Nafion–Zirconium Phosphate Composite Membrane: A New Approach to Prepare 32 P Patches for Superficial Brachytherapy Applications

Abstract

This article describes a method for the preparation of ³²P patch for the treatment of skin cancer. It is based on the surface modification of a Nafion film by treatment with ZrOCl₂ solution, impregnation of a predicted quantity of ³²P into the film, and its subsequent immobilization into a nonleachable matrix by lamination. The effect of variations of critical parameters on the incorporation of ³²P into the membrane, such as solution pH, contact time, reaction volume, inactive carrier concentration of the feed, reaction temperature, and so on, was investigated to arrive at the conditions resulting in optimum retention of ³²P activity. The morphology of the membrane was evaluated by scanning electron microscope and energy dispersive spectral analyses. Quality control tests were carried out to ensure nonleachability, uniform distribution of activity, and stability of the patches.

Introduction

Basal cell carcinoma is the most common skin cancer in humans mainly occurring in middle-aged people.¹ The tumors are slow growing, rarely metastasize, and their size can vary from a few millimeters to several centimeters in diameter. This form of cancer is treated by various modalities, such as radiotherapy, surgical excision, cryosurgery, laser ablation, curettage, Mohs' microsurgery, ionizing radiation, cryotherapy, photodynamic therapy, chemotherapy, and surgery.^2
–4 Mould brachytherapy using β⁻ emitting radionuclides, such as ⁹⁰Y-, ¹⁸⁶Re-, ¹⁶⁶Ho-, and ³²P-incorporated patches, has been reported as one of a promising therapeutic modality for topical treatment of skin cancer in areas that are difficult to excise, especially on the face, including eyelids, nose, and lips.^{5

–14} This mode of treatment is simple, noninvasive, and precludes the need of expensive therapeutic units. Among the radionuclides used for preparation of patches, ³²P is attractive owing to long half-life of 14.2 days, suitable beta energy, and commercial availability on demand.

A number of approaches have previously been reported for the preparation of ³²P patches and evaluation of efficacy of the radioactive patches in controlling tumor growth is documented.^10

–16 Considering the wide potential for their application, development of technique for the preparation of nonleachable ³²P patch still remains an interesting area for further investigation. In the quest for an innovative approach for the preparation of ³²P patches, away from the existing paradigms, our attention turned toward the use of Nafion film, a perfluorosulfonate ionomer that is commercially available. We feel that the reactive surface of Nafion film can be suitably modified to impregnate ³²P activity. Such approach would have higher flexibility in ³²P loading and could be an advantageous attribute in the endeavor of preparing ³²P patches. Although the potential of Nafion film to prepare Nafion–zirconium phosphate composite for its application as proton-exchange membrane in fuel cells has been thoroughly exploited,^17

–23 research about the preparation of radioactive film is not reported. We report a successful laboratory-scale preparation of ³²P patches using Nafion membrane.

Materials and Methods

Chemicals

The perfluorosulfonate ionomer membrane Nafion^® 117 was purchased from Aldrich Chemical Company through a local supplier. Zirconyl oxychloride (ZrOCl₂.8H₂O) was obtained from Fluka and was used as supplied. Carrier-free ³²P as orthophosphoric acid (specific activity ∼11.1 MBq/mg) in dilute HCl was available in-house. The liquid scintillator used was Aquasafe 300 Plus of Zinsser Analytic GmbH, which is suitable for low-to-medium ionic strength aqueous samples with a high counting efficiency.

Instrumentation

The scanning electron microscope Vega MV-2300T/40, supplied by TESCAN, was used for scanning electron microscopy (SEM) analysis. The liquid scintillation counter used for the radioactivity measurement of ³²P during tracer experiment was Tricarb 2100TR (Packard Instrument Co.). Radiochromic densitometer was used for optical density measurements of exposed GAF-Chromic films. Radiochromic densitometer and GAF-Chromic films were used for the measurement of optical density in autoradiography experiments. Nontoxic, laminating films were obtained from Hi-Tech Poly Flex Pvt. Ltd. and industrial X-ray films were obtained from Agfa India Pvt. Ltd. GM counter procured from PLA Electro Appliance Pvt. Ltd. was used for radioactivity measurements. A portable laminating unit obtained from Avanti Pvt. Ltd. was used to laminate the ³²P-adsorbed paper. Radioactive strength of individual ³²P patches was measured using a precalibrated isotope dose calibrator.

