# Development of tunable materials from well-defined alendronic acid functionalized polyacrylamide: An opportunity for actinide decontamination

Vincent Darcos, Loona Ferrie, Carlos Arrambide, Gabriele Vecchio, Nicolas Dacheux, Stephane Pellet-Rostaing, Benedicte Prelot, Sophie Monge

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Vincent Darcos, Loona Ferrie, Carlos Arrambide, Gabriele Vecchio, Nicolas Dacheux, et al. Development of tunable materials from well-defined alendronic acid functionalized polyacrylamide: An opportunity for actinide decontamination. Journal of Polymer Science, 2026, 10.1002/pol.20250876. hal-05493386

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Submitted on 4 Feb 2026

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Development of tunable materials from well-defined alendronic acid
functionalized polyacrylamide: an opportunity for actinide
decontamination

Vincent Darcos,<fnref n="1" />* Loona Ferrie,<fnref n="2" /> Carlos Arrambide,<fnref n="1" /> Gabriele Vecchio,<fnref n="2" />
Nicolas Dacheux,<fnref n="3" /> Stephane Pellet-Rostaing,<fnref n="3" /> Benedicte Prelot,<fnref n="2" /> Sophie Monge<fnref n="2" />*

<footnote n="1">¹ IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France</footnote>

<footnote n="2">² ICGM, Univ Montpellier, CNRS, ENSCM, Montpellier, France</footnote>

<footnote n="3">³ ICSM, Univ Montpellier, CEA, CNRS, ENSCM, Marcoule, France</footnote>

<footnote>* Corresponding authors:</footnote>

<footnote>V. Darcos (vincent.darcos@umontpellier.fr)</footnote>

<footnote>S. Monge (sophie.monge-darcos@umontpellier.fr)</footnote>
Bisphosphonic acid groups are emerging as promising functionalities for actinide decontamination, due to their high density of chelating sites. However, the chemistry of bisphosphonate (in particular alendronate) materials remains complex and underexplored. Herein, the synthesis of novel valuable materials, namely poly(N-isopropylacrylamide)-*b*-poly(acryloylmorpholine-*co*-alendronate acrylamide) (PNIPAAm-*b*-P(NAM-*co*-AleAAm)) was reported. These copolymers were synthesized in three steps. First, poly(N-isopropylacrylamide)-*b*-poly(acryloylmorpholine-*co*-N-acryloxysuccinimide) (PNIPAAm-*b*-P(NAM-*co*-NAS)) diblock copolymers were prepared by RAFT polymerization. Then, bisphosphonic acid groups were grafted onto the preformed copolymers by a post-polymerization modification reaction. Original produced alendronate-based functional copolymers were either water-soluble or capable of forming hydrogels under suitable concentration and temperature conditions. Sorption properties of such materials for actinides were investigated. For such purpose, the binding affinities of these functionalized copolymers for actinide surrogates, Nd(III) and Ce(III), were evaluated by isothermal titration calorimetry (ITC). Experimental results demonstrated good complexation efficiency, which logically raised with increasing bisphosphonic acid content. These results highlight the potential of well-defined, tunable hydrosoluble/hydrogel bisphosphonate-based polymers as high potential candidates for actinide decorporation applications.

**Keywords:** actinide decontamination, bisphosphonate, complexing polymers, hydrogel, ITC, polyacrylamide
# 1 | Introduction

The use of actinides in nuclear energy, military applications, and medicine brings significant benefits, but it also introduces important environmental challenges. Actinides are highly radioactive elements, and their long-lived isotopes, such as $^{238}$U or $^{239}$Pu, present substantial risks over extended periods, requiring meticulous management to prevent contamination. The environmental concerns arise primarily from the radioactive waste generated during their use and the potential for pollution if not properly controlled [1]. In the case of nuclear reactors, the handling of UOx (i.e. UO$_2$) and MOx (i.e. (U,Pu)O$_2$) fuels, especially uranium and plutonium, results in the production of spent fuel and nuclear by-products, that can remain hazardous for thousands of years. This High-Level Radioactive Waste (HLW) requires long-term storage in geological repositories to prevent its release into the environment. The risk of accidents, such as radiation leaks or improper disposal, can have serious consequences for ecosystems [2] and human populations [3, 4]. Additionally, the military use of actinides, particularly in nuclear weapons, poses significant risks related to nuclear proliferation, the spread of hazardous materials, and environmental contamination [5]. Finally, while actinides have medical applications in treating cancer and in diagnostic procedures, the disposal of medical isotopes also requires careful handling to avoid release into the environment. The risks associated with actinides require a strong regulatory framework combined with advanced decontamination techniques.

In recent years, an increasing focus on innovative materials and technologies for radionuclide decontamination has been observed, notably motivated by the growing need to safeguard the environment and protect public health [6]. Several approaches have been developed for the removal of actinides from environment such as wastewater [7], including membrane filtration [8], ion exchange [9], chemical precipitation [10], or electrochemical treatment [11]. While each method has distinct advantages, they also present certain limitations, such as prolonged extraction times or low efficiency under specific conditions [12]. These challenges emphasize the necessity for innovative, efficient, and environmentally friendly solutions to address actinide decontamination effectively. Among all possibilities, polymer-based materials have attracted attention for their remarkable versatility and effectiveness in solving a wide range of contamination problems [7]. Indeed, chelating polymers are particularly
noteworthy for their ability to bind metal ions through functional groups such as hydroxy
[13], carboxyl [14], amine [15, 16], amide [17], or phosphonic acid [18]. The formation
of stable complexes makes them highly effective in sequestering radionuclides.
Besides water-soluble polymers, hydrogels based on natural and synthetic polymers
appeared to be of great interest for metals adsorption [19]. For instance, alginate
hydrogel beads have recently been described for the competitive sorption of metal ions
such as Ca²⁺, Cu²⁺, Ni²⁺, and Pb²⁺ [20]. Other bio-based materials, i.e. cellulose-based
hydrogels, have been reported by Akter et al. as potential candidates for the
remediation of pollutants from the wastewater [21]. On the other hand, hydrogels
based on synthetic polymers were also considered. Poly(vinyl alcohol)-based
hydrogels were used for the surface decontamination of the radioactive cesium isotope
(¹³⁷Cs) [22, 23]. More recently, a new hydrogel based on poly(amidoxime) and polyvinyl
alcohol with effective binding sites has demonstrated outstanding performance for the
uranium extraction from seawater, achieving excellent stability and reusability [24].
Other classes of crosslinked polymers such as polyacrylates and polyacrylamides
were also reported as good hydrogel candidates for sorption of heavy-metal ions [25,
26].

