Short communicationTuning polymers grafted on upconversion nanoparticles for the delivery of 5-fluorouracil
Graphical abstract
Introduction
Theranostics is a fascinating field in biomedicine combining the delivery of a therapeutic drug and diagnostics through bioimaging on a same carrier [1]. While bioimaging is strongly dominated by the use of organic dyes, [2] the development in nanotechnologies has influenced this field leading notably to the use of inorganic nanoparticles [3]. A wide range of nanoparticles have been investigated including iron oxide nanoparticles for magnetic resonance imaging, [4], [5] but also quantum dots [6], [7] and upconversion nanoparticles [8], [9], [10] (UCNPs) as optical contrast agents. Lanthanide-doped UCNPs are anti-Stokes shift luminescent materials able to convert low energy excitation (i.e. near-infrared (NIR) excitation) into higher energy emission (i.e. visible and ultraviolet (UV–vis) emission). These materials have recently received an increased interest as bioimaging probes due to their properties including high optical penetration depth of light in biological tissues, low phototoxicity, and high signal-to-noise ratio. However, UCNPs generally are capped with hydrophobic ligands altering their dispersion in aqueous solution and suffer from limited stability in aqueous media, which has led to the development of various strategies to modify their surface including adding polymers at the surface of UCNPs. Polymers can be introduced either by ligand exchange using polymers bearing anchoring moieties (e.g. amine, [11] carboxylic acid, [11], [12], [13] sulfonic acid, [12], [14] phosphate, [12], [15] and phosphonates [16]), or by performing polymerization at or from the surface of UCNPs. Wu et al. have removed the oleic acid ligands from the surface of UCNPs by acid treatment to induce the electrostatic adsorption of dopamine that was polymerized under oxidative conditions [17]. UCNPs have also been explored to trigger photopolymerization upon NIR irradiation in the presence of Eosin Y as photoinitiator to prepare crosslinked polymers at the surface of UCNPs [18], [19]. Ricinoleic acid has been used as ligand to prepare UCNPs bearing hydroxyl groups able to initiate cationic ring-opening polymerization from the surface of UCNPs for the synthesis of hyperbranched polyglycerol [20], [21] and linear poly(ε-caprolactone) [21] affording UCNPs with high water dispersibility and upconversion luminescence. Polymerization at the surface of UCNPs has been also considered by building up a silica shell with suitable functional groups around the UCNPs. UCNPs with a silica shell bearing thiol groups have permitted the introduction of oxime-ester coumarin photoinitiators able to initiate thiol-ene and conventional radical polymerization from their surface, [22] while the presence of amines on the silica shell have permitted the insertion of the suitable initiators for atom transfer radical polymerization [23] or chain transfer agents for reversible addition-fragmentation chain transfer (RAFT) polymerization [24], [25] used to grow methacrylate-based polymer from the surface of UCNPs.
We recently reported the polymerization of N-(2-hydroxypropyl) methacrylamide (HPMA) with linear and hyperbranched topologies from the surface of UCNPs (UCNP@polyHPMA and UCNP@HBP respectively) under RAFT conditions [26]. UCNP@HBP showed a strong emission exhibiting their potential as imaging probes. If the polymer shell could be tuned to induce controlled release of a drug, these nanoobjects could be promising for theranostics. 5-Fluorouracil (5-FU) was chosen as model drug for this work. 5-FU is an anticancer agent used for the treatment of a wide range of cancers, [27], [28] but its short plasma half-life, low selectivity towards cancer cells, and severe side effects have limited its clinical use [29], [30]. Recent developments have aimed at improving its bioavailability through encapsulation in polymer particles [31], [32], [33] or liposomes, [34] but also the preparation of prodrugs [35] and its conjugation to polymers [36], [37], [38]. Herein, UCNPs decorated with linear and hyperbranched poly(N-(2-hydroxypropyl) methacrylamide) were investigated as 5-FU carriers though passive encapsulation in the polymer shell or conjugation to the polymer. The structure of the polymers was further tuned through the insertion of redox-degradable branching points to trigger the release of 5-FU under conditions specifically met in cancer cells.
Section snippets
Passive loading of 5-FU in UCNP@polyHPMA and UCNP@HBP
The RAFT polymerization of HPMA was performed from UCNP functionalized with 0.24 mmol of 4–cyano-4-(thiobenzoylthio)pentanoic acid (CPABD) per gram of UCNPs (UCNP@CPABD) having a diameter of 45 nm as previously described [26]. Nanohybrids with linear (UCNP@polyHPMA) and hyperbranched polymers (UCNP@HBP with a degree of branching of 0.17) were prepared. The synthesis of UCNP@HBP was conducted in the presence of 4–cyano-4-(phenylcarbonothioylthio)pentanoate (MA-CPABD) as transmer inducing the
Conclusion
The potential of nanohybrids consisting in UCNPs modified with HPMA-based polymers obtained by RAFT polymerization from the surface of UCNPs for drug vectorization were investigated using 5-FU as model anticancer drug. The introduction of branching points on the polymer led to an increased drug loading in the polymer shell due to the presence of cavities in hyperbranched polymers as compared to linear analogs. As 5-FU loading in UCNP@HBP remained low and was associated to a pronounced burst
Materials
1–Hydroxybenzotriazole hydrate (HOBt, ≥97%), 2,2′–azobis(isobutyronitrile) (AIBN, 98%), 4–cyano-4-(thiobenzoylthio)pentanoic acid (CPABD, >98%), dithiothreitol (DTT, ≥98%), phosphate buffered saline tablets (PBS), anhydrous N,N-dimethylformamide (anhydrous DMF, 99.8%), anhydrous dichloromethane (anhydrous DCM, ≥99.8%), and N,N-dimethylformamide (DMF, >99%), were purchased from Sigma-Aldrich. N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU, 99%) was purchased from
Data availability
The raw/processed data required to reproduce these findings cannot be shared at this time due to technical or time limitations.
