Repurposing radiopharmaceutical carriers for targeted drug delivery and theranostics: A translational framework

Abstract

Radiopharmaceuticals have long demonstrated precise, organ- and receptor-specific targeting in humans, supported by well-characterized pharmacokinetics, standardized formulation, and regulatory validation; however, the carrier systems underlying these agents remain largely underexplored as platforms for therapeutic delivery. This review introduces a translational framework that repositions clinically validated radiopharmaceutical carriers, including peptides, nanocolloids, lipophilic complexes, and antibody fragments, as ready-to-deploy scaffolds for targeted drug delivery and theranostic applications. Integrating classical radiopharmaceutical principles with advances from 2018 to 2025, this work examines how established systems based on technetium-99m (⁹⁹ᵐTc), gallium, lutetium, rhenium, copper, iodine, and actinium can be systematically re-engineered through linker design, bifunctional chelation, and payload integration. Unlike conventional nanocarriers that rely heavily on preclinical optimization and passive targeting mechanisms, these platforms offer pre-validated human biodistribution, reproducible pharmacokinetics, and compatibility with good manufacturing practice (GMP), providing a distinct advantage for clinical translation. Emerging clinical evidence, including peptide–drug conjugates and antibody-based systems, highlights both the feasibility and current limitations of this approach, particularly the gap between diagnostic success and therapeutic adaptation. By integrating mechanistic insights, design strategies, and translational considerations, this review proposes a shift from de novo carrier design toward the strategic repurposing of clinically proven systems, with the potential to reduce translational attrition and accelerate the development of precision therapeutics and next-generation theranostic platforms.

Graphical abstract

Abbreviations

⁹⁹ᵐTc

Technetium-99m

APC

Antigen-presenting cells

BBB

Blood–brain barrier

BFC

Bifunctional chelator

DOTA

1,4,7,10-tetraazacyclododecane tetraacetic acid

DTPA

Diethylenetriaminepentaacetic acid

ECD

Ethyl cysteinate dimer

GMP

Good Manufacturing Practice

HMPAO

Hexamethylpropyleneamine oxime

MAG3

Mercaptoacetyltriglycine

MDP

Methylene diphosphonate

NETs

Neuroendocrine tumors

NIS

Sodium–iodide symporter

PEG

Polyethylene glycol

PSMA

Prostate-specific membrane antigen

RBCs

Red blood cells

RES

Reticuloendothelial system

SPECT

Single-photon emission computed tomography

1. Introduction

Targeted drug delivery remains a central challenge in pharmaceutical sciences, despite decades of progress in nanomedicine, ligand conjugation, and controlled-release systems. While many nanoparticle-based platforms demonstrate promising preclinical outcomes, their clinical translation has been limited by issues such as poor pharmacokinetic predictability, rapid immune clearance, off-target accumulation, and lack of reproducibility across patient populations [1]. In contrast, nuclear medicines have consistently achieved precise organ- and receptor-specific targeting in humans and are developed, standardized, and administered under well-established regulatory frameworks. These systems provide reproducible biodistribution profiles and clinically validated targeting mechanisms [2,3].

Among these, technetium-99m (⁹⁹ᵐTc) plays a central role, accounting for the majority of diagnostic nuclear medicine procedures due to its favorable physical and chemical properties, including a short half-life (∼6 h), optimal gamma emission for imaging, and generator-based availability [2,4]. Importantly, ⁹⁹ᵐTc-based radiopharmaceutical kits incorporate biologically active carriers, such as peptides, lipophilic complexes, nanocolloids, and antibody fragments, that determine tissue specificity. These carriers are not merely auxiliary components but are the primary determinants of pharmacokinetics and targeting behavior and have undergone extensive human validation. Despite this, their potential as pre-validated scaffolds for therapeutic payload delivery remains largely underexplored.

