Developments in radionanotheranostic strategies for precision diagnosis and treatment of prostate cancer

Abstract

Background

Prostate Cancer (PCa) is the second most diagnosed urological cancer among men worldwide. Conventional methods used for diagnosis of PCa have several pitfalls which include lack of sensitivity and specificity. On the other hand, traditional treatment of PCa poses challenges such as long-term side effects and the development of multidrug resistance (MDR).

Main body

Hence, there is a need for novel PCa agents with the potential to lessen the burden of these adverse effects on patients. Nanotechnology has emerged as a promising approach to support both early diagnosis and effective treatment of tumours by ensuring precise delivery of the drug to the targeted site of the disease. Most cancer-related biological processes occur on the nanoscale hence application of nanotechnology has been greatly appreciated and implemented in the management and therapeutics of cancer. Nuclear medicine plays a significant role in the non-invasive diagnosis and treatment of PCa using appropriate radiopharmaceuticals. This review aims to explore the different radiolabelled nanomaterials to enhance the specific delivery of imaging and therapeutic agents to cancer cells. Thereafter, the review appraises the advantages and disadvantages of these modalities and then discusses and outlines the benefits of radiolabelled nanomaterials in targeting cancerous prostatic tumours. Moreover, the nanoradiotheranostic approaches currently developed for PCa are discussed and finally the prospects of combining radiopharmaceuticals with nanotechnology in improving PCa outcomes will be highlighted.

Conclusion

Nanomaterials have great potential, but safety and biocompatibility issues remain. Notwithstanding, the combination of nanomaterials with radiotherapeutics may improve patient outcomes and quality of life.

Background

Among all causes of death, cancer ranks second in the world in terms of mortality rate. Prostate cancer is the fourth most frequently diagnosed cancer worldwide and the most prevalent cancer in men (Soerjomataram and Global cancer statistics 2022). According to the information obtained from the Global Cancer Observatory (GLOBOCAN), approximately 1,467,854 men were diagnosed with PCa, in 2022 and the incidence rate is predicted to increase by 35% to ~ 2,241,795 in 2040. Furthermore, 397,430 deaths were reported in 2022, and the number is predicted to increase to 693,737 by 2040 as depicted in Fig. 1 (Ferlay et al. 2024).

Fig. 1.

Diagrammatic representation of A Estimated number of prostate cancer incidence worldwide (2022 and 2040) and B percentage estimate of prostate cancer mortality in 2022 and 2040

While the precise cause of PCa is still unknown, multiple studies have revealed that several modifiable and non-modifiable risk factors may play a role in the development of the disease. Hormones, ethnicity, advancing age, family history of cancer, lifestyle choices, diabetes, dietary risk factors, obesity, specific medications, and some genetic variants are a few of the risk factors linked to PCa. These elements have been shown to affect the prevalence and mortality of PCa (Bott Simon and Lim 2021; Wang et al. 2000).

Presently, the diagnosis of PCa primarily involves digital rectal examination, prostate specific antigen (PSA) analysis, prostate biopsy, and magnetic resonance imaging (MRI). Similarly, current treatment approaches include active surveillance, surgery, radiation therapy, cryotherapy, androgen deprivation therapy (ADT) and chemotherapy (Sekhoacha et al. 2022). The therapeutic efficacy of most of the systemic chemotherapy is limited by insufficient tumour selectivity and drug solubility.

Traditional chemotherapeutic options exhibit unfavourable pharmacokinetics and exhibit unfavourable side effect profiles including erectile dysfunction, urinary incontinence, myelosuppression, peripheral neuropathy and development of resistance to previous treatment (Siesling et al. 2018).

Nanomaterials, defined as materials with at least one dimension in the nanometric range, play a significant role in overcoming most of the drawbacks posed by conventional drug delivery in cancer. Owing to their unique characteristics such as high surface-to-volume ratios which enable them to bind, adsorb and convey small molecules such as drugs, DNA, RNA, and proteins to targeted sites nanomaterials have the capability of enhancing the therapeutic efficacy (Barani et al. 2021). Additionally, nanomaterials offer advantages such as tumour targeting, enhanced bioavailability, good biodegradability, reduced toxicity, enhanced circulation time and enhanced therapeutic impact compared to free-drug (Thakur 2021). Furthermore, NPs improve pharmacokinetics and reduce the systemic toxicities of conventional chemotherapeutic agents by selectively targeting and delivering anticancer drugs to tumour tissues.

Radionuclide distribution to lesions is frequently insufficient when targeting tumours, hence, locoregional delivery of radiolabelled nanoparticles may circumvent this challenge. Novel drug delivery systems including liposomes, dendrimers, and many more have been developed. These provide opportunities for multiple target recognition on cancer cells, substantially amplify the delivery of radionuclides to cancer cells and selectively route them to more radiosensitive compartments (Reilly 2007). Targeted drug delivery and the potential of nano formulations as theranostic agents which integrates both diagnostic and therapeutic properties have gained a considerable amount of interest in PCa management (Azzawi et al. 2016).

In this review, we provide an overview of different nanomaterial-based drug delivery methods in the theranostics of PCa. We also discuss the benefits, drawbacks, and clinical application of these versatile new delivery platforms.

Main texts

Prostate cancer

Etiology and risk factors

Although the etiology of PCa remains elusive and has not been fully elucidated several factors are associated with its development. Age and race are amongst the most common risk factors attributed to the development of PCa. While men of black ancestry are more prone to the disease, the risk increases in African American men with a family history of PCa aged 40 years and above while it is prominent in white men above the age of 50 years without any history of PCa (Ng 2021; Barsouk et al. 2020; Phua 2021). Studies indicates that genetic predisposition play a key role in PCa more than other types of cancers. Several hereditary mutations for PCa exist including BRCA1 and BRCA2 (both recombination proteins) and the most notable being BRCA2 genes identified with a major risk of PCa (Bergengren et al. 2023; Habib et al. 2021). Prostate carcinogenesis can be attributed to consumption of saturated and trans fatty acids which lead to the disruption of prostate hormonal regulation and alteration of growth factor signalling and lipid metabolism. Other risk factors include family history, obesity, a sedentary lifestyle and smoking (Oczkowski et al. 2021).

Pathology and prognosis

Histologically, the prostate is a glandular tissue with a basal layer of low cuboidal epithelial cells covered by a layer of columnar secretory cells with abundant fibromuscular stroma separating individual glands. Androgens regulate growth and survival of the cells composing the prostate tissue (Coleman 2020). PCa typically arises from the epithelial cells lining the prostate gland and is characterised by the formation of cancerous cells that have lost their ability to regulate normal cell growth and division. The cancer cells often form small gland-like structures called adenocarcinomas and they exhibit a variety of histological patterns including acinar (comprises 95% of PCa), ductal and cribriform subtypes (Shi, et al. 2024). The prognosis of PCa depends on a variety of factors, including the stage of the diseases, the patient’s age, overall wellbeing, the presence of specific genetic alterations. The progress is generally favourable at an early stage when the disease is confined to the prostate gland. However, prognosis decreases as the cancer progresses to other organs. Advanced or metastatic PCa can manifest with a wide range of clinical outcomes from slow-growing tumours to more aggressive forms that can lead to significant morbidity and mortality. Prognostic tools such as the PSA level, Gleason’s score and imaging modalities are commonly used to assess the prognosis and guide treatment decisions in prostate cancer (Siegel et al. 2022; Epstein et al. 2016).

Staging of prostate cancer

Prostate specific antigen (PSA) testing is the most commonly used diagnostic test for PCa, where PSA level of 4–10 ng/mL is considered borderline while > 10 ng/mL is associated with greater than 50% risk of the disease while the Gleason’s score is the leading histopathological scoring system for PCa (Barsouk et al. 2020). Grade 1 corresponds to well differentiated, low grade dysplastic tissue while grade 5 corresponds to the most abnormal dysplastic tissue and scores are summated for total score. Gleason’s score is used to stratify PCa into Low grade (< 6), intermediate grade 7 and high (8–10) grade disease. Risk stratification is then made based on PSA level, grade group and clinical stage: Tumour, Node, Metastasis (TNM) (Barsouk et al. 2020). Pathologically PCa can be classified based on the aggressiveness of the tumour determined by the Gleason Score which assesses the tumour aggressiveness, extend of spread evaluated by Tumour, Node, Metastasis (TNM) staging (ranging from 1 to 4) and molecular features such as presence of specific genetic mutations. The prognosis largely depends on the Gleason Score. The staging system helps determine the extent of disease and guide treatment decision (Tzelepi 2023; Kim et al. 2021).

