Search Results (1,409)

Background/Objectives: The continuous emergence of immune-evasive SARS-CoV-2 variants underscores the need for adaptable and accessible therapeutics that complement vaccination. Single-domain antibodies (sdAbs) offer advantages in size, stability, and production costs compared to conventional monoclonal antibodies, but their clinical utility is limited by rapid clearance. This study aimed to develop a rabbit-derived sdAb with broad SARS-CoV-2 neutralization capacity and improved pharmacokinetic properties. Methods: A rabbit-derived variable light-chain (VL) sdAb library was constructed and subjected to phage display selection to identify high-affinity binders. Candidate sdAbs were characterized for cross-variant binding and neutralization. The lead sdAb, B3, was fused to the albumin-binding domain (ABD) of the Streptococcus zooepidemicus Zag protein to enhance in vivo half-life. Expression, albumin-binding capacity, and in vitro neutralization were assessed, followed by biodistribution studies in mice. Results: The selected sdAb, B3, showed strong binding and cross-variant neutralization against multiple SARS-CoV-2 lineages, including Delta and Omicron. Fusion to ABD(Zag) preserved neutralization potency, increased expression yields ~5-fold, and enabled cross-species albumin binding. In vivo, B3-ABD(Zag) exhibited markedly extended blood retention, showing a 21.2-fold increase at 24 h post-injection (5.30 vs. 0.25% I.A./g), and reduced renal uptake by 40% compared with unmodified B3. Conclusions: Rabbit-derived VL sdAbs fused to ABD(Zag) provide a promising platform for next-generation SARS-CoV-2 biologics. The enhanced pharmacokinetic profile of B3-ABD(Zag) supports its potential as a scalable therapeutic modality and highlights the broader utility of this approach for future emerging infectious threats. Full article

Background/Objectives: The neonatal Fc receptor (FcRn) plays a crucial role in extending the systemic half-life of monoclonal antibodies (mAbs), but its influence on ocular distribution remains incompletely understood. This study investigated the impact of FcRn on the ocular disposition of mAbs following systemic administration in rabbits. Methods: New Zealand White rabbits received a single intravenous dose (1 mg/kg) of either wild-type trastuzumab (TS-WT) or its FcRn non-binding variant (IHH). Plasma and ocular tissues (retina, iris–ciliary body, vitreous humor, aqueous humor, cornea, conjunctiva, and tears) were collected at terminal time points up to 336 h for TS-WT and 168 h for IHH. Antibody concentrations were quantified using a validated sandwich ELISA. Pharmacokinetic parameters and antibody biodistribution coefficients (ABC) were calculated to assess the FcRn-mediated effects on ocular distribution. Results: TS-WT demonstrated 2-fold higher systemic exposure compared to IHH. The iris–ciliary body exhibited the highest absolute exposure for both antibodies, with TS-WT showing significantly higher accumulation (ABC_0–168h: 14.95% vs. 8.89%). Retinal distribution remained comparable between antibodies (5.96% vs. 5.51%). Both antibodies were detectable in tears, with ABC value of ~4% reported for TS-WT. TS-WT also demonstrated markedly increased distribution in vitreous humor and tear fluid (3.5- and 5.5-fold higher ABC values, respectively) compared to IHH. The cornea (5.76% vs. 5.57%) and conjunctiva (7.71% vs. 7.21%) showed comparable relative distribution between TS-WT and IHH, while aqueous humor showed minimal differences (0.44% vs. 0.52%). Conclusions: This investigation reveals distinct tissue-specific patterns of FcRn-mediated mAb distribution within the eye. FcRn binding significantly enhanced antibody distribution in ocular tissues, such as the iris–ciliary body, and tears, with less pronounced effects on the retina, cornea, conjunctiva and aqueous humor. These findings provide mechanistic insights for optimizing mAb-based therapeutics for ocular disease and understanding the ocular toxicity of mAb-based therapeutics, such as antibody–drug conjugates. Full article