Modern macromolecular engineering techniques such as controlled radical
polymerization enable structures to be designed for specific decontamination needs,
reinforcing their applicability in a variety of environmental scenarios [27]. Chelating
agents with a strong affinity for actinides can be incorporated through post-
polymerization modification of preformed polymers. Currently, chelating agents can be
categorized in four main classes: (i) polyaminocarboxylic acids such as DTPA [28], (ii)
siderophores such as catecholates (CAM) or hydroxylpyridonates (HOPO) [29], (iii)
macrocycles such as calixarenes or crown-ethers [30] and (iv) phosphonates such as
1-hydroxyethane-1',1-diphosphonic acid (HEDP) [31]. Among those chelating ligands,
phosphonate-bearing compounds are of particular interest due to their selectivity and
complexing ability towards actinides. For instance, carbamoylmethylphosphine oxide
(CMPO) is able to selectively bind many types of actinides and ions derived from fission
products [32, 33]. Among the phosphonate chelators, ligands bearing bisphosphonates
are very interesting due to the presence of two phosphonic acid groups available for
actinides complexation and can therefore exhibit increased efficiency compared to
monofunctional ones [34]. Chelating resins containing bisphosphonate groups were
firstly described by Alexandratos et al. with respect to the europium complexation,
thus showing high chelation affinity towards lanthanides [35]. Then, those resins have been developed under the name of Diphonix™ resin and were used as actinides sorbents for the decontamination of radioactive nuclear wastes [36, 37]. Actinide™ resin was also developed concurrently, resulting into even higher actinides complexation properties [38]. Magnetic nanoparticles functionalized with bisphosphonates have been as well reported for uranium complexation and body decontamination [39]. Therefore, these few examples show that bisphosphonate bearing materials such as resins or nanoparticles are promising elements for the complexation of actinides. From those results, grafting chelating moieties such as bisphosphonates onto polymers represents an attractive strategy for actinide complexation and/or extraction.

Water-soluble polymers bearing bisphosphonic acid groups are quite rare [40, 41]. In a recent contribution, our group highlighted the interest of bisphosphonic acid moieties provided by alendronate molecule to efficiently sorb neodymium (III) cations [42]. Additionally, to the best of our knowledge, physical hydrogels from this kind of materials were not reported yet in the literature, except when metallic cations were added to create weak bonds with phosphorus-based moiety, thus promoting hydrogel formation [43]. In the present contribution, we report, to our knowledge, the first example of water-soluble alendronate-based copolymers able to form physical hydrogels as a function of both temperature and concentration in water. These novel materials were synthesized by the combination of controlled radical polymerization and post-polymerization modification. For such purpose, amphiphilic block copolymers based on tunable thermosensitive poly(N-isopropyl acrylamide) (PNIPAAm) and statistical poly(acryloylmorpholine-co-N-acryloxysuccinimide) (P(NAM-co-NAS)) moieties have been designed to obtain materials showing a hydrophilic-hydrophobic balance depending on the temperature, favouring gel formation. Functional and highly reactive N-acryloxysuccinimide co-monomer was employed to graft bisphosphonic acid-containing ligands (Ale) onto the copolymer. Those copolymers were synthesized by RAFT polymerization and the ligands were grafted with different amounts (10 and 25%) in order to study their effect on the complexing capacities of the polymers. Preliminary studies of hydrogel formation from PNIPAAm-*b*-P(NAM-co-AleAAm) complexing copolymers were carried out as a function of concentration and temperature. Finally, the sorption behaviour of the PNIPAAm-*b*-P(NAM-co-NAS) and functionalized PNIPAAm-*b*-P(NAM-co-AleAAm) developed materials was investigated using
Isothermal Titration Calorimetry (ITC), carried out with lanthanides (neodymium (III) and cerium (III)), used as surrogates of actinides. The obtained results highlighted the potential of the copolymer structures developed for actinide sorption, and the influence of ligand density onto metal-binding capacity of the polymers. They provided insights into the potential application of such materials in nuclear waste remediation in aqueous solution or hydrogel form. More specifically, copolymers could be used in the external body decontamination of actinides. Indeed, they could enable the development of complexing aqueous solutions or hydrogels. It is important to note that the latter could have the great advantage of not dripping, thus allowing for increased decontamination.
## 2. | Materials et Methods

### 2.1 | Materials

N-isopropylacrylamide (97%) (NIPAAm), 2-cyano-2-propyl dodecyl trithiocarbonate (97%), dioxane, neodymium (III) nitrate hexahydrate (Nd(NO₃)₃·6H₂O), cerium (III) nitrate hexahydrate (Ce(NO₃)₃·6H₂O) were obtained from Sigma-Aldrich (St-Quentin Fallavier, France) and used without further purification. 2,2'-azobis(2-methylpropionitrile) (AIBN) (Sigma-Aldrich, St-Quentin Fallavier, France) was purified by recrystallisation from ethanol. 4-Acryloylmorpholine (97%, Sigma-Aldrich, St-Quentin Fallavier, France) (NAM) was purified through a basic aluminium oxide column. Alendronic acid (Ale acid) was obtained from TCI Europe (Zwijndrecht, Belgium) and used as received. N-acryloxysuccinimide (NAS) was synthesized as previously described.[44] Ultrapure water with resistivity of 18 MΩ·cm was produced through a Millipore Milli-Q water system.

### 2.2 | Characterization

*Nuclear Magnetic Resonance (NMR) spectroscopy.* ¹H NMR spectra were recorded on a Bruker Avance III HD 400 MHz spectrometer. Chemical shifts were referenced to the peak of residual non-deuterated solvents.