This review focuses on repurposing radiopharmaceutical carriers as platforms for targeted drug delivery and theranostics, a concept that shifts from designing targeting systems de novo to leveraging clinically established ones. Unlike conventional nanocarriers, which often rely on passive accumulation mechanisms such as the enhanced permeability and retention (EPR) effect, radiopharmaceutical carriers exploit well-defined biological pathways, including receptor-mediated binding, transporter-driven uptake, and physiological sequestration (e.g., reticuloendothelial system localization). Their formulation as standardized kits under good manufacturing practice (GMP) conditions further provides a unique translational advantage by ensuring reproducibility, stability, and regulatory familiarity.

The manuscript is structured first to examine clinically validated radiopharmaceutical carrier systems, including technetium-based and non-technetium platforms, followed by strategies for therapeutic payload incorporation and theranostic integration. Subsequent sections address mechanistic considerations, translational challenges, and future perspectives for clinical development. Importantly, this review introduces a novel translational framework by integrating recent advances (2018-2025) in radiochemistry, nanotechnology, and bioconjugation, highlighting how existing radiopharmaceutical architectures can be rationally re-engineered into multifunctional delivery systems.

A particularly compelling opportunity lies in these carriers' ability to bridge the gap between preclinical innovation and clinical implementation. By leveraging systems with established human safety and biodistribution, it may be possible to reduce translational attrition, streamline regulatory pathways, and accelerate the development of precision therapeutics. This convergence of nuclear medicine and drug delivery science, therefore, represents not only a conceptual advance but also a pragmatic strategy for next generation theranostic development.

2. Translational opportunities for drug delivery

Radiopharmaceutical carriers provide a unique intersection between regulatory maturity and technological adaptability. From a translational perspective, such systems already satisfy key prerequisites for nanomedicine development: reproducible synthesis, organ-specific localization, and compliance with good manufacturing practice (GMP) standards [5]. Exploring these features through the lens of drug delivery science reveals how radiopharmaceuticals can serve not only as diagnostic tools but also as pre-validated starting scaffolds for targeted therapy. The following subsections outline the conceptual and technological avenues for this transformation, beginning with commercial radiopharmaceutical kits, which represent the accessible, clinically established entry point for translation.

2.1. Radiopharmaceutical kits as ready-to-use delivery matrices

Radiopharmaceutical kits, originally developed for diagnostic imaging, are formulated with biologically active carriers such as peptides, albumin nanocolloids, lipophilic complexes, and antibody fragments. These carriers have undergone extensive clinical validation, establishing their safety, biodistribution, and organ- or receptor-specific targeting properties [6]. Such attributes make them highly attractive candidates for repurposing as drug delivery systems, either independently of their radionuclide component or in combination with therapeutic payloads to generate dual-functional constructs.

Table 1 highlights the diversity of technetium-based carrier systems, spanning lipophilic cations, nanocolloids, peptides, antibody fragments, and autologous cells, each of which achieves clinically validated organ- and tissue-specific localization. Rather than designing targeting systems de novo, these carriers offer clinically validated toolkits for drug delivery. Importantly, these radiopharmaceutical kits embody a level of regulatory and manufacturing maturity rarely achieved by experimental nanocarriers. Their standardized composition, validated sterilization procedures, and established quality control protocols enable direct compatibility with good manufacturing practice (GMP) environments. This maturity provides a distinct translational advantage, allowing repurposed systems to advance from bench to clinical evaluation with minimal reformulation and reduced regulatory uncertainty.

Table 1.

Clinically validated⁹⁹ᵐTc-labeled carriers, their biological targets, and repurposing strategies for drug delivery applications [[7], [8], [9], [10]].

