Transarterial Radioembolization Agents: a Review of the Radionuclide Agents and the Carriers

Abstract

Liver tumors, both primary and secondary to metastatic disease, remain a major challenge, with an increasing incidence. In this context, taking advantage of the dual blood supply of the liver, and the fact that liver tumors derive majority of their blood supply from the hepatic artery, intraarterial therapies are gaining popularity. Intraarterial liver-directed therapy (IALDT) is the option when the surgery is not feasible due to the number of metastases or for other reasons. Transarterial radioembolization (TARE) is a specific type of IALDT, where a carrier particle/microsphere is labeled with a radioactive substance and then is injected into hepatic artery for therapeutic purposes. As this field is rapidly evolving, with multiple agents being investigated and being introduced into clinical practice, it is hard for the practitioners and researchers to encompass all the available information concisely. This article aims to present a comprehensive review of the prominent TARE technologies.

Introduction

Liver tumors, both primary and secondary to metastatic disease, remain a major challenge, with an increasing incidence [1]. The majority of liver tumors are secondary tumors [2]. Many primary tumors, e.g. colorectal tumors, neuroendocrine tumors, etc. have a high incidence of metastatic disease to the liver [3, 4]. Incidence of hepatocellular carcinoma is increasing worldwide, especially in the eastern hemisphere [5]. Although a wide range of treatment options have become available [6], the overall survival is still poor [7]. In this context, taking advantage of the dual blood supply of the liver and the fact that liver tumors derive majority of their blood supply from the hepatic artery, intraarterial therapies are gaining popularity [8, 9].

Intraarterial liver-directed therapy (IALDT) is used when the surgery is not feasible due to the number of metastases or for other reasons. IALDT can be further classified depending on the agent that is intra-arterially delivered. The first classification is transarterial embolization (TAE) which includes bland agents like Gelfoam and Polyvinyl alcohol and are used to occlude the hepatic tumor blood supply. An additional classification includes transarterial chemoembolization (TACE) where standard chemotherapeutic drugs like doxorubicin or irinotecan are delivered. Further refinement of this technique includes use of drug eluting beads (DEB).

The final classification is transarterial radioembolization (TARE). In this type of IALDT, a carrier particle/microsphere is labeled with a radioactive substance. This conjugate particle is injected in the hepatic artery. Of note, the carrier molecule is inert, and its sole purpose is to carry the radionuclide substance to the desired location [10]. However, the carrier molecules may cause additional embolization of the blood supply of the tumor which may enhance its tumoricidal effect. TARE is useful because tumor cells have no cellular means to evade or negate the tumoricidal effect of radiation. Radiation from these radionuclides is universally cytotoxic and hence highly effective [11]. The basic mechanism of radionuclide at molecular level is by chemical change of DNA and breakage, which leads to inhibiting growth and replication of the tumor [12]. An additional advantage of TARE over external radiation therapy is that a higher dose can be administered to targeted tissue with minimal radiation for healthy tissue.

As this field is rapidly evolving, with multiple agents being investigated and being introduced into clinical practice, it is hard for the practitioners and researchers to encompass all the available information concisely. This article attempts to present a comprehensive review of the prominent TARE technologies.

Materials and Method

For the purposes of this review article, microspheres were thoroughly investigated. Microspheres are characterized as powders consisting of a natural or synthetic material, having a spherical geometry and the size range from 1 to 1000 µm and ideally having a particle size less than 200 µm [12].

Other technologies such as nanoparticles or microparticles activated by some external energy application, e.g. magnetic or ultrasound energy were not included in this review, as they were beyond the scope of this article.

PUBMED and Medline were searched for almost all of the relevant articles concerning radionuclide therapy in cancer. Keywords that were used to identify such articles were a combination of ‘liver tumors, intraarterial radionuclide therapy, microspheres, liver cancer therapy’. Abstracts obtained from this search were evaluated. The references of the articles found in the literature search were also examined.

The information thus obtained was reviewed for selecting the relevant articles. Then, the information obtained from the selected articles was arranged in the following order: first, prominent radionuclide and carrier materials were classified and presented in a tabulated form (Table 1) then a review of the studied/available carrier materials was presented. In this section, description of carriers and their combinations with relevant radionuclides is provided.