Treatment of Nafion membrane

A Nafion-117 membrane of ∼100-μm thickness was cut into 1 cm×1 cm size. It was activated by heating in 3% H₂O₂ solution at 60°C–70°C for 30 min followed by washing with de-ionized water. The membranes were subsequently loaded with zirconium following the reported method with minor modifications.²⁴ In each experiment, the Nafion-117 membrane (1 cm×1 cm) was taken in a tweezers suspended horizontally with respect to the base in 20 mL solution containing 0.1 M ZrOCl₂ solution in a stoppered conical flask and shaken in a mechanical shaker for 90 minutes at 60°C to facilitate the incorporation of Zr(IV) ions. After the treatment, the membranes were removed using a tweezers, thoroughly washed with double-distilled water, blotted, and vacuum dried in a desicator for 24 hours.

Optimization of ³²P absorptive parameters

The effect of variation of critical parameters on the incorporation of ³²P into the zirconium-treated membrane was investigated by conducting a series of tracer-level experiments, wherein a measured volume of feed solutions was taken and spiked with ∼370 kBq (10 μCi) of ³²P as orthophosphoric acid. A measured aliquot of the ³²P solution was withdrawn before and after absorption for activity measurement. Phosphorization of zirconium-treated membrane was carried out by dipping the zirconium-treated membrane in H₃PO₄ solution for a predetermined time. Subsequently, the membranes were taken out carefully from the solution using a tweezers. The membranes were then held with tweezers and carefully rinsed with known volume of distilled water and the washing was collected. The activity of the washing was measured by taking suitable aliquot to calculate the percentage absorption of ³²P on membranes. The amount of ³²P taken up by the film was estimated as the difference in activity of the solution before and after absorption, as measured by liquid scintillation counting. The percent absorption (%) was calculated using the relationship \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland, xspace}\usepackage{amsmath, amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document} \begin{align*}{ \rm Absorption} = ( A_i - A_f ) / A_i \times 100 \tag{1}\end{align*} \end{document}

Where A_i and A_f are the measure of initial and final radioactivity of ³²P, respectively. A_f is the total activity of the feed left in the absorbing solution and activity washed out.

The absorption experiments were performed by varying experimental parameters of the feed solution, such as amount of phosphorous carrier (25–400 μg), pH of the solution (1–9), reaction volume (1–5 mL), reaction time (1–60 hours), and reaction temperature (23°C–60°C).

Capacity of zirconium-treated Nafion membrane

The capacity measurement was carried out to estimate the amount of phosphorous (in terms of weight) that was incorporated per unit weight of dry zirconium-treated Nafion membrane (ZNM). The influence of pH on the adsorption of ³²P on the ZNM was studied and the optimum pH range was found to be between 0 and 1. Therefore, this pH range was maintained throughout the capacity-determination study. For this purpose, the weight of a 1 cm×1 cm size of the ZNM was measured before the adsorption of phosphorous. The capacity of ZNM was determined by keeping a 1 cm×1 cm size of the membrane in a 5 mL solution of H₃PO₄ (2 mg of phosphorous per mL) spiked with ∼3.7 MBq (100 μCi) of ³²P in a tightly stoppered conical flask wrapped with Parafilm at pH=0–1.0, maintained at 60°C over a period of 6 hours. After 6 hours, the flask was removed from the shaker and allowed to cool to room temperature and the membrane was taken out with the help of a tweezers. Samples of 1 mL of aliquots before adsorption were counted in a liquid scintillation counter, where counts obtained correspond to 2 mg of phosphorous. This provides a relationship between the counts and phosphorous concentration. Initial and final concentrations of phosphorous in the solution were then computed from the aforesaid correlation. The loss of solution during capacity measurement was precluded owing to use of air tight stoppered conical flask wrapped with Parafilm. During cooling, the evaporated liquid droplets sticking on the walls coalesced, dripped down the inside walls of the conical flask, and got mixed with the liquid. The radioactivity associated with the solution after absorption was finally measured by withdrawing 1 mL aliquots in a liquid scintillation counter. All measurements were carried out in triplicate. The capacity was calculated using the following expression: \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland, xspace}\usepackage{amsmath, amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document} \begin{align*} { \rm Capacity } = \frac { \rm ( C_i - C_f ) V } { \rm m } \tag { 2 } \end{align*} \end{document}