Carrier (Type)	Target	Uptake Mechanism	Clinical Use	Repurposing Strategy
Sestamibi (lipophilic cation)	Myocardium, tumors	Mitochondrial uptake	Perfusion, tumor imaging	Mitochondria-targeted drug delivery
Tetrofosmin (diphosphine complex)	Myocardium	Passive diffusion; uptake driven by lipophilicity and transmembrane electrochemical gradients	Perfusion imaging	Lipophilic drug delivery to cardiac/tumor tissue
Sulfur colloid (nanocolloid)	Liver, spleen	RES phagocytosis	Liver–spleen imaging	Immunomodulator delivery to RES
MAA (albumin aggregates)	Lung capillaries	Capillary trapping	Pulmonary perfusion	Localized embolic drug delivery
HMPAO (lipophilic chelate)	Brain	BBB diffusion followed by intracellular conversion to hydrophilic species and trapping	Cerebral perfusion; also used for ex vivo leukocyte labeling	CNS drug delivery across the BBB
ECD (lipophilic ester)	Brain	BBB diffusion followed by intracellular enzymatic conversion and trapping	Brain perfusion	Controlled intracellular neurodrug delivery
DMSA (small molecule complex)	Renal cortex	Cortical retention via proximal tubular binding/reabsorption	Renal imaging	Renal-targeted therapeutics
MAG3 (chelating ligand)	Kidneys	Predominantly tubular secretion (effective renal plasma flow)	Dynamic renal imaging	Renal delivery of small molecules
Pyrophosphate (phosphate analog)	Bone, infarct tissue	Binding to calcium/hydroxyapatite in mineralized or damaged tissue	Bone/infarct imaging	Bone-targeted drug delivery
MDP (diphosphonate)	Bone	Hydroxyapatite binding (bone mineral affinity)	Bone scintigraphy	Anti-resorptive drug delivery
RBCs (autologous cells)	Blood pool	Intravascular confinement of labeled erythrocytes	GI bleeding, cardiac function	Long-circulating vascular delivery
Sulesomab (antibody fragment)	Infection sites	Binding to granulocyte-associated antigens (CD66/NCA-90) with contribution from increased vascular permeability	Infection imaging (musculoskeletal)	Targeted anti-inflammatory delivery
Nanocolloids (albumin colloids)	Lymph nodes	Lymphatic drainage and macrophage uptake	Sentinel node mapping	Lymphatic immunotherapy delivery
99mTc-octreotide analogs (peptide)	Neuroendocrine tumors	Somatostatin receptor binding	Tumor imaging	Receptor-targeted drug conjugates
Depreotide (peptide)	Lung tumors	Somatostatin receptor binding	Pulmonary tumor imaging (lung nodules)	Targeted tumor drug delivery
Tilmanocept (mannose-dextran ligand)	Lymphatic tissue	Mannose receptor (CD206) mediated uptake by macrophages/APCs	Lymphoscintigraphy	APC-targeted immunotherapy

For instance, Nanocolloids naturally accumulate in the liver and spleen via RES mechanisms [6] can be rationally engineered to deliver anti-inflammatory or immunotherapeutic agents. Albumin-based nanocolloids, routinely used in lymphoscintigraphy, could serve as carriers for peptide- or protein-based therapeutics, conjugated via amine or thiol functional groups without significantly altering the biodistribution of the original radiopharmaceutical. Similarly, lipophilic formulations, such as those used for cerebral perfusion imaging (e.g., 99mTc-HMPAO), may provide a design template for BBB-penetrant delivery of therapeutics.

2.2. Non-technetium radiopharmaceutical platforms

While ^99mTc-based systems represent the most extensively validated and widely utilized radiopharmaceutical kits, the underlying principle of clinically proven, organ-specific carrier systems extends across multiple radionuclide platforms. A diverse range of non-technetium radiopharmaceuticals, originally developed for diagnostic imaging or radionuclide therapy, exhibit comparable targeting precision and chemical versatility, making them attractive candidates for repurposing as drug delivery scaffolds. A comparative overview of these systems is presented in Table 2.

Table 2.

Clinically validated non-technetium radiopharmaceuticals and related radiometal platforms with potential for therapeutic delivery [5,[11], [12], [13], [14], [15]].