Radionuclides utilised in prostate cancer

Radionuclides, also termed radioisotopes are atoms that have an unstable nucleus and emit radiation as they undergo radioactive decay. Radioactive forms of elements that emit radiation and are used in nuclear medicine for diagnostic and therapeutic purposes depending on the type of particles they emit. γ-Emitting radionuclides are used for diagnosis while β- and α- emitting are used for treatment.

Radioimaging

Risk stratification is essential in PCa care, and imaging and precise diagnosis are critical in determining the degree of the disease. When detected at an early stage, suitable decisions regarding the treatment options may be undertaken to take into consideration the stage of the disease, hence improving prognosis (Luining et al. 2022).

In nuclear medicine, single photon emission tomography (SPECT), computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET), are non-invasive techniques used to diagnose PCa. Functional alterations occur before observable anatomical changes are detected by CT and MRI, hence nuclear imaging techniques are clinically significant for the early identification of cancer (Evangelista and Zucchetta 2021).

To increase the 5-year survival rate among patients, it is crucial to identify distant metastases as early as possible and to diagnose them accurately. With improved technetium-99 m (^99mTc) uptake at metastatic locations, the use of Tc-99 m methylene diphosphate (^99mTc-MDP) continues to be the gold standard for the identification of bone metastases (Adam et al. 2021).

While SPECT is more accurate than planar imaging at detecting bone metastasis, it may still be necessary to have additional tests, such as an MRI, in cases when the uptake of the radiotracer is ambiguous. Numerous studies have demonstrated that SPECT/CT has stronger lesion-to-background contrast and better anatomic localization of lesions, increasing diagnostic accuracy (Cuccurullo et al. 2018; Buck et al. 2008; Mariani et al. 2010).

As of 2018, the National Comprehensive Cancer Network (NCCN) recommendations advised against utilising 2-deoxy-2-[¹⁸F] fluoro-D-glucose([¹⁸F] FDG) PET/CT to stage PCa, rather reserved to assess biochemical recurrence or the potential for metastatic illness (Carroll and Mohler 2018).

Due to the faster turnover of defective osteoblasts, [¹⁸F] fluorides absorbed by bone metastases, according to their osteoblastic activity, exhibits a strong contrast between normal and abnormal bone. The clinical management of patients with a high risk of PCa may be positively impacted by the additional value of PET/CT, which is a highly sensitive and specific modality for the identification of bone metastases (Zhou et al. 2019). Hence more lesions are detected on SPECT compared with planar images and on ¹⁸F-Fluoride PET compared with SPECT.

Metastatic bone disease is a common and severe condition suffered by patients with advanced PCa disease. Studies have indicated that approximately 90% of patients with advanced PCa experience excruciating cancer-related pain. According to the European Association of Nuclear Medicine (EANM), treatment of cancer-induced bone pain progresses from non-steroidal analgesics to opioids often in combination with radiotherapy, and radionuclide therapy being initiated as the last line of treatment (Poeppel et al. 2018; Handkiewicz-Junak et al. 2018).

The most commonly available radionuclide treatments agents for metastatic bone pain include phosphorous-32 (³²P), samarium-153 (¹⁵³Sm), and strontium-89 (⁸⁹Sr) which are beta minus emitters (β⁻). Radium-225 (²²⁵ Ra) is an alpha (α) emitter indicated for the radionuclide treatment of metastatic castrate-resistant prostate cancer (mCRPC) in patients showing symptoms of bone metastases (Poeppel et al. 2018). With the development of more sophisticated PET/CT radiopharmaceuticals, such as gallium-68 (⁶⁸Ga)-labelled prostate specific membrane antigen (PSMA) ligands, it is now possible to stage, localise, and choose patients for PSMA-targeted molecular radiotherapy (Hagaman et al. 2021).

Radiolabelled prostate specific membrane antigen (PSMA)

Prostate specific membrane antigen (PSMA), a type II transmembrane glycoprotein with both intracellular and extracellular domains is found in many different types of cells, including normal prostate epithelial cells, salivary gland cells, small intestine cells, stomach, colon, and renal tubules (Meher et al. 2023). PSMA is present in the cell membranes, but it is excessively produced in prostate cancer cells. It plays a role in the cleavage of folate in the small intestine.

Additionally, several studies have demonstrated the expression of PSMA in neural tissue, hence the different nerve types and neurotransmitters present in the tumour microenvironment play a significant role in the development of PCa (Zhou et al. 2021; Sejda et al. 2020; Maguid et al. 2023; Hyväkkä et al. 2021). PSMA is expressed 100–1000 times more in PCa than in normal cells, making it a viable target for prostate cancer-specific imaging (Patell et al. 2023). PCa cells express PSMA selectively within the organ itself and in metastases to lymph nodes and bone. PSMA is superior to a prostate-specific antigen (PSA) in that it increases with a higher grade of tumour (Foley et al. 2020).

Peptide ligands of PSMA are radiolabelled to target PCa both for diagnosis (PSMA-11) and therapeutic purposes (PSMA-617) in prostate cancer management (Barani et al. 2020). There are ongoing clinical trials that use PSMA-targeted agents for diagnostic and therapeutic purposes (Abou et al. 2020). Lutetium-177-PSMA-617 ([¹⁷⁷Lu] Lu-PSMA) is inherently a radiolabelled theranostic agent. The simultaneous emission of imageable gamma photon [(206 keV (11%) and 113 keV (6.4%)] along with particulate β⁻emission (β_max = 497 keV) makes ¹⁷⁷Lu a theranostically desirable radioisotope. Nevertheless, the abundance of the gamma photon is only 11%, hence not ideal for imaging. In most instances patients are imaged with ⁶⁸Ga or ¹⁸F -labelled PSMA targeted agents as a theranostic pair (Das and Banerjee 2015).

Lutetium labelled small molecule inhibitors of PSMA such as [¹⁷⁷Lu] Lu-PSMA-617 and [¹⁷⁷Lu] Lu-PSMA I&T are radioligand therapy agents that deliver β-emitting particles to PSMA exhibiting cells. The structure of PSMA-617 small molecule inhibitor is linked to the extracellular domain of PSMA as illustrated in Fig. 2 (Plichta et al. 2021).

Fig. 2.

Structure of PSMA-617 small molecule inhibitor of PSMA showing the extracellular binding site on PSMA. Adapted from (Plichta et al. 2021)

Despite castration, most men with PCa will ultimately experience disease progression and a poor prognosis. [¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto^®) was approved by United States Food and Drug Administration (FDA) in 2022 for the treatment of patients with PSMA-positive metastatic castration resistant PCa (mCRPC) who have received at least one treatment with an androgen-receptor (AR) pathway inhibitor and one with a taxane-based chemotherapy, such as docetaxel or cabaxitaxel (Parent and Kase 2022; Parihar et al. 2022).

Currently, ⁶⁸Ga-PSMA-11 and ¹⁸F-2-(3-{1-carboxy-5-[(6-¹⁸F-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentaacetic acid)(¹⁸F-DCFPyL) are PET radiopharmaceuticals approved by the FDA (2020 and 2021, respectively) for patients selected for metastatic PCa treatment with [¹⁷⁷Lu]Lu-PSMA-617 (Plichta et al. 2021; Calais et al. 2021). Baseline [Ga]Ga-PSMA-11 PET/CT imaging and lesion uptake exceeding mean uptake of the liver is a prerequisite for radioligand therapy with [¹⁷⁷Lu]Lu-PSMA-617 (Groener et al. 2023).