Where C_i and C_f represented initial and final concentrations of phosphorous, respectively, V was the volume of solution, and m was the mass (g) of the ZNM.

Preparation of ³²P–Nafion patches

Radioactive patches were prepared by keeping ZNM in a 5 mL solution of H₃ ³²PO₄ containing 100 μg of inactive phosphorous carrier at pH=0–1.0, maintained at 60°C over a period of 6 hours. The patches were then taken out from the solution and washed with double-distilled water to remove loosely bound activity. In one batch only one membrane was used for activity loading. The membranes were subsequently dried under an infrared lamp. A number of radioactive patches were prepared using different sizes of zirconium-treated membrane. Radioactivity content of the feed was varied to prepare radioactive patches of different strength.

The radioactive patches thus prepared were immobilized within thermoplastic polyurethane (TPU) sheets of 40-μm thick with the help of a laminating unit kept in a well-ventilated fume hood provided with a perspex shield for reducing radiation exposure. Several radioactive patches were made under the optimized preparative conditions.

Surface characterization

SEM and energy-dispersive X-ray spectra (EDS) analyses were carried out for both zirconium-incorporated Nafion film and zirconium-phosphate impregnated Nafion films, using a dummy patch using inactive H₃PO₄ solution prepared in an identical manner used for source fabrication.

Quality control of ³²P–Nafion patches

Determination of source strength

Radioactivity content of individual patches was assayed in a calibrated isotope dose calibrator for appropriate time at a suitable geometry.

Uniformity of ³²P in the patches

Uniformity of ³²P in the sources of different shapes (∼37–74 MBq/cm²) was checked by autoradiography by exposing the industrial X-ray films and radiosensitive GAF-chromic films with ³²P patches for a period of 30 seconds and 5 hours, respectively. To optimize the exposition time, several experiments were carried out by varying the exposition time to obtain the best possible result. Experimentally it was seen that the exposition time used in this study was ideal for radioactive membranes containing 37–74 MBq/cm². At the end of these experiments, optical densities were measured at various points of exposed films.

Determination of surface contamination

The radioactive patches were tested for absence of loosely held activity (surface contamination) by swiping the sources using alcohol-immersed cotton wool and measuring the radioactivity associated in swipe-by-swipe test using a GM counter of known efficiency.

Leachability of ³²P patches

Leachability of the immobilized ³²P patches containing up to ∼37–74 MBq/cm² of ³²P was assessed with the help of a GM counter of known efficiency by determining the release of radioactivity on immersing them in 100 mL of distilled water at room temperature over a period of 48 hours as per the method prescribed by the Atomic Energy Regulatory Board, India.²⁵ At the end of the tests, a measured aliquot of test solution was transferred over an aluminum planchette¹⁰ and the radioactivity content was monitored for appropriate time at a suitable geometry and the counts acquired were used for the assay of activity. The total activity associated with 100 mL of the test solution was calculated. A similar test was carried out in saline solution for 48 hours at a temperature of 37°C.

Results

The present investigation deals with the process of making ³²P skin patches using Nafion-117 membranes and evaluation of their suitability for brachytherapy applications. We chose to explore the possibility of absorbing zirconium onto a Nafion membrane followed by the precipitation of zirconium phosphate by treatment with phosphoric acid.

Treatment of Nafion films

Zirconium was retained by the Nafion-117 membranes by exchange of H⁺ ions (present on Nafion backbone). Experimentally it was found that retention of zirconium on Nafion membranes was best when 0.1 M ZrOCl₂ was used. Hence, this concentration was used for all subsequent absorption experiments.

