Theranostics In Oncology: A Review of Imaging Modalities, Radiopharmaceuticals, And Emerging Approaches

Fig 1: Theranostic Closed loop concept

2.         TYPES OF RADIATION IN THERANOSTICS

Radionuclides used in theranostics fall into two broad categories based on their emission type. Diagnostic isotopes emit gamma rays (used in SPECT) or positrons (used in PET). Therapeutic isotopes emit either beta-minus particles or alpha particles, which deposit their energy within tissue to kill tumour cells.(5)

¹⁷⁷Lutetium occupies a unique position because it emits both: therapeutic beta-minus particles and gamma rays of sufficient energy for post-treatment scintigraphic imaging.(5) This means a single

¹⁷⁷Lu-labelled compound can treat and image simultaneously — which is why it has become the dominant radionuclide in current theranostic practice.

Alpha particles work differently. Their linear energy transfer (LET) is approximately 100 keV/μm, and their range in tissue is only 50–100 μm.(6) Within that tiny path length they deposit a concentrated burst of ionising energy that produces clustered DNA double-strand breaks — the most lethal form of radiation damage. Because the range is so short, adjacent healthy tissue is largely spared. This makes alpha emitters particularly well-suited to micrometastatic disease, where small clusters of tumour cells sit within normal tissue.

3.         IMAGING MODALITIES IN THERANOSTICS

3.1       PET Imaging

PET detects coincident 511 keV photon pairs produced when a positron emitted from a radiotracer annihilates with a local electron.(7) The high sensitivity and spatial accuracy of this technique has made it the standard method for assessing whether a patient is a suitable candidate for a given radiopharmaceutical therapy. Common PET tracers in theranostics include ⁶⁸Ga, ¹⁸F, ⁸⁹Zr, and ⁶⁴Cu. When combined with CT (PET/CT) or MRI (PET/MRI), it provides complementary anatomical context — PET/MRI being especially useful for soft tissue tumours and vascularised pelvic masses where MRI contrast is superior.(1)

At the preclinical level, ⁶⁴Cu-DOTA-labelled iron oxide nanoparticles have been used to demonstrate that combined PET and near-infrared fluorescence imaging can achieve higher signal- to-noise ratios than MRI alone for distribution mapping — though MRI/micro-CT still provides better spatial resolution when that is the priority.(8)

3.2       SPECT Imaging

Unlike PET, SPECT detects gamma rays emitted directly by the radioisotope without requiring positron annihilation. Commonly used SPECT isotopes include ⁹⁹ᵐTc, ¹¹¹In, and ¹²³I. Compared to PET, SPECT has broader isotope availability and lower cost, and it can image longer-lived radionuclides that PET cannot handle well.(7)

Combining SPECT with PET in the same session — or with MRI or CT — allows more information to be extracted from a single imaging encounter.(7) In the context of ¹⁷⁷Lu-based therapies specifically, post-treatment SPECT using the gamma emissions of lutetium is now routinely used to verify tumour uptake, calculate absorbed dose, and assess early treatment response.(4)

3.3       MRI-Based Theranostics

MRI offers excellent soft tissue contrast without ionising radiation, and has been integrated into theranostics primarily through superparamagnetic iron oxide nanoparticles (SPIONs). These act as T2/T2* contrast agents by influencing the relaxation of surrounding water protons.(9) SPIONs are versatile — they have been used in theranostic platforms for drug delivery, magnetic hyperthermia (where an external alternating magnetic field heats the particles to kill nearby tumour cells), and ferroptosis induction.(10)

The Nanotherm system, an intratumoral SPION formulation activated by an external magnetic field, has received both FDA and EMA approval for glioblastoma treatment via magnetic hyperthermia — one of the clearer examples of a nanotheranostic system reaching clinical use.(10) More complex multimodal systems have also been developed, such as nanocarriers combining MRI contrast (Gd-DOTA), NIR fluorescence (IRDye), SPECT (⁹⁹ᵐTc), and PET (⁶⁴Cu) in a single platform.(8)