*DMF Size Exclusion Chromatography (SEC)*. DMF SEC was performed at room temperature using a Shimadzu Prominence system (Shimadzu Corp, Kyoto, Japan) equipped with a PLgel MIXED-C guard column (Agilent, 5 µm, 50 x 7.5 mm), two mixed medium columns PLgel MIXED-C (5 µm, 300 x 7.8 mm) and a Shimadzu RI detector 20-A. The mobile phase was DMF with a flow of 1 mL·min⁻¹ at 35 °C. Poly(methyl methacrylate) (PMMA) standards were used for calibration and polymers characteristics were expressed according to those standards.

*Aqueous Size Exclusion Chromatography (SEC)*. Aqueous SEC was conducted on a Shimadzu Nexera LC system equipped with a LC-40D pump (Shimadzu), a DGU-403 degassing unit (Shimadzu), a SIL-40 autosampler (Shimadzu), a CTO-40C column
oven (Shimadzu), 1×PL aquagel-OH 8µm guard column (50 × 7.5 mm, Agilent), 2 × PL aquagel Mixed-M 8µm column (300 × 7.5 mm, Agilent), a RID-20A refractive index detector, and a SPD-40 UV detector (Shimadzu). The mobile phase was composed of 0.2M NaNO₃, 0.1M NaH₂PO4 (pH 7), and 200ppm NaN₃. The flow rate was 1 mL.min⁻¹. The number-average and weight-average molar masses (Mn and Mw, respectively) and the dispersity (D) were expressed according to calibration using poly(ethylene glycol) (PEG) standards.

*Multi-detection Size Exclusion Chromatography (SEC MALS)*. SEC-MALS was conducted on a Shimadzu Nexera LC system equipped with a LC-40D pump (Shimadzu), a DGU-403 degassing unit (Shimadzu), a SIL-40 autosampler (Shimadzu), a CTO-40C column oven (Shimadzu), 1×PL aquagel-OH 8µm guard column (50 × 7.5 mm, Agilent), 2 × PL aquagel Mixed-M 8µm column (300 × 7.5 mm, Agilent), a SPD-40 UV detector (Shimadzu), a Dawn8® light scattering detector (Wyatt Technology), a ViscoStar® detector (Wyatt Technology), an Optilab® refractive index detector (Wyatt Technology). The mobile phase was composed of 0.2M NaNO₃, 0.1M NaH₂PO4 (pH 7), and 200ppm NaN₃. The flow rate was 1 mL.min⁻¹. Molecular weights were calculated using measured dn/dc values determined by an offline batch method, in which the refractive index change of polymer solutions of known concentrations was measured with a refractive index detector.

*Isothermal Titration Calorimetry (ITC)*. ITC measurements were performed using a TAM III multichannel calorimetric device with a Micro Reaction System and nanocalorimeters. The experiments were carried out at 298 K. In a single measurement, 25 injections of 10 µL of cations solution, each one lasting 10 seconds, were performed in the cells containing 800 µL of polymer solution. The injections were spaced by 45 minutes apart in order to allow the system stabilizing before the next one. Data analysis was performed using a One-Site binding Model (NanoAnalyze TA Waters software). The measurements were performed in triplicate, the experimental error was estimated at approximately 10 %.
## 2.3 | Synthetic procedure

Typical procedure for the RAFT polymerization of N-isopropylacrylamide. Polymerization was carried out using standard Schlenk technique under argon atmosphere. N-isopropylacrylamide (10 g, 88.4 mmol, 100 eq.), AIBN (29 mg, 0.177 mmol, 0.2 eq.), 2-cyano-2-propyl dodecyl trithiocarbonate (308 µL, 305 mg, 0.883 mmol, 1 eq.), and dioxane (44 mL, 2 mol·L⁻¹) were placed in a Schlenk tube. The tube was fitted with a rubber septum. The solution was degassed by three freeze-thaw-pump cycles. The resulting mixture was placed in a thermostatically controlled oil bath at 70 °C for 2 hours. The reaction was stopped with liquid nitrogen, and the crude material was purified by precipitation in diethyl ether. The resulting product was collected by filtration and dried in vacuo to yield a yellow powder (7.5 g, yield: 75%).

$$M_{n,SEC} \text{DMF} = 10200 \text{ g} \cdot \text{mol}^{-1}, D = 1.08$$

$$\text{Conversion} = 79 \%$$

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 7.16 (m, 1H, NH), 3.84 (m, 1H, NH-CH-(CH₃)₂), 1.97 (m, 1H, CH₂-CH(CONH)-), 1.45 (m, 2H, CH₂-CH(CONH)-), 1.23 (s, 5H, SCH₂-(CH₂)₁₀CH₃), 1.04 (s, 6H, CH-(CH₃)₂), 0.85 (t, 20H, SCH₂-(CH₂)₁₀CH₃).

Typical procedure for the synthesis of poly(N-isopropylacrylamide)-b-poly(acryloylmorpholine-co-N-acryloxysuccinimide). Polymerization was carried out using standard Schlenk technique under argon atmosphere. Poly(N-isopropylacrylamide) (4.39 g, 0.472 mmol, M<sub>n,NMR</sub> = 9300 g·mol⁻¹, 1 eq.), 4-acryoylmorpholine (10 g, 70.8 mmol, 150 eq), N-acryloxysuccinimide (3.99 g, 23.6 mmol, 50 eq.), AIBN (15.5 mg, 9.44·10⁻² mmol, 0.2 eq.), trioxane (213 mg, 2.36 mmol, 5 eq.), and dioxane (63 mL, 1.5 mol·L⁻¹) were placed in a Schlenk tube. The tube was fitted with a rubber septum. The solution was degassed by three freeze-thaw-pump cycles. The resulting mixture was placed in a thermostatically controlled oil bath at 70 °C for 3 hours. The reaction was stopped with liquid nitrogen, and the crude material was purified by precipitation in diethyl ether. The resulting product was collected by filtration and dried in vacuo to yield a yellow powder (13.6 g, yield: 93 %).

$$M_{n,SEC} \text{DMF} = 39400 \text{ g} \cdot \text{mol}^{-1}, D = 1.23$$

$$\text{Conversion (NAM)} = 99 \%, \text{ conversion (NAS)} = 100\%$$
¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 7.16 (m, 1H, NH), 3.84 (m, 1H, NH-CH-(CH₃)₂ (NIPAAm)), 3.57 (8H, CH₂-CH₂ (NAM)), 2.84 (m, 4H, CH₂-CH₂ (NAS)), 2.56-1.58 (m, 9H, CH₂-CH (PNIPAAm, PNAM, PNAS)), 1.24 (s, 5H, SCH₂(CH₂)₁₀CH₃), 1.04 (m, 6H, CH₃-CH-CH₃ (NIPAAm)), 0.85 (t, 20H, SCH₂(CH₂)₁₀CH₃).

