. Syst."},{"key":"ref_22","first-page":"e51015","article-title":"PLGA nanoparticles formed by single- or double-emulsion with vitamin E-TPGS","volume":"82","author":"McCall","year":"2013","journal-title":"J. Vis. Exp."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.jconrel.2019.05.003","article-title":"Injectable, long-acting PLGA formulations: Analyzing PLGA and understanding microparticle formation","volume":"304","author":"Park","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/157341309787314566","article-title":"Poly(lactide-co-glycolide)-based Micro and Nanoparticles for the Controlled Drug Delivery of Vitamins","volume":"5","author":"Stevanovic","year":"2009","journal-title":"Curr. Nanosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.jsps.2013.12.002","article-title":"Nanoprecipitation is more efficient than emulsion solvent evaporation method to encapsulate cucurbitacin I in PLGA nanoparticles","volume":"22","author":"Alshamsan","year":"2014","journal-title":"Saudi Pharm. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1080\/02652040600682390","article-title":"Celecoxib-loaded poly(d,l-lactide-co-glycolide) nanoparticles prepared using a novel and controllable combination of diffusion and emulsification steps as part of the salting-out procedure","volume":"23","author":"McCarron","year":"2006","journal-title":"J. Microencapsul."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.jsps.2018.11.011","article-title":"Employing a PLGA-TPGS based nanoparticle to improve the ocular delivery of Acyclovir","volume":"27","author":"Alkholief","year":"2018","journal-title":"Saudi Pharm. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.biopha.2017.07.110","article-title":"Poly (d,l-lactide-co-glycolide) nanoparticles for sustained release of tacrolimus in rabbit eyes","volume":"94","author":"Kalam","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.ejps.2010.06.007","article-title":"Preparation of nanoparticles by solvent displacement for drug delivery: A shift in the \u201couzo region\u201d upon drug loading","volume":"41","author":"Rytting","year":"2010","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1002\/jps.21158","article-title":"PLGA Nanoparticles for Oral Delivery of Hydrophobic Drugs: Influence of Organic Solvent on Nanoparticle Formation and Release Behavior In Vitro and In Vivo Using Estradiol as a Model Drug","volume":"97","author":"Sahana","year":"2008","journal-title":"J. Pharm. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.jconrel.2019.02.030","article-title":"Measuring particle size distribution of nanoparticle enabled medicinal products, the joint view of EUNCL and NCI-NCL. A step by step approach combining orthogonal measurements with increasing complexity","volume":"299","author":"Caputo","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1111\/head.12769","article-title":"The Pharmacology of Indomethacin","volume":"56","author":"Lucas","year":"2016","journal-title":"Headache J. Head Face Pain"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/0048-9697(91)90214-Y","article-title":"Data base of aqueous solubility for organic non-electrolytes","volume":"109\u2013110","author":"Dannenfelser","year":"1991","journal-title":"Sci. Total Environ."},{"key":"ref_34","first-page":"1917","article-title":"Using medications appropriately in older adults","volume":"66","author":"Williams","year":"2002","journal-title":"Am. Fam. Physician"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.ijbiomac.2016.02.033","article-title":"Optimizing indomethacin-loaded chitosan nanoparticle size, encapsulation, and release using Box\u2013Behnken experimental design","volume":"87","author":"Kalam","year":"2016","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1093\/chromsci\/44.1.41","article-title":"High-Performance Liquid Chromatographic Assay of Indomethacin in Porcine Plasma with Applicability to Human Levels","volume":"44","author":"Boon","year":"2006","journal-title":"J. Chromatogr. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/j.jpba.2004.09.012","article-title":"Development and validation of HPLC method for determination of indomethacin and its two degradation products in topical gel","volume":"37","author":"Novakova","year":"2005","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1021\/acsomega.8b02767","article-title":"Optimization of Rutin-Loaded PLGA Nanoparticles Synthesized by Single-Emulsion Solvent Evaporation Method","volume":"4","year":"2019","journal-title":"ACS Omega"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.jconrel.2017.01.019","article-title":"Freeze concentration-induced PLGA and polystyrene nanoparticle aggregation: Imaging and rational design of lyoprotection","volume":"248","author":"Niu","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.mimet.2019.01.020","article-title":"Antifungal efficacy of Itraconazole loaded PLGA-nanoparticles stabilized by vitamin-E TPGS: In vitro and ex vivo studies","volume":"161","author":"Alhowyan","year":"2019","journal-title":"J. Microbiol. Methods"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1590\/S0104-66322013000300024","article-title":"Influence of polyvinylpyrrolidone on the interaction between water and methanol","volume":"30","author":"Guettari","year":"2013","journal-title":"Braz. J. Chem. Eng."