Radium-223 and Actinium-225 α-Emitter Radiopharmaceuticals in Treatment of Metastatic Castration-Resistant Prostate Cancer

Abstract

In recent decades, multiple radiopharmaceutical conjugates have been tested and shown to be efficacious in treating metastasized castration-resistant prostate cancer (mCRPC). Several types of research have been published on the therapeutic use of α-emitter radiopharmaceuticals, and several authors suggested their treatment superiority. One of the suggested methods is targeted alpha therapy. In this method, alpha radiation delivers energy to cancer cells and the tumor microenvironment while minimizing toxicity to surrounding tissues. In this chapter, the alpha emitter radiopharmaceutical applications in castration-resistant prostate cancer patients were investigated. Hence, we studied the 223Ra and 225Ac α-emitter radiopharmaceuticals application method and distribution of dose throughout human body organs.

1. Introduction

The prostate gland weighs around 20 g and is located at the base of the bladder, near the prostatic urethra. It is split into four zones: peripheral, central, transitional, and peri-urethral. The most frequent location of prostate cancer in the peripheral zone, and adenocarcinoma accounts for the majority of cases, generally arising from acinar cells in the prostate gland and accompanied by a rise in serum prostate-specific antigen (PSA). PSA is unaffected by some tumor forms, including neuroendocrine tumors, small-cell carcinoma, and transitional cell carcinoma [1].

According to a study conducted in the United States, 241,740 men were diagnosed with prostate cancer in 2012, resulting in 28,170 fatalities. In the United States, about 160,000 men will be diagnosed with prostate cancer in 2017. Prostate cancer is the third largest cause of cancer mortality in males, despite its generally indolent course. Since 2011, there has been significant progress in finding treatment alternatives and defining illness risk [2].

Prostate cancer is the third most common cancer worldwide among males and the fourth in terms of incidence worldwide [3]. Patients with PCa may be treated with radical prostatectomy or radiation as initial therapies, although disease recurrence is possible. A prostatic-specific antigen (PSA) in the clinical setting of PCa screening has resulted in earlier detection. The first symptom of disease recurrence is an increase in PSA levels, referred to as biochemical recurrence (BR). Early recurrence can be treated with potentially curative salvage treatments such as additional lymphadenectomy or targeted radiation, although both need the disease to be localized [4].

Several radiopharmaceutical conjugates have been tried and proved to be effective in treating bone metastases [5, 6, 7] and metastasized castration-resistant prostate cancer in recent decades (mCRPC). In addition, various research on the therapeutic use of α-emitter radiopharmaceuticals have been published, and several writers have indicated that they are preferable in terms of therapy [8, 9, 10, 11, 12, 13, 14, 15, 16]. Targeted alpha treatment targets cancer cells and the tumor microenvironment while limiting damage to adjacent organs. Radiopharmaceuticals are specific radioisotope formulations used for diagnosis and treatment in important clinical domains. ²²³Ra and ²²⁵Ac radionuclides are the major radiopharmaceuticals utilized in treating prostate cancer [17].

The linear energy transfer (LET) causes damage to the cell DNA owing to the movement of the α-particle into the tissue, but the shortened range of the α-particle restricts tumor damage to the adjacent healthy cells, decreasing the damage. However, α particles may cause serious harm at both cellular and genetic levels, if breathed or eaten. External body exposure to an α-particle is insignificant. The possible harmful kind of radiation is α-particles [2].

Routines throughout the world include systemic chemotherapy, hormone therapies, and targeted bone drugs such as radium-223 dichloride (²²³Ra) and actinium-225 (²²⁵Ac) for skeleton metastases [18].

2. Radium-223

²²³Ra (T_1/2 = 11.43 day) is α-emitter radiopharmaceutical with an average energy of 5.78 MeV (accounting for 93.5 percent of emitted energy), 4% as particles, and 2% as radiation utilized in prostate cancer bone metastases. The dichloride-²²³Ra is a targeted emitter that binds to accelerated bone turnover in bone metastases and releases high-energy alpha particles with a short-range (100 m) [19, 20]. ²²³Ra treatment with a targeted-emitter provides radiation energy to cancer cells and tumor tissue while limiting damage to healthy tissues. Table 1 shows ²²³Ra radiopharmaceutical characteristics. Also, the decay chain of ²²³Ra radiopharmaceuticals is presented in Figure 1.