Carrier (Type)	Target	Uptake Mechanism	Clinical Application	Repurposing Strategy
DOTATATE (peptide-chelator)	Neuroendocrine tumors	Somatostatin receptor binding	PET imaging (68Ga), radionuclide therapy (177Lu)	Peptide-guided delivery of cytotoxic drugs or radionuclides
PSMA-targeting ligands (small-molecule radioligands)	Prostate cancer	PSMA receptor-mediated binding and internalization	PET imaging, radionuclide therapy	Targeted delivery of small molecules or gene therapeutics
DOTA-antibody conjugates (antibody-chelator)	Solid and hematologic tumors	Antigen-specific binding	Targeted radionuclide therapy	Antibody-based drug or immunotherapy delivery
Chelator platforms (DTPA/MAG3)	Renal and tumor systems	Modulation of metal complex pharmacokinetics and clearance	Diagnostic imaging (primarily renal) and radiolabeling platforms	Adaptation for nanoparticle or drug conjugation platforms
Rhenium analogs (Tc-like complexes)	Bone, tumors	Similar coordination chemistry and biodistribution to Tc-based agents	Radionuclide therapy	Direct translation of Tc coordination chemistry into therapeutic carriers
Copper-chelator complexes (peptide/antibody-based)	Tumors	Receptor-mediated uptake (vector-dependent)	PET imaging (64Cu), radionuclide therapy (67Cu)	Redox-responsive or theranostic drug delivery systems
Iodinated ligands (small molecules)	Thyroid, NIS-expressing tissues	Sodium–iodide symporter (NIS)-mediated uptake	Thyroid imaging and therapy	NIS-targeted nanoparticle or liposomal delivery
Actinium-based antibody/ligand conjugates; thorium-227 antibody conjugates (clinical-stage)	Tumors	Antigen-specific targeting	Targeted alpha therapy	Delivery of highly potent cytotoxic or gene-based payloads

DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; DOTATATE: DOTA-Tyr3-octreotate; PSMA: Prostate-Specific Membrane Antigen; MAG3: Mercaptoacetyltriglycine; DTPA: Diethylenetriaminepentaacetic acid.

Gallium-68–based agents, such as DOTATATE and prostate-specific membrane antigen (PSMA) ligands, have demonstrated high affinity and specificity for neuroendocrine tumors and prostate cancer, respectively. These systems rely on well-defined chelator–peptide or small-molecule architectures, typically involving DOTA or NOTA frameworks, which enable stable coordination and predictable in vivo behavior [5]. Their modular design can permit structural modification while preserving receptor-binding affinity, provided that the pharmacophore is not perturbed.

Similarly, therapeutic radiopharmaceuticals based on lutetium-177 and rhenium isotopes (¹⁸⁶Re, ¹⁸⁸Re) utilize ligand systems optimized for stability, biodistribution, and target specificity. These systems frequently employ bifunctional chelators such as DOTA or MAG3, which facilitate both radionuclide coordination and potential conjugation with therapeutic agents. The chemical similarity between rhenium and technetium further supports the translational adaptability of technetium-based kit chemistry into analogous therapeutic delivery platforms [12].

Alpha-emitting radiopharmaceuticals, including actinium-225 and thorium-227 conjugates, typically involve antibody- or peptide-based targeting systems designed for highly specific tumor localization [13]. These constructs demonstrate the feasibility of delivering potent cytotoxic payloads with high spatial precision, a principle that can be extended beyond radionuclide therapy to encompass drug conjugates and biologics. In parallel, copper isotopes (⁶⁴Cu, ⁶⁷Cu) provide additional flexibility, with coordination chemistries that support receptor-targeted delivery and the incorporation of redox-responsive elements for controlled therapeutic release [14]. Iodine-based systems represent another clinically established platform, in which iodinated ligands exploit the sodium–iodide symporter (NIS) to achieve highly selective uptake in thyroid and NIS-expressing tissues [15]. This biologically driven transport mechanism offers a unique opportunity to design carrier systems that mimic endogenous uptake pathways, potentially enabling targeted delivery of therapeutics via NIS-mediated mechanisms. These clinically validated systems can be conceptualized within a translational engineering framework that bridges carrier selection, molecular adaptation, and theranostic integration (Fig. 1).

Fig. 1.

Translational framework for repurposing radiopharmaceutical carriers into therapeutic and theranostic systems.