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.msec.2017.03.088","article-title":"Oral bioavailability enhancement and hepatoprotective effects of thymoquinone by self-nanoemulsifying drug delivery system","volume":"76","author":"Kalam","year":"2017","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.molliq.2013.01.008","article-title":"Ultra fine super self-nanoemulsifying drug delivery system (SNEDDS) enhanced solubility and dissolution of indomethacin","volume":"180","author":"Shakeel","year":"2013","journal-title":"J. Mol. Liq."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3387","DOI":"10.1016\/j.xphs.2016.08.011","article-title":"In Vitro Release Mechanisms of Doxorubicin From a Clinical Bead Drug-Delivery System","volume":"105","author":"Ahnfelt","year":"2016","journal-title":"J. Pharm. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.jddst.2019.04.012","article-title":"Optimization of Lecithin-Chitosan nanoparticles for simultaneous encapsulation of doxorubicin and piperine","volume":"52","author":"Alkholief","year":"2019","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.ijpharm.2017.03.049","article-title":"Delivery of doxorubicin-loaded PLGA nanoparticles into U87 human glioblastoma cells","volume":"524","author":"Malinovskaya","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.md.2016.12.002","article-title":"Formulation, optimization, characterization and in-vitro drug release kinetics of atenolol loaded PLGA nanoparticles using 3 3 factorial design for oral delivery","volume":"5","author":"Chourasiya","year":"2016","journal-title":"Mater. Discov."},{"key":"ref_48","first-page":"217","article-title":"Kinetic modeling on drug release from controlled drug delivery systems","volume":"67","author":"Dash","year":"2010","journal-title":"Acta Pol. Pharm."},{"key":"ref_49","first-page":"30","article-title":"Release kinetics of modified pharmaceutical dosage forms: A review","volume":"1","author":"Kalam","year":"2007","journal-title":"Cont. J. Pharm. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.ijpharm.2006.03.024","article-title":"Sigmoidal release of indomethacin from pectin matrix tablets: Effect of in situ crosslinking by calcium cations","volume":"318","author":"Wei","year":"2006","journal-title":"Int. J. Pharm."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"446","DOI":"10.3109\/03639045.2015.1075033","article-title":"Use of the Flory\u2013Huggins theory to predict the solubility of nifedipine and sulfamethoxazole in the triblock, graft copolymer Soluplus","volume":"42","author":"Altamimi","year":"2016","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.ajps.2016.08.006","article-title":"The studies of PLGA nanoparticles loading atorvastatin calcium for oral administration in vitro and in vivo","volume":"12","author":"Li","year":"2017","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Raish, M., Kalam, M.A., Ahmad, A., Shahid, M., Ansari, M.A., Ahad, A., Ali, R., Bin Jardan, Y.A., Alshamsan, A., and Alkholief, M. (2021). Eudragit-Coated Sporopollenin Exine Microcapsules (SEMC) of Phoenix dactylifera L. of 5-Fluorouracil for Colon-Specific Drug Delivery. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13111921"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"103036","DOI":"10.1016\/j.jddst.2021.103036","article-title":"Chitosan-coated poly (lactic-co-glycolide) nanoparticles for dual delivery of doxorubicin and naringin against MCF-7 cells","volume":"68","author":"Alshememry","year":"2022","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.ijpharm.2004.11.027","article-title":"PLGA nanoparticles containing praziquantel: Effect of formulation variables on size distribution","volume":"290","author":"Mainardes","year":"2005","journal-title":"Int. J. Pharm."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0378-5173(99)00187-8","article-title":"Preparation of poly(dl-lactide-co-glycolide) nanoparticles by modified spontaneous emulsification solvent diffusion method","volume":"187","author":"Murakami","year":"1999","journal-title":"Int. J. Pharm."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S0927-7757(00)00825-6","article-title":"Preparation of PLGA nanoparticles containing estrogen by emulsification\u2013diffusion method","volume":"182","author":"Kwon","year":"2001","journal-title":"Colloids Surfaces A Physicochem. Eng. Asp."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S0378-5173(96)04697-2","article-title":"Influence of stabilizing agents and preparative variables on the formation of poly (D, L-lactic acid) nanoparticles by an emulsification-diffusion technique","volume":"143","author":"Fessi","year":"1996","journal-title":"Int. J. Pharm."