Production of PLGA Nanoparticles via Nanoprecipitation: A Systemic Study on Synthesis Conditions

Abstract

Poly(lactic-co-glycolic acid) (PLGA)-based nanomedicines exhibit significant potential for biomedical applications. Despite the approval and clinical use of PLGA microparticle products, no PLGA nanomedicine is currently available due to challenges including scaling up production. Nanoprecipitation is a one-step method with simplicity and efficiency that is capable of scaling up. However, studies on the preparation of PLGA nanoparticles (NPs) via nanoprecipitation exhibit significant variability in synthesis conditions, leading to inconsistencies in NP properties. Herein, we systematically evaluated the factors influencing the preparation of PLGA NPs through nanoprecipitation. Our results indicate that a rapid bolus injection of PLGA into aqueous solution with vigorous stirring yields smaller NPs (e.g., 125 nm with bolus versus 190 nm with 0.05 mL/min dropwise, 75 nm at 1500 r/min versus 106 nm at 100 r/min). Besides, low-concentration PLGA solutions, low ion concentrations, alkaline pH aqueous solutions, water-miscible solvents capable of dissolving PLGA, and carboxyl-terminated low molecular weight PLGA are beneficial for synthesizing NPs with smaller sizes. Importantly, this method was successfully scaled up to 1 L while maintaining consistent NP properties. The consistency, reproducibility, and scalability of this optimized method provide valuable guidance for the design and preparation of PLGA NPs, potentially facilitating their industrial production and clinical translation.

Keywords

Poly(lactic-co-glycolic acid) (PLGA) nanoparticle / Nanoparticle synthesis / Nanoprecipitation / Chemical Sciences / Physical Chemistry (incl. Structural)

References

[1] HarguindeyA, DomailleD W, FairbanksB D, WagnerJ, BowmanC N, ChaJ NAdv. Mater., 2017, 29: 1700743.

[2] MakadiaH K, SiegelS JPolymers, 2011, 3: 1377.

[3] HanF Y, ThurechtK J, WhittakerA K, SmithM TFront. Pharmacol., 2016, 7: 185.

[4] OpertiM C, BernhardtA, GrimmS, EngelA, FigdorC G, TagitOInt. J. Pharm., 2021, 605: 120807.

[5] RezvantalabS, DrudeN I, MoravejiM K, GuvenerN, KoonsE K, ShiY, LammersT, KiesslingFFront. Pharmacol., 2018, 9: 1260.

[6] SivadasanD, SultanM H, MadkhaliO, AlmoshariY, ThangavelNPharmaceutics, 2021, 13: 1291.

[7] AlsaabH O, AlharbiF D, AlhibsA S, AlanaziN B, AlshehriB Y, SalehM A, AlshehriF S, AlgarniM A, AlmugaiteebT, UddinM N, AlzhraniR MPharmaceutics, 2022, 14: 2728.

[8] HuaF J, ParkT G, LeeD SPolymer, 2003, 44: 1911.

[9] JainR ABiomaterials, 2000, 21: 2475.

[10] SharmaS, ParmarA, KoriS, SandhirRTrac-Trend. Anal. Chem., 2016, 80: 30.

[11] MaoS, XuJ, CaiC, GermershausO, SchaperA, KisselTInt. J. Pharm., 2007, 334: 137.

[12] McCall R. L., Sirianni R. W., J. Vis. Exp., 2013, e51015.

[13] ChengJ, TeplyB A, SherifiI, SungJ, LutherG, GuF X, Levy-NissenbaumE, Radovic-MorenoA F, LangerR, FarokhzadO CBiomaterials, 2007, 28: 869.

[14] WangF, ShanQ, ChangX, LiZ, GuiSInt. J. Pharmaceut., 2021, 602: 120617.

[15] BaghirovaL, Kaya TilkiE, ÖztürkA AACS Omega, 2023, 8: 2658.

[16] HamdallahS I, ZoqlamR, YangB, CampbellA, BoothR, BoothJ, BeltonP, QiSNanoscale Adv., 2024, 6: 3188.

[17] GaballahE Y, BorgT M, MohamedE ADrug Deliv., 2022, 29: 3304.