CRediT authorship contribution statement
Alireza Kavand: Conceptualization, Methodology, Investigation, Visualization. Nicolas Anton: Supervision. Thierry Vandamme: Supervision. Christophe A. Serra: Funding acquisition, Supervision. Delphine Chan-Seng: Funding acquisition, Conceptualization, Supervision, Visualization.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was funded by the French National Research Agency (ANR) through the Programme d’Investissement d'Avenir under contract ANR-11-LABX-0058_NIE within the Investissement d’Avenir program ANR-10-IDEX-0002-02. This work was financially supported by the CNRS and the University of Strasbourg. The doctoral position of AK is supported by the University of Strasbourg through a doctoral contract from the Physics and Chemistry-Physics doctoral school and his postdoctoral position by the
References (50)
- et al.
NIR dyes for bioimaging applications
Curr. Opin. Chem. Biol.
(2010) - et al.
Nanoparticles for bioimaging
Adv. Colloid Interface Sci.
(2006) - et al.
High-quality quantum dots for multiplexed bioimaging: A critical review
Adv. Colloid Interface Sci.
(2020) - et al.
Upconversion nanoparticles: A versatile solution to multiscale biological imaging
Bioconjug. Chem.
(2015) - et al.
Investigating the growth of hyperbranched polymers by self-condensing vinyl RAFT copolymerization from the surface of upconversion nanoparticles
Polym. Chem.
(2020) - et al.
5-Fluorouracil encapsulated alginate beads for the treatment of breast cancer
Int. J. Pharm.
(2002) - et al.
Poly(alkylcyanoacrylate) colloidal particles as vehicles for antitumour drug delivery: A comparative study
Colloids Surf. B
(2008) - et al.
Characterization of 5-fluorouracil loaded liposomes prepared by reverse-phase evaporation or freezing-thawing extrusion methods: Study of drug release
Biochim. Biophys. Acta, Biomembr.
(1993) Development of HPMA copolymer–anticancer conjugates: Clinical experience and lessons learnt
Adv. Drug Deliv. Rev.
(2009)- et al.
Highly selective and sensitive ratiometric fluorescent polymer dots for detecting hypochlorite in 100% aqueous media
Spectrochim. Acta Part A Mol. Biomol. Spectrosc.
(2019)
One-pot synthesis of hyperbranched polymers using small molecule and macro RAFT inimers
Polymer
Theranostics: Combining imaging and therapy
Bioconjug. Chem.
Iron oxide nanoparticle based contrast agents for magnetic resonance imaging
Mol. Pharm.
Magnetic iron oxide nanoparticles as T1 contrast agents for magnetic resonance imaging
J. Mater. Chem. C
Application of semiconductor quantum dots in bioimaging and biosensing
J. Mater. Chem. B
Upconversion nanoparticles: Design, nanochemistry, and applications in theranostics
Chem. Rev.
Upconversion luminescent materials: Advances and applications
Chem. Rev.
Polymer-coated NaYF4:Yb3+, Er3+ upconversion nanoparticles for charge-dependent cellular imaging
ACS Nano
Systematic investigation of functional ligands for colloidal stable upconversion nanoparticles
RSC Adv.
Thermo-activatable PNIPAM-functionalized lanthanide-doped upconversion luminescence nanocomposites used for in vitro imaging
RSC Adv.
Upconversion nanoparticles with a strong acid-resistant capping
Nanoscale
Surface modification of upconverting NaYF4 nanoparticles with PEG−phosphate ligands for NIR (800 nm) biolabeling within the biological window
Langmuir
Polymer-coated ultrastable and biofunctionalizable lanthanide nanoparticles
ACS Appl. Mater. Interfaces
Formation and degradation tracking of a composite hydrogel based on UCNPs@PDA
Macromolecules
Novel multifunctional NaYF4:Er3+, Yb3+/PEGDA hybrid microspheres: NIR-light-activated photopolymerization and drug delivery
Chem. Commun.
Cited by (3)
Effects of the molecular weight of hyaluronan on the conformation and release kinetics of self-assembled 5-fluorouracil-loaded lysozyme-hyaluronan colloidal nanoparticles
2022, International Journal of Biological MacromoleculesCitation Excerpt :However, the application of 5-Fu was limited due to its poor bioavailability, short plasma half-life, and chemical instability [2]. Recently, researchers have designed some encapsulation and delivery systems such as liposomes, microemulsions, and colloidal nanoparticles to overcome the above-mentioned shortcomings [3,4]. Among them, colloidal nanoparticles based on natural biodegradable biomacromolecules have attracted widespread attention because of their versatility, excellent biocompatibility, high encapsulation efficiency, and long circulation time [5].