Optimization of ³²P absorptive parameters

Effect of amount of carrier

The effect of inactive carrier concentration of phosphorous in the feed solution on the percentage retention of ³²P on the treated film was examined and the result is depicted in Figure 1. Ignoring some fluctuations, the percentage retention of ³²P on the substrate was nearly ∼86% when the carrier concentration was between 25 and 100 μg. When the carrier concentration was >100 μg, the percentage retention of ³²P decreased sharply and finally at 400 μg it reached to only 13.8%. Hence, a carrier concentration of 25–100 μg could be used for optimum retention.

FIG. 1.

Effect of carrier concentration on the adsorption of ³²P.

The decrease in the percentage uptake of ³²P at higher carrier concentration could probably be due to the attainment of saturation beyond 100 μg.

Effect of pH

The influence of pH on the adsorption of ³²P on the zirconium–Nafion composite membrane is shown in Figure 2. Optimum uptake was noticed at pH ≤1.0 and hence this pH was selected for preparation of radioactive ³²P patches. The decrease in the percentage uptake of ³²P at higher carrier concentration could probably be due to the hydrolysis of zirconium present on Nafion membrane or solubility of zirconium phosphate at alkaline pH.

FIG. 2.

Effect of pH on adsorption of ³²P on zirconium–Nafion membrane.

Effect of temperature

The influence of temperature on the uptake of ³²P on the treated Nafion membrane is shown in Figure 3. It is seen that retention of ³²P on the substrate increased with increasing temperature, reaching the maximum between 60°C and 70°C. Above 70°C, the uptake studies of ³²P ions were not carried out because the membrane got hardened. To ensure the flexibility of membrane, radioactive patches were subsequently prepared at 60°C.

FIG. 3.

Effect of temperature on the uptake of ³²P.

Effect of contact time

The influence of contact time on the adsorption of ³²P on the ZNM at different temperatures is depicted in Figure 4. It is seen that, within the range of contact time investigated, the retention of ³²P on the substrate increased with increasing contact time. At room temperature, optimum retention of activity was feasible only after 48 hours of contact. To reduce the contact time, experiments were conducted at elevated temperature. Experimentally it was found that optimum retention of activity could be achieved at 6 hours when the ZNM with the radioactive solution was heated to 60°C.

FIG. 4.

Effect of contact time on uptake of ³²P.

Effect of reaction volume

The reaction volume of the ¹³⁷Cs solution was a critical factor for the incorporation of ³²P into ZNM. Experimentally it was observed that reaction volumes up to 5 mL could be used to obtain optimum retention of activity on the membrane.

Capacity of ZNM

The sorption capacity of ZNM toward phosphorous was experimentally found to be ∼4.3 mg/g, which works out to be ∼0.14 meq of phosphorous per gram of composite membrane.

It was seen that about 86 μg of phosphorous could be incorporated into ZNMs of 1 cm×1 cm size. This amount works out to be ∼925 GBq (25 Ci) of ³²P (assuming specific activity of ³²P as 2.9×10⁵ Ci/g). The ³²P content of a therapeutic patch is about 37–74 MBq (1–2 mCi) of ³²P/cm². The amount of ³²P activity that could be loaded into the ZNM is much higher than the activity needed for therapeutic applications.

Characterization of Nafion films

The SEM images of Nafion-117 membrane and zirconium-coated Nafion-117 are shown in Figure 5. The SEM image of Nafion-117 membrane as depicted in Figure 5A indicates a smooth surface without any cracks and/or voids. The morphology of the zirconium-coated Nafion-117 composite as seen through the SEM depicted in Figure 5B indicates that a very compact volume of coating is formed with significant adhesion with irregular microscopic cracks. The appearance of cracks indicated that the membrane has dried up completely.

FIG. 5.

Microstructure of (A) Nafion-117 membrane and (B) zirconium-coated Nafion-117 composite membrane.

The SEM images of phosphorous-loaded zirconium-treated Nafion-117 membrane, as shown in Figure 6, indicate a smooth surface with minor irregular voids.

FIG. 6.

Microstructure of ZrP–Nafion membrane.

To assess the elemental composition of the Nafion-117 membranes at various stages of impregnations, EDS analysis was carried out. Figure 7 depicts the EDS spectra of Nafion-117 membrane, zirconium-treated Nafion-117 membrane, and phosphorous-loaded zirconium–Nafion-117 composite membrane. As EDS analysis is only confined to the top surface of the sample of few micrometers depth, this result clearly demonstrates the difference in the elements present on the surface of membranes at various stages of impregnations. As expected, Nafion-117 contains peaks (Fig. 7A) pertaining to the elements C, O, F, and S. The zirconium-treated Nafion-117 membrane shows peaks (Fig. 7B) pertaining to the elements C, O, F, S, and Zr. This indicates that zirconium ion is firmly bound to the matrix and did not get removed during washing. Figure 7C provides information about the elemental composition of phosphorous-loaded zirconium-treated Nafion-117 composite membrane. To ascertain the homogeneity of phosphorous in the deposited film, the EDS spectra were recorded at various locations and the quantification of results as weight percentage is given in Table 1. The results revealed that the atomic ratio of phosphorous and zirconium was 1.82, which is very close to 2, giving an evidence of possible molecular formula ZrO(H₂PO₄)₂. Further, the variation in distribution of phosphorous along the surface of the substrate is within±6.4%.

FIG. 7.

Energy-dispersive X-ray spectral pattern of (A) Nafion membrane, (B) zirconium-coated Nafion-117 composite membrane, and (C) ZrP–Nafion-117 composite membrane.

Table 1.

Elemental Composition of Phosphorous-Loaded Zirconium–Nafion-117 Composite

	Atom (%) of element
Position	C	F	O	S	P	Zr
1.	22.5	67.15	8.1	1.80	0.29	0.16
2.	21.5	68.78	7.6	1.62	0.32	0.18
3.	23.6	66.52	7.7	1.71	0.31	0.16
4.	22.3	68.81	6.8	1.62	0.29	0.18
5.	22.1	68.63	7.1	1.65	0.33	0.19
Mean±standard deviation	22.4±0.8	67.9±1.1	7.5±0.51	1.50±0.07	0.31±0.02	0.17±0.01

Preparation of ³²P patch

Following the procedure described previously, several batches of patches were prepared. To evaluate the efficacy of the zirconium-treated membrane to incorporate ³²P activity, a comparative evaluation study was undertaken using various sizes of membrane. Table 2 depicts the ³²P activity retained by various sizes of ZNM. It is seen from the result that the efficiency of ³²P adsorption remains unaltered with all sizes of substrate paving the way to use diverse sizes of substrate.

Table 2.

Preparation of ³² P Patches Using Different Sizes of Zirconium-Treated Nafion Membranes

S. No.	Size of ZrP–Nafion membrane (cm)	Feed activity of ³²P (MBq)	Source strength (MBq/cm²)	Activity retained on membrane (%)
1.	1×1	42.5	36.8	86.5
2.	2×1	86.3	37.7	87.3
3.	2×2	173.7	37.3	85.9
4.	2.5×1	103.8	36.7	88.4
5.	2.5×2	219.5	37.8	86.1

Reaction volume=5 mL, amount of carrier=100 μg, pH=0–1, temperature=60°C, time=6 hours.

A comparative evaluation study was also undertaken to explore the possibility of preparing ³²P-embedded Nafion membrane of requisite strength (activity/cm²) using feed activity of different strength and the results are depicted in Table 3. It is clear from the results of Table 3 that the activity embedded into the membrane (activity/cm²) can be tuned by adjusting the feed activity. The efficiency of activity deposition is always >85%. The amount of ³²P activity impregnated into the membrane of custom sizes depending upon the therapeutic requirement can be tuned by adjusting the radioactive concentration of the H₃ ³²PO₄ feed solution.

Table 3.