Typical procedure for the synthesis of poly(N-isopropylacrylamide)-b-poly(acryloylmorpholine-co-alendronate acrylamide). Alendronic acid (1.86 g, 7.47 mmol, 1.2 eq.) was added to a solution of poly(N-isopropylacrylamide)-b-poly(acryloylmorpholine-co-N-acryloxysuccinimide) (5 g, 6.24 mmol of NAS unit, 1 eq.) in water (50 mL). The pH was adjusted between 11 and 12 using a sodium hydroxide solution (2M), and the mixture was stirred at room temperature. After 48 hours, the pH was adjusted to 7 using hydrochloric acid solution (2M) and the mixture was transferred into a dialysis tube (MWCO: 1000 Da) and dialyzed against deionized water for 72 hours and lyophilized to isolate the final copolymer (3.46 g, yield: 69%).

¹H NMR (300 MHz, D₂O): δ (ppm): 3.71 (m, 1H, NH-CH-(CH₃)₂ (NIPAAm)), 2.73 (8H, CH₂-CH₂ (NAM)), 2.9 (2H, CH₂-CH₂-CH₂-C(OH)P₂- (Ale)), 2.50-1.50 (m, 13H, CH₂-CH (PNIPAm, PNAM, PAleAAm) and CH₂-CH₂-C(OH)P₂-Ale)), 0.94 (m, 6H, CH₃-CH-CH₃ (NIPAAm)).

³¹P NMR (300 MHz, D₂O): δ (ppm): 18.66 (s, 2P).

## 2.4 | Preparation of copolymer-based hydrogels

Copolymers (PNIPAAm-b-PNAM, PNIPAAm-b-P(NAM-co-AleAAm)₁₀% or PNIPAAm-b-P(NAM-co-AleAAm)₂₅%) were dissolved in milli-Q water at appropriate weight concentration (10, 20 or 30 wt%). Vials were then placed in thermostated water bath at 20 °C during 2 hours. Resulting solutions were then heating whether at 25 or 37 °C, thus leading to hydrogels depending on copolymer chemical structure, concentration, and temperature.

## 2.5 | Solutions for Isothermal Titration Calorimetry

*Preparation of polymeric aqueous solutions.* Polymer solutions of PNIPAAm-b-PNAM, PNIPAAm-b-P(NAM-co-AleAAm)₁₀% and PNIPAAm-b-P(NAM-co-AleAAm)₂₅% were
prepared for the complexation of Nd(III) and Ce(III). Samples were prepared by dissolving the polymers in Milli-Q water and adjusting the pH to 5.5 by adding small amounts of 0.5 mol·L⁻¹ solutions of HNO₃ or NaOH. Thus, solutions of PNIPAAm-**b**-PNAM at concentrations of 1.3, 5 and 10 g·L⁻¹, a solution of PNIPAAm-**b**-P(NAM-co-AleAAm)₁₀% at 1.3 g.L⁻¹ and solutions of PNIPAAm-**b**-P(NAM-co-AleAAm)₂₅% at 3 and 4 g·L⁻¹ were prepared. pH was adjusted to 5.5 using sodium hydroxide solution (2 mol.L⁻¹).

*Preparation of cation aqueous solutions.* Cation solutions of Nd(III) and Ce(III) were prepared in order to be injected into the polymer solutions and to study their complexation. Thus, neodymium (III) nitrate hexahydrate or cerium (III) nitrate hexahydrate were dissolved in milli-Q water and the pH adjusted to 5.5 using the same acidic or basic solutions as for the polymer solutions. Respectively to the previous polymer solutions, cation solutions were prepared at 3 mM of Nd(III) for PNIPAAm-**b**-PNAM, 8 mM of Nd(III) and Ce(III) for PNIPAAm-**b**-P(NAM-co-AleAAm)₁₀%, and 8 mM of Ce(III) and 10.5 mM of Nd(III) for PNIPAAm-**b**-P(NAM-co-AleAAm)₂₅%.
## 3 | Results and Discussion

### 3.1 | Synthesis of poly(N-isopropylacrylamide)-b-poly(acryloylmorpholine-co-alendronate acrylamide) (PNIPAAm-b-P(NAM-co-AleAAm)) copolymers

The synthesis of poly(N-isopropylacrylamide)-b-poly(acryloylmorpholine-co-alendronate acrylamide) (PNIPAAm-b-P(NAM-co-AleAAm)), was achieved in three steps (Scheme 1) according to the following reaction sequence: (i) synthesis of poly(N-isopropylacrylamide) (PNIPAAm) by RAFT polymerization, (ii) synthesis of poly(N-isopropylacrylamide)-b-poly(acryloylmorpholine-co-N-acryloxysuccinimide) (PNIPAAm-b-P(NAM-co-NAS)) by RAFT copolymerization using PNIPAAm as macro-RAFT agent, and (iii) post-polymerization modification reaction of PNIPAAm-b-P(NAM-co-NAS) to afford PNIPAAm-b-P(NAM-co-AleAAm) copolymers, which contain alendronate complexing groups.

<figure><img src="image_3.png" /><figcaption>**SCHEME 1** | Reaction pathway for the synthesis of PNIPAAm-b-P(NAM-co-AleAAm) copolymers by RAFT polymerization and post-polymerization reaction.</figcaption></figure>
First step dealt with the synthesis of PNIPAAm by RAFT polymerization of N-isopropyl
acrylamide in dioxane at 70 °C using 2-cyano-2-propyl dodecyl trithiocarbonate as
transfer agent and AIBN as initiator. Controlled polymerization of NIPAAm by RAFT
polymerization has been widely reported in the literature to yield well-defined
thermosensitive PNIPAAm [45]. Consequently, polymerization proceeded with good
control over the molecular weight and low dispersity index. Indeed, size exclusion
chromatography (SEC) in DMF gave a monomodal curve with dispersity (D) less than
1.1 (Figure 1). Furthermore, the molecular weight determined by SEC (Mn,SEC = 10200
g·mol⁻¹) was in good agreement with the theoretical value (Mn,th = 9300 g·mol⁻¹). RAFT
polymerization was stopped at approximately 90% conversion to ensure a high
degree of thiocarbonylthio end-group functionality, as PNIPAAm was then used as
macrochain transfer agent in the following step of the synthesis. The pure PNIPAAm
was characterized by ¹H NMR spectroscopy in DMSO-d₆ (Figure S1). First, no residual
monomer was observed, indicating that the polymer was well purified. Then, peaks at
δ 1.04 and 3.84 ppm were ascribed to methyl (CH₃) and methine (CH) protons of the
isopropyl unit, respectively. The broad signals between δ 1.2 and 2.1 ppm were
assigned to the protons on the PNIPAAm backbone.