Table 1.

Discussion of available radionucleotides and their respective properties. This includes half-life in days, typical carriers for the radionucleotide, beta-emission, gamma emission, tissue penetration range, and typical production method. Significance of each radionucleotide is further broken down into its typical use be it historical, clinical, or for research purposes

Radionucleotide	Half life	Carrier	Beta emission (MeV) (%)	Gamma emission (KeV) (%)	Tissue penetration range (mm)	Production method	Typical use
Ph-32	14.3	Glass	1.71 (100)	/	7.9	Nuclear Reactor	Historical
Ho-166 Microspheres	1.1	Glass, resin, polymer	1.84 (50.5)	81(6.4)	8.7	Nuclear Reactor	Clinical
Ho Glass Microspheres	1.1	Glass	1.84 (50.5)	81(6.4)	8.7	Nuclear Reactor	Clinical
Ho Resin Microspheres	1.1	Resin	1.84 (50.5)	81(6.4)	8.7	Acrylic polymer with carboxylic group	Clinical
Ho Polymer Microspheres	1.1	Polymer	1.84 (50.5)	81(6.4)	8.7	Nuclear Reactor	Clinical
Re-188 Microspheres	0.7	Glass, resin, polymer	2.12	155 (15)	11	W188/Re188 generator, nuclear reactor	Research
Re Glass Microspheres	0.7	Glass	2.12	156 (15)	11	Neutron irradiated in high flux nuclear reactor	Research
Re Resin Microspheres	0.7	Resin	2.12	157 (15)	11	Boiled, centrifuged, suspended in saline	Research
Re Polymer Microspheres	0.7	Polymer	2.12	158 (15)	11	Solvent evaporation	Research
Re-186	3.8	Polymer	1.07 (72)	137 (9)	4.5	Nuclear reactor	Research
Y-90	2.7	Glass, resin	2.284 (100)	/	12	90 Sr/ Y 90 generator, nuclear reactor for microsphere labeling	Clinical
I-131	8	Polymer	0.81 (90)	0.364 (81)	2	Nuclear Reactor	Research
Lu-177	6.7	Polymer	0.497 (79)	113 (6.4) and 208 (11)	2.2	Nuclear reactor	Historical

Discussion

TARE Radionuclide Agents Currently in Use or Under Investigation

Carrier Microspheres

Broadly, carriers can be divided into two main categories based on the targeting mechanism: active targeting and passive targeting. Active targeting drug carriers are modified with active targeting ligands, possessing a high affinity for binding to a specific cell type or tissue in the organism [13]. In passive targeting, drug carrier vehicles are concentrated at a particular site due to the inherent pathophysiological, physicochemical or pharmacological factors [14]. The currently used microsphere carrier particles fall in the passive targeting category. A vast array of carriers with a variety of materials have been studied in the form of microspheres. However, to simplify, we categorized them in major material categories and then further subdivided according to their ability to degrade naturally in the body. A brief overview is summarized in Table 1.

In general, some of the considerations for an ideal vehicle agent would be chemical durability and bioavailability of the radionucleotide. Chemical durability implies that the microsphere remains intact longer than half-life of the radionuclide to prevent the radionuclide from leaching out and reaching non-targeted regions. However, if microparticle is too durable, then it stays in the patient’s body after treatment for a long time, to some extreme even years. High biodegradability of the microsphere on the other hand can lead to fast release of the radionuclide and exceeding its safe levels in the body. The radionuclide should be optimally bound to the microparticle. If it is too loose, then leaching out would be detrimental by causing exposure to the non-target tissue. If it is too strong, then the radionuclide would not be able to exert its efficacy. Optimization and balance between biodegradability, biocompatibility of the carrier vehicle, and bioavailability of the radionuclide are necessary for achieving the optimal safety and efficacy level of radioembolization therapy option. In the following discussion, we will go over these aspects for the currently available microspheres. Major carrier vehicle agents used as microspheres include resin, glass, polymers (natural and synthetic), lipiodol, alginate, and phosphate Tables 2, 3, 4 and 5.

Table 2.