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.colsurfa.2007.07.011","article-title":"Comparison of the preparation of PLGA\u2013BSA nano-and microparticles by PVA, poloxamer and PVP","volume":"319","author":"Gyenis","year":"2008","journal-title":"Colloids Surf. A"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/S0168-3659(98)00006-6","article-title":"The control of protein release from poly(dl-lactide co-glycolide) microparticles by variation of the external aqueous phase surfactant in the water-in oil-in water method","volume":"52","author":"Coombes","year":"1998","journal-title":"J. Control. Release"},{"key":"ref_61","first-page":"175","article-title":"Preparation of protein-loaded PLGA-PVP blend nanoparticles by nanoprecipitation method: Entrapment, Initial burst and drug release kinetic studies","volume":"2","author":"Shakeri","year":"2015","journal-title":"Nanomed. J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1080\/17458080701393137","article-title":"Preparation of PLGA nanoparticles using TPGS in the spontaneous emulsification solvent diffusion method","volume":"2","author":"Esmaeili","year":"2007","journal-title":"J. Exp. Nanosci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S0168-3659(00)00201-7","article-title":"Sulfobutylated poly(vinyl alcohol)-graft-poly(lactide-co-glycolide)s facilitate the preparation of small negatively charged biodegradable nanospheres","volume":"67","author":"Jung","year":"2000","journal-title":"J. Control. Release"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S0168-3659(01)00230-9","article-title":"Design of rolipram-loaded nanoparticles: Comparison of two preparation methods","volume":"71","author":"Lamprecht","year":"2001","journal-title":"J. Control. Release"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.colsurfb.2010.07.047","article-title":"Preparation and physicochemical characterization of naproxen\u2013PLGA nanoparticles","volume":"81","author":"Javadzadeh","year":"2010","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Aur\u00eda-Soro, C., Nesma, T., Juanes-Velasco, P., Landeira-Vi\u00f1uela, A., Fidalgo-Gomez, H., Acebes-Fernandez, V., Gongora, R., Almendral Parra, M.J., Manzano-Roman, R., and Fuentes, M. (2019). Interactions of Nanoparticles and Biosystems: Microenvironment of Nanoparticles and Biomolecules in Nanomedicine. Nanomaterials, 9.","DOI":"10.20944\/preprints201907.0195.v1"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0168-3659(00)00291-1","article-title":"Effect of preparation temperature on the characteristics and release profiles of PLGA microspheres containing protein fabricated by double-emulsion solvent extraction\/evaporation method","volume":"69","author":"Yang","year":"2000","journal-title":"J. Control. Release"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S0142-9612(00)00178-2","article-title":"Morphology, drug distribution, and in vitro release profiles of biodegradable polymeric microspheres containing protein fabricated by double-emulsion solvent extraction\/evaporation method","volume":"22","author":"Yang","year":"2001","journal-title":"Biomaterials"},{"key":"ref_69","unstructured":"Vanderhoff, J.W., El-Aasser, M.S., and Ugelstad, J. (1979). Polymer Emulsification Process. (US4177177A), U.S. Patent."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1089\/jop.2007.0039","article-title":"Inhibition of Endotoxin-Induced Uveitis by Methylprednisolone Acetate Nanosuspension in Rabbits","volume":"23","author":"Adibkia","year":"2007","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"6675","DOI":"10.1038\/s41598-020-63767-1","article-title":"Mitigation of Tacrolimus-Associated Nephrotoxicity by PLGA Nanoparticulate Delivery Following Multiple Dosing to Mice while Maintaining its Immunosuppressive Activity","volume":"10","author":"Alshamsan","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1080\/10611860701453125","article-title":"Piroxicam nanoparticles for ocular delivery: Physicochemical characterization and implementation in endotoxin-induced uveitis","volume":"15","author":"Adibkia","year":"2007","journal-title":"J. Drug Target."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1023\/B:PHAM.0000016250.56402.99","article-title":"Critical determinants in PLGA\/PLA nanoparticle-mediated gene expression","volume":"21","author":"Prabha","year":"2004","journal-title":"Pharm. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.nano.2007.03.006","article-title":"Chitosan-coated PLGA nanoparticles for DNA\/RNA delivery: Effect of the formulation parameters on complexation and transfection of antisense oligonucleotides","volume":"3","author":"Nafee","year":"2007","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.3389\/fphar.2018.01260","article-title":"PLGA-Based Nanoparticles in Cancer Treatment","volume":"9","author":"Rezvantalab","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"4","DOI":"10.4172\/2155-983X.1000138","article-title":"Preparation and Characterization and Biodistribution Studies of Lomustine Loaded PLGA Nanoparticles by Interfacial Deposition Method","volume":"5","author":"Mehrotra","year":"2015","journal-title":"J. Nanomed. Biother. Discov."