Deuterated water

The 5-fluorouracil (5-FU) was purchased from Applichem for Pharmaceuticals Co., GmbH (Darmstadt, Germany). Methotrexate (MTX) was obtained from Haupt Pharma Wolfratshausen GmbH (Chemajet Co., (Wolfratshausen, Bayern, Germany). β-Cyclodextrin (β-CD) and epichlorohydrin (EP) were obtained from Wacker Fine Chemicals (Wacker Chemie AG, Burghausen, Germany). Diisopropyl azodicarboxylate (DIAD), brine, Toluene, and succinic anhydride (SA) were delivered from Sigma-Aldrich (Schnelldorf, Germany). Cholesterol, triphenylphosphine (PPh3), phthalimide, dibutyltin dilaurate (DBDL), and dimethyl aminopropyl-ethyl carbodiimide (EDC) were obtained from Acros Organics (Geel, Belgium). Linear eight-armed poly (ethylene glycol) with a molecular weight of 20 kDa (8armPEG20k-OH) was delivered from Jenkem Technology (Beijing, China). Ethanol, tetrahydrofuran (THF), triethylamine (TEA) dichloromethane (DCM), and the other chemicals of an analytical grade were obtained from Merck KGaA (Darmstadt, Germany). Phosphate buffered saline (PBS), deuterated water, and chloroform (respectively, d6-D₂O and d₆-CDCl₃) were purchased from Deutero (Kastellaun, Germany). Celite 503 were obtained from Fluka (Taufkirchen, Germany).

1D and 2D NMR spectra were acquired in deuterated water (Deutero, Kastellaun, Germany) on a Bruker Avance Neo 500 spectrometer equipped with a 5 mm TXI prodigy cryoprobe (Bruker BioSpin GmbH, Rheinstetten, Germany) at 298 K. NMR chemical shifts were reported in parts per million (ppm) relative to the residual solvent signal D₂O at δ 4.79. NMR data were analyzed using Topspin, version 4.06 (Bruker, Biospin GmbH, Rheinstetten, Germany) and ACD/Spectrus Processor 2020.2.1 (ACD/Labs, Toronto, Canada).