[18] FessiH, PuisieuxF, DevissaguetJ P, AmmouryN, BenitaSInt. J. Pharmaceut., 1989, 55: R1.

[19] KostagM, KöhlerS, LiebertT, HeinzeTMacromol. Symp., 2010, 294: 96.

[20] NieH, LeeL Y, TongH, WangC-HJ. Control. Release, 2008, 129: 207.

[21] MishimaKAdv. Drug Deliver. Rev., 2008, 60: 411.

[22] RaoJ P, GeckelerK EProg. Polym. Sci., 2011, 36: 887.

[23] ZhangD, LiuL, WangJ, ZhangH, ZhangZ, XingG, WangX, LiuMFront. Pharmacol., 2022, 13: 990505.

[24] DingD, ZhuQMater. Sci. Eng. C. Mater. Biol. Appl., 2018, 92: 1041.

[25] KshirsagarS M, ShresthaN, KippingT, BangaA KEur. J. Pharm. Biopharm., 2024, 200: 114346.

[26] LamchŁ, WilkK A, DékányI, DeákŁ, HornokV, JanovákLLangmuir, 2022, 38: 5404.

[27] BoltnarovaB, KubackovaJ, SkodaJ, StefelaA, SmekalovaM, SvacinovaP, PavkovaI, DittrichM, SchermanD, ZbytovskaJ, PavekP, HolasONanomaterials, 2021, 11: 749.

[28] Caballero-FloránI, CortésH, Borbolla-JiménezF, Florán-HernándezC, Del Prado-AudeloM, MagañaJ, FloránB, Leyva-GómezGPharmaceutics, 2023, 15: 1594.

[29] T CruzJ, ÁlvarezK, H. OrozcoV, RojasM, A Morales-LuckieR, F GiraldoLNanomedicine, 2024, 19: 1407.

[30] KimJ-K, UchiyamaS, GongH, StreamA, ZhangL, NizetVEngineering, 2021, 7: 1149.

[31] ThamphiwatanaS, AngsantikulP, EscajadilloT, ZhangQ, OlsonJ, LukB T, ZhangS, FangR H, GaoW, NizetV, ZhangLProc. Natl. Acad. Sci. USA, 2017, 114: 11488.

[32] ParasharS, ChauhanC, RajasekharanA, RautelaJ, JainT, RazaKFront. Bioeng. Biotechnol., 2022, 10: 833456.

[33] TodaroB, MoscardiniA, LuinSInt. J. Mol. Sci., 2022, 23: 2522.

[34] ZhouJ, VenturaC J, YuY, GaoW, FangR H, ZhangLNano Lett., 2022, 22: 7057.

[35] Hernández-GiottoniniK Y, Rodríguez-CórdovaR J, Gutiérrez-ValenzuelaC A, Penunuri-MirandaO, Zavala-RiveraP, Guerrero-GermánP, Lucero-AcuñaARSC Adv., 2020, 10: 4218.

[36] ZhangQ, HonkoA, ZhouJ, GongH, DownsS N, VasquezJ H, FangR H, GaoW, GriffithsA, ZhangLNano Lett., 2020, 20: 5570.

[37] GongH, ZhangQ, KomarlaA, WangS, DuanY, ZhouZ, ChenF, FangR H, XuS, GaoW, ZhangLNano Lett., 2021, 21: 2603.

[38] JiangY, KrishnanN, ZhouJ, ChekuriS, WeiX, KrollA V, YuC L, DuanY, GaoW, FangR H, ZhangLAdv. Mater., 2020, 32: e2001808.

[39] HuC M, ZhangL, AryalS, CheungC, FangR H, ZhangLProc. Natl. Acad. Sci. USA, 2011, 108: 10980.

[40] QiuE, LiuFFront. Bioeng. Biotechnol., 2023, 11: 1199343.

[41] TuW Q, DongX W, OuL P, ZhangX K, YuanB, YangKChem. Res. Chinese Universities, 2023, 39: 829.

[42] YanX B, BernardJ, GanachaudFAdv. Colloid Interface Sci., 2021, 294: 102474.

[43] SaadW S, Prud’hommeR KNano Today, 2016, 11: 212.

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Jilin University, The Editorial Department of Chemical Research in Chinese Universities and Springer-Verlag GmbH