Examination of different resin microspheres including Bio-Rad, Bio-Rex, Aminex®, and Aminex-27®. Specific advantages and disadvantages of Bio-Rad are discussed including its new production method which eases previous concerns about high particle load leading to postembolization syndrome

Common vehicles
Bio-Rad: Polystyrene based, cation exchange, SIR-sphere. Sodium used to exchange radionucleotide (Y90 typically) with phosphate salt immobilization
Advantages:
• Biocompatible
• Improved sphere load from novel production methods
Disadvantages:
• Not biodegradable
• Low specific activity
• Can lead to post embolization syndrome
• Not for patients with impeded venous flow
• High particle administration
• Non target delivery
Bio-Rex: Acrylic Polymer. Carboxylic group exchanges to bind radiometal. Ho-166. Good stability and retention
Aminex®: styrene divinylbenzene copolymer with sulphonic acid functional group
Aminex-27®: Re-188 labeling

Table 3.

Glass microspheres are commercially used in clinical practice. Therasphere® is the most readily available. Typically, it is loaded with Y-90 and is advantageous for several reasons. Disadvantages are also discussed including long half-life and length required to achieve therapeutic activity

Microsphere carriers	Common vehicles	Advantages	Disadvantages
Glass	Therasphere®: Insoluble, glass based loaded with Y-90, heavier than blood and resin microspheres	• Nontoxic substance	• Long half-lives
		• Resistance to radiation	• High specific gravity
		• Ability to be spherodized in uniform size	• Concern for fluid drag, pressure force, and gravity
		• Minimal chance of leaching out
		• High durability
		• Different sizes are available

Table 4.

Summary of existing synthetic and non-synthetic polymers. These can be further broken down by their biodegradability or composition

Synthetic

Biodegradable: Polyanhydride, poly lactic acid, poly alkyl cyanoacrylates, Lactides, glucolides

Non-biodegradables: Epoxy polymers, glycidyl methacrylate, poly methylmethacrylate

Non-synthetic

Proteins: Albumin, Gelatin, Collagen

Carbohydrates: Agarose, carrageenan, starch, chitosan

Chemically Modified: Poly starch, poly dextran

Table 5.

Specific polymers, both synthetic and not synthetic, are further discussed by their advantages and disadvantages. Their respective properties are defined when applicable. Biodegradability, biocompatibility, toxicity profile, and immunogenicity were all considered when reviewing these polymers

Specific polymers	Advantages	Disadvantages
Poly Vinyl Alcohol	• Biodegradable	• Irregular shape
	• Biocompatible	• Aggregates/obstructs catheter
	• Near plasma density	• Occlusion of large vessels
		• Premature disintegration of particle, release, and delabeling which leads to surrounding tissue damage
Human Serum Albumin	• High availability	• Heat sensitivity
	• Wide range of ligand binding	High risk of contamination
	• Biodegradable
	• Biocompatible
	• Non-antigenic
	• Uniform size
	• Long half life
	• Soluble and stable at different pH and temperatures
Gelatin: colorless, odorless, flavorless. Can have different isoelectric points which means it can form a wide variety of complexes	• Biodegradable	• Getting uniform size is difficult
	• Biocompatible	• Less control over level of occlusion
	• Easy to handle	• Long period of degradation needed
	• Nontoxic
	• Nonimmunogenic
	• Can make microspheres of various sizes
	• Can be positive or negatively charged
	• Can be used for controlled and sustained drug release
Starch (EmboCept®): inert. Made by recrystallization and crosslinking	• Biodegradable	• Ischemia of non-target tissue
	• Biocompatible
	• Nontoxic
	• Cost effective
	• Nonagglomerated discrete form
	• Short half life
	• Less chance of postembolization syndrome
Chitosan: Positively charged polysaccharide polymer made of d-glucosamine	• Biodegradable	• Long degradation period
	• Low toxicity	• Lack of multi-model visibility
	• Low immunogenicity	• Linear polymer
	• Biocompatible

Resin Microspheres

The resin matrix essentially is composed of cross-linking hydrocarbon chains by polymerization. Polystyrene or acrylic are the most commonly used compounds. The resin polymer is then further treated chemically to bind functional groups to the ion exchange sites located throughout the matrix. Based on whether they attract negative or positive charged ions, the resins are named anion or cation resins [15].