⁶⁸Ga is a positron-emitting radionuclide that is produced from a Germanium-68/ Gallium-68 (⁶⁸Ge/⁶⁸Ga) generator and has a short half-life of 68 min. The long physical half-life of the parent radionuclide germanium which is 270.8 days allows the generator to be eluted for up to one year providing cost effectiveness although it is associated with high set-up capital cost thereby limiting widespread use (Okarvi 2019). The energy of the emitted positron from ⁶⁸Ga is higher than that of ¹⁸F which can lead to lower resolution and a compromised ability to detect smaller lesions. [⁶⁸Ga] Ga-PSMA-11 is said to have higher sensitivity and specificity than other radionuclides used in the detection of PCa lesions and is also effective in monitoring recurrence and response to therapy (Rodnick et al. 2022).

¹⁸F is a cyclotron-produced radionuclide and as such more costly. [¹⁸F] PSMA-1007 can detect PCa lesions in patients with biochemical recurrence (BCR) at PSA levels lower than those of conventional imaging techniques. Unlike ⁶⁸Ga, which has a half-life of 68 min and requires an in-house generator, its half-life of 109.7 min allows the radionuclide to be transported to other centres. [¹⁸F] F-PSMA-1007 has a much greater uptake within PCa cells (Awenat et al. 2021), improved visualisation of the metastatic lymph nodes in the abdomen and increased sensitivity in assessing for nodal disease (Giesel et al. 2017). Owing to the commonly used radiotracer [¹⁸F] FDG, the use of ¹⁸F-labelled PSMA has been adopted (Werner et al. 2020).

Chen and colleagues investigated the diagnostic efficiency of F-FDG PET/CT and ⁶⁸Ga radiolabelled PSMA in 56 patients with CRPC from 2018 to 2021 and results indicated that although both detection rate and number of lesions detected was superior for ⁶⁸Ga-PSMA than ¹⁸F-FDG (75% vs. 51.8% and 135 vs. 95) respectively, ¹⁸F-FDG added value in 23.2% of CRPC patients. In addition patients with a Gleason Score > 8 and PSA > 7.9 ng/ml could benefit from ¹⁸F-FDG PET/CT (Chen et al. 2022).

A study by Wu et al., compared the efficiency of [⁶⁸Ga] Ga-PSMA PET/CT and MRI as diagnostic modalities for staging lymph nodes metastases in PCa. The data suggested that [⁶⁸Ga] Ga-PSMA has more sensitivity compared to magnetic resonance imaging (MRI) (65% vs. 41% respectively). Overall specificity was comparable between the two diagnostic methods (94% for [⁶⁸Ga] PSMA vs. 92% for MRI). Finally it was concluded that [⁶⁸Ga] Ga-PSMA PET/CT proved to be a more efficient imaging modality compared to MRI (Wu et al. 2020).

In a phase III diagnostic trial to assess the accuracy of [⁶⁸Ga] Ga-PSMA-11 PET/CT, 764men (aged between 63 and 93 years) underwent [⁶⁸Ga] Ga-PSMA-11 imaging scintigraphy for primary staging of PCa. Of the 764 men, 277 subsequently underwent radical prostatectomy with lymph node dissection and 487 men did not undergo prostatectomy. This phase III trial demonstrated that sensitivity and specificity of [⁶⁸Ga] Ga-PSMA-11 PET were 40% and 95% respectively in the former cohort compared to histopathology. Low sensitivity observed was due to a high population of patients who did not undergo prostatectomy exhibiting larger size and number of nodes treated with non-surgical approaches. This study formed the foundation of a new drug application of [⁶⁸Ga] Ga-PSMA-11. Owing to its high specificity, a positive [⁶⁸Ga] Ga-PSMA-11 PET indicates presence of disease and has been widely used for PCa imaging before therapy initiation (Hope et al. 2021).

A phase II/III prospective multicentre study was conducted to assess the diagnostic accuracy of ¹⁸F-DCFPyL PET/CT. Cohort A enrolled patients with high risk PCa undergoing prostatectomy to determine pelvic nodal disease with specificity, sensitivity and extrapelvic metastases evaluation (Pienta et al. 2021). Sensitivity and positive predictive value for PCa with biopsied lesions were evaluated in Cohort B men with suspected recurrent or metastatic PCa to conventional imaging. Study results supported the potential use of ¹⁸F-DCFPyl to stage men with high risk PCa for distal metastases and reliably detect sites of disease in men with metastatic PCa (Pienta et al. 2021).

Sergieva et al. investigated the clinical application of SPECT/CT imaging in patients with recurring PCa using small molecule PSMA ligand (PSMA-T4) radiolabelled with [^99mTc] Tc-PSMA-T4. A dose of 6,3 MBq/Kg of 70 kg men was intravenously injected in all 36 patients and whole-body imaging examination carried out 1–3 h post IV injection of [^99mTc] Tc-PSMA-T4. Out of the patients enrolled, five patients were negative. Sensitivity was 84.37%, specificity 100% (4/4) and accuracy was measured as 86.11%. The study concluded that SPECT/CT imaging with [^99mTc] Tc-PSMA-T4 could be a promising for staging patients with recurrent disease to determine personalised treatment (Sergieva et al. 2021).In another study by Maurin and colleagues [^99mTc] Tc-PSMA-T4, showed effectiveness in studies in humans anticipating phase 2/3 clinical studies(Maurin et al. 2022).

A study by Klingenburg and colleagues to stage treatment naïve, high risk PCa patients conducted in 691patients revealed 83.1% accuracy in detecting Lymph nodes metastasis (LNM) and 35,3% advanced disease (35,3%) on [⁶⁸Ga] Ga-PSMA PET/CT imaging done 60 min after IV administration of 2.14 MBq [⁶⁸Ga] Ga-PSMA /Kg of body weight. Sensitivity, specificity and accuracy for LNM was 30,6% (attributed to a massive selection bias), 95% and 81% respectively. Another study by Hofman et al., found lower sensitivity (38%) ad specificity of 91% (Klingenberg et al. 2021).

Rauscher and colleagues evaluated the lesion detection efficacy of [⁶⁸Ga] Ga-PSMA-11 and [¹⁸F] F-PSMA-1007 in biochemical recurrence after radical prostatectomy and frequency of non-tumour related uptake. Increased PSMA ligand uptake was observed from [¹⁸F] F-PSMA-1007 compared to [⁶⁸Ga] Ga-PSMA-11. [¹⁸F] F-PSMA-1007 revealed approximately five times more lesions attributed to benign origin than did [⁶⁸Ga] Ga-PSMA-11. Similar number of lesions attributed to recurrent PCa were observed for both agents (Rauscher et al. 2020). A summary of radionuclides used in PCa detection is provided in Table 1.

Table 1.

Radionuclides for prostate cancer diagnosis

Radionuclide	Half-life	Mode of Production	Mode of decay %	Energy emitted	Application	References
Technetium-99 m (99mTc)	6 h	99Mo/99mTc generator	IT (100)	140 keV	SPECT imaging	Pijeira et al. (2022)
Carbon-11 (11C)	20.3 min	Cyclotron	β+ (100)	155 keV	PET Imaging	Silva et al. (2021)
Fluorine -18 (18F)	109.7 min	Cyclotron	β+ (97), EC (3)	635 keV Emax	PET imaging	Jacobson et al. (2015)
Gallium-68 (68 Ga)	67.8 min	68Ge/68 Ga generator	β+ (90), EC (10)	1.9 keV Emax	PET imaging	Silva et al. (2021)
Nitrogen-13 (13N)	10 min	Cyclotron	Β+(100)	511 keV gamma energy	PET imaging	Damiana and Dalm (2021)
Copper-64 (64Cu)	12.7 h	Nuclear reactor	β− (40), EC (40), β+(19)	β+ 655 keV Emax 278 keV Emin	PET imaging	Silva et al. (2021)
Gallium -67 (67 Ga)	3.27 d	Cyclotron	EC (100)	93 keV, 184 keV, 300 keV, relevant to imaging	SPECT imaging	Silva et al. (2021)
Zirconium-89 (89Zr)	78.4 h	Cyclotron	β+ (100)	245 keV Emax	PET imaging	Silva et al. (2021)
Indium-111 (111In)	2.83 d	Cyclotron	EC (100)	245 keV	SPECT imaging	Silva et al. (2021)
Iodine-124 (124I)	100.8 h	Cyclotron	β+ (100)	511 keV positron energy	PET imaging	Sweeney (2015)
Iodine -123 (123I)	13.2 h	Cyclotron	EC (100)	159 keV gamma energy	SPECT imaging	Sweeney (2015)
Yttrium -86 (86Y)	14.7 h	Cyclotron	EC, β+	902 keV	PET imaging	Damiana and Dalm (2021)
Thallium 201 (201Tl)	73 h	Cyclotron	EC	69–81 keV, gamma rays at 135-167 keV	SPECT imaging	Silva et al. (2021)

IT isomeric transition, EC electron capture

Radiotherapy

Treatment for cancer using radionuclides is safe and effective and has shown efficacy with minimal toxicity. It is accomplished by utilising radiopharmaceuticals that provide ionising radiation and either bind to cancer cells or accumulate through physiological mechanisms (Sgouros et al. 2020). The radiopharmaceuticals are made with radionuclides that emit β⁻-particles, α-particles, and Auger electrons (AE) releasing the ionisation particles in the proximity of the target (Czerwińska et al. 2020). β-emitting particles, α-emitting particles, and AE damage DNA by decreasing penetration range and increasing DNA damage, respectively as illustrated in Fig. 3.