3.4       Optical and Photoacoustic Imaging

Photoacoustic imaging (PAI) uses pulsed laser light to generate ultrasound waves from tissue chromophores and nanoparticles — producing images with optical-level contrast at ultrasound- level depth.(11) Gold nanoparticles (AuNPs) are among the more studied agents here. Folic acid- conjugated AuNPs have shown stable, pH-independent behaviour in cervical cancer cell lines, with significantly enhanced reactive oxygen species production — relevant for photodynamic killing of tumour cells.(7)

Phthalocyanine (PC) and naphthalocyanine (NC) dyes have attracted attention as combined PAI/photothermal agents due to their NIR absorption and photostability.(11) Studies testing roughly 40 different NC/PC dye formulations in polymeric micelles have identified several candidates capable of achieving effective photothermal tumour ablation alongside PAI contrast — though most of this work remains preclinical.

3.5       RADIOPHARMACEUTICAL        THERANOSTIC       PAIRS:            CLINICAL         APPLICATIONS

3.6       Thyroid Cancer: ¹²³I / Na¹³¹I

The radioiodine pair for thyroid cancer has been in clinical use since 1946 and is, in many ways, the original theranostic system.(4) Both diagnostic (¹²³I or ⁹⁹ᵐTc) and therapeutic (Na¹³¹I) agents exploit the sodium-iodide symporter expressed on thyroid follicular cells. Diagnostic imaging confirms symporter expression and maps the extent of disease; Na¹³¹I then delivers beta-minus radiation via the same mechanism to ablate residual thyroid tissue and any metastases.

What makes this pair historically important is not just its efficacy — it's the conceptual clarity it demonstrates. Confirm the target with a diagnostic agent, then destroy it with a therapeutic one using the same molecular pathway. That principle has guided every theranostic system developed since. Seventy-plus years of clinical data from radioiodine therapy have also provided a safety and efficacy foundation that newer platforms are still building toward.

3.7       Neuroendocrine Tumours: ⁶⁸Ga-DOTATATE / ¹⁷⁷Lu-DOTATATE

Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) express somatostatin receptors at high surface density, which makes them well suited to receptor-targeted theranostics. ⁶⁸Ga- DOTATATE PET/CT provides whole-body SSTR mapping with high sensitivity and is used to confirm receptor expression before treatment.(12)

Lutathera (¹⁷⁷Lu-DOTATATE) shares the same DOTATATE peptide backbone but is labelled with ¹⁷⁷Lutetium rather than ⁶⁸Gallium, delivering beta-minus radiation to SSTR-expressing tumour cells. The FDA approved it in 2018 for metastatic pancreatic and midgut NETs based on the phase III NETTER-1 trial.(1) The low-energy gamma co-emissions of ¹⁷⁷Lu allow post- treatment SPECT for biodistribution verification and dosimetry calculation,(13) completing the imaging-therapy loop.

3.8       Prostate Cancer: PSMA-Based Theranostics

3.8.1    Molecular Target

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein overexpressed in prostate cancer cells at levels roughly 100–1000 times higher than normal tissue, with expression increasing further in castration-resistant and poorly differentiated disease.(14) It is rapidly internalised upon ligand binding, which concentrates a therapeutic payload intracellularly. These properties — high expression, tumour specificity, and efficient internalisation — make PSMA the most clinically exploited molecular target in prostate cancer theranostics.

3.8.2    ⁶⁸Ga-PSMA-11 PET

⁶⁸Ga-PSMA-11 PET/CT is now the standard imaging approach for staging and restaging PSMA- expressing prostate cancer, and it serves as the gating criterion for radioligand therapy — patients who are not PSMA-avid on PET are not eligible for ¹⁷⁷Lu-PSMA treatment. Quantitative PET

metrics also appear to carry prognostic value; higher SUVmean on whole-body ⁶⁸Ga-PSMA-11 PET/CT has been associated with better therapeutic outcomes from PSMA-targeted therapy.(15)

3.8.3    The VISION Trial

The phase III VISION trial (NCT03511664) enrolled patients with mCRPC who were PSMA- positive on ⁶⁸Ga-PSMA-11 PET/CT and had received at least one androgen receptor inhibitor and one or two prior taxane regimens. Patients were randomised to ¹⁷⁷Lu-PSMA-617 (7.4 GBq every six weeks for four to six cycles) plus standard care, or standard care alone.(16)

¹⁷⁷Lu-PSMA-617 produced significant improvements in both imaging-based progression-free survival and overall survival.(16) Quality-of-life analyses showed delayed worsening of HRQOL scores, pain, and time to first symptomatic skeletal event.(17) These results were significant not just for the efficacy data but because they confirmed that a companion diagnostic — PSMA PET — could be used to select patients for a targeted radionuclide therapy and that this selection strategy worked.