In the second step, PNIPAAm-b-P(NAM-co-NAS) copolymer was synthesized by
RAFT statistical copolymerization of acryloylmorpholine (NAM) and N-
acryloxysuccinimide (NAS) using PNIPAAm as macro-RAFT agent and AIBN as
initiator. A series of copolymers with NAS molar ratio (F_NAS = DP_NAS/(DP_NAS+DP_NAM))
equal to 0, 10 and 25%, were prepared and their characteristics are listed in Table 1.
Globally, the co-monomers/PNIPAAm ratio was equal to 200/1, mol/mol. Whatever the
polymerization, conversion of monomers was quantitative, reasonably meaning that
the experimental molar ratios F_NAS were close from the theoretical ones. The
experimental molar masses determined by SEC in DMF (Mn,SEC) were close from the
theoretical values (Mn,th) as well. SEC curves of the copolymers (Figure 1) showed
monomodal profiles, clearly shifting toward higher molar masses compared to
PNIPAAm, and with narrow molecular weight distributions (dispersities lower than
1.30). The ¹H NMR normalized spectra of PNIPAAm-b-PNAM, PNIPAAm-b-P(NAM-
co-NAS)₁₀%, and PNIPAAm-b-P(NAM-co-NAS)₂₅% are shown in Figure 2. An increase
in the intensity of the representative peak of the protons belonging to the NAS
monomer unit at δ 2.83 ppm (denoted l) was observed with the increase of the
theoretical ratio, proving the effectiveness of its incorporation. Unfortunately, the
determination of the experimental molar ratio of the NAS monomer units by ¹H NMR was not enough accurate due to the overlapping of the signals assigned to the different monomer units. Nevertheless, all the analysis performed showed that the copolymers were successfully synthesized. In any case, the copolymerization was well controlled, resulting in the preparation of well-defined copolymers showing narrow molecular weight distribution.

<table><caption>**TABLE 1** | Characteristics of poly(N-isopropylacrylamide) (PNIPAAm), poly(N-isopropyl acrylamide)-b-poly(acryloylmorpholine) (PNIPAAm-b-PNAM), and poly(N-isopropylacrylamide)-b-poly(acryloylmorpholine-co-N-acryloxysuccinimide) (PNIPAAm-b-P(NAM-co-NAS)) synthesized by RAFT polymerization.</caption><thead><tr><th>Copolymer</th><th>[NAM]/[NAS]/[macro-CTA]</th><th>conv<sub>NAM</sub><sup>a</sup></th><th>conv<sub>NAS</sub><sup>a</sup></th><th>F<sub>NAS</sub><sup>b</sup> (%)</th><th>M<sub>n,th</sub><sup>c</sup> (g.mol<sup>-1</sup>)</th><th>M<sub>n,SEC</sub><sup>d</sup> (g.mol<sup>-1</sup>)</th><th>D<sup>d</sup></th></tr></thead><tbody><tr><td>PNIPAAm</td><td>-</td><td>-</td><td>-</td><td>0</td><td>9300</td><td>10200</td><td>1.09</td></tr><tr><td>PNIPAAm-b-PNAM</td><td>200/0/1</td><td>98</td><td>-</td><td>0</td><td>38900</td><td>32500</td><td>1.25</td></tr><tr><td>PNIPAAm-b-P(NAM-co-NAS)<sub>10%</sub></td><td>180/20/1</td><td>99</td><td>100</td><td>10</td><td>37800</td><td>38000</td><td>1.30</td></tr><tr><td>PNIPAAm-b-P(NAM-co-NAS)<sub>25%</sub></td><td>150/50/1</td><td>99</td><td>100</td><td>25</td><td>38700</td><td>39400</td><td>1.23</td></tr></tbody></table>

Conditions of RAFT: [macro-CTA]/[AIBN] = 1/0.2, [dioxane]=1.7 M, T = 70 °C, time of polymerization = 3 hours. <sup>a</sup> conversion in NAM and NAS determined by ¹H NMR using trioxane as internal standard; <sup>b</sup> F<sub>NAS</sub> = DP<sub>NAS</sub>/(DP<sub>NAM</sub> + DP<sub>NAS</sub>) with DP<sub>NAM</sub> = ([NAM]<sub>0</sub>/[CTA]<sub>0</sub>) × conv<sub>NAM</sub> and DP<sub>NAS</sub> = ([NAS]<sub>0</sub>/[CTA]<sub>0</sub>) × conv<sub>NAS</sub>; <sup>c</sup> calculated using eq. M<sub>n,th</sub> = M<sub>n,th,PNIPAAm</sub> + ((([NAM]<sub>0</sub>/[CTA]<sub>0</sub>) × M<sub>NAM</sub>) × conv<sub>NAM</sub> + ((([NAS]<sub>0</sub>/[CTA]<sub>0</sub>) × M<sub>NAS</sub>) × conv<sub>NAS</sub>); <sup>d</sup> determined by SEC in DMF using poly(methyl methacrylate) standards.