The commonly used resin-based vehicles for TARE are Bio Rad, Bio-Rex 70, and Aminex®. Bio Rad (Bio-Rad Inc. Hercules, CA, USA) is a polystyrene based, cation exchange resin, used in the manufacture of SIR-sphere®. Sodium of the molecule is exchanged for radionuclide, (yttrium in case of SIR-sphere®). The yttrium is immobilized using a phosphate salt. Bio-Rex 70 (Bio Rad Inc. Hercules, CA, USA): this is an acrylic polymer, with carboxylic groups used to bind the radiometal [16]. More recently Bio-Rex has been used with holmium-166 [17]. They demonstrated high in vivo stability and showed very good retention in the liver (94.94 ± 1.51% at 72 h pi.). Another agent investigated is Aminex® resins (Bio-Rad Inc, Hercules CA, USA) based on styrene divinylbenzene copolymer with sulphonic acid functional groups [18]. Aminex-27® (Bio-Rad Inc, Hercules CA, USA) resin microspheres have also been labeled with rhenium 188. This was done by adding [188Re]-perrhenate and SnCl₂ to vacuum dried resin particles. The mixture was boiled, centrifuged, and microspheres were separated and resuspended in saline [19].

The resin microspheres are biocompatible but not biodegradable. They suffer from low specific activities and require administration of high amounts of particles, which in turn is responsible for adverse side-effects like postembolization syndrome. Because of its strong embolizing effect 90Y resin microspheres sometimes are not considered suitable for patients with impeded venous flow [20]. This effect is controversial with conflicting reports from different investigators [21, 22]. Another factor to be considered when using resin-based carrier vehicle is that each individual particle carries a low radiation activity (50 Bq/microspheres). This necessitates use of large number of particles.

The implication is that large numbers of resin particles need to be used for adequate delivery of the radionuclide, but increased number of particles may lead to stasis in the blood vessel being injected. Then, due to backflow, non-target delivery of the therapy can happen [23]. However recently, with the new production process resulting in fewer than 40 million resin microspheres per vial and the ability to deliver fewer spheres with higher specific activity the day before calibration process, the number of spheres delivered for a given prescribed activity has decreased, easing some of these concerns.

The effect of fluid dynamics on the resin microspheres, which was studied by injecting microspheres in a surrogate hepatic arterial system should be noted. It is demonstrated that the penetration depths of microspheres into the tumor is dependent on fluid drag, gravity, and pressure forces. The effect of these parameters is different between resin microsphere and the glass microspheres, with resin microspheres being affected more with higher specific gravity [24].

The stabilization of the radionuclide on the resin microsphere surface must be considered. Despite its immobilization, exposure to ionic material is not recommended [15]. Even in sterile water 0.01% to 0.4% of 90Y is released from the microsphere after 20 min [25].

Glass Microspheres

Glass as a delivery carrier is valuable because it is nontoxic in the microparticle form and resistance to radiation, can be spherodized in uniform size, and has low leaching out rate [26], and high specific activity loading capacity (2500 Bq per sphere at the time of calibration [27]). Typically, glass is made by melting aluminum oxide and silicone dioxide together at 1500–1600° centigrade. The base metal (yttrium-89 or holmium-165) is then neutron bombarded in a nuclear reactor to get the desired beta emitting radionuclide (yttrium-90 or holmium-166). Since yttrium/holmium molecules are integral part of the structure, breakdown and leaching out phenomenon is at its least. The specific activity loading capacity of each particle is high, 2500 Bq per sphere at the time of calibration. However, glass particles do contain radioactive aluminum and silicone with long half-lives (yttrium-88, 107 days, and europium-154, 8 years) [28]. The neutron activation takes between two to three weeks to achieve the required therapeutic activity due to the small thermal neutron cross section of yttrium [29].

Glass microspheres are currently in clinical use. Thera-Sphere® is the commercially available insoluble glass-based microspheres that are loaded with yttrium-90 with mean diameter range between 20 to 30 µm. The number of spheres in a vial with activity size 3 GBq is 1.2 million spheres with 2500 GBq activity per microsphere. The glass microspheres are heavier than the blood and resin microspheres, (glass, 3.7 g/dL; blood, 1.05 g/dL) [30].