In search of a non-surgical alternative for male animal sterilization, this study investigated the use of gold-coated maghemite nanoparticles (γ-Fe₂O₃@Au) functionalized with citrate to produce testicular photohyperthermia (PHT). Wistar rats received an intratesticular injection of the fluid containing the nanoparticles (150 µL/testicle) followed by testicular irradiation with an LED light (808 nm). Testicular temperature was maintained at ~45 °C for 15 min. The results demonstrated a significant reduction in testicular volume and weight and sperm motility and normal morphology in PHT-treated animals, together with histopathological degeneration of seminiferous tubules. No treatment-related side effects or signs of systemic toxicity were observed. The biodistribution of the gold (Au) and iron (Fe) from the nanoparticles showed that the testes were the primary site of nanoparticle accumulation until day 56 post-treatment with possible renal excretion of Au. These findings support the prospect of testicular PHT mediated by γ-Fe₂O₃@Au nanoparticles as a neutering method for male animals. Full article

Background/Objectives: Radiolabeled bevacizumab-based immuno-PET tracers enable a non-invasive quantification of VEGF-A expression in gynecologic malignancies. While the previously reported [⁵²Mn]Mn-DOTAGA-bevacizumab demonstrated selective VEGF-A-targeted uptake in a KB-3-1 cervix carcinoma mouse model, further improvements in chelator stability and tumor-to-background contrast remain desirable. The recently developed BPPA chelator exhibits exceptionally high Mn(II) complex stability and favorable radiolabeling characteristics. This study aimed to characterize the in vivo biodistribution of [⁵²Mn]Mn-BPPA-bevacizumab, and to compare the tumor-to-background ratios of [⁵²Mn]Mn-BPPA-bevacizumab with the previously published values of [⁵²Mn]Mn-DOTAGA-bevacizumab in VEGF-A-expressing cervix carcinoma. Methods: Female KB-3-1 tumor-bearing CB17 SCID mice underwent PET/MRI imaging following intravenous administration of [⁵²Mn]Mn-BPPA-bevacizumab. SUV_mean values were measured in various organs and in the subcutaneously injected tumor, and tumor-to-organ ratios were calculated at various time points up to 10 days post-injection. Results: [⁵²Mn]Mn-BPPA-bevacizumab demonstrated sustained tumor uptake, with tumor SUVmean values increasing from approximately 1.0 at 4 h to peak values of approximately 2.4–2.5 at 72 h post-injection. Tumor-to-background ratios increased progressively over time and were significantly higher for [⁵²Mn]Mn-BPPA-bevacizumab compared with previously reported [52Mn]Mn-DOTAGA-bevacizumab, particularly for tumor-to-blood, tumor-to-liver and tumor-to-lung ratios at later imaging time points (p < 0.0001). Conclusions: The novel [⁵²Mn]Mn-BPPA-bevacizumab tracer exhibits satisfactory in vitro and in vivo stability for PET imaging, high VEGF-A-specific tumor uptake, and markedly improved tumor-to-background ratios compared to the previously published DOTAGA-based probe. These results position [⁵²Mn]Mn-BPPA-bevacizumab as a highly promising next-generation immuno-PET agent for imaging VEGF-A-expressing gynecologic malignancies and for guiding anti-angiogenic therapies. Full article

Background/Objectives: Malignant mesothelioma has a poor prognosis and limited therapeutic options. C-ERC/mesothelin is highly expressed in mesotheliomas and is a potential target for radioimmunotherapy (RIT). This study evaluated the radiolabeled anti-C-ERC/mesothelin antibody mAb 22A31 as a therapeutic agent. Methods: C-ERC/mesothelin expression in mesothelioma cell lines was assessed by Western blotting, and the specific binding of ¹²⁵I-labeled mAb 22A31 was examined. Biodistribution of ¹¹¹In-labeled mAb 22A31 was evaluated in a mesothelioma cell line, MSTO-211H tumor-bearing mice. The therapeutic efficacy of ⁹⁰Y-labeled mAb 22A31 was evaluated in subcutaneous and pleural dissemination models. Results: mAb 22A31 showed specific binding considering the level of C-ERC/mesothelin expression in each mesothelioma cell line. ¹¹¹In-mAb 22A31 accumulated in tumors with minimal uptake in normal tissues. ⁹⁰Y-mAb 22A31 significantly delayed the growth of subcutaneous tumors and improved survival in a pleural dissemination model. Conclusions: Radiolabeled mAb 22A31 specifically targeted C-ERC/mesothelin and demonstrated therapeutic efficacy in a mesothelioma xerograph model. Therefore, ⁹⁰Y-mAb 22A31 is a promising RIT agent and supports the further development of C-ERC/mesothelin-targeted therapy for mesothelioma. Full article