While these platforms collectively demonstrate that radiopharmaceutical targeting strategies are robust, adaptable, and clinically validated, their direct translation into non-radioactive drug delivery systems remains limited. To date, only a small number of clinical-stage examples illustrate the use of radiopharmaceutical-inspired targeting scaffolds for therapeutic payload delivery. One such example is PEN-221, a somatostatin receptor-targeting peptide–drug conjugate in which a somatostatin analog is linked to the cytotoxic agent DM1 via a cleavable linker, enabling selective delivery to SSTR2-expressing tumors. Early-phase clinical studies supports the feasibility of this approach, highlighting the potential of peptide-based radiopharmaceutical scaffolds as drug-delivery vectors [16]. Similarly, prostate-specific membrane antigen (PSMA)-targeted antibody–drug conjugates (PSMA-ADCs) have been evaluated in clinical trials for metastatic prostate cancer, further supporting the concept that clinically validated targeting ligands can be repurposed for selective payload delivery [17].

Notably, these clinical examples are currently limited to receptor-targeting ligand systems. In contrast, most technetium-based kit carriers remain primarily confined to diagnostic or radionuclide applications, with little direct translation into dedicated drug delivery platforms. This distinction highlights a critical translational gap between clinically validated targeting capability and therapeutic payload integration.

Collectively, these observations demonstrate that radiopharmaceutical targeting strategies are chemically transferable across isotopes and ligand systems, enabling flexible adaptation of chelator–ligand architectures for therapeutic conjugation. From a translational standpoint, these systems share key attributes, including reproducible pharmacokinetics, selective tissue accumulation, and established human safety profiles. However, the limited number of clinically validated drug-delivery analogs underscores the need for systematic design strategies to enable payload incorporation while preserving targeting fidelity. Addressing this challenge underpins the design considerations discussed in the following section.

2.3. Design adaptations for therapeutic payload incorporation

The translational potential of radiopharmaceutical carriers stems from their well-defined, clinically validated targeting mechanisms. Following systemic administration, biodistribution is governed by intrinsic physicochemical properties, including size, charge, and lipophilicity, which dictate vascular transport and tissue permeability [18,19]. Targeting is subsequently achieved through biologically deterministic pathways, including receptor-mediated binding, reticuloendothelial sequestration, and capillary trapping [5]. In receptor-targeted systems, ligand–receptor interactions may further enable endocytic internalization and intracellular delivery of payloads [20], whereas particulate carriers often rely on localized retention. These mechanisms also govern payload release, which can be engineered using pH-, redox-, or enzyme-responsive linkers [21,22]. Together, these features confer a level of targeting precision that contrasts with the largely passive accumulation observed in conventional nanocarriers. Therapeutic adaptation requires preservation of this targeting fidelity while enabling payload integration. In technetium-based systems, removal of the radionuclide eliminates the need for reducing agents such as stannous chloride, thereby avoiding associated cytotoxicity [23]. Formulations can instead be stabilized using biocompatible excipients, including histidine buffers, polysorbates, and antioxidants, to maintain the integrity of peptides, antibodies, or nucleic acids.

A key challenge lies in re-engineering ligand environments originally optimized for metal coordination into architectures compatible with drug conjugation. Bioorthogonal chemistries, including maleimide–thiol coupling and click reactions, enable site-specific conjugation under mild conditions [24,25]. Cleavable linkers, such as pH-sensitive or enzyme-labile systems, facilitate controlled release at the target site while limiting systemic exposure [21,22]. Hydrophilic spacers, including polyethylene glycol, can further modulate pharmacokinetics without compromising receptor affinity [26]. Crucially, these modifications must avoid perturbing the targeting domain, which ultimately governs biodistribution.

Preserving the pharmacokinetic profile of the parent radiopharmaceutical is essential for maintaining tissue specificity. This requires careful control of conjugation density, charge, lipophilicity, and particle size. For example, albumin nanocolloids can be adapted for lymphatic delivery of immunomodulators or nucleic acids while retaining nodal uptake [18]. In contrast, peptide-based ligands such as somatostatin and PSMA analogs can be re-engineered using bifunctional linkers that preserve receptor binding [27,28]. Lipophilic brain imaging agents, including HMPAO and ECD, similarly provide opportunities for central nervous system drug delivery by leveraging intrinsic blood–brain barrier permeability [29,30].

Established radiopharmaceutical quality-control frameworks provide a translational advantage in this context, enabling rapid evaluation of conjugation efficiency, stability, and release kinetics using established analytical techniques [20].

