Tuning polymers grafted on upconversion nanoparticles for the delivery of 5-fluorouracil

Abstract

Efficient and safe delivery of anticancer drugs such as 5-fluorouracil (5-FU) is still a challenge in chemotherapy. The combination of polymers with a luminescent probe offers a promising venue to develop nanoobjects for theranostics. Herein, upconversion nanoparticles (UCNPs) decorated with polymers based on N-(2-hydroxypropyl) methacrylamide at their surface were investigated as potential carriers of 5-FU. The hyperbranched topology of the polymer offered a higher loading capacity of the polymer shell as compared to its linear analog even though the loading in 5-FU remained low and its release was fast (few hours). To overcome these limitations, 5-FU was conjugated to the polymer through esterification leading to a four-fold increase of the loading and a more sustained release over few days. The introduction of branching points with a disulfide bridge on the polymer afforded nanohybrids susceptible to degradation in the reductive environment of cancer cells. The degradation of the polymer was confirmed by incubating the polymer with dithiothreitol. These results pave the way to theranostics through the use of luminescent properties of UCNPs and the tuning of the polymer architecture.

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.