Triple-negative breast cancer (TNBC) represents 10–20% of breast cancers and is characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, leaving cytotoxic chemotherapy as the main systemic treatment. However, rapid development of resistance, via drug efflux, enhanced DNA repair, apoptosis evasion, epithelial-to-mesenchymal transition, and tumor microenvironment protection, limit long-term efficacy. Small interfering RNA (siRNA) therapeutics can silence key resistance drivers, but their clinical potential is hindered by instability, poor biodistribution, and off-target effects. Nanocarrier-based delivery systems offer solutions by protecting siRNA, enhancing tumor accumulation, enabling targeted intracellular release, and permitting co-delivery with chemotherapeutics for synergistic effects. We conducted a narrative review in PubMed from database inception to August 2025. The included studies demonstrated that lipid, polymeric, inorganic, and hybrid nanocarriers can achieve efficient target knockdown, reverse drug resistance mechanisms, and significantly enhance antitumor responses in resistant TNBC models. Several platforms also reduced metastatic spread and improved survival in vivo. While preclinical results are compelling, clinical translation remains limited by incomplete safety profiling and heterogeneity in delivery efficiency. This review synthesizes mechanistic insights and delivery innovations, outlining a roadmap for translating siRNA-loaded nanocarriers into effective therapies for chemoresistant TNBC. Full article

Plant-derived extracellular vesicles (PDEVs), engineered phytosomes, bioinspired polymeric plant-based nanoparticles (PBNPs), hybrid phyto-inorganic nanocomposites, green-synthesized metal nanoparticles, self-assembled nanoarchitectures, and multifunctional composites represent a rapidly advancing class of sustainable, nature-inspired nanocarriers. These platforms combine exceptional biocompatibility, negligible immunogenicity, and renewable sourcing with tunable drug loading, targeted delivery, and controlled release properties. This review synthesizes translational advances from 2020 to 2026, covering scalable isolation/bioprocessing (bioreactors, elicitation), multi-parametric physicochemical/multi-omics characterization, rational engineering/hybridization, and rigorous in vitro/in vivo assessments of uptake, biodistribution, pharmacokinetic (PK), and efficacy. Phytosomes and PBNPs markedly enhance oral bioavailability and targeted delivery of lipophilic phytochemicals, while PDEVs offer unique immunomodulatory, anti-inflammatory, and gene-regulatory activities. Hybrid and green-synthesized systems provide structural stability, redox modulation, and synergistic effects, and self-assembled/multifunctional composites address solubilization barriers with stimuli-responsive design. Early-phase human studies on grapefruit-, ginger-, turmeric-, and ginseng-derived PDEVs report excellent short-term safety, favorable PK, and preliminary bioactivity signals, with no observed immunogenicity or dose-limiting toxicities; however, these trials remain exploratory, constrained by small sample sizes and safety-focused endpoints. Despite challenges, including methodological heterogeneity, variable yields, long-term safety uncertainties (notably for inorganic hybrids), and regulatory ambiguities, emerging strategies such as clustered regularly interspaced short palindromic repeats (CRISPR)-engineered plant line; artificial-intelligence-driven process optimization; standardized guidelines, and integrated clinical, intellectual property, and commercialization frameworks are progressively addressing these barriers. Collectively, these advances position plant-derived nanocarriers as immunologically privileged, eco-friendly alternatives to synthetic and mammalian platforms, laying the foundation for a sustainable era of precision phytomedicine. Full article

Neuroinflammation is a central hallmark of numerous neurological disorders, including Alzheimer’s disease, Parkinson’s disease, traumatic brain injury, and spinal cord damage. Its persistent and dysregulated nature not only accelerates neuronal loss but also impedes endogenous repair, posing a major challenge for effective therapeutic intervention. Recent advances in nanobiotechnology have opened transformative opportunities to modulate neuroinflammation with unprecedented precision while simultaneously supporting neural regeneration. This review highlights emerging nanomaterial-based strategies including lipid-based, polymeric, inorganic nanoparticles designed to traverse the blood–brain barrier (BBB), deliver anti-inflammatory agents, modulate immune cell behavior, and attenuate glial activation. Extending beyond nanoparticle-based delivery systems, recent advances also emphasize the integration of nanomaterials into biomimetic architectures to provide structural and functional cues for neural repair. We further summarize how these functional nanostructured scaffolds, such as extracellular matrix (ECM) mimetic, nanofibrous and conductive hydrogels, are being leveraged in neural tissue engineering to direct stem cell fate, promote axonal outgrowth, and rebuild damaged neuroarchitectures. Moreover, pharmacokinetics, biodistribution, safety, clinical trials, regulatory considerations and limitations of nanotherapeutics in neurodegenerative diseases are discussed. By outlining the current progress, mechanistic insights, and translational challenges, this review underscores the potential of nanobiotechnology-enabled therapeutics to revolutionize the treatment of neuroinflammatory conditions and advance next-generation neural repair technologies. Full article