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1208\/s12249-013-0048-9","article-title":"Formulation and Optimization of Nonionic Surfactants Emulsified Nimesulide-Loaded PLGA-Based Nanoparticles by Design of Experiments","volume":"15","author":"Turk","year":"2014","journal-title":"AAPS PharmSciTech."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S0168-3659(03)00328-6","article-title":"Polymer degradation and in vitro release of a model protein from poly(d,l-lactide-co-glycolide) nano- and microparticles","volume":"92","author":"Panyam","year":"2003","journal-title":"J. Control. Release"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.jconrel.2004.01.011","article-title":"Effect of the size of biodegradable microparticles on drug release: Experiment and theory","volume":"96","author":"Siepmann","year":"2004","journal-title":"J. Control. Release"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.jconrel.2003.08.021","article-title":"A new process for making reservoir-type microcapsules using ink-jet technology and interfacial phase separation","volume":"93","author":"Yeo","year":"2003","journal-title":"J. Control. Release"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2790","DOI":"10.1016\/j.biomaterials.2009.01.057","article-title":"The uptake and intracellular fate of PLGA nanoparticles in epithelial cells","volume":"30","author":"Cartiera","year":"2009","journal-title":"Biomaterials"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.ijpharm.2008.04.042","article-title":"Principles of encapsulating hydrophobic drugs in PLA\/PLGA microparticles","volume":"364","author":"Wischke","year":"2008","journal-title":"Int. J. Pharm."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0378-5173(96)04854-5","article-title":"Influence of the degrees of hydrolyzation and polymerization of poly(vinylalcohol) on the preparation and properties of poly(dl-lactide-co-glycolide) nanoparticle","volume":"149","author":"Murakami","year":"1997","journal-title":"Int. J. Pharm."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.memsci.2007.02.011","article-title":"Enhanced permeation performance of cellulose acetate ultrafiltration membrane by incorporation of Pluronic F127","volume":"294","author":"Lv","year":"2007","journal-title":"J. Membr. Sci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s40005-012-0050-3","article-title":"Osmotically regulated asymmetric capsular system for sustained delivery of indomethacin","volume":"43","author":"Jain","year":"2013","journal-title":"J. Pharm. Investig."},{"key":"ref_86","first-page":"153","article-title":"Synthesis, characterization and in vitro degradation of poly (dl-lactide)\/poly (dl-lactide-co-glycolide) films","volume":"23","author":"Deniz","year":"1999","journal-title":"Turk. J. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.matdes.2017.09.052","article-title":"Core\/shell microencapsulation of indomethacin\/paracetamol by co-axial electrohydrodynamic atomization","volume":"136","author":"Shams","year":"2017","journal-title":"Mater. Des."},{"key":"ref_88","first-page":"30","article-title":"Recent biomedical applications and patents on biodegradable polymer-PLGA","volume":"1","author":"Singh","year":"2014","journal-title":"Int. J. Pharmacol. Pharm. Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"443","DOI":"10.13005\/msri\/070214","article-title":"Viscosity studies of polyvinyl alcohol (PVA, Mw = 1,25,000) in solvent distilled water and aqueous solution of urea","volume":"7","author":"Panda","year":"2010","journal-title":"Mater. Sci. Res. India"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"16538","DOI":"10.1038\/s41598-018-34986-4","article-title":"Viscosity measurement of Xanthan\u2013Poly(vinyl alcohol) mixture and its effect on the mechanical properties of the hydrogel for 3D modeling","volume":"8","author":"Shimizu","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.jfoodeng.2012.03.015","article-title":"Effect of high pressure homogenization (HPH) on the rheological properties of tomato juice: Time-dependent and steady-state shear","volume":"111","author":"Augusto","year":"2012","journal-title":"J. Food Eng."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1002\/app.10989","article-title":"Comparison of relative viscosity measurement of polyvinylpyrrolidone in water by glass capillary viscometer and differential dual-capillary viscometer","volume":"86","author":"Wu","year":"2002","journal-title":"J. Appl. Polym. Sci."