Overall, successful repurposing of radiopharmaceutical carriers depends on three principles: replacing metal-dependent redox systems with biocompatible formulations, converting coordination chemistry into functional conjugation architectures, and preserving the physicochemical determinants of targeting. This paradigm shifts drug delivery design from de novo engineering toward the strategic reuse of clinically validated targeting systems.

2.3.1. Linker engineering tailored to radiopharmaceutical carrier scaffolds

Linker engineering represents the critical interface between targeting and therapeutic function in radiopharmaceutical-inspired systems. Unlike conventional nanocarriers, in which linkers are introduced onto synthetic platforms, these systems require minimal, site-specific modification of clinically validated scaffolds. Linker design is therefore inherently constrained by carrier structure and must preserve biodistribution and receptor affinity. Carrier-specific constraints and corresponding linker design strategies are summarized in Fig. 2.

Fig. 2.

Carrier-dependent design principles for therapeutic adaptation.

In lipophilic small-molecule carriers such as sestamibi, tetrofosmin, HMPAO, and ECD, targeting depends on membrane permeability and intracellular trapping. Even minor structural changes can alter pharmacokinetics; accordingly, linker strategies must prioritize minimal modification or prodrug-like approaches [31].

By contrast, albumin-based nanocolloids provide accessible functional groups that support surface conjugation via NHS ester or maleimide chemistries, although excessive modification may disrupt reticuloendothelial uptake or lymphatic trafficking [18]. Macroaggregated albumin presents stricter constraints, as biodistribution is governed by particle size and capillary trapping, necessitating non-disruptive modification strategies.

Peptide-based carriers, including somatostatin and PSMA ligands, offer greater flexibility, provided that linkers are positioned away from receptor-binding domains. Clinical examples such as PEN-221 demonstrate that cleavable linkers can enable targeted drug delivery while preserving receptor specificity [32,33]. Similarly, linker design in PSMA-targeted systems influences tumor uptake and pharmacokinetics, underscoring the importance of structure-guided optimization [34,35].

Antibody-based systems require precise control of conjugation sites and drug-to-antibody ratios to maintain antigen binding and therapeutic efficacy, with linker stability playing a critical role in intracellular release [35]. In chelator-based architectures, bifunctional designs are often required to decouple targeting, coordination, and payload attachment functions [36].

Overall, linker design in radiopharmaceutical-inspired systems is not a generalized conjugation strategy but a scaffold-specific optimization process. Effective approaches balance stability, targeting fidelity, and controlled release while minimizing structural perturbation. This minimal-modification paradigm distinguishes these systems from conventional nanocarriers and underpins their translational potential.

2.4. Theranostic potential through dual-function systems

In addition to repurposing radiopharmaceutical carriers as non-radioactive delivery systems, an alternative and clinically more advanced strategy is to retain the radionuclide component while incorporating therapeutic payloads, thereby generating dual-function theranostic constructs. This approach leverages the intrinsic modularity of radiopharmaceutical chemistry, where targeting ligands, chelators, and payloads can be rationally integrated into a single platform capable of simultaneous imaging and therapy [37]. Such systems enable real-time visualization of biodistribution, target engagement, and therapeutic response, providing a level of pharmacological feedback that is rarely achievable with conventional drug delivery systems.

Central to this strategy is the use of bifunctional chelators (BFCs), which allow stable coordination of radionuclides while enabling covalent attachment of therapeutic agents. Chelators such as hydrazinonicotinamide (HYNIC), mercaptoacetyltriglycine (MAG3), and diethylenetriaminepentaacetic acid (DTPA) have been widely used in radiopharmaceutical chemistry due to their favorable stability and compatibility with biomolecules [37,38]. These systems can be adapted to conjugate small molecules, peptides, antibodies, or nanoparticles, forming integrated constructs that combine targeting, imaging, and therapeutic functionality. Importantly, such architectures preserve the targeting fidelity of the original radiopharmaceutical while expanding its functional scope.