Fig. 3.

Diagrammatic representation of DNA damage by A beta-emitting particles, B alpha-radiation and C Auger electrons respectively

β⁻-Emitting particles widely used in cancer therapy, have a profound tissue penetration of approximately 20–130 mm with low linear energy transfer (LET) (Reuvers and Kanaar 2020). The limitation of β-emitting radionuclides is their inability to target small clusters of cancerous cells due to their long-range that causes damage to healthy cells (Mi et al. 2016).

α-Emitters are extremely energetic particles that have a limited penetration and release their entire energy within a few diameters (50–100 µm) in tissue. However, they inflict more damage to tumour cells (approximately 500 times cytotoxic potency than β-particles) with less radioactivity and have lower toxicity to nearby healthy tissue (Pandit-Taskar 2019). High energy delivery results in increased ionisation energy, which damages double-strand DNA and causes cluster breaks, which increase the likelihood of cell death, apoptosis, and necrosis (Czerwińska et al. 2020; Kratochwil et al. 2019).

²²³Radium-dichloride (²²³RaCl₂) is an radiopharmaceutical that emits α particles and is used for pain alleviation in PCa patients with bone metastases (Therapy et al. 2020). Actinium-225 (²²⁵Ac)is employed for PCa therapy when ¹⁷⁷Lu-PSMA and other radiotherapy modalities fail (Feuerecker et al. 2020). Owing to the higher LET exhibited by the alpha-emitting ²²⁵Ac, PSMA-617 radiolabelled with ²²⁵ Ac has more potential to induce cell damage compared to beta-emitting radionuclides such as ¹⁷⁷Lu-PSMA-617 (Sathekge et al. 2019). Hence targeted alpha therapy (TAT) could be an effective option for advanced mCRPC resistant to β⁻ emitting ¹⁷⁷Lu-PSMA-617.

²²⁵Ac-PSMA exhibits dose-limiting toxicity due to accumulation of radiolabelled small molecules in the salivary gland giving rise to severe xerostomia, although it is not clear why PSMA radioligands localise in the salivary glands. Hammer et al., investigated a novel antibody based targeted ²²⁷ Th conjugate (PSMA-TTC) undergoing phase 1 clinical trials (Hammer et al. 2020). In-vitro studies were carried out to investigate cytotoxicity activity and in-vivo antitumour efficacy was performed in cell lines and patient-derived xenografts models of PCa (Hammer et al. 2020).

AEs are very low energy electrons that are emitted by radionuclides that decay by electron capture. They exhibit the shortest range when compared to both β⁻ and α-emitting radionuclides and induce a high biological effect locally causing lethal damage to cancer cells (Pijeira et al. 2022; Ku et al. 2019). Radionuclides such as ¹¹¹In, ⁶⁷Ga, ¹²³I, ¹²⁴I, and terbium-161 (¹⁶¹Tb) emit Auger electrons.

¹⁶¹Tb is a newly introduced radionuclide of interest and exhibits similar chemical properties to the widely used ¹⁷⁷Lu radionuclide for therapeutic purposes in PCa. In contrast to ¹⁷⁷Lu, ¹⁶¹Tb yields a substantial amount of short-range Auger/conversion electrons in addition to β-particles responsible for therapy (Müller et al. 2019). Studies have shown that ¹⁶¹Tb is more potent than ¹⁷⁷Lu for tumour therapy (Haller et al. 2016).

Radionuclides used for radiotherapy PCa treatment are provided in Table 2

Table 2.

Radionuclides used for prostate cancer therapy

Radionuclide	t1/2	Mode of production	Mode of decay	Energy Emitted (MeV)	Application	References
Yttrium-90 (90Y)	64.1 h	90Sr/90Y Generator	β−(100)	2, 280	Targeted radiotherapy	Czerwińska et al. (2020)
Lutetium-177 (177Lu)	6.73d	176Lu(n,γ)177Lu Cyclotron	β−(100) γ	0, 497	Targeted radiotherapy	Czerwińska et al. (2020)
Iodine -131(131I)	8.1d	natTe(n,γ)131I Nuclear Reactor	β− (100)	0, 970	Targeted radiotherapy	Czerwińska et al. (2020)
Radium-223(223Ra)	11.4d	227Ac/223Ra Generator	α (100)	2, 820	Treatment of bone metastases	Majkowska-Pilip et al. (2020)
Actinium-225(225Ac)	10d	229Th/225Ac 226Ra (p, 2n)225Ac Cyclotron	α (100)	28	Targeted radiotherapy	Majkowska-Pilip et al. (2020)
Thorium-227(227Th)	11.43d	227Ac/227Th Generator	α	6, 140	Targeted radiotherapy	Majkowska-Pilip et al. (2020)
Lead-212(212Pb)	10.6	228Th/224Ra/212Pb Generator	β−/α decays to 212Bi	6, 050	Targeted radiotherapy	Majkowska-Pilip et al. (2020)
Terbium-161(161 Tb)	6.89d	Nuclear reaction 160Gd (n,γ) 161Gd-161 Tb	β−/Auger &CE	0, 154	Targeted Radiotherapy	Müller et al. (2019)
Astatine-211 (211At)	7.2 h	Cyclotron	α (100)	5, 870 7, 450	Targeted Radiotherapy	Zalutsky, Pruszynski (2012)
Copper-67 (67Cu)	61.83 h	Nuclear reactor	β−	Emin 0,141	Targeted radiotherapy	Lee et al. (2022)
32P	14.26d	Neutron activation	β−	Max 1,710 Min 0,700	Treatment of bone metastases pain	Handkiewicz-Junak et al. (2018)
153Sm	1.94 d	Neutron activation	β−	Max 0.81, Min 0.23	Treatment of bone metastases pain	Handkiewicz-Junak et al. (2018)

The availability of most radionuclides with high therapeutic potential due to their favourable decay characteristics is limited by cost. The various physical decay properties such as the emission of high and low LET particles and the variable half-life could allow the application of the most appropriate radionuclide for a given malignancy for specific individual treatment, hence radionuclide therapy fits personalised medicine perfectly. Radionuclide therapy is among the most modern therapeutic strategies to be pursued.

Clinical applications of radionuclide therapy and efficacy

The use of radionuclides in clinical settings has been reported with different outcomes. For instance, Rahbar et al., evaluated tumour responses, side effects, and survival rates in 28 patients suffering from mCRPC undergoing radioligand therapy with ¹⁷⁷Lu PSMA-617 and results showed optimally tolerated therapy with a 75% decline in PSA levels and an increased survival rate after two cycles of therapy (Rahbar et al. 2016).

Schuchardt and colleagues conducted a study in a cohort of 138 patients with mCRPC undergoing PSMA radioligand therapy to investigate the safety, biodistribution and possible side effects of ¹⁷⁷Lu labelled PSMA-617 and PSMA-I&T small molecules. Eighty-seven patients received 6.5 ± 1.1 GBq of PSMA-617 and Fifty-one patients received 6.1 ± 1.0 GBq of PSMA-I&T. The mean absorbed tumour doses were comparable for both ¹⁷⁷Lu-PSMA I&T and PSMA-617 (5.8 vs 5.9 Gy/GBq) respectively. Both PSMA small molecules demonstrated a comparable dose of 0.5 Gy/Gbq to the parotid gland and exhibited the highest mean absorbed doses in the lacrimal glands. The renal dose was lower for Lu-PSMA-617. Both PSMA-617 and PSMA-I&T demonstrated favourable safety in mCRPC patients with no significant adverse effects (Schuchardt et al. 2022).