<figure><img src="image_4.png" /><figcaption>**FIGURE 1** | Size exclusion chromatography (SEC) traces (in DMF) of PNIPAAm (black), and copolymers PNIPAAm-b-PNAM (blue), PNIPAAm-b-P(NAM-co-NAS)<sub>10%</sub> (red) and PNIPAAm-b-P(NAM-co-NAS)<sub>25%</sub> (orange).</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>**FIGURE 2** | Comparison of ¹H NMR spectra of PNIPAAm-*b*-PNAM (bottom spectrum), PNIPAAm-*b*-P(NAM-*co*-NAS)₁₀% (middle spectrum) and PNIPAAm-*b*-P(NAM-*co*-NAS)₂₅% (top spectrum) (in DMSO-*d*₆).</figcaption></figure>

Finally, the last step of the synthesis consisted in the chemical modification of the copolymer samples bearing pendent NHS-activated carboxyl groups. For such purpose, commercial bisphosphonate, namely alendronic acid, bearing a primary amine end-group was chosen as chelating ligand. So, this bisphosphonate was attached to the PNIPAAm-*b*-P(NAM-*co*-NAS) copolymer by reaction of the primary amine end-group of alendronic acid with the NHS-activated carboxyl groups. The bisphosphonic acid functionalization was carried out on both copolymers containing 10 and 25% of NAS functions. Copolymers were dissolved in water, then alendronic acid was added and dissolved by adjusting the pH of the solution to 11-12, for both obtaining the primary amine function of the alendronate derivative [46], and solubilizing it in water. After 48 hours at room temperature, the PNIPAAm-*b*-P(NAM-*co*-AleAAm) final copolymers were purified by dialysis (yield: 69 %) with pH adjusted to 7. The efficiency of the reaction was confirmed by ¹H and ³¹P NMR (Figure 3). ¹H NMR spectrum in deuterated water showed that the reaction was successful, with the appearance of signals associated to the phosphonic acid moieties δ 2.95 and 1.80 ppm (peaks *p*, *q*,
r) demonstrating the incorporation of alendronate onto the PNIPAAm-b-P(NAM-co-NAS) polymer on NAS units. As succinimide group is highly reactive, it was assumed that the nucleophilic substitution reaction was efficient. Grafting efficiency was determined by ³¹P NMR (Table 2, and Figure S2), comparing the intensity of signals at δ 18.66 and 17.96 ppm, corresponding to the grafted, and free alendronate at t = 0, respectively, taking into account that alendronate was introduced in excess (1.2 eq. regards to NAS number of moles) at the beginning of the functionalization reaction.

<table><caption>**TABLE 2** | Bisphosphonic acid grafted percentages determined by ³¹P NMR</caption><thead><tr><td>Copolymer</td><td>Grafting efficiency (%) <sup>a</sup></td></tr></thead><tbody><tr><td>PNIPAAm-b-P(NAM-co-AleAAm)<sub>10%</sub></td><td>60</td></tr><tr><td>PNIPAAm-b-P(NAM-co-AleAAm)<sub>25%</sub></td><td>70</td></tr></tbody></table>

The grafting efficiency is similar in both cases, reaching 70% in the case of PNIPAAm-b-P(NAM-co-AleAAm)<sub>25%</sub> copolymer. After purification step using a dialysis tube (MWCO: 1000 Da) against deionized water and lyophilization, pure copolymers were obtained with 70% yield. ³¹P NMR confirmed the success of the purification step as only one signal was obtained at δ 18.66 ppm. SEC analyses of PNIPAAm-b-P(NAM-co-AleAAm) functionalized copolymers were carried out in a phosphate buffer (0.2M NaNO<sub>3</sub>, 0.1M NaH<sub>2</sub>PO<sub>4</sub>, pH 7) (Figure S3). For the PNIPAAm-b-P(NAM-co-AleAAm)<sub>10%</sub> and PNIPAAm-b-P(NAM-co-AleAAm)<sub>25%</sub> copolymers, the number average molecular weights M<sub>n</sub> were equal to 15400 and 14300 g.mol<sup>-1</sup> with dispersity D of 1.30 and 1.29, respectively. The molar masses were clearly underestimated. To circumvent this, SEC MALS using light scattering detection was performed in order to determine the true molar masses. Using a dn/dc value of 0.15 mL.g<sup>-1</sup>, both copolymers exhibited number-average molar masses M<sub>n</sub> of about 45000 g.mol<sup>-1</sup>, in good agreement with the excepted values. Additionally, it is known in the literature that the thiocarbonylthio groups present in polymers synthesized by RAFT react with primary amines to form terminal thiols [47]. This was confirmed by SEC (Figure S3) using both refractive index (RI) and UV detection at 320 nm, a wavelength characteristic of trithiocarbonate groups. An intense RI signal was recorded for the bisphosphonate copolymer, whereas only negligible UV absorbance at 320 nm was observed.

<footnote><sup>a</sup> Calculated using the following equation: Grafting efficiency = Int. δ<sub>18.66 ppm</sub> / δ<sub>17.96 ppm at t = 0</sub> x [Ale]/[NAS]</footnote>
<figure><img src="image_6.png" /><figcaption>FIGURE 3 | ¹H and ³¹P NMR spectra of PNIPAAm-*b*-P(NAM-co-AleAAm)₂₅% (in D₂O).</figcaption></figure>

In summary, PNIPAAm-*b*-P(NAM-co-NAS) copolymers were synthesized by RAFT polymerization with precise control over composition and molecular weight (close to 40000 g·mol⁻¹). Post-polymerization reaction allowed an efficient incorporation of alendronic acid from NHS-activated sites, which was confirmed by ¹H and ³¹P NMR spectroscopies. Final PNIPAAm-*b*-P(NAM-co-AleAAm) functionalized copolymers contain bisphosphonic acid groups, with potential chelating properties, and thermoresponsive PNIPAAm, with a lower critical solution temperature (LCST) equal to 32 °C. Preliminary tests were then carried out to assess the potential of these materials to form hydrogels as a function of concentration in water and temperature.