3.8.4    The TheraP Trial

The TheraP phase II randomised trial (NCT03392428), run across 11 Australian sites, took a different approach: it directly compared ¹⁷⁷Lu-PSMA-617 against cabazitaxel in mCRPC patients who had progressed on docetaxel. Unusually, it required dual PET imaging — both ⁶⁸Ga-PSMA- 11 and ¹⁸F-FDG PET/CT — to confirm PSMA-avid disease and exclude patients with discordant FDG-avid lesions that might indicate disease unlikely to respond to PSMA-targeted treatment.(2)

¹⁷⁷Lu-PSMA-617 showed superior PSA response rates, better quality of life scores, and a considerably more favourable toxicity profile compared to cabazitaxel.(2) The dual-imaging selection strategy used in TheraP has since become an important reference point for how PSMA theranostic candidates should be identified — particularly because it explicitly defined a subgroup of scordant FDG-avid patients who were unlikely to benefit.

Table 1 — FDA-approved theranostic agents: key characteristics

4.         NANOPARTICLE-BASED THERANOSTIC PLATFORMS

4.1       Overview

Nanotheranostics brings diagnostic imaging and therapeutic capabilities together within a single nanoscale construct.(18) The primary advantage over conventional small molecules is the capacity to carry multiple functional payloads simultaneously — an imaging agent, a therapeutic drug, and a targeting ligand — within the same particle. Tumour accumulation occurs partly through the enhanced permeability and retention (EPR) effect, whereby nanoparticles leak preferentially through the abnormally large pores in tumour vasculature.(19) Surface chemistry can also be tuned to attach targeting ligands, further improving selectivity.(19)

The main categories of nanotheranostic platform are: metal nanoparticles (gold, iron oxide, platinum, silver); lipid-based systems (liposomes); polymeric nanoparticles (PLGA, PEG-PCL micelles); and biomimetic systems. Each has different properties suited to specific imaging modalities and therapeutic combinations.

4.2       Iron Oxide Nanoparticles (SPIONs)

SPIONs function as T2/T2* MRI contrast agents and can simultaneously produce magnetic particle imaging (MPI) signals and generate heat for hyperthermia therapy.(20) In preclinical work, SPIONs can be loaded with anticancer drugs or siRNA to serve as both imaging agents and drug delivery vehicles. Cross-linked iron oxide (CLIO) nanoparticles conjugated to an angiogenesis inhibitor (ICT2552) have been tested in glioblastoma mouse models, allowing real-time MRI tracking of nanoparticle delivery alongside radiation therapy.(20) The Nanotherm product — already approved by the FDA and EMA for glioblastoma — represents the most direct clinical translation of this technology.

4.3       Gold Nanoparticles

AuNPs are stable, biocompatible, and can be tuned in size and shape to exploit surface plasmon resonance for near-infrared light absorption — making them useful for photoacoustic contrast and

photothermal ablation.(7) Gold nanorods (AuNRs) co-loaded with the NIR dye IR780 and doxorubicin, and functionalised with an RGD peptide targeting αvβ3 integrin, have demonstrated synergistic chemo-photothermal therapy combined with PAI. The temperature increase in these composites was more than 2.5-fold greater than individual components, and photoacoustic signal was roughly three times stronger.(7)

4.4       Polymeric Nanoparticles and Liposomes

Polymeric nanoparticles made from materials like PLGA or PEGylated polymers offer controlled drug release, extended circulation time, and low immunogenicity.(21) Liposomes have been used as theranostic carriers by co-encapsulating radionuclides alongside therapeutic agents. Polymeric micelles — self-assembling nanostructures with a hydrophobic drug-carrying core and a PEG corona — range from 10 to 100 nm and accumulate in tumours via the EPR effect. When radiolabelled, they can provide simultaneous PET/SPECT imaging and drug delivery within a single system.(21)