Background/Objectives: The limited targeting efficiency and systemic toxicity of conventional medicine present significant challenges in the treatment of skeletal disorders, such as bone tuberculosis. To address these limitations, we developed a bone-targeting nanomicelle delivery system functionalized with alendronate (ALN), designated ALN-PLGA-mPEG@RPT, to improve the targeted delivery and therapeutic efficacy of rifapentine (RPT) in bone tissue. Methods: The ALN-PLGA-mPEG blank micelles, prepared in accordance with our research group’s optimized protocol, were loaded with RPT and subjected to systematic formulation optimization. The resulting nanomicellar system was comprehensively characterized in terms of its physicochemical properties, including particle size and polydispersity index (PDI). Additionally, drug-loading capacity, encapsulation efficiency, and in vitro release curve were evaluated. Bone-targeting efficacy was assessed using in vivo imaging techniques, while biodistribution and safety profiles were determined through in vivo distribution studies and histopathological examination. Results: The optimized ALN-PLGA-mPEG@RPT nanomicelles exhibited a mean particle size of 101.90 ± 4.17 nm, and a PDI of 0.242 ± 0.021. The formulation achieved a drug loading of 16.74 ± 0.51% with an encapsulation efficiency of 50.27 ± 1.91%. In vitro release studies confirmed a sustained-release profile, with only 25% of RPT released within 12 h. In vivo imaging revealed significantly enhanced bone-targeting capability in the ALN-modified group, showing a 1.93-fold higher drug accumulation in bone tissue compared to blood. Histopathological analysis indicated no observable pathological alterations in major organs. Conclusions: The ALN-PLGA-mPEG@RPT nanomicelle system exhibits favorable bone-targeting efficiency, sustained-release properties, and biocompatibility, representing a promising strategy for the precise treatment of bone tuberculosis and other skeletal diseases. Full article

Background/Objectives: Magnetite nanoparticles represent promising candidates for a broad spectrum of biomedical applications, ranging from in vitro diagnostic assays to in vivo imaging, hyperthermia, and targeted drug and gene delivery, with some nanoagents already approved for clinical use. A critical determinant of their functionality is the nanoparticle coating, which facilitates beneficial interactions within biological systems. In the context of tumor-targeted therapeutic delivery, key design parameters—particularly surface coatings—can be optimized to enhance treatment efficacy by modulating blood circulation kinetics, biodistribution, and other critical properties. However, current preclinical screening methods primarily rely on cell culture models to identify potential nanocarriers, yet these systems often poorly correlate with actual in vivo performance. This discrepancy highlights the necessity of incorporating more biologically relevant testing platforms, such as high-throughput in vivo assays. Methods: In this work, we employed an original magnetic particle quantification (MPQ) technology to systematically evaluate the blood circulation kinetics and biodistribution patterns for magnetite nanoparticles with 17 different coatings across multiple organs and tissues, including the liver, spleen, lungs, kidneys, heart, tumor, brain, peripheral blood, muscle, and bone. This methodology offers high sensitivity, user-friendly operation, and provides quantitative measurements across a broad dynamic range of nanoparticle concentrations. These advantages enabled high-throughput acquisition of precise blood circulation and biodistribution data. In addition, histological analysis was conducted to evaluate nanoparticle penetration depth within tumor tissue. Results: Here we conducted a comprehensive study of the effect of 17 different polymer-, lectin-, and small molecule-based coatings on the behavior of magnetite nanoparticles in vivo. For each type of obtained nanoparticles, we implemented passive targeting as well as magnetic targeting, the latter using an external magnetic field localized in the tumor area. Conclusions: The collected dataset provides critical insights into how surface modifications influence nanoparticle performance in complex biological systems, offering valuable guidance for optimizing therapeutic nanocarrier design. Full article