## 3.2 | Hydrogel formation from PNIPAAm-*b*-P(NAM-co-AleAAm) copolymers

Preliminary gelation studies were carried out with the PNIPAAm-*b*-PNAM, PNIPAAm-*b*-P(NAM-co-AleAAm)₁₀% and PNIPAAm-*b*-P(NAM-co-AleAAm)₂₅% at different weight percent (10, 20 and 30 wt%) in water at two temperatures (25 and 37 °C) in order to evaluate the influence of the thermosensitive PNIPAAm block on the formation of hydrogels. For such purpose, copolymers were dissolved first in water at 20 °C at different weight concentrations and the temperature has been then set at 25 or 37 °C,
thus leading to the formation of gels in some cases (Figure 4). First, it is important to mention that at the concentration equal to 10% wt, PNIPAAm-**b**-PNAM and PNIPAAm-**b**-P(NAM-**co**-AleAm) were soluble in water whatever the temperature. They did not show thermoresponsive behavior. When measuring transmittance as a function of the temperature from 20 to 80 °C, no cloud point temperature was determined (UV-Visible spectroscopy measurements at 500 nm) and transmittance remained equal to 100%. At higher concentration, hydrogels were obtained at 37 °C. As Lower Critical Solution Temperature of PNIPAAm (LCST) is largely reported in the literature to be 32 °C [48], we can assume that PNIPAAm block was soluble in water below 32 °C, and collapsed in water above. As a result, copolymers became amphiphilic (as PNAM or P(NAM-**co**-AleAAm are water-soluble), and could self-organize thus promoting the formation of hydrogels.

More accurately, at 10 wt%, no gelation was obtained, whatever the copolymer. By increasing the weight concentration to 20 wt%, gel formation took place at 37 °C for PNIPAAm-**b**-P(NAM-**co**-AleAm) but not at 25 °C. Finally, at a concentration of 30 wt%, formation of hydrogels was observed regardless the polymer chemical structure or the temperature.
PNIPAAm-*b*-PNAM

<figure><img src="image_7.png" /></figure>

PNIPAAm-*b*-P(NAM-co-*AleAAm*)$_{10%}$

<figure><img src="image_8.png" /></figure>

PNIPAAm-*b*-P(NAM-co-*AleAAm*)$_{25%}$

<figure><img src="image_9.png" /></figure>

**FIGURE 4** | Photos of hydrogels without alendronate (top photos), with 10% alendronate (middle photos) and with 25% alendronate (bottom photos), at concentrations equal to 10, 20, and 30 wt% in water, at 25 and 37 °C. Red arrows highlight the obtaining of hydrogels.

At low concentration (10 wt%), there was not enough polymer to form physical bonds. Even when increasing the temperature at 37 °C, thus inducing collapsing of PNIPAAm block, copolymers remained fully soluble in water. As mentioned above, no cloud point temperature was observed, transmittance (UV-Visible spectroscopy measurements achieved at 500 nm) remained equal to 100% from 20 to 80 °C. At a concentration of 20 wt% and at 37 °C (above the PNIPAAm LCST), the thermosensitive PNIPAAm formed physical cross-links allowing the formation of hydrogels whatever the copolymer chemical structure (PNIPAAm-*b*-PNAM or PNIPAAm-*b*-P(NAM-co-*AleAAm) copolymers). Below the LCST of the PNIPAAm, the copolymers were soluble in water and none of the copolymers led to hydrogels. Finally, at a concentration equal to 30 wt%, copolymers containing bisphosphonic acid moieties (PNIPAAm-*b*-P(NAM-
co-AleAAm)) led to hydrogel below the LCST value (at 25 °C), due to the presence of large hydrophobic blocks and to the aggregation of bisphosphonic acid groups by inter-chain interactions. Above the LCST, polymeric weight concentration was sufficient enough to produce hydrogels.

To conclude, these preliminary tests showed that the synthesized copolymers could effectively form hydrogels with thermogelling properties under specific conditions. This result was of great interest as it meant that it was possible to tune physical aspect of the material playing on both the temperature and the concentration in water, thus spreading potential use of these copolymers for decontamination. Last step of the work consisted in performing complexation studies with lanthanides to evaluate the sorption efficiency of these materials.

### 3.3 | Complexation studies by ITC

Isothermal titration calorimetry (ITC) was used to study the complexation behaviour of a series of copolymers, namely PNIPAAm-*b*-PNAM, PNIPAAm-*b*-P(NAM-*co*-AleAAm)₁₀%, and PNIPAAm-*b*-P(NAM-*co*-AleAAm)₂₅% in order to determine the influence of the presence of bisphosphonic acid groups on the complexation ability of the copolymers. Neodymium (Nd(III)) and cerium (Ce(III)) lanthanide elements serving as actinide surrogates, were selected for their ease of handling. Experiments were carried out at 25 °C, at a pH equal to 5.5, which corresponded to the pH of the skin, as the objective of this work was external body decontamination. First, the ITC thermograph of non-functionalized PNIPAAm-*b*-PNAM for the complexation of Nd(III) (Figure S4) overlapped with the Nd(III) dilution trace, indicating that in the absence of bisphosphonic acid groups, only dilution effects were observed (exothermic peaks with constant intensities corresponding to those of the dilution). So, under these conditions, the non-functionalized polymer did not show any complexation with the tested ions. In contrast, ITC thermographs of polymers containing bisphosphonic acid moieties displayed significant heat variations and distinct behaviours, depending on the alendronate content. ITC traces of PNIPAAm-*b*-P(NAM-*co*-AleAAm)₁₀% complexed with Ce(III) (Figure 5) and Nd(III) (Figure S5) exhibited similar profiles. During the first injections of Ce(III), the peaks were endothermic, with the absolute value increasing to a maximum of -1.8 µW, then gradually decreasing until the peaks became exothermic and stabilized at 0.3 µW after nine injections. Beyond this point, only dilution effects
were observed, meaning that complexation was finished and the polymers were
saturated with ions. Initially, the complexation took place at the available sites, and the
change in polymer configuration could subsequently make other sites accessible,
which were previously unavailable. Thus, the complexation capacity resulted increased
as well as the intensity of the peaks. Once all binding sites were occupied, the peak
intensity decreased, indicating that the polymer was fully saturated and could no longer
chelate additional ions.