Preparation of ³² P Patches of Different Strengths

S. No.	Size of Zr–Nafion membrane (cm)	Feed activity of ³²P (MBq)	Source strength (MBq/cm²)	Activity retained on membrane (%)
1.	1×1	42.7	37.2	87.1
2.	1×1	51.4	44.3	86.3
3.	1×1	60.5	52.9	87.4
4.	1×1	72.3	60.8	84.1
5.	1×1	87.2	74.4	85.3

Reaction volume=5 mL, amount of carrier=100 μg, pH=0–1, temperature=60°C, time=6 hours.

The thickness of TPU laminating sheet was optimized and the 40-μm thickness was found to be the most suitable for sealing the sources. Sources sealed with such films were adequately flexible with acceptable β⁻ radiation attenuation within 3.4%±0.5%, which can be accounted by dosimetric calculations. Beyond this thickness, the resulting sealed sources were not flexible enough to cover the areas contoured on the surface and thus not pursued.

Quality control of ³²P–Nafion patches

Determination of source strength

Radioactivity content of the final patch was determined by measuring the ³²P activity in a calibrated isotope dose calibrator.

Evaluation of distribution of ³²P

The spatial distribution of ³²P on the matrix was ascertained by autoradiography examination of the active samples by using X-ray films as well as GAF-Chromic films. The optical density (OD) of the exposed film was measured at different positions and percentage variation was calculated for each prepared film. Table 4 depicts the variations in the measured optical densities in the exposed radiographic films. Analysis of the result revealed that the variation of optical density in two different types of exposed films was within±3.9%, which is reasonably good for clinical applications.

Table 4.

Uniformity of ³² P on ZrP–Nafion Composite Membranes

Source strength (MBq/cm²)	OD variations on exposed X-ray film (±%)	OD variations on exposed GAF-Chromic film (±%)
37.4	3.8	2.6
39.6	2.9	1.9
42.7	3.9	2.1
38.2	2.7	1.8
36.8	3.4	2.1

OD, optical density.

Evaluation of leachability

The release of radioactivity from the laminated patch was very low, as very few counts were recorded when the planchets were counted for 10 minutes. Therefore, the leach solution was concentrated and the activity was determined using liquid scintillation counter. From a prior knowledge of the counter efficiency, the leachability of the source was determined and found to be 27–33 Bq. Hence, the leachability was well within the permissible level of 185 Bq. It was observed that there was negligible difference in the release of radioactivity, when the sources were immersed in water at room temperature over a period of 48 hours, as well as in saline solutions at 37°C, respectively.

Evaluation of surface contamination

The results of surface contamination tests carried out on TPU-laminated sources revealed that the release of radioactivity on swabs was almost negligible and below the detection limits of the GM counter. The samples counted for 20-minute duration showed almost background counts and hence the surface contamination was far below the permissible level of 185 Bq.

Discussion

Application of radioactive patch has emerged as an effective and convenient modality for the treatment of skin cancers. It is imperative to evolve viable approaches for the preparation of radioactive patches to ensure their reliable availability in order to derive the benefit of this modality of treatment.

Selection of radioisotopes for this application is an important criterion to be addressed adequately. ³²P was selected as it offers several advantages over other possible radionuclides. Its half-life of 14.2 days provides logistic advantage for facilitating the preparation of skin patches in a laboratory and supply to places far away from the laboratory without much depletion in the radioactivity. Another advantage of ³²P is the absence of γ-radiation, thereby avoiding the radiation dose to the laboratory personals preparing skin patches, patient undergoing treatment, and paramedical staffs. The 1.7 MeV β-radiation emitted by ³²P has a maximum range in tissue of 8 mm (average ∼3 mm), thereby avoiding the radiation dose to the underlying bone and healthy tissues. In-house accessibility of ³²P of requisite purity in GBq quantities is a cost-effective proposition for its use in the preparation of skin patches.

Nafion is a copolymer of perfluorosulfonic acid with hydrophobic fluorocarbon backbone and hydrophilic sulfonic acid pendent side chains. The surge of interest in Nafion-117 in various applications is due to its thermal stability (up to 200°C), mechanical strength, chemical stability, easy handling, biological inertness, and ability to take up metallic cations from aqueous solution under appropriate condition. \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland, xspace}\usepackage{amsmath, amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document} \begin{align*} &[ ( { \rm CF}_2{ \rm CF} ) _n{ \rm CFCF}_2 ] _x \\ &\mid \\ &( { \rm OCF}_2{ \rm CF} ) _m{ \rm OCF}_3 { \rm CF}_2{ \rm SO}_3^ - { \rm H}^ + \\ &\mid \\ &{ \rm CF}_3\end{align*} \end{document}

Nafion, with its hydrophobic polyethylene backbone and pendant hydrophilic sulfonated side chains, offers a series of ion channels to facilitate the sorption of zirconium ion from an aqueous solution. Treatment with H₃PO₄ results in the formation of zirconium phosphate incorporated into the polymeric matrix. In this process, zirconium-treated Nafion film acts as a template for the deposition of ³²P activity. Hydrophilic zirconium phosphate becomes entrapped in membrane pores by replacing unassociated bulk water. The main advantage of this technique is the ability to modify the surface of the Nafion film without altering the geometry and capability to impregnate required amount of ³²P activity. The effect of variation of critical parameters on the incorporation of ³²P activity into the polymeric matrix was hence investigated to arrive at the optimum conditions of immobilizing ³²P in Nafion matrix. The percentage of absorption by the ZNM indicates the ability of the membrane to retain ³²P from the aqueous solution resulting from the chemical interaction between the ZNM framework and the ³²P ions. This was essential to evaluate the affinity of the ZNM for ³²P. At the same time, it is crucial to know the amount of ³²P that can be loaded onto the ZNM, which is nothing but capacity. The amount of zirconium phosphate retained by Nafion surface is understandably low. The no carrier added form of ³²P facilitates the loading of therapeutic quantity of activity into the Nafion membrane. Addition of inactive phosphorous was essential to obtain uniform distribution of activity on the membrane. Nafion membrane embedded with zirconium (IV) phosphate containing ³²P has chemical stability in ambient atmosphere and low toxicity.

Contact brachytherapy treatments were carried out either on a single or a fractionated dose regimen depending upon the case. For the single-dose protocols, one session of 40 to 60 Gy was used. For the fractionated dose schemes, two sessions of 40 and 60 Gy each were administered with an interval of 1 week between them. Therefore, the mechanical strength of the patch should be adequate to amenable for multiple applications. The ³²P-impregnated membrane was laminated using TPU sheet in order to secure the ³²P activity in place and to ensure the integrity of the film during application. We have used thermoplastic polyurethane (TPU) film owing to its high toughness, mechanical strength, biocompatibility, and resistance against atmospheric moisture and bacteria. The laminated layer protects the impregnated ³²P layer from mechanical abrasion, prevents damage, and precludes the release of radioactivity from the source. Autoradiography based on scanning film densitometry has been shown to be a useful method in the qualitative assessment of activity distribution and thus adapted. Owing to the in vitro use of radioactive membranes, the surface contamination and leachability tests with aqueous physiological buffers of different pHs were not considered essential and thus not pursued. To ensure compliance with mandatory regulatory requirement, these tests were carried out as per prescribed protocols.

Exploiting the potential utility of absorbent paper to retain ³²P, we have reported the preparation of ³²P patches with extremely good reproducibility.¹⁶ The method has the merits of easy adaptability, less demanding, and relatively inexpensive. Although effective, the inherent drawbacks of this method are the requirement of ³²P feed of very high radioactive concentrations (∼7.4–9.3 GBq/mL), necessity of skilled personal, and difficulty encountered during lamination owing to the poor mechanical strength of the absorbent paper. To mitigate the aforesaid drawbacks, our attention was directed toward the use of Nafion film. The concept of using Nafion film seemed very attractive as it would use ³²P feed of very low radioactive concentrations (∼9–10 MBq/mL) and at the same time possessed sufficient mechanical strength to permit convenient lamination.

The important features of the ³²P patches developed by the aforesaid procedure are as follows: (i) amount of ³²P activity impregnated into the membrane can be easily tuned by adjusting the radioactive concentration of the H₃ ³²PO₄ feed solution, (ii) radioactive deposit adhered firmly to the substrate and sheathed with a biocompatible protective film to prevent the loss of the radioactivity during normal use and handling, (iii) flexibility in making ³²P patches matching with the size and shape of the tumor, (iv) the ³²P patch is similar to a sealed one owing to the presence of laminated layer, (v) uniform distribution of ³²P on the substrate for homogeneous delivery of β-radiation, and (vi) adherence to the regulatory norms.