A research team headed by Hofman conducted a single-arm, single centre phase II trial to investigate the safety, efficacy, and effect on quality of life of [¹⁷⁷Lu] Lu-PSMA-617 in men with mCRPC who progressed after standard therapy. Eligibility of patients was determined by imaging (by Response Evaluation Criteria in Solid Tumors (RECIST)) or bone scan to confirm progression of disease. Selected patients received four cycles of [¹⁷⁷Lu] Lu-PSMA-617 every six weeks. Findings of the study demonstrated high efficacy, low toxicity and reduction in pain (Hofman et al. 2018).

One of the greatest success stories is the VISION Trial, the largest phase III trial on PSMA therapy whose results were published on 3 June 2021 (Sartor et al. 2021). Results provided the first evidence of a significantly improved progression-free (60%) and overall survival (OS) of 38% in late-stage PCa who were treated with ¹⁷⁷Lu-PSMA-617 when compared with standard of care (SOC) (Czernin and Calais 2021).

Although [¹⁷⁷Lu] Lu-PSMA treatment produced survival benefit for pretreated patients with mCRPC, response rate had been approximately 60% with marked progression of the disease. The bone marrow is the main site of progression owing to a lower dose delivered to the micrometastases in the bone. α-emitting particles could be more effective than β-emitters (Kratochwil et al. 2023).

Sathekge et al., exploited the efficacy of ²²⁵Ac-PSMA-617 therapy in patients with metastatic PCa who had previously received first line and second line treatment options available in South Africa. Therapy was initiated in two months interval with initial doses of 8 megabecquerel (MBq) or 10 MBq in more advanced disease and 6 or 4 MBq in good response. Baseline staging and imaging follow up with ⁶⁸ Ga-PSMA PET/CT was done every two months. Fifty-seven patients were divided in two groups (A: patients that have received standard therapy and second line therapies, B: patients who received standard therapy only). Improved anti-tumour activity was observed in 71% in group A while a significant 92% response rate was observed in group B and both groups presented with remarkable palliation of bone pain (Sathekge et al. 2019).

The efficacy of [¹⁶¹Tb] Tb-PSMA-617 as a potentially more effective alternative to the clinically established ¹⁷⁷Lu-PSMA-617 [¹⁷⁷Lu] Lu-PSMA-617 has been investigated (Müller et al. 2019). The viability and survival of PC-3 tumour cells were reduced after exposure to [¹⁶¹Tb] Tb-PSMA-617 compared to the effects observed with the same dose activity of [¹⁷⁷Lu] Lu-PSMA-617. Treatment of mice with [¹⁶¹Tb] Tb-PSMA-617 (5.0 MBq and 10.0 MBq) resulted in activity-dependent increase in median survival of 36 and 65 days respectively compared to 19 days for untreated mice. Hence [¹⁶¹Tb]Tb-PSMA-617 indicated superior in-vitro and in-vivo results compared to [¹⁷⁷Lu]Lu-PSMA-617 (Müller et al. 2019).

Current state-of-the-art

There are promising radionuclides under study for the treatment of PCa which include astatine-211 (²¹¹At), bismuth-212 (²¹²Bi), bismuth-213 (²¹³Bi), lead-212 (²¹²Pb), terbium-149 (¹⁴⁹Tb), and thorium-227 (²²⁷Th) (Ling et al. 2022). Treatment with ¹⁷⁷Lu-PSMA-617 and ²²⁵Ac-PSMA-617 have promising results to improve survival and quality of life in patients with metastatic advanced PCa (Ling et al. 2022).

α-emitters exhibit a higher linear energy transfer (LET) and limited range in tissue giving rise to double-strand DNA and DNA cluster breaks, hence they are more effective in selectively killing tumour cells while sparing healthy tissue compared to β⁻ emitters such as ¹⁷⁷Lu-PSMA-617 (Therapy et al. 2020; Ling et al. 2022).

The Alphaβet trial is an ongoing Phase I/II trial to assess the efficacy of a combination treatment of ²²⁵Ra and [¹⁷⁷Lu]Lu-PSMA-I&T in men with mCRPC. Kostos and colleagues anticipated that the combination will improve eradication of micrometastases osseous disease (Kostos et al. 2022).

Nilsson et al., carried out an analysis on patients with CRPC in phase III ALSYMPCA study to determine the treatment effects of ²²³Ra. Patients receiving ²²³Ra experienced improvement on treatment accompanied by significant quality of life (QoL) compared to the placebo group (Nilsson et al. 2016).

A follow up of a phase II prospective study was conducted by Violet and co-workers on 50 patients with mCRPC who had previously received standard therapies. Four cycles of ¹⁷⁷Lu-PSMA-617 were administered every six weeks and 50% decline in PSA levels were achieved in 32 patients including 22 patients with at least 80% decrease. An overall survival of 18.4 months was achieved in patients with a PSA decline of at least 50% (Violet et al. 2022).

Gastrin-releasing peptide receptors (GRPRs) tend to be overexpressed in human PCa cells, hence provide a platform for molecular imaging. Nock and co-workers generated a novel potent GRPR inhibitor DOTA-p-aminomethylaniline-diglycolic acid-DPhe-Gln-Try-Ala-val-Gly-His-NH-CH [CH₂-CH(CH₃)₂]₂ (formerly known as NeoBOMB1 and now referred to as NeoB) radiolabelled with ⁶⁸Ga, ¹¹¹In and ¹⁷⁷Lu for theranostic purposes. After injection in mice ⁶⁸Ga, ¹¹¹In and ¹⁷⁷Lu exhibited comparable GRPR specificity and high uptake of radionuclides in PC-3 xenografts (30,6 ± 3.9, 28.6 ± 6.0 and > 35% injected dose per gram at 4 h after injection respectively). The first translational study in PCa patients using ⁶⁸Ga-NeoB as a PET tracer proved to be efficient and rapid localisation in the tumour tissue was observed achieving high contrast imaging, hence proving its efficiency (Nock et al. 2017).

Ruigrok et al. investigated the safety of [¹⁷⁷Lu] Lu-NeoB treatment in a preclinical study. Repeated administration of [¹⁷⁷Lu] Lu-NeoB was tolerated and biodistribution studies in mice bearing GRPR-expressing human PCa (PC-3) xenografts demonstrated favourable in-vivo stability and high tumor uptake and retention. Results showed highest absorbed doses in GRPR-expressing pancreas, the liver, and kidneys. A small first in human study was performed in four PCa patients using [⁶⁸Ga] Ga-NeoB diagnostic PET/CT imaging. Implementation of NeoB theranostics into clinical trials is ongoing (Ruigrok et al. 2022).

A phase I/II trial evaluation of [¹⁶¹Tb] Tb-PSMA- I&T radioligand therapy on men with mCRPC is ongoing. Buteau et al. hypothesized that [¹⁶¹Tb]Tb-PSMA-I&T will deliver effective radiation to sites of metastatic PCa with an acceptable safety profile(Buteau et al. 2023).

Combination of radionuclides and nanotechnology for diagnosis and therapy

The enhanced targeting and delivery of radiopharmaceuticals by nanoparticles which can be attributed to their increased surface area-to-volume ratio, high radionuclide loading capacity and labelling efficiency, the ability of passive and active targeting of cancerous tissue and potential for multiplexing diagnostic and therapeutic radionuclides within one construct, makes the integration of nuclear medicine and nanoparticles noteworthy. The combination, therefore, enhances PCa patient diagnostic precision and therapy monitoring.

Potential benefits and drawbacks of combination of radionuclides and nanotechnology

The concept of fabricating small NPs with radioactive nuclides is a useful strategy for the effective diagnosis and treatment of cancer. Radioactive NPs have the advantage that they can be accurately and precisely traced during each of the steps of their application (Farzin et al. 2019). Due to their smaller size, nanoparticles may easily accumulate in tumour tissues and have a special advantage when it comes to targeting prostate cancer cells. When used in conjunction with radiopharmaceuticals, these nanoparticles can directly carry radioisotopes to malignant cells while preserving healthy tissues, hence reducing adverse effects (Huclier-Markai et al. 2020).