A landmark example of this concept is the somatostatin receptor-targeting scaffold, where diagnostic imaging with ⁶⁸Ga-DOTATATE is directly paired with therapeutic administration of ¹⁷⁷Lu-DOTATATE. The phase III NETTER-1 trial demonstrated significantly prolonged progression-free survival and improved clinical outcomes in patients with advanced neuroendocrine tumors treated with ¹⁷⁷Lu-DOTATATE, establishing a clinical benchmark for theranostic success [39]. Similarly, prostate-specific membrane antigen (PSMA)-targeted ligands have enabled paired diagnostic and therapeutic strategies, with ⁶⁸Ga-PSMA-11 used for imaging and ¹⁷⁷Lu-PSMA-617 demonstrating improved overall survival in metastatic castration-resistant prostate cancer in the VISION trial [40]. These examples illustrate how clinically validated targeting ligands can serve as stable scaffolds for iterative therapeutic development.

Beyond peptide-based systems, nanoparticle and liposomal theranostic platforms have also been explored, where radiolabeling is combined with drug encapsulation to enable simultaneous imaging and therapy. Preclinical studies using ⁹⁹ᵐTc- or ⁶⁴Cu-labeled liposomes, polymeric micelles, and hybrid nanocarriers have demonstrated the feasibility of tracking drug distribution while maintaining therapeutic activity [[40], [41], [42], [43]]. These systems highlight the potential of integrating radiopharmaceutical carriers with stimuli-responsive materials to achieve controlled release and real-time monitoring of therapeutic delivery [16,17].

From a translational perspective, the success of theranostic systems lies in their ability to preserve targeting specificity while incorporating additional functional elements. Linker chemistry, spacer design, and surface modifications play critical roles in maintaining receptor affinity, optimizing pharmacokinetics, and enabling controlled payload release. Hydrophilic spacers such as polyethylene glycol (PEG) can improve circulation time and reduce non-specific uptake, while cleavable linkers responsive to enzymatic or pH triggers enable site-specific drug release [17,21,22].

3. Translational c-hallenges

Although radiopharmaceutical carriers have demonstrated robust tissue-specific targeting in clinical settings, their repurposing for therapeutic delivery introduces several scientific and technical challenges. Technetium chemistry relies on delicate coordination reactions that are not always compatible with therapeutic conjugation. Labeling strategies typically involve attaching technetium to tissue-specific biomolecules such as receptor ligands, peptides, proteins, antibodies, or antibiotics, with the expectation that these biomolecules retain their native biochemical and physiological activities [8,9]. Achieving this balance is not always straightforward, and even subtle modifications in labeling chemistry can compromise biological function.

A key constraint arises from the original formulation of technetium kits. Technetium is produced as sodium pertechnetate (Na-^99mTcO₄) directly from the generator, existing in an inert +7 oxidation state [4]. For complexation with biological ligands, it must first be reduced, often to the +3 or +5 oxidation state, under carefully controlled conditions [10]. To facilitate this process, commercial kits include a reducing agent, commonly stannous chloride (SnCl₂), along with carefully designed ligand systems that stabilize the reduced technetium. These reactions require precise control of pH, redox potential, and oxygen exclusion to ensure stable radiolabeling [44]. If these conditions are not met, undesirable chemical species such as colloidal or hydrolyzed technetium may form, resulting in reduced target specificity, lower stability, and potential off-target accumulation [45]. Such risks are less problematic in short-lived diagnostic applications, where radiopharmaceuticals are cleared rapidly. Still they become more critical when adapting carriers for therapeutic drug delivery, where greater payload burdens, longer exposure windows, and stricter control of off-target distribution required.

Another limitation concerns the inherent half-lives of radionuclides. For ^99mTc, the short half-life is advantageous for diagnostic imaging but may complicate its integration into therapeutic systems, particularly those intended for prolonged delivery or theranostic use. This constraint requires either the development of modified formulations that maintain therapeutic activity independent of the radionuclide or the pairing of technetium-inspired scaffolds with isotopes more suitable for therapy.

Together, these challenges highlight the complexity of adapting radiopharmaceutical carriers for nanomedicine applications. Success will depend on strategies that preserve the targeting fidelity of the original radiopharmaceuticals while ensuring chemical stability, payload compatibility, and reproducibility under therapeutic conditions. Addressing these barriers is essential to realize the full translational potential of radiopharmaceutical-inspired drug delivery.