Glass microspheres have high chemical durability. They are three times heavier than blood, so the initial concern was that because of their higher specific gravity, glass microspheres must be injected more forcefully, which may lead to microspheres achieving velocities greater than the native artery velocity and subsequent suboptimal distribution into liver tumors. Basciano studied a flow model and determined that if microspheres were injected at velocities greater than the native arterial velocity, they would be diverted from the normal flow patterns in the low-resistance tumor vessels into higher resistance vessels not supplying tumors. Since glass microspheres may need higher pressure due to their higher specific gravity, this issue may be more pronounced for them [28]. However, another study concluded this is not the case [31]. Similarly issues of fluid drag, pressure forces, and gravity are probably less important for heavier glass particles compared to lighter resin microparticles [24]. Different sizes of glass microspheres have been used, ranging from 2–5 µm to 20–50 µm for different applications [16, 32].

Polymer-based Microspheres

Polymers have many advantages over non-polymers (resin and glass materials) for fabricating embolic microspheres as they are degradable and biocompatible, and having density similar to plasma blood. However, they have limitation as they cannot tolerate the high thermal-neutron flux associated with generating neutron flux. This issue can be overcome by changing the parameters of irradiation and adding some additives [33].

Polymers based carrier vehicles have striking control over the mechanical properties of the particle. The biodegradable microspheres have an advantage over non-biodegradable microspheres as they can be degraded in the body without the need to be removed after administration [34].

Poly lactic-co-glycolic acid (PLGA) is degradable linear polymers with hydrophobic nature that consists of two monomers (lactic acid and glycolic acids) that are bonded with ester bond. Different forms of PLGA can be synthesized depending on the different ratio between lactic acid and glycolic acid. The degradation rate differs with molecular weight, where the low molecular weight PLGA has faster degradation rate in comparison with high molecular weight. The PLGA microspheres exert their occlusion effect mechanically and biologically. The mechanical occlusion effect happens as the microspheres form aggregate within the vessels. Then around one month after the treatment, the aggregation of microspheres starts to from fibrous matrix that hold the microsphere while they are degrading, making the occlusion extend to nine months. After 12 months the occluded vessels re-open again. Even PLGA is biodegradable polymer and degrade in-vivo. The lengthy occlusion cannot provide the transient effect that is intended with using biodegradable polymer for embolization [35].

Polylactic acid is a synthetic, biocompatible, and biodegradable polymer has been used as matrix base for embolic microspheres. Non-active radionuclides such as 165Ho and metallic rhenium-185 to rhenium-186 can be incorporated before the fabrication of PLLA microspheres, and other radionuclides such as yttrium-90 or a rhenium-188 salt can be added after the fabrication of Poly lactic acid based microspheres [36]. One of the advantages of using poly lactic acid as matrix based for synthesizing embolic microsphere are the low density and biocompatibility of the PLA microspheres that make them a suitable option for radioembolization.

Polyvinyl Alcohol

Polyvinyl alcohol (PVA)-based microspheres are irregular in shape and poorly spherical. That leads to them aggregating and obstructing the catheter and occluding the large vessels instead of small vessels [37]. Polymers (natural and synthetic) have many prized features as delivery carrier, namely biodegradability, biocompatibility, and near plasma density. This carrier does come with disadvantages though including premature disintegration of the particle, releasing and de-labeling the radioactive materials/radionuclide during degradation that may reach non-targeted tissue, and damage to surrounding tissue [38]. An additional disadvantage is heat sensitivity. These materials do not withstand the high thermal fluxes produced during neutron irradiation [39, 40]. However, with special precautions and techniques these drawbacks have been successfully circumvented [41, 42].

Human Serum Albumin (HSA)

HSA is a suitable carrier vehicle for the radionuclides. It has high availability as it is the most abundant protein in human blood. Moreover, human serum albumin has ability to bind to wide range of ligands including radioisotopes and fluorescent molecules [43]. Its use is well studied. In example, lung perfusion imaging with 99mTc-labeled macroaggregates of albumin (MAA) are the current methods of choice to assess lung shunts and predict 90Y-microspheres dosimetry [44].