Radiopharmaceutical-nanoparticle conjugates enable highly accurate imaging of prostate cancer cells, which also help in the exact detection of tumours and metastases. With the use of this sophisticated imaging, physicians may create individualised treatment regimens and track the advancement of their patients by learning vital details about the location, size, and features of tumours (Roy et al. 2022).

Nanoparticles can be used to provide targeted and concentrated dosages of treatment directly to prostate cancer cells by incorporating therapeutic isotopes or medicines. This focused strategy lessens the systemic toxicity linked to traditional chemotherapy while increasing therapeutic efficacy (Shende and Gandhi 2021). Furthermore, their slow clearance from the body can restrict their ability to be administered repeatedly (Zhao et al. 2022). Even though nanoparticles have a lot of promise, certain nanoparticles can cause unintended immunological reactions or have inherent cytotoxicity, thorough preclinical and clinical research is necessary to guarantee patient safety. Specialised manufacturing procedures are needed for the manufacture of nanoparticles and their subsequent functionalisation with radiopharmaceutical substances, which can be quite complex (Datta and Ray 2020).

There are many obstacles to overcome before such procedures may be widely used in medicine, particularly regarding cost-effectiveness, repeatability, and quality control. Clinical trials, safety evaluations, toxicological assessments, and other stringent regulatory approvals are necessary before novel nanoparticles can be used as therapeutic agents. This procedure can be expensive and time-consuming, which makes it more difficult for them to be effectively transferred from the lab to clinical practice (Rashidi et al. 2024).

Radiolabelling nanomaterials

Radiolabelling nanomaterials (NMs) could provide whole body, non-invasive, real time and dynamic imaging capability and enables quantification of NM concentration in targeted organs over time which provides invaluable information for NMs -based diagnosis and therapy (Dai et al. 2021).

In general, there are two ways to label NPs viz direct radiolabelling when the radioisotope is encapsulated into the core of NPs or conjugated to the surface, or indirect labelling when a chelator is being used to bridge the NP with the isotope. Most studies in literature focus on the use of NPs that are radiolabelled with positron emitting radioisotopes for tumour imaging (Chelator et al. 2022).

During radiolabelling procedure, it is important to consider the biological half-life of the NPs and the radioisotope to allow visualisation of the NPs until the target is reached as well as avoiding unnecessary radiation exposure to the patient. Radiolabelling procedure should not affect the physical and chemical properties of the NPs. Factors such as radiolabelling efficiency, specific activity and radiochemical yield should be considered after radiolabelling.

Direct labelling of nanomaterials

Direct labelling has several advantages, such as the preservation of the nanomaterial structure and a reduction in the number of processes, which shortens the processing time, obviates the need for bulky chelates that link the radionuclide to NPs thereby improving the in-vivo activity. Some of the reaction techniques employed are halogenation, physical interaction, chemical adsorption, radioisotope exchange and coprecipitation (Goel et al. 2023).

Suchankova and colleagues directly radiolabelled titanium dioxide and hydroxyapatite nanoparticles with ^99mTc for diagnosis and ²²³Ra for therapy respectively. Radionuclide sorption on formulated titanium dioxide NPs and direct incorporation of ²²³Ra into the hydroxyapatite NP structure were used and the radiolabelling efficiency was greater than 94% for both methods (Suchánková et al. 2020).

Biomimetic synthetic apatite NPs have gained popularity in nanomedicine for use in bone cancer due to their chemical similarity with the mineral phase of bone. In another study, [¹⁸F] NaF was directly incorporated into the crystal lattice of the AP-NP while labelling by surface functionalisation was accomplished by using ⁶⁸Ga-NO₂AP. Both tracers were fast, facile and reproducible (Sandhöfer et al. 2015).

Salvanou et al. demonstrated a simple direct radiolabelling of iron oxide NPs by ⁶⁸Ga and ¹⁷⁷Lu The NPs coated with alginic acid (MA) and stabilised with polyethylene glycol (MAPEG demonstrated high radiochemical yield of greater than 90% after 30 min incubation for both MA and MAPEG. Radiochemical yield of 94,53 ± 2,76% and 94.53 ± for [⁶⁸Ga]Ga-Ma and [⁶⁸Ga]Ga-MAPEG respectively and 95 ± 1,25 and 93,65 ± 1,03 for [¹⁷⁷Lu]Lu-MA and [¹⁷⁷Lu]Lu-MAPEG respectively (Salvanou et al. 2022).

Indirect labelling of nanomaterials

Indirect radiolabelling involves the use of chelators or prosthetic groups to link or bind a NP to a radionuclide via chemical linkages (Bentivoglio et al. 2022). Bifunctional chelators (BFCs) can be linked to the NPs and then to the radioisotope or can be linked first to the radioisotope then to the nanoparticle as illustrated in Fig. 4.

Fig. 4.

Approaches of indirect radiolabelling nanoparticles using Bifunctional Chelators. A-represents a Nanoparticle, B- Bifunctional chelator attached to a radioisotope. C Schematic representation of radiolabelling a nanoparticle

The chelating agent can be acyclic or linear, like deferoxamine (DFO) or diethylenetriamine pentaacetic acid (DTPA) as illustrated in Fig. 5 and is typically rigid and requires lower temperatures and quicker reaction times than macrocyclic chelating agents (Varani et al. 2022). Radiometal-based drugs are of substantial interest because of their versatility for clinical translation compared to none-metal radionuclides.

Fig. 5.

Chemical structure of DTPA

The use of macrolytic chelators such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) and (1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) are complex structures and hence require a higher temperature slow binding kinetics giving rise to a higher degree of stability as illustrated in Fig. 6.

Fig. 6.

Chemical structure of chelating agents used to bridge carrier molecules and radioisotopes

BFCs are characterised by a double function, where the chelator can bind the radioisotope and another one can bind the NPs through a functional group on their surface (Lemaître et al. 2022). Carrier molecules such as a peptide, antibody, amino acid or small molecule act as vehicles for radiopharmaceuticals by bringing the radionuclide to the molecule of interest whereas BFCs build a chelate complex between carrier molecule and the radioisotope (Khabibullin et al. 2018).

Different NPs such as organic (liposomes, micelles and polymers) and inorganic (gold, iron oxide, etc.) can be radiolabelled with different radionuclides depending on their chemical properties (Micha 2017).

For instance, PEGylated liposomes were loaded with ²²⁵Ac and labelled with the mouse antihuman PSMA J591 antibody in a study conducted by Bandekar and co-workers and the loading efficiency ranged from 58 to 85.6% of introduced radioactivity (Bandekar et al. 2014).

Wong et al. evaluated radiolabelled ⁶⁴Cu-DOTA-anti PSMA single chain (scFv) antibody-cysteine(cys) fragment alone and its conjugate to DSPE-PEG free thiol lipid nanoparticles (LNP) by PET imaging. Radiolabelled ⁶⁴Cu-DOTA-anti PSMA scFv-cys antibody exhibited 100% binding to the soluble form of recombinant PSMA antigen (Wong et al. 2017).

A study by Meher and co-workers suggested that PSMA targeting with multivalent ACUPA ligands may increase nanocarrier delivery to PCa. The yield of ⁸⁹Zr radiolabelling of the nanocarriers was 90–95%. A linear chelator deferoxamine (DFB) was used to link the radioisotope to the ACUPA ligand (Meher et al. 2023).

Application of radiolabelled nanoparticles

The route of administration of radiolabelled nanoparticles plays a significant role on how well radiolabelled nanoparticles target prostate cancer cells. When choosing the delivery method, factors including tumour microenvironment, blood–brain barrier, and nanoparticle size should be considered. The most popular route that is used is intravenous (IV) administration which provides ease of access and systemic distribution. PCa specificity by radiolabelled NPs can be improved by active targeting PSA and PSMA ligands unique to PCa (Kauffman et al. 2023). Intra-arterial administration reduces systemic exposure and permits higher concentrations at the target site, which enhances treatment of PCA by directly delivering radiolabelled nanoparticles to the tumour site via the arterial supply. However, this technique is less frequently employed due to constraints including technical skills and potential complications (Sayman et al. 2022).