4. Roadmap and f-uture p-erspectives

The limited integration between radiopharmaceuticals and drug delivery science reflects disciplinary separation rather than technological barriers. Nuclear medicine has long achieved organ- and tissue-specific targeting in humans, whereas pharmaceutical sciences often continue to design targeting systems de novo. Bridging these domains requires deliberate co-disciplinary collaboration and recognition of radiopharmaceutical carriers as clinically validated templates for therapeutic innovation.

A practical translational roadmap should begin with the formation of interdisciplinary consortia uniting nuclear chemists, formulation scientists, nanotechnologists, and regulatory experts. Such collaborations could curate libraries of radiopharmaceutical carriers, including technetium-, gallium-, lutetium-, rhenium-, copper-, iodine-, and actinium-based systems, and systematically assess their feasibility for drug conjugation, stability, and biodistribution. Establishing centralized repositories and standardized characterization protocols would streamline preclinical evaluation, minimize duplication, and accelerate the identification of repurposable scaffolds suitable for therapeutic development.

Regulatory pathways represent a key enabler of this transition. Because many radiopharmaceutical carriers have already undergone human validation for biodistribution and safety, repurposed or dual-functional formulations may qualify for abbreviated toxicology or pharmacology requirements under a data-bridging framework. Early dialogue with regulatory agencies and the adaptation of radiopharmaceutical dossiers for drug delivery purposes can therefore shorten development timelines and lower translational risk.

Future advances in linker chemistry, polymer science, and stimuli-responsive nanotechnology will further expand the adaptability of radiopharmaceutical scaffolds. Integrating these platforms with gene therapies, immunomodulators, or antibody–drug conjugates can create multifunctional systems capable of controlled release, imaging-guided therapy, and feedback-driven dosing. Computational modeling and artificial intelligence hold additional promises for optimizing conjugation design, predicting biodistribution, and enabling patient-specific treatment planning.

Equally important is investment in education and skill convergence. Researchers trained to bridge radionuclide coordination chemistry with pharmaceutical formulation science should be best positioned to drive this emerging field. Dedicated training programs and inter-laboratory fellowships could cultivate expertise essential for realizing the translational potential of radiopharmaceutical-inspired drug delivery.

Collectively, these efforts can transform radiopharmaceuticals from diagnostic instruments into versatile therapeutic delivery platforms, establishing a new cross-disciplinary paradigm for precision medicine.

5. Conclusion

Repurposing radiopharmaceutical carriers offers a practical, clinically grounded pathway to accelerate targeted drug delivery. Beyond technetium-^99m, other isotopic systems such as gallium, lutetium, rhenium, copper, iodine, and actinium provide pre-validated scaffolds whose biodistribution and safety have already been demonstrated in humans. These carriers, originally developed under rigorous clinical and regulatory oversight, can be intelligently modified to transport small molecules, biologics, or nucleic acids while preserving their intrinsic organ specificity.

Their modular coordination chemistry also supports the development of theranostic constructs that integrate imaging and treatment into a single formulation, enabling real-time visualization of drug distribution and therapeutic response. The integration of these pre-validated platforms into drug delivery research, therefore, presents a tangible opportunity to reduce translational attrition, improve regulatory predictability, and accelerate clinical impact.

Progress in this direction will depend on co-disciplinary collaboration, harmonized regulatory frameworks, and the use of computational modeling and artificial intelligence to refine carrier-payload design. By combining the precision of nuclear medicine with the innovation of pharmaceutical technology, radiopharmaceutical-inspired delivery systems can become a central pillar of personalized, image-guided therapy. This convergence represents not only a scientific opportunity but also a pragmatic translational pathway, turning decades of radiopharmaceutical experience into a foundation for the next-generation of targeted drug delivery and theranostic innovation.

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During the preparation of this work, the author used OpenAI ChatGPT (GPT-5, 2025) to assist with formatting and language polishing. After using this tool/service, the author reviewed and edited the content as needed and takes full responsibility for the content of the published article.

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Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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