The properties and advantages of using HSA in embolic radiotherapy are biodegradability, biocompatibility, non-antigenicity, uniformity in size, long half-life of 19 days as it has size too big to be filtrated through kidney, solubility and stability at different circumstances of pH and temperatures, and the many binding sites to form many complexes with several compounds such as metal ions and orogenic compounds [43, 45, 46].

Human blood is the source of human serum albumin that is used in synthesis of 99mTc-MAA. This has the risk of contamination. Recombinant DNA technology has been proposed as a potential replacement for HSA to avoid contamination risk associated with Human-derived HSA [47].

Physical parameters are an additional consideration. Tc99m-MAA microsphere’s diameter is around 90Y microsphere with mean dimeter 35 µm and maximum diameter of 150 µm. MAA procedure includes injection/using of 3–5 mCi Tc99m-MAA, and after one hour of the injection time, following that with scintigraphy imaging [11, 44].

Various methods of making HSA microspheres have been described, and one method using Rhenium radiolabeling is more recent. A 1.6% solution of human serum albumin (Sigma, St. Louis, MO, USA) was added dropwise to a 1000 mL flat-bottomed glass beaker, containing refined olive oil (800 mL) during continuous stirring with a stirring bar on a magnetic heat plate. The HSA solution was reacted at 60–110 °C, continuously stirring with a different speed. After removing all oil form HSA microspheres, 200 mL acetone was added to wash free oil and dried with 40 °C. Finally, the HSA microspheres were filtered with 20–53 μm sieves [48]. Commercial preparations as well as a cold kit method have been described. A further optimization with microwave energy is also described [49, 50].

Gelatin Microspheres

Gelatin is a colorless, odorless, flavorless protein that is derivatized from collagen, usually from skin, connective tissue, and bones. It can form gel in pH with range of 4–8. Gelatin microspheres are synthesized by dispersing the glutaraldehyde-crosslinked aqueous solution of gelatin in surfactant-free oil phase [51]. Gelatin can have different isoelectric points depending on whether the treatment of collagen is acidic or alkaline. With different isoelectric points, gelatin can have either positive or negative charge that allows interaction with wide range of materials to form different complexes. In addition, the degradation can be changing/leveled by changing the degree of crosslinking [52]. Gelatin is usually prepared by coacervation method where aqueous solution of gelatin is dispersed in oil phase forming a water–oil emulsion [53].

Gelatin has advantageous features making it appealing for pharmaceutical and biomedical purposes as it is biodegradable [54], biocompatible, and easy to handle, with no toxicity or immunogenic problem that are associated with non-biological origin polymer, and microspheres of varying sizes can be made. Positively or negatively charged microspheres can be made by using different isoelectric points, allowing it to interact with wide range of materials by electrostatic interaction to form complexes. These charged spheres can be used by attaching carboxyl group of the active moiety to the amino group of the microspheres [55]. An added advantage is the ability for controlled degradation of gelatin microspheres by changing the degree of cross linkage, allowing use for controlled and sustained release drug [56]. The radionuclides can be attached to gelatin in an electrophilic substitution reaction between iodine and tyrosine residues in gelatin. Though primarily studied in radioiodination of antibodies, similar mechanism has been used for iodination of the microspheres [52].

A major disadvantage of Gelatin is that it is cut manually so getting a uniform size is difficult. Consequently, this leads to less control over the level of occlusion. Moreover, there is the issue of long period needed for degradation when using gelatin sponge for microembolization [57, 58].

Starch Microspheres

Starch is an inert substance. The starch particles are advantageous because of biodegradability, biocompatibility, non-toxicity, and cost-effectiveness. Based on the Manufacturing techniques, broadly, starch particles can be classified into two major groups, made by recrystallization and made by cross-linking. In general, crosslinked starch microspheres (CSMs) are considered to be more attractive because of the swelling property and degradability of CSMs can be designed conveniently by controlling the degree of crosslinking reaction. CSMs have excellent spherical shape and a non-agglomerated discrete form can be synthesized by a novel two-stage water-in-water emulsion method but this particle has not been studied in conjunction with any radionuclide attachments [59].

