Ilhami F.BYang Y.-TLee A.-WChiao Y.-HChen J.-KLee D.-JLai J.-YCheng C.-C.DUU-JONG LEE2022-03-222022-03-22202115257797https://www.scopus.com/inward/record.uri?eid=2-s2.0-85115935571&doi=10.1021%2facs.biomac.1c01022&partnerID=40&md5=336b3183673bbdf15861f23399688828https://scholars.lib.ntu.edu.tw/handle/123456789/598174This study provides a significant contribution to the development of multiple hydrogen-bonded supramolecular nanocarrier systems by demonstrating that controlling the hydrogen bond strength within supramolecular polymers represents a crucial factor to tailor the drug delivery performance and enhance the effectiveness of cancer therapy. Herein, we successfully developed two kinds of poly(ethylene glycol)-based telechelic polymers Cy-PEG and UrCy-PEG having self-constituted double and quadruple hydrogen-bonding cytosine (Cy) and ureido-cytosine (UrCy) end-capped groups, respectively, which directly assemble into spherical nanogels with a number of interesting physical characteristics in aqueous solutions. The UrCy-PEG nanogels containing quadruple hydrogen-bonded UrCy dimers exhibited excellent long-term structural stability in a serum-containing biological medium, whereas the double hydrogen-bonded Cy moieties could not maintain the structural integrity of the Cy-PEG nanogels. More importantly, after the drug encapsulation process, a series of in vitro experiments clearly confirmed that drug-loaded UrCy-PEG nanogels induced selective apoptotic cell death in cancer cells without causing significant cytotoxicity to healthy cells, while drug-loaded Cy-PEG nanogels exerted nonselective cytotoxicity toward both cancer and normal cells, indicating that increasing the strength of hydrogen bonds in nanogels plays a key role in enhancing the selective cellular uptake and cytotoxicity of drugs and the subsequent induction of apoptosis in cancer cells. ? 2021 American Chemical Society.Bond strength (materials)Cell deathControlled drug deliveryCytotoxicityDiseasesHydrogen bondsNanostructured materialsPolyethylenesSelf assemblyStabilitySupramolecular chemistryCancer cellsCancer therapyDelivery performanceHydrogen bond strengthNanocarriersNanogelsPhysical characteristicsQuadruple hydrogen bondingSupramolecular polymersTelechelic polymersPolyethylene glycolscytosinedimerdoxorubicinhydrogenmacrogolnanocarriernanogelpolymerdrug carrierapoptosisaqueous solutionArticlecancer cellcancer therapycatalysischemical interactioncontrolled studycytotoxicitydrug delivery systemencapsulationfemaleflow cytometryfluorescence intensityHeLa cell linehumanhuman cellhydrodynamicshydrogen bondhydrophilicityhydrophobicityin vitro studyincubation timeinternalization (cell)matrix assisted laser desorption ionization time of flight mass spectrometryMichael additionmolecular weightMTT assayNIH 3T3 cell lineparticle sizepHquantitative analysisrelease assayscanning electron microscopyspectrofluorometrysustained drug releasesynthesiszeta potentialmicelleneoplasmDrug CarriersHumansHydrogenHydrogen BondingMicellesNeoplasmsPolyethylene Glycols[SDGs]SDG3journal article10.1021/acs.biomac.1c01022345061112-s2.0-85115935571