Radionuclide	Half-life (day)	Emission particles (parent and daughters)	Emean (MeV) (%)	Tissue penetration average (mm)
Ac-225	10.0	α	5.8 (54%), 6.4 (82%), 7.1 (>99%), 5.7 (2%), 8.8 (100%)	0.051
		β	1.8 (98%), 1.4 (98%), 0.64 (100%)	11.21
Ra-223	11.4	α	5.7 (100%), 6.9 (100%), 7.5 (99%), 6.6 (99%), 7.4 (100%)	0.062
		β	0.47 (0.3%), 0.47 (100%), 0.35 (100%)	8.56

Table 1.

The properties of ²²³Ra and ²²⁵Ac radiopharmaceuticals in the treatment of bone metastases prostate cancer.

Figure 1.

The decay chain of ²²³Ra radiopharmaceuticals.

Radium-223 dichloride is a targeted alpha emitter that preferentially binds to regions where the bone turnover is enhanced in bones and produces short-range (<100 μm) high-energy alpha particulates. As osteoblastic calcium mimesis, ²²³Ra is linked into newly developed osteoblast or sclerotic metastasis, especially in the microenvironment. The high-energy radiation of alpha-particles leads largely to dual-stranded DNA breaks with a powerful and highly localized cytotoxic impact on the target areas. The alpha particles’ short distance also minimizes the harmful effects on nearby healthy tissue, especially bone marrow [21].

In phase I and phase II trials involving bone metastasis patients, radium-223 has been shown to have a good safety profile with little myelotoxicity [22]. Studies of Phase two showed the reduction of pain and improvement of biomarkers associated with diseases (e.g., bone-alkaline phosphatase and prostate-specific antigen [PSA]) and suggest a survival advantage among patients who have castration-resistant prostate cancer and bone metastases [23]. In order to investigate radium-223’s survival impact, we conducted a Phase 3 randomized, two-blind multi-national research that compared ²²³Ra effectiveness and safety to placebo in patients with castration-resistant prostate cancer and bone metastases in Symptomatic Prostate Cancer Painters (ALSYMPCA).

3. Actinium-225

²²⁵Ac (T_1/2 = 10 days), like ²²³Ra, is α-emitter radiopharmaceutical that decays to stable ²⁰⁹Bi through six radionuclides [24]. The ²²⁵Ac radioelement is a targeted alpha treatment that improves survival in individuals with metastatic castration-resistant prostate cancer. ²²⁵Ac emits a particle with E_α = 6 MeV energy when it decays, yielding net four particles and three-particle disintegrations, the majority of which are high energy and useful gamma emissions, including ²¹³Bi (T_1/2 = 45.6 m; E_α = 6 MeV E_max(β) = 444 keV and Eγ=440 keV), where this line has been used in imaging drug distribution [18]. Other daughters include ²²¹Fr (T_1/2 = 4.8 min; E_α = 5 Mev and 218 keV γ energy line emission), ²¹⁷At (T_1/2 = 32.3 ms; E_α = 7 MeV), ²¹³Po (T_1/2 = 4.2 μs; E_α = 8 MeV), ²⁰⁹Tl (T_1/2 = 2.2 m; E_max(β) = 659 keV) (stable). Given ²²⁵Ac with a 10 d half-life, the high emission of alpha particles, and the favorable, fast ²⁰⁹Bi stable decay chain, this radionuclide is recognized to have a promising potential for cancer usage [2]. Figure 2 illustrates the decay pattern for ²²⁵Ac. Also, Table 1 shows ²²⁵Ac characteristics of radiopharmaceuticals. ²²⁵Ac is a potential candidate among the α particle-producing ions with characteristics suited for usage in targeted α therapy (TAT) (Figure 3).

Figure 2.

The ²²⁵Ac radiopharmaceuticals position in radioactive ²³³U decay series.

Figure 3.