Off target accumulation of radiolabelled NPs prevents effective targeted delivery and raises questions about possible toxicity. Achieving an optimal ratio of uptake from tumour to normal tissue is essential for reducing side effects and optimizing the therapeutic effects. By exploiting the enhanced permeability retention (EPR) effect, normal tissue accumulation can be minimized while nanoparticle absorption in prostate cancers is increased (Sun et al. 2020).

Hu et al., developed a ⁶⁴Cu-labelled multifunctional nanoprobe targeting integrin α₂β₁ based on europium (Eu³⁺⁾ doped gadolinium vanadate NPs for in-vitro fluorescent study, in vivo MRI, and micro-PET imaging of PCa. The nanostructure (⁶⁴Cu-DOTA-GDVO₄:4%Eu-DGEA) imparted excellent fluorescent and paramagnetic properties. Surface modification afforded target function, biocompatibility, and enhanced water solubility. The study successfully demonstrated the application of integrin α₂β₁ targeted NS multifunctional imaging study in animal model (Hu et al. 2014).

Lamichhane et al. utilised ¹¹¹In labelled liposomes as a drug delivery vehicle encapsulating ¹⁸F-labelled carboplatin drug derivative ([¹⁸F]-FCP) as a dual molecular imaging tool as both radiolabeled drug and radiolabeled carrier. The approach has the potential for clinical translation in individual patients. The nano-construct was investigated in-vivo using the dual tracer PET and SPECT imaging in a nude mouse. Results showed significant uptake in the liver and spleen in both PET and SPECT images (Lamichhane et al. 2017).

Paiva and co-workers synthesized a polymeric micellar nanoparticles surface modified with the peptide GE11 targeting the epidermal growth factor receptor (EGFR) radiolabeled with ⁶⁴Cu for PET imaging. In-vitro studies demonstrated significant enhanced internalization of the GE11 micelles into the EGFR-expressing HCT 116 colon cancer cells. In-vivo analysis of Cu-labelled micelles showed prolonged blood circulation and accumulation in tumor cells was higher compared with non-targeting HW 12 decorated micelles (Paiva et al. 2020).

Meher and colleagues designed and synthesized PCa targeting PEG nanocarriers radiolabelled with ⁸⁹Zr, [⁸⁹Zr] PEG-(DFB)₃ (ACUPA)₁ and [⁸⁹Zr] PEG-(DFB)₁ (ACUPA)₃ with PSMA-targeting 2-3-5-amino-1-carboxypentyl ureido) pentanedioic acid ACUPA ligands. The background clearance and PC3/blood ratio were greater with the multivalent [⁸⁹Zr] PEG-(DFB). Overall, PC3 Pip xenografts with ACUPA coupled PEG greatly increase tumour retention with deep tumour tissue penetration. Therefore, these targeted multivalent nanocarriers could be used for PCa diagnostic and therapeutic purposes (Meher et al. 2022).

The proposed hypothesis by Shukla and co-workers that PCa specific phytochemical epigallocatechin-gallate (EGCg) functionalised radioactive gold nanoparticles (AuNPs) when delivered intratumorally would circumvent transport barriers resulting in targeted delivery of therapeutic payloads was supported by positive results after the development of a nano-radiopharmaceutical, ¹⁹⁸AuNPs-EGCg. In-vitro studies showed approximately 72% retention in tumours 24 h after administration of ¹⁹⁸AuNPs-EGCg and therapeutic studies revealed 80% reduction of tumour volumes after 28 days demonstrating significant inhibition of tumour compared to the control group (Shukla et al. 2012).

A novel bifunctional lipid liquid-crystalline (cubosome) containing a chemotherapeutic agent doxorubicin (DOX) and ¹⁷⁷ Lu radionuclide was proposed to be a potential strategy for effective local therapy for various cancers. Cytryniak et al. synthesized a monoolein-based cubosome encapsulating DOX and beta minus emitter ¹⁷⁷Lu complexed with a long-chain derivative of the bifunctional chelate 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA-OA). In-vitro studies showed decreased metabolic activity of HeLa cells in time and dose-dependent manner (47.4 ± 3.54% for the highest applied radioactivity of 15 MBq/mL over 72-h incubation time. Results of this study concluded that the use of cubosomes as drug carriers allows smaller amounts of chemotherapeutic agents (Cytryniak et al. 2020).

Katti et al., investigated the therapeutic effects of radioactivate gold nanoparticles (¹⁹⁸AuNPs) functionalised with mangiferin (MGF). The in-vivo studies in SCID mice bearing prostate tumour xenografts revealed significant therapeutic efficacy. In comparison to untreated control groups, a single dosage of the nano-radiopharmaceutical MGF-¹⁹⁸AuNPs resulted in a greater than 85% reduction in tumour sizes. This effect was attributable to the fact that the tumour retained more than 90% of the amount administered for a longer time. Results revealed that MGF-198 AuNPs had little to no lymphatic drainage to tissues that were not intended for them, which is a desirable property for the therapeutic use to treat prostate cancer in humans (Katti et al. 2018).

Tailored liposomes loaded with ²²⁵Ac were tested for selectivity in PSMA-expressing cells by Bandekar and colleagues. The PSMA J591 antibody or the A10 PSMA aptamer were used to mark the PEGylated liposomes for the study. Human LNCaP, human umbilical vein endothelial (HUVEC) cells and rat Mat-Lu cells were employed as single layers of PCa cells to test for targeting selectivity, degree of internalisation, and efficiency of the liposomes in killing cancer cells. In comparison to A10 aptamer-labelled liposomes, J591-labeled liposomes showed higher levels of total specific binding to all cell lines. These results showed that anti-PSMA tagged liposomes loaded with ²²⁵Ac specifically bind to, internalise, and kill PSMA expressing cells. These results raise the possibility of an α-particle emitter-encapsulating liposome that targets PSMA for targeted anti-vascular alpha radiation (Bandekar et al. 2014).

Yau and colleagues synthesised a theranostic platform comprising a PSMA ligand (PSMAL), polyethylene glycol (PEG), post-inserted into the surface of a preformulated liposome to produce a lipopolymer (P3). To learn more about its theranostic properties, the P3-liposomes were filled with DOX and radiolabelled with ^99mTc. Expression of PSMA on LNCaP and PC3 cells was confirmed by uptake of PSMAL radiolabelled with ¹⁸F radionuclide. Reported results indicated that uptake of ^99mTc -labelled P³—liposomes by LNCaP cells and amount of DOX delivered to LNCaP was more than threefold higher than ^99mTc-labelled plain liposomes and by P³-liposomes respectively. Cytotoxicity assay results confirmed that DOX loaded P³-liposomes were more toxic to LNCaP cells compared to DOX loaded plain liposomes (Yari et al. 2019).

Wang and co-workers prepared a theranostic nanosystem for simultaneous investigation of the in vivo behaviour of the nanocarriers and their drug delivery efficiency enabled by radiolabelling with ¹¹¹In. The hydrophobic antiangiogenic sorafenib was loaded in porous silicon NPs to enhance drug dissolution rate and enhance cancer therapy. The data obtained demonstrated enhanced tumour uptake of NPs and efficient tumour growth suppression in PC3 mouse xenografts (Wang et al. 2015).

Xia et al., constructed a nanoprobe anticipated to be used in the integrated theranostics of PCa. Organic melanin NPs were used to directly label ¹²⁴I and PSMA small molecular groups were bonded on the surface of the NPs. The study indicated that the radioiodine PSMA-PEG-MNPs (¹²⁴I-PPMN) nanoprobe could substantially aggregate in the tumour of PCa xenograft mice (Xia et al. 2021). ¹²⁴I-PPMN micro-PET imaging was performed 72 h after administration of drug related to the radionuclide. Hence, the nanoprobe could be used for precise imaging of PCa with high PSMA expression. High specificity and biocompatibility were demonstrated by the nanoprobe. Moreover, the ¹²⁴I-PPMN nanoprobe has the potential to increase tumour uptake and prolong residence time (Xia et al. 2021). A summary of radiolabelled nanoparticles and their application is provided in Table 3.

Table 3.