},{"key":"ref_93","first-page":"22","article-title":"Intrinsic viscosity of PVP polymers in extremely diluted solutions","volume":"13","year":"2013","journal-title":"e-Polymers"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"S67","DOI":"10.1016\/j.clae.2018.03.082","article-title":"The shear rate and concentration dependence of viscosity in concentrated solutions of PVP and Bovine Mucin","volume":"41","author":"Maggio","year":"2018","journal-title":"Contact Lens Anterior Eye"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.jconrel.2007.05.034","article-title":"Effect of acidic pH on PLGA microsphere degradation and release","volume":"122","author":"Zolnik","year":"2007","journal-title":"J. Control. Release"},{"key":"ref_96","first-page":"1","article-title":"Application of mathematical models in drug release kinetics of carbidopa and levodopa ER tablets","volume":"6","author":"Gouda","year":"2017","journal-title":"J. Dev. Drugs"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.ijbiomac.2018.06.043","article-title":"Magnetic nanocellulose alginate hydrogel beads as potential drug delivery system","volume":"118","author":"Supramaniam","year":"2018","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_98","first-page":"77","article-title":"Review: In vitro drug release characterization models","volume":"2","author":"Singhvi","year":"2011","journal-title":"Int. J. Pharm. Stud. Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"23592","DOI":"10.1039\/D0RA03733H","article-title":"Tough, stretchable and compressive alginate-based hydrogels achieved by non-covalent interactions","volume":"10","author":"Jing","year":"2020","journal-title":"RSC Adv."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1016\/j.actbio.2008.02.027","article-title":"Modeling vancomycin release kinetics from microporous calcium phosphate ceramics comparing static and dynamic immersion conditions","volume":"4","author":"Gbureck","year":"2008","journal-title":"Acta Biomater."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.ejps.2017.12.012","article-title":"Drug transport mechanisms and in vitro release kinetics of vancomycin encapsulated chitosan-alginate polyelectrolyte microparticles as a controlled drug delivery system","volume":"114","author":"Unagolla","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"33234","DOI":"10.1038\/srep33234","article-title":"PLGA nanoparticle encapsulation reduces toxicity while retaining the therapeutic efficacy of EtNBS-PDT in vitro","volume":"6","author":"Hung","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1007\/s00204-012-0938-8","article-title":"Size influences the cytotoxicity of poly (lactic-co-glycolic acid) (PLGA) and titanium dioxide (TiO2) nanoparticles","volume":"87","author":"Xiong","year":"2012","journal-title":"Arch. Toxicol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"9433","DOI":"10.1039\/D1RA00074H","article-title":"Cytotoxicity of targeted PLGA nanoparticles: A systematic review","volume":"11","author":"Chiu","year":"2021","journal-title":"RSC Adv."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.ijpharm.2015.12.066","article-title":"Improved antitumor activity of epirubicin-loaded CXCR4-targeted polymeric nanoparticles in liver cancers","volume":"500","author":"Pan","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1124\/mol.56.6.1324","article-title":"Protective Effects of Triterpene Compounds Against the Cytotoxicity of Cadmium in HepG2 Cells","volume":"56","author":"Miura","year":"1999","journal-title":"Mol. Pharmacol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"104","DOI":"10.4103\/2277-9175.183664","article-title":"Differential expression of several drug transporter genes in HepG2 and Huh-7 cell lines","volume":"5","author":"Louisa","year":"2016","journal-title":"Adv. Biomed. Res."},{"key":"ref_108","first-page":"299","article-title":"Determining population doubling time and the appropriate number of HepG2 cells for culturing in 6-well plate","volume":"10","author":"Norouzzadeh","year":"2016","journal-title":"Int. Res. Bas. Sci."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1038\/sj.onc.1206237","article-title":"ERK signaling pathway is involved in p15INK4b\/p16INK4a expression and HepG2 growth inhibition triggered by TPA and Saikosaponin a","volume":"22","year":"2003","journal-title":"Oncogene"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"5253623","DOI":"10.1155\/2018\/5253623","article-title":"Hepatotoxicity of Nonsteroidal Anti-Inflammatory Drugs: A Systematic Review of Randomized Controlled Trials","volume":"2018","author":"Sriuttha","year":"2018","journal-title":"Int. J. Hepatol."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/4\/870\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:55:07Z","timestamp":1760136907000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/4\/870"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,15]]},"references-count":110,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["pharmaceutics14040870"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14040870","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,15]]}}}