4.5       Biomimetic Nanotheranostics

Biomimetic platforms try to solve several persistent problems with conventional nanoparticles — multidrug resistance, poor tumour penetration, and immune-mediated clearance — by drawing on biological design principles.(22) Approaches include nanoparticles coated with cancer cell membranes or erythrocyte membranes to evade immune detection, exosomes used as inherently biocompatible drug carriers, and bioinspired pretargeting ligands to improve radiotherapeutic uptake at the tumour site.(22)

Biomimetic systems have been applied in breast, prostate, and skin cancers for applications ranging from immune checkpoint blockade to photothermal ablation.(23) The translational challenge is scalable, consistent manufacturing — biological sourcing of membrane components and exosomes introduces variability that will need to be addressed before these systems move into routine clinical use.

Table 2 - Approved cancer drug therapies based on nanotechnology(24)

5.         TARGETED ALPHA THERAPY

5.1       Why Alpha Emitters?

The case for alpha particles in cancer therapy comes down to physics. A LET of ~100 keV/μm deposited over a 50–100 μm path in tissue means concentrated, highly lethal DNA damage within a microscopic footprint.(33) The resulting double-strand breaks are dense enough to overwhelm cellular repair mechanisms. And because the range of an alpha particle barely extends beyond a few cell diameters, surrounding healthy tissue is largely spared.(4) This is particularly relevant for micrometastatic disease and haematological malignancies, where tumour cells are dispersed among normal tissue — exactly the setting where the crossfire effect of beta emitters becomes a liability.

5.2       Actinium-225

Among the alpha emitters in clinical development, ²²⁵Ac has attracted the most attention. Its 9.92- day half-life is logistically workable, and each decay generates four alpha particles, three beta-like emissions, and two gamma emissions before the chain ends at stable ²⁰⁹Bismuth.(30) This makes

²²⁵Ac a kind of in vivo nanogenerator: one administered atom produces a cascade of cytotoxic radiation events at the tumour site.(34) The gamma emissions, while limited, also allow SPECT imaging of biodistribution — preserving the theranostic principle.

Clinical trials of ²²⁵Ac in prostate cancer are primarily using PSMA-targeted agents: [²²⁵Ac]Ac- PSMA-617, [²²⁵Ac]Ac-PSMA-I&T, and [²²⁵Ac]Ac-J591.(27) The idea of targeting cancer with ²²⁵Ac has been around since 1993, and three decades of work have moved it from concept to active clinical evaluation.(29)

5.3       Other Alpha Emitters

²²³Radium (t½ = 11.4 days) is already FDA-approved for bone-metastatic prostate cancer. Its calcium-mimetic chemistry drives natural bone uptake, and its short path length limits bone marrow exposure — a meaningful safety advantage in a site that is inherently radiation- sensitive.(32) A range of other alpha emitters are also under active investigation: ²¹¹At, ²¹³Bi, ²¹²Pb,

²²⁷Th, and ¹⁴⁹Tb each have distinct half-lives, energy profiles, and daughter isotope characteristics

suited to different clinical contexts.(29) Phase I trials are ongoing across multiple tumour types for most of these, with Phase III recruitment for neuroendocrine tumours beginning for some.

5.4       Challenges

The main bottleneck for ²²⁵Ac is supply — global production is estimated at around 1,000 Ci/year, which is far below what would be needed for widespread clinical use. Production via thorium-229 decay or particle accelerators is geographically concentrated and logistically complex. Daughter recoil — the displacement of progeny isotopes from the target site after alpha emission — carries a risk of off-target irradiation. The limited gamma signal from small administered quantities also makes SPECT-based dosimetry difficult. Cyclotron-based regional production of ²²⁵Ac and ²¹¹At is in development as a way to reduce dependence on centralised supply, and progress in chelation chemistry and dosimetry modelling will be necessary before the full clinical potential of alpha therapy can be realised.

Fig 2: Targeted alpha cancer theraphy mechanism