Summary of Radiolabelled nanoparticles

Radiolabelled Nanoparticle	Radionuclide	Nanoparticle	Evaluated Application	RY (%)	References
[64Cu] Cu-DOTA-GDVO4	64Cu	Ultrathin nanosheets	PET/MR Image guided	–	Hu et al. (2014)
[18F] F-carboplatin	18F, 111In	Liposome	PET/CT and SPECT/CT	–	Lamichhane et al. (2017)
[64Cu] Cu-GE11 micelles	64Cu	Polymeric Micelle	PET/CT	23	Paiva et al. (2020)
[89Zr] Zr-PEG-(DFB)3 ACUPA	89Zr	Polymeric nanocarriers	PET/CT	–	Meher et al. (2022)
[198Au] Au-EGC	198Au	AuNP	Therapy	–	Shukla et al. (2012)
[177Lu] Lu-Cubosome (DOX)	177Lu	Cubosome	Radionuclide therapy combined with chemotherapy	99	Cytryniak et al. (2020)
[198Au] Au-Mangiferin	198Au	AuNP	Theranostics	–	Katti et al. (2018)
[223Ac] Ac-labelled liposome	223Ac	Liposome	Radiothaerapy	–	Bandekar et al. (2014)
[99mTc]-Lipopolymer Liposomes	99mTc	Liposome	Theranostics	–	Yari et al. (2019)
[111In] In-Sorafenib-silicon NPs	111In	Silicon nanoparticles	Theranostics	59 ± 12.2% (SiNP) 31.9 ± 7.2% (Si-iRGD NPs)	Wang et al. (2015)
[124I] I-Melanin	124I	Melanin nanoparticles	Theranostics	–	Xia et al. (2021)

Future directions

With its significant potential to transform PCa diagnosis and treatment, nanoradiotheranostics also plays a key role in early disease detection, tailored treatment approaches, and targeted therapy, opening the door to more accurate, effective, and patient-centered healthcare solutions. Researchers may produce site-specific imaging by functionalising nanoparticles with targeted ligands, and theranostic platforms have enormous potential for assisting in treatment decisions and continuously monitoring therapy responses.

Biomimetic approaches aim to mimic natural processes to create more efficient drug delivery systems. Many biological systems have evolved to selectively target specific cells or tissues hence, researchers hope to replicate and enhance these mechanisms using nanomaterials. By mimicking the features of cancer-targeting proteins or antibodies, nanoradiotheranotic agents can be designed to specifically seek out and bind to cancer cells, thereby increasing the effectiveness of radiotherapy and improving overall cancer treatment outcomes. These biomimetic approaches may significantly contribute to the development of more personalised cancer treatment in the future (Anitha et al. 2024; Liu et al. 2023). Kahts et al., developed a reliable and versatile radiolabelling technique to monitor leukocytes using PET imaging (Kahts et al. 2023). While this technology on its own has significant promise for further applications in inflammatory cell and other types of cell trafficking studies, combining this with nanomaterials delivery would be capable of delivering payloads to areas of inflammation.

The immunosuppressive tumour microenvironment (ITM) can be modified by nanomedicine to enhance the anti-tumour immune response. Research should be conducted on the specific molecules or proteins to elucidate the mechanisms by which they work to inhibit or enhance the response of the immune system to prostate tumours and hence develop appropriate radiolabelled nanoparticles to combat the unfavourable effects caused on the prostate. Advanced nano biomaterials such polymers, liposomes, and silica are essential for co-delivering immunomodulators and radiopharmaceuticals to specific cancer tissue. These delivery strategies based on nanobiomaterials could successfully encourage anti-tumour immune responses while concurrently reducing harmful side effects (Yu and Geest 2020; Xu et al. 2022).

Nanoparticles can be tailored to have stimuli-triggered drug release. pH fluctuations, glutathione concentrations, and extracellular matrix enzymes are examples of signals that cause therapeutic payloads to be released from nanomaterials (Nikolova et al. 2022). To create nanoparticles for diagnosis and treatment, one can take advantage of pathological and physical alterations in the tumour microenvironment. Because stimulus-sensitive nanoradiotheranostics allow for early detection of treatment response, they hold significant potential for customised cancer therapy. To improve the prognosis of PCa patients, research in this area should attempt to further optimise NP design, improve targeting techniques, and clinical translation (Li et al. 2023).

The drawbacks associated with conventional methods of PCa therapy can be overcome by utilising microneedles (MNs) which are an effective approach designed to directly deliver therapeutic agents and immunologicals to the specific site of tumour. Additionally, these MNs can be fabricated and altered in shape, size and the material polymer can be selected depending on the use and release mechanism intended. Radioactive needles can be designed for transdermal use with minimal handling of radioactivity where the microneedles are inserted directly to the prostate tumour. The concept offers the potential for highly targeted therapy and precise delivery of high doses of radiation minimising exposure to surrounding healthy tissues. However, determination of optimal dosage of radiation to deliver via microneedles can be a challenge and needs careful consideration (Seetharam et al. 2020).

Conclusions

The overarching issue with PCa is its heterogeneous nature ranging from asymptomatic to rapidly progressive life-threatening systemic malignancy. Of concern is the rapidly evolving diagnostic and therapeutic landscapes of PCa.

The advent of nanotechnology presents a paradigm shift in medical diagnosis and therapy offering opportunities for precision medicine and personalised healthcare. The use of nanotechnology has been demonstrated to show strong potential for theranostic purposes and have the advantage of reduction of multi-step procedures, selective accumulation in cancer cells, capability of tailoring patient’s treatment regimens producing improved outcomes, reduced costs, and fewer side effects. The use of radiolabelled nanoparticles has a promising future in eradicating the condition, improving prognosis and quality of life on the horizon. Targeted drug delivery has long been a problem for medical researchers, to get medicine to the correct intended cancer site in the body and to control the release of the drug to prevent toxicity and side effects.

A comprehensive understanding of radionanotechnology in medicine is required to improve the success rates of nanomedicine in clinical studies. While this paper highlights the successful use of radionanotheranostics, it appears challenging to design optimal formulations with all the desirable characteristics for a specific application such as cancer chemotherapy. Most of the data available from research are obtained from animal models whereas very few are approved for clinical use in humans. On the other hand, few investigations have correlated the obtained data to predict the safety and efficacy of radiolabelled nanoparticles. Researchers must evaluate the status and future directions of nanomedicine research. The development of theranostic nanoparticles is envisaged to improve the quality of therapy in prostate cancer patients.

Nevertheless, although nanomaterials hold a lot of potential, there are some challenges regarding the safety and biocompatibility thereof. While, challenges remain, the future of nanoradiotheranostics appears bright with the prospect of improved patient outcomes and enhanced quality of life.

Abbreviations

ADT

Androgen deprivation therapy

AR

Androgen receptor

AE

Auger electron

CT

Computed tomography

DNA

Deoxyribonucleic acid

EC

Electron capture

EGFR

Epidermal growth factor receptor

FDG

Fluorodeoxyglucose

FDA

Food and drug administration

GRPRs

Gastrin releasing peptide receptors

⁶⁸Ge/⁶⁸Ga

Germanium-68/Gallium-68 generator

GBq

Giga-becquerel

GLOBOCAN

Global cancer observatory

Gy

Gray

IT

Isomeric transition

LET

Linear energy transfer

MRI

Magnetic resonance imaging

MBq

Megabecquerel

mCRPC

Metastatic castration-resistant prostate cancer

PEG

Polyethylene glycol

PET

Positron emission tomography

Pca

Prostate cancer

PSMA

Prostate-specific membrane antigen

PSA

Prostate-specific antigen

RECIST

Response evaluation criteria in solid tumours

RNA

Ribonucleic acid

¹⁵³Sm

Samarium-153

SPECT

Single photon emission computed tomography

⁸⁹Sr

Strontium-89

TAT

Targeted alpha therapy

EANM

The european association of nuclear medicine

²²⁷Th

Thorium-227

⁹⁰Y

Yttrium-90

⁸⁹Zr

Zirconium-89

Author contributions

JA was involved in the original draft writing and visualisation in the article; AE was involved in conceptualisation, original draft writing and supervision; BAW was involved in conceptualisation, original draft writing and supervision.

Funding

Not applicable.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

Not applicable.