Degradable starch microspheres (DSM) are used for intra-arterial hepatic chemoembolization for hepatic cellular carcinoma. EmboCept® (PharmaCept, Berlin-Schöneberg, Germany) is the only commercially available degradable starch-based microspheres. Degradable starch embolic microspheres are small-sized, which leads to short-time embolization of small arteries with half-life of around 40 min. The advantage of this approach is a relatively lesser chance of post-embolization syndrome and systemic toxicity. Also, chemotherapy agents such as epirubicin can be administered with DSM, allowing for a targeted accumulation which leads to decreased side effect and increased efficacy [60, 61]. Usually starch microspheres are obtained from hydrolyzed potato starch that is prepared by emulsion-crosslinking method [62].

Degradable starch comprises of cross-linked hydrophilic starch matrix that is degradable by amylase enzyme. Starch microspheres swell in aqueous environment and degrade completely by amylase enzyme. The starch microspheres can be designed to be biodegradable which allows for repeat transcatheter therapy when necessary [63]. One of the useful features of degradable starch matrix is that they can provide transient occlusion as they are degradable by amylase, and consequently leads to less post-embolization syndromes. In comparison to gelatin sponges that have occlusion time that can reach several weeks, degradable starch microspheres have transient occlusion as they are degraded in the blood stream by serum amylase. This in turn allows blood flow to get back to a normal rate in one hour to one and half hours [63].

The available commercial degradable starch microspheres in the market is EmboCept® S DSM 35/50 (PharmaCept GmbH, Berlin, Germany) and consists of 50 µm degradable starch microspheres that are degradable by serum alpha-amylase to provide transient effect with half-life of 35–40 min. However, one of the risks associated specifically with transient occlusion is the backflow of the embolizing agent to untargeted tissue, leading to ischemia and severe pain [64].

Chitosan Microspheres

Chitosan is a positively charged polysaccharides polymer composed of a d-glucosamine unit that can bind to heavy metals, and form gel in neutral and basic medium [11]. Chitosan is biodegradable, has low toxicity and immunogenicity, and is biocompatible.

Chitosan is a deacetylated form of chitin polymer of 2-deoxy-2-amino- D –glucose building units. It is dissolved in acidic aqueous medium to form clear solution that can turn into a solid state in basic medium like blood [65, 66]. The degree of deacetylation is the factor that determines the solubility properties of chitosan. Chitosan has hydrophilic functional groups, amine and hydroxyl groups. Its solid state is semi-crystalline particles that can form hydrogen bond when it is dissolved in water by forming salt with organic acid. Chitosan can bind to metal cations through its un-protonated amine groups and with anionic compound and anionic dyes with protonated amine groups. The amine groups of acetylglucosamine and glucosamine units can bind either to metal cations or anionic dyes depending on the protonation status [67]. Chitosan is degraded by breaking the bonds between glucosamine compounds, n-acetyl-glucosamine subunits, and the bond between the glucosamine and n-acetyl-glucosamine. These bonds are broken in vivo by lysozyme to leave only glucosamine that can be used to synthesize glycolipids, proteoglycans, and glycosaminoglycans. The degradation rate is affected by the degree of acetylation where more acetylation results in faster degradation as it becomes more crystalline [35].

One of the limitations of using chitosan microspheres for radioembolization is long degradation period in range between 24 and 34 weeks [35]. Furthermore, a limitation of using chitosan for micro-radioembolization is the lack of multi-model visibility. There is no evidence in the literature that different size ranges of chitosan microspheres can be produced [35]. Chitosan is a linear polymer soluble in acidic media which limits its usage for biomedical application [67].

Alginate Microspheres

Alginate is polysaccharide polymer with two subunits b-D-mannuronic acid and a-L-guluronic acid and length ranging from 50 to 200,000 units. The hydrogel form of the alginate can be prepared by adding an aqueous alginate solution in CaCl₂ solution where Ca²⁺ ions bind to carboxylic acid group of the guluronic unit of alginate. Alginate can bind to divalent ions as well as trivalent lanthanides [68]. The preparation techniques and other aspects have been well covered in a recent review article [69].