The findings of the present investigation of preparing ³²P patches meet the design and production specifications of a contact brachytherapy device. They can be used to treat skin cancer for patients with large and multiple lesions. The size, shape, and radioactive contents of the patches are dictated by the shape of the lesion and can be custom-made according to requirement. Typically, the ³²P patches would extend for ∼1–5 mm beyond the lesion in all directions. The radiation dose imparted to the tumor could be calculated for determining the radioactive content of the patch and the amount of time it has to be kept in contact with the lesion.

In view of facile preparation methodology, ease of making custom-shaped patches, and low cost, the reported method of preparing ³²P patches holds significant promises for successful clinical translation. Future perspectives will be focused to evaluate the biological effects of the patch using animal experiments and would form the theme of an independent communication.

Conclusions

A successful laboratory-scale preparation of ³²P patches using Nafion membrane to prepare ³²P patches containing 37–74 MBq/cm² of activity was demonstrated. In brief, surface modification of a Nafion film by treating with ZrOCl₂ solution, impregnation of a predicted quantity of ³²P into the film, covering the active area with a polymeric film, and quality assurance of the radioactive patch to meet regulatory requirement are reported. Using this methodology, it is possible to individualize the ³²P patch in terms of size and activity content according to the patient's requirement. The reported procedure is facile, robust, and inexpensive and has excellent batch-to-batch reproducibility. The ³²P patch prepared by this method complied with the safety standard requirements of Atomic Energy Regulatory Board, India.

Footnotes

Acknowledgments

The authors are grateful to Prof. M.R.A. Pillai, Head of Radiopharmaceuticals Division, for his helpful suggestions, stimulating scientific discussions, patiently editing and styling the manuscript. The authors wish to express their thanks to Mr. K.P. Muthe of Technical Physics Division and Mr. A.S. Tapase of Isotope Applications Division of our Institute for providing necessary help in the characterization of the composite Nafion membranes. The authors extend their thanks to Dr. (Mrs.) Usha Pandey and Dr. (Mrs.) Archana Mukherjee for their efforts in initiating β-emitting patch development work in our division.

Disclosure Statement

The authors have neither received any outside funding nor any grants from any external agencies in support of this study. Our institutions do not have a financial relationship with any commercial entity that has an interest in the subject matter or materials discussed in this manuscript. None of the authors in this manuscript have any conflict of interest, financial, or otherwise in the publication of this material.

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Nafion–Zirconium Phosphate Composite Membrane: A New Approach to Prepare 32 P Patches for Superficial Brachytherapy Applications

Abstract

Introduction

Materials and Methods

Chemicals

Instrumentation

Treatment of Nafion membrane

Optimization of 32P absorptive parameters

Capacity of zirconium-treated Nafion membrane

Preparation of 32P–Nafion patches

Surface characterization

Quality control of 32P–Nafion patches

Determination of source strength

Uniformity of 32P in the patches

Determination of surface contamination

Leachability of 32P patches

Results

Treatment of Nafion films

Optimization of 32P absorptive parameters

Effect of amount of carrier

Effect of pH

Effect of temperature

Effect of contact time

Effect of reaction volume

Capacity of ZNM

Characterization of Nafion films

Preparation of 32P patch

Quality control of 32P–Nafion patches

Determination of source strength

Evaluation of distribution of 32P

Evaluation of leachability

Evaluation of surface contamination

Discussion

Conclusions

Footnotes

Acknowledgments

Disclosure Statement

References

Optimization of ³²P absorptive parameters

Preparation of ³²P–Nafion patches

Quality control of ³²P–Nafion patches

Uniformity of ³²P in the patches

Leachability of ³²P patches

Optimization of ³²P absorptive parameters

Preparation of ³²P patch

Quality control of ³²P–Nafion patches

Evaluation of distribution of ³²P