Schematic diagram depicting the concept of targeted radionuclide therapy employing alpha (α) particles in a tumor-targeting construct. The high linear energy transfer (LET) and short-range of particles make them highly desirable for use in cancer therapy.

The radiological half-life of ²²⁵Ac is 9.92 days, allowing it to be sent to clinics distant from the location of manufacture. Furthermore, this lengthy half-life is compatible with the use of macromolecular targeting vectors, such as antibodies or nanoparticles, which have long in-vivo circulation durations. As it decays to stable ²⁰⁹Bi, ²²⁵Ac produces eight short-lived progenies, producing a total of four high-energy a particle that kill cancer cells (Figure 2). Notably, in both in vitro and in vivo settings, ²²⁵Ac is far more potent than its daughter nuclide, ²¹³Bi.

4. Dose calculations

The estimations of the doses were carried out with the application “Internal Computer Dose Assessment” (IDAC-Dose2.1). The dose coefficients of patients having radiopharmaceutical exams in nuclear medicine were calculated using this program by ICRP. In addition, dose estimates using the same ICRP computer architecture for the internal dose evaluation are the basis of the IDAC-Dose2.1 program.

For a time-independent system, the mean absorbed dose (D) to a target region (r_T) is calculated using the equation below [25]:

$$\left(r_T,T_D\right)=\sum _{r_S}\stackrel{\sim }{A}\left(r_S,T_D\right).S\left(r_T\leftarrow r_S\right)$$E1

where $\stackrel{\sim }{A}\left(r_S,T_D\right)$ is the cumulated activity (Bq) in source region $r_S$ over the integration period $T_D$, and $S\left(r_T\leftarrow r_S\right)$ is the mean absorbed dose (Gy/Bq) in the target tissue per nuclear transformation in the source region and defined by this Equation [26]:

$$S\left({\mathrm{r}}_{\mathrm{T}}\leftarrow {\mathrm{r}}_{\mathrm{S}}\right)={\sum }_{\mathrm{i}}{∆}_{\mathrm{i}}.\mathrm{\phi }\left({\mathrm{r}}_{\mathrm{T}}\leftarrow {\mathrm{r}}_{\mathrm{S}},{\mathrm{E}}_{\mathrm{i}}\right)$$E2

where $\mathrm{\phi }\left({\mathrm{r}}_{\mathrm{T}}\leftarrow {\mathrm{r}}_{\mathrm{S}},{\mathrm{E}}_{\mathrm{i}}\right)$ is the specific absorbed fractions (SAFs) value, and; ${∆}_{\mathrm{i}}=E_i{Y}_i$ (where $E_i$ is the yield and $Y_i$ is the mean energy or part of the energy distribution for β-decay) of the $i-\mathit{th}$the nuclear transition of the radionuclide in joules [27].

The absorbed dose of radiopharmaceuticals ²²³Ra and ²²⁵Ac was estimated with IDAC-Dose2.1 and given in Table 2. The findings were computed after one hour of intravenous doses. In the prostate organ, the absorbed doses of ²²³Ra and ²²⁵Ac radiopharmaceuticals were determined to be 9.47 × 10⁻⁹ Gy/Bq and 1.91E-9Gy/Bq, respectively. This number represents 1% of the total body dosage. The greatest and least absorbed doses of ²²³Ra were observed in the Thymus (9.53 × 10⁻⁸ Gy/Bq) and Eye lenses (1.30 × 10⁻¹⁰ Gy/Bq) organs, respectively, according to biokinetics distribution. In addition, the ²²⁵Ac distribution in bodily organs reveals that the Spleen (1.47 × 10⁻⁸ Gy/Bq) has the greatest concentration absorbed dosage and the Eye lenses have the lowest.

