This paper explores the development and characterization of epichlorohydrin-crosslinked β-cyclodextrin nanoparticles (βCDNPs) for drug delivery, focusing on their interaction with hydrophobic drugs and biocompatibility. We synthesized βCDNPs using β-cyclodextrin (βCD) and epichlorohydrin (ECH). Our study assessed the biocompatibility and safety of βCDNPs, particularly in avoiding nephrotoxicity commonly associated with βCD, by examining their interaction with cholesterol and conducting survival analyses in mice at various dosing concentrations. Additionally, we highlight the advantages of using diffusion-ordered NMR spectroscopy (DOSY) to determine the enhanced binding constants of βCDNPs with hydrophobic compounds, in comparison with the solubility method, Job plot analysis, and isothermal titration calorimetry (ITC). We demonstrated the enhanced binding capacity of βCDNPs compared to βCD alone and established the polymerization of βCD as a significant factor in this enhancement. Our findings suggest that βCDNPs show promise as drug delivery systems due to their improved solubility, stability, and safety profiles.
HogarthCArnoldKMcLauchlinA, et al. Evaluating the impact of systematic hydrophobic modification of model drugs on the control, stability and loading of lipid-based nanoparticles. J Mater Chem B2021; 9: 9874–9884.
2.
KalepuSNekkantiV. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharm Sin B2015; 5: 442–453.
3.
BegSSwainSRizwanM, et al. Bioavailability enhancement strategies: basics, formulation approaches and regulatory considerations. Curr Drug Delivery2011; 8: 691–702.
4.
DavisMEBrewsterME. Cyclodextrin-based pharmaceutics: past, present and future. Nat Rev Drug Discovery2004; 3: 1023–1035.
5.
OkaNMatsubaraHImaiT, et al. Protective effects of alpha-mangostin encapsulated in cyclodextrin-nanoparticle on cerebral ischemia. J Control Release2023; 353: 216–228.
6.
McNeilSE. Nanoparticle therapeutics: a personal perspective. WIREs Nanomed Nanobiotechnol2009; 1: 264–271.
7.
OwensDEPeppasNA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm2006; 307: 93–102.
8.
DoanVTHKatsukiJTakanoS, et al. Determining the critical quality attribute for the delivery of α-mangostin by β-cyclodextrin-based nanoparticles in cancer treatment. Polym J2023; 55: 1367-1378.
9.
VanDTHAnhDTNFujiiS, et al. Enhanced binding constant of cyclodextrin to alpha-mangostin in hyperbranched polymer. Chem Lett2020; 49: 1144–1146.
10.
DoanATNDoanVTHKatsukiJ, et al. Dramatically increased binding constant of water-soluble cyclodextrin hyperbranched polymers: Explored with diffusion ordered NMR spectroscopy (DOSY). ACS Omega2022; 7: 10890–10900.
11.
ChatzigiannisCMKiriakidiSTzakosAG, et al. 2D DOSY NMR: a valuable tool to confirm the complexation in drug delivery system. In: MavromoustakosTTzakosAGDurdagiS (eds.) Supramolecules in drug discovery and drug delivery methods in molecular biology. New York, NY: Humana, 2021, pp. 235–246.
12.
FerrazzaRRossiBGuellaG. DOSY-NMR and Raman investigations on the self-aggregation and cyclodextrin complexation of vanillin. J Phys Chem B2014; 118: 7147–7155.
StellaVJRajewskiRA. Sulfobutylether-β-cyclodextrin. Int J Pharm2020; 583: 119396.
17.
PuskásIVargaETuzaK, et al. Sulfobutylether-cyclodextrins: structure, degree of substitution and functional performance. In: RamirezFG (ed.) Cyclodextrins: synthesis, chemical applications and role in drug delivery. Hauppauge, NY: Nova Science Publishers Inc., 2015, pp. 293–320.
18.
YangZXiaoDLingKHJ, et al. The determination of Sulfobutylether β-Cyclodextrin Sodium (SBECD) by LC-MS/MS and its application in remdesivir pharmacokinetics study for pediatric patients. J Pharm Biomed Anal2022; 212: 114646.
19.
DoanVTHLeeJHTakahashiR, et al. Cyclodextrin-based nanoparticles encapsulating α-mangostin and their drug release behavior: potential carriers of α-mangostin for cancer therapy. Polym J2020; 52: 457–466.
20.
DoanVTHTakanoSDoanNAT, et al. Anticancer efficacy of cyclodextrin-based hyperbranched polymer nanoparticles containing alpha-mangostin. Polym J2021; 53: 481–492.
ChristoforidesEPapaioannouABethanisK. Crystal structure of the inclusion complex of cholesterol in β-cyclodextrin and molecular dynamics studies. Beilstein J Org Chem2018; 14: 838–848. 20180411.
23.
DaiYZhongJLiJ, et al. Interaction mechanism of cholesterol/β-cyclodextrin complexation by combined experimental and computational approaches. Food Hydrocolloids2022; 130: 107725.
GergelyVSebestyénGVirágS. Toxicity studies of beta-cyclodextrin. In: Proceedings of the first international symposium on cyclodextrins (ed SzejtliJ), Dordrecht, 1982, pp. 109–113. Springer.
26.
DoanATNSakuraiK. Unraveling the molecular mechanism of the interaction between cyclodextrin-based nanoparticles (CDNPs) and paroxetine hydrochloride. Bull Chem Soc Jpn2024; 97: uoae042.
27.
BerniniASpigaOCiuttiA, et al. NMR studies of the inclusion complex between beta-cyclodextrin and paroxetine. Eur J Pharm Sci2004; 22: 445–450.
28.
DamianL. Isothermal titration calorimetry for studying protein-ligand interactions. In: WilliamsMDaviterT (eds) Methods in molecular biology. Totowa, NJ: Humana Press, 2013, pp. 103–118.
29.
RaquelG-CElisePAudeC, et al. Isothermal calorimetry: molecular interactions between small molecules in organic solvents. In: JoséLuis R-ACynthiaGraciela F-H (eds.) Applications of calorimetry. Rijeka: IntechOpen, 2022, pp. 1–23.
30.
KellettKSlochowerDRSchauperlM, et al. Experimental characterization of the association of β-cyclodextrin and eight novel cyclodextrin derivatives with two guest compounds. J Comput Aided Mol Des2021; 35: 95–104.
31.
AreeT. Inclusion scenarios and conformational flexibility of the SSRI paroxetine as perceived from polymorphism of β-cyclodextrin-paroxetine complex. Pharmaceuticals2022; 15: 98
32.
ClaridgeTDW. Chapter 10—Diffusion NMR spectroscopy. In: ClaridgeTDW (ed.) High-resolution NMR techniques in organic chemistry. 3rd ed.Boston: Elsevier, 2016, pp. 381–419.
33.
ThordarsonP. Determining association constants from titration experiments in supramolecular chemistry. Chem Soc Rev2011; 40: 1305–1323.