Besides inexpensiveness, nontoxicity, biocompatibility and biodegradability features of alginate microspheres, they also can be loaded with rare metals to help visualization with cross sectional imaging modalities [68]. Alginate microspheres labeled/loaded with different cations have been tested for their ability and feasibility to form/make MRI-detectable microspheres. Alginate microspheres were made with Jet Cutter technique and subsequently cross-linked with nine different cations: lanthanides (Eu³⁺, Gd³⁺, Tb³⁺, Dy³⁺, Ho³⁺, Tm³⁺, Yb³⁺), alkaline earth metals (Ca²⁺), and transition metals (Fe³⁺). The nine formulations are found to be spherical and uniform in size. However, among the nine cations-alginate microspheres, alginate-lanthanide microsphere formulations showed higher sensitivity as MR contrast agent, especially, Ho³⁺-alginate microspheres which showed a higher level of detailed examination of microsphere biodistribution. In ex vivo, MRI images of Ho³⁺-alginate microspheres showed clearly a specific accumulation and embolization of the targeted vessels after administration/infusion/intravascularly through catherization of ex vivo tissue [70].

Pure Sodium alginate microsphere and pure silk-fibroin are poorly spherical which is not suitable for embolization; however, sodium alginate-modified silk fibroin microspheres have a good sphericity. However, these microspheres showed ischemic necrosis in rabbit ear models used [37].

Lipoidol

Though not technically falling into the microsphere realm of carrier vehicles, we would like to discuss Lipoidal in brief here, due to its long history of being used as a carrier vehicle.

Lipiodol is a highly viscous and highly lipophilic, iodinated, and esterified form of poppy seed oil that have been used for diagnostic imaging studies as well as for liver cancer therapy [71]. Its selective uptake by malignant cells has been used for targeting primary as well as secondary liver malignancies, for last several decades. Lipiodol accumulate in liver when it is injected through hepatic artery, which is an advantageous feature to be used as carrier in embolization therapy. However, the iodine-133 labeled lipiodol has limited usage due to two main factors: its long life, high gamma energy and consequently, high external radiation [11, 72, 73].

Lipiodol is an ethyl ester of iodinated fatty acids with a proportion of iodine of approximately 38% by weight (i.e., 475 mg/mL).Radiolabeling of lipoidal with iodine-131 has been successfully done by an exchange reaction [74]. However, due to inherent issues with iodine-131 radiation, e.g. use of iodine-131 labeled lipiodol, lipiodol demonstrated a high incidence of lung uptake [75] and its long life, effort was diverted towards yttrium-90 and rhenium-188, which have a more favorable radiation profile.

Labeling lipiodol with rhenium-188 is not an easy task as both of them are available in different media that are not miscible. Re-188 is prepared in water where lipiodol is prepared as an oil. To overcome this issue, rhenium or technetium can be chelated to DD (2,2,9,9-tetramethyl-4,7-diaza-1,10-decanedithiol), and this step can be done in aqueous media. As the chelate is lipophilic in a nature, it can be extracted with lipiodol. 188-Re-DD showed high stability in lipiodol phase in vitro, and high accumulation/uptake in liver tumor tissue when it is administered by hepatic artery. However, 188Re-DD-lipodiol did not show a high retention level in liver tumor tissue. The alkyl derivative of DD showed higher liver tumor tissue retention in comparison to non-alkylated DD. The conclusion is 188-Re-HDD is stable in vitro and vivo with high retention in the liver tumor tissue [71]. The only commercially available lipiodol based microsphere that is labeled with 131-iodine is Lipiocis®, (Schering S.A.) [76].

Conclusions

With growing data on different agents, it is of utmost importance for both practitioners and researchers to understand the utility as well as specifications on each agent available in transarterial radioembolization. Several agents have been investigated over the years in clinical and research settings ranging from resins, glass, and polymers as carrier agents. Understanding the advantages and disadvantages allows for appropriate use in clinical practice, and ultimately for the evolution of the carrier agents.

Author Contribution

Aysheh Alrfooh: Data collection, manuscript preparation.

Aditi Patel,: Data collection, manuscript preparation.

Sandeep Laroia: Conceptualization, data collection, manuscript preparation.

Availability of Data and Material

Not applicable.

Declarations

Conflict of Interest

Aysheh Alrfooh, Aditi Patel, and Sandeep Laroia declare that they have no conflict of interest.

Ethics Approval

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