Organ	Dose coefficients				Absorbed dose (Gy/Bq)
	Gy/Bq*		Sv/Bq**		^223Ra (×10^−9)	^225Ac (×10^−9)
	^223Ra (×10^−8)	^225Ac (×10^−9)	^223Ra (×10^−9)	^225Ac (×10^−9)
Adrenals	2.06	4.14	8.24	1.65	41.2	8.27
Brain	0.471	0.945	1.88	0.378	9.41	1.89
Breast	0.477	0.955	1.91	0.382	9.54	1.91
Colon wall	2.65	5.35	10.6	2.14	52.9	10.7
Endosteum (bone surface)	0.660	1.31	2.64	0.524	13.2	2.62
Extra thoracic region	0.474	0.955	1.89	0.382	9.47	1.91
Eye lenses	0.0065	0.003	0.002	0.001	0.130	0.007
Gallbladder wall	0.478	9.55	1.91	0.382	9.55	1.91
Heart wall	1.57	3.11	6.28	1.24	31.4	6.21
Kidneys	2.81	0.056	11.2	2.26	56.2	11.3
Liver	2.52	5.05	10.1	2.02	50.4	10.1
Lung	3.40	6.85	13.6	2.74	67.9	13.7
Lymphatic nodes	0.635	1.27	2.54	0.506	12.7	2.53
Muscle	0.282	0.056	1.13	0.226	5.64	1.13
Esophagus	2.42	4.86	9.68	1.94	48.4	9.72
Oral mucosa	0.478	0.095	1.91	0.382	9.56	1.91
Pancreas	2.06	4.14	8.24	1.65	41.2	8.27
Prostate	0.475	0.095	1.89	0.382	9.47	1.91
Red (active) bone marrow	1.72	3.44	6.88	1.37	34.4	6.87
Salivary glands	0.474	0.955	1.89	0.382	9.47	1.91
Skin	0.515	1.04	2.06	0.414	10.3	2.07
Small intestine wall	2.61	5.25	10.4	2.10	52.2	10.5
Spleen	3.64	7.35	14.6	2.94	72.8	14.7
Stomach wall	2.42	4.86	9.68	1.94	48.4	9.72
Testes	0.63	1.29	2.54	0.514	12.7	2.57
Thymus	4.77	0.955	19.1	0.382	95.3	1.91
Thyroid	1.53	3.07	6.10	1.23	30.5	6.14
Urinary bladder wall	0.237	0.469	0.946	0.187	4.73	0.937
Total body	—	—	—	—	849	153

Table 2.

Intravenous ²²³Ra and ²²⁵Ac radiopharmaceutical doses and the doses absorbed (Gy/Bq) determined by computer-assessing computer-dose 2.1 in human body organs.

*

Radiation weighting factor for α-radiation is 5, unit Gy/Bq as proposed by the ICRP [26].

**

Radiation weighting factor of 20 for α-radiation with unit Sv/Bq.

ICRP = International Commission on Radiological Protection.

Figures 4 and 5 indicates doses taken in some human body organs by ²²³Ra and ²²⁵Ac radiopharmaceuticals, respectively. The histogram shows that 50 percent of the absorbed dosage is accumulated in six organs in both radiopharmaceuticals. These six organs are thymus, Spleen, lunge, kidney, colon wall, small intestine wall, Spleen, lung, kidney, colon wall, small intestine wall, and liver.

Figure 4.

The absorbed dose distribution of ²²³Ra radiopharmaceutical in somebody organs.

Figure 5.

The absorbed dose distribution of ²²⁵Ac radiopharmaceutical in some body organs.

5. Conclusions

The alpha-emitting radionuclides of ²²³Ra and ²²⁵Ra are a targeted alpha emitter radiopharmaceutical used to treat prostate cancer. The properties and absorbed dose value of those radiopharmaceuticals in body organs are reviewed in this chapter. Total body absorbed dose value (Gy/Bq) per intravenous injections of ²²³Ra was higher than ²²⁵Ac radiopharmaceuticals. This difference is related to the energy of alpha particles and the half-life of the radiopharmaceuticals. The results of this study will assist in evaluating and analyzing human body organ doses from the application of ²²³Ra and ²²⁵Ac that are used in mCRPC patients. The main obstacles using of ²²³Ra and ²²⁵Ac radiopharmaceuticals are that the daughter nuclides will always dissociate from the targeting construct upon their formation. Therefore, they can make unwanted doses in other organs.

Conflict of interest

The authors declare no conflict of interest.