Study On The Synthesis Of Upconversion Nanoparticles And Their Application In Drug Delivery And Imaging

Upconversion nanoparticles (UCNPs), particularly lanthanide-doped rare-earth nanocrystals,which are able to emit high-energy photons under excitatinby near-infrared (NIR) light, possess three important features: the remarkablelight penetration depth, the absence of background fluorescence in biologicalsamples and no significant advantage of biological tissue injury. Theseadvantages make UCNPs have potential applications in biomedical imaging. Inrecent years, preparation method of upconversion nanoparticles are mainlyhydrothermal synthesis method and high-temperature solvent method. TheUCNPs synthetized by hydrothermal synthesis method is not stable and size ofUCNPs is too large to be applicated in biochemical analysis; while the UCNPssynthetized by high-temperature solvent has good dispersity, regular shape,uniform size, good stability. Thus, in this paper, we chosed the high-temperature solvent scheme to synthetise the UCNPs and used it forsimultaneous pH-triggered anticancer drug delivery and imaging. The mainworks were summarized as follows:1. Study on the synthesis of upconversion nanoparticles and surfacemodificationIn this work, the hexagonal-phase NaYF4(β-NaYF4) nanocrystals dopedwith Yb3+, Er3+were synthesized by high-temperature solvent. The size, shapeand fluorescence of the UCNPs have been investigated in different reactionconditions, including the effects of ratio of OA and OM, reaction temperatureand other rare earth elements. The results showed that the shape of UCNPsevolved from irregular to nearly hexagonal with the temperature increasingfrom260to340℃. The formation of thermodynamically stable hexagonalnanoparticles should be facilitated at higher temperature under certainconditions. At lower temperature, non-spherical particles would be easilyobtained along specific directions under a dynamic growth regime. We studiedthe influence of the ratio of OA and OM. The results demonstrated when theOA is the majority in the system, the acquired UCNPs is morphology, sizeuniformity and gradually increasing to100nm; when the OM is the majorityin the system, irregular in morphology. However, doping with other rare earthelements (Tm, Gd) has certain influence on the morphology, size and luminous efficiency of UCNPs. Finally,320℃and OA:OM=2:1was utilized to prepareβ-NaYF4:Yb, Er (80:18:2) nanoparticles, and oleic acid coated particles(OA-UCNPs) are modificated by PAA ligand exchange, silica modification or directoxidation the OA. Zeta results showed that the PAA-UCNPs are stablest.Therefore, the PAA modified up-conversion nanoparticles was chosen in drugrelease system for imaging.2. Polyacrylic acid modified upconversion nanophosphors forsimultaneous pH-triggered anticancer drug delivery and imagingIn this work, the PAA(Mw=1200) chains was selected as a pH-sensitivenanovalve for loading drug molecules because of its hydrophilicity andabundance of carboxyl groups, a PAA-modified NaYF4:Yb,Er upconversionnanoparticles (PAA-UCNPs) with dual functions of drug delivery and releaseimaging have been successfully developed. The PAA polymer coated on thesurface of UCNPs serve as a pH-sensitive nanovalve for loading drugmolecules via electrostatic interaction. The drug-loading efficiency of thePAA-UCNPs is investigated by using doxorubicin hydrochloride (DOX) as amodel anticancer drug to evaluate their potential as a delivery system. Resultsshow loading and releasing of DOX from PAA-UCNPs are controlled byvarying pH, with high encapsulation at weak alkaline conditions and anincreased drug dissociation rate in acidic environment, which is favorable forconstruct a pH-responsive controlled drug delivery system. The in vitrocytotoxicity test using HeLa cell line indicated that the DOX loaded PAA-UCNPs (DOX@PAA-UCNPs) were distinctly cytotoxic to HeLa cells, whilethe PAA-UCNPs were highly biocompatible and suitable to use as drugcarriers. Furthermore, the upconversion fluorescence resonance energytransfer (UFRET) imaging through the two-photon laser scanning microscopy(TLSM) revealed the time course of intracellular delivery of DOX fromDOX@PAA-UCNPs. Thus, PAA-UCNPs are effective for constructing pH-responsive controlled drug delivery fluorescence systems for multi-functionalcancer therapy and imaging.