The ITC thermographs for PNIPAAm-b-P(NAM-co-AleAAm)₂₅%, (Figure 6 and Figure S6) differed significantly from those of PNIPAAm-b-P(NAM-co-AleAAm)₁₀%. During the first injections the peaks were exothermic, then their intensity decreased over time, eventually becoming endothermic. In this case, equilibrium was not reached, making interpretation of the thermographs challenging without further analysis. A possible hypothesis is that during the initial injections, cation complexation occurred, initiating a reconfiguration of the polymer chains organized into micelles (given the low polymer mass concentration in water). This structural rearrangement may explain the transition from exothermic to endothermic signals, reflecting the dynamic changes in the polymer chain organization. Subsequently, the titration curves representing the enthalpy of reaction as a function of the molar ratio were obtained by integrating the peak areas from the thermographs. Fitting these curves provided the thermodynamic parameters of the system (stoichiometry, bond strength, entropy and enthalpy changes) based on One-Site binding Model. Since the non-functionalized polymer did not show any complexation with the tested ions, it was considered that the bisphosphonate group represents the sole relevant binding site.
<figure><img src="image_10.png" /><figcaption>**FIGURE 5** | ITC thermograph (top) and titration curve (bottom) of PNIPAAm-β-P(NAM-co-AleAAm)10% (1.3 g.L⁻¹) with Ce(III) (8 mM).</figcaption></figure>

<figure><img src="image_11.png" /><figcaption>**FIGURE 6** | ITC thermograph of PNIPAAm-β-P(NAM-co-AleAAm)25% (3 g.L⁻¹) with Ce(III) (8 mM).</figcaption></figure>
The polymer at a lower alendronic acid group concentration did not exhibit the same rearrangement behaviour. This made it possible to obtain titration curves for Nd(III) and Ce(III) from the maximum of complexation to equilibrium of the system (Figure 5 and Figure S6). Thus, the thermodynamic parameters were obtained for Nd(III) and Ce(III) and are summarized in Table 3 (n represents the stoichiometry, i.e. the number of complexing groups necessary to bind one metal ion). The constants obtained for the complexation of Nd(III) and Ce(III) were comparable, but the complexation of Ce(III) was slightly more efficient than that of Nd(III) since fewer bisphosphonic acid functions were needed to bind one Ce(III) ion, meaning that a given amount of polymer could complex more Ce(III) ions than Nd(III). However, it was not possible to model the curve with a comparable strategy for the titration curve obtained with the polymer containing 25% of alendronate functions due to the simultaneous occurrence of two phenomena (complexation and polymer chain rearrangement). Since these processes could not be distinguished, the thermodynamic parameters specific to complexation could not be determined for this polymer.

<table><caption>**TABLE 3** | Thermodynamic parameters of PNIPAAm-b-P(NAM-co-AleAAm)₁₀% complexation with Nd(III) and Ce(III)</caption><thead><tr><th>Cation</th><th>n<br>(bisphosphonic<br>acid/cation)</th><th>Ka<br>(M<sup>-1</sup>)</th><th>ΔH<br>(kJ.mol<sup>-1</sup>)</th><th>-TΔS<br>(kJ.mol<sup>-1</sup>)</th><th>ΔG<br>(kJ.mol<sup>-1</sup>)</th></tr></thead><tbody><tr><td>Nd(III)</td><td>2.1</td><td>8.5 10<sup>4</sup></td><td>11.2</td><td>-39.3</td><td>-28.1</td></tr><tr><td>Ce(III)</td><td>1.2</td><td>1.1 10<sup>5</sup></td><td>10.8</td><td>-39.6</td><td>-28.8</td></tr></tbody></table>

n represent the number of bisphosphonic acids functions necessary to complex one ion (Nd or Ce), Ka the binding constants, ΔH the enthalpy variation, ΔS the entropy variation and ΔG the Gibbs free energy. Triplicate measurements have been carried out and experimental error is evaluated at 10%.

These ITC studies demonstrated the complexation capacities of the two synthesized polymers, PNIPAAm-b-P(NAM-co-AleAAm)₁₀% and PNIPAAm-b-P(NAM-co-AleAAm)₂₅%, with Nd(III) and Ce(III), despite the configurational changes of the polymers that occurred during ion chelation. The results also confirmed that in the absence of bisphosphonic acid groups, no complexation of these cations occurred, highlighting the effectiveness of these chemical groups in complexation. To conclude, PNIPAAm-b-P(NAM-co-AleAAm) functional copolymers showed good efficiency for the complexation of Nd(III) and Ce(III) when solubilized in water. In addition to good sorption properties, the advantage of the chemical structures developed lied on the
ability to control the shaping of the lanthanide complexing materials, so that they could
be used in a wide range of decontamination situations.
4 | Conclusion

The synthesis of original poly(N-isopropylacrylamide)-b-poly(acryloylmorpholine-co-alendronate acrylamide) (PNIPAAm-b-P(NAM-co-AleAAm)) copolymers was successfully achieved combining RAFT polymerization, followed by post-polymerization reaction in order to introduce bisphosphonic acid groups, known in the literature for effective actinide complexing properties. The resulting copolymers exhibited well-defined architectures with precise control over composition and molecular weight. Two bisphosphonic acid functionalization rates were obtained: 10 and 25%. Then, the ability of the bisphosphonic acid-containing PNIPAAm-b-P(NAM-co-AleAAm) copolymers to form hydrogel was investigated. It was shown that the functional copolymers could form hydrogels, at appropriate concentration and temperature. Finally, complexation studies were carried out, using Nd(III) and Ce(III) lanthanides, used as surrogates of actinides. Isothermal titration Calorimetry experiments confirmed that the presence of bisphosphonic acid groups on the copolymers significantly enhanced their ability to bind lanthanide, and it was also demonstrated that the complexation efficiency is better for Cerium compared to Neodymium.

To conclude, the reported work highlighted the potential of the PNIPAAm-β-P(NAM-co-AleAAm) functionalized copolymers for complexation of actinides. Additionally, the possibility of tuning physical state of the material (in water-soluble state or hydrogel form) as a function of the concentration and/or temperature is of great importance and opens the way for the use of such functional derivatives in different decontamination situations (decontamination of water, body, etc.) in different processes due to various possible formulations depending on the state of the material. Consequently, uranium sorption study was carried out to investigate the sorption capacities of polymers in details, either in soluble state or as hydrogel in water. Obtained results will be the subject in a forthcoming publication.

**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**

The authors thank "Agence Innovation Défense" (AID) (PhD grant (LF)), and ANR DECAP (ANR-18-ASTR-0001) (CA)) for funding this work. They also thank the "Plateforme d'Analyses et de Caractérisation" (PAC Balard) for technical support in analysis and characterizations, and the SynBio3 platform for SEC analyses.

**Supporting Information**

Additional supporting information can be found online in the Supporting Information section.

**Data availability**

Data will be made available on request.
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