“Smart” nanoparticles are often presented as the vanguard of precision cancer therapy, defined by engineered abilities to sense predefined stimuli, enhance targeting, and control therapeutic release. Yet this notion of smartness remains largely material-centric and only partially reflects how nanomedicines behave in vivo. Cells exposed to nanoparticles are not passive recipients of engineered functions; they actively interpret these perturbations through integrated stress-response, metabolic, transcriptional, and innate immune programs. These cell-state trajectories can determine efficacy, tolerance, resistance, or toxicity, and can do so independently of uptake, biodistribution, or triggerable release efficiency. Accordingly, evaluation strategies that prioritize delivery metrics and limited a priori molecular markers may misestimate functional performance and durability. This Perspective proposes a cell-aware reframing in which smartness is defined by biological controllability: the capacity of a nanoparticle system to elicit predictable, mechanistically interpretable, and therapeutically favorable cell-state trajectories across relevant malignant and non-malignant compartments. A practical path forward is to integrate time-resolved functional profiling into benchmarking using compact response signatures that report stress buffering, immune activation or suppression, and the emergence of tolerant states. A practical path forward is to integrate time-resolved functional profiling into benchmarking using compact response signatures that report stress buffering, immune activation or suppression, and the emergence of tolerant states. Here, biological controllability refers to the ability of a nanoparticle system to reproducibly steer integrated cellular stress, metabolic, and immune programs toward predefined therapeutic endpoints while minimizing adaptive escape across heterogeneous compartments. Full article

Background: In this study, we aimed to compare metabolomic profiles, biodistribution, and detoxification patterns of the novel SN-38 derivative NMe with irinotecan (IR), and to identify NMe-specific metabolites to evaluate its preclinical pharmacokinetic advantages. Methods: In vivo ADME studies were conducted for NMe, a 9-aminomethyl SN-38 derivative, and IR following a single intraperitoneal dose of 40 mg/kg in mice. Additionally, ADMET properties were predicted using ADMETlab and SwissADME tools for comparison. Levels of NMe and irinotecan absorbed into plasma, distributed to tissues, and metabolized were monitored in liver, lung, spleen, kidney, and stool samples at 15, 30, and 60 min post-administration. Tissue extracts were analysed using high-performance liquid chromatography (HPLC), liquid chromatography–electrospray ionization quadrupole time-of-flight-tandem mass spectrometry (LC-ESI-QTOF-MS), and nuclear magnetic resonance (NMR) techniques after lyophilization and reconstitution. We compared the metabolomic profiles of irinotecan and NMe. Results: We identified and confirmed NMe-specific metabolites, including 9-CH₂-S-cysteine conjugate, 9-CH₂OH, and NMe-formyl. Notably, novel irinotecan metabolites (IR-OH and IR-ΔE) were detected in small amounts in kidney samples. In some cases, two literature-known photodegradation products of irinotecan were present. NMe was found to quickly metabolize with different distribution to tissues, significantly greater to kidney and liver. Two SN-38 glucuronides, SN-38G(α) and SN-38G(β), were detected corresponding to α- and β-anomers. Where it was possible, NMe, IR and SN-38 were quantified using external calibration curves. In IR group, controlled and prolonged release of SN-38 was confirmed in all samples, yet SN-38G was observed in minority only in plasma, kidney, or lungs. In NMe groups, great relative amounts of SN-38 and SN-38G were detected. Greater content of SN-38G in NMe group than in irinotecan is expected to contribute to modulation and alleviation of some side effects in irinotecan-involved therapies, such as gastrointestinal toxicities (GIT). Conclusions: NMe shows a distinct metabolic profile characterized by rapid biotransformation, higher systemic glucuronidation of SN-38, and formation of unique metabolites, suggesting a potentially wider therapeutic window and reduced toxicity compared with IR. Full article

Intravenous delivery of recombinant adeno-associated virus serotype 9 can lead to reporter activation in cell types beyond the vasculature, but the routes enabling downstream parenchymal labeling remain unclear. Here, we provide a systematic, time-resolved map of parenchymal labeling after a single intravenous dose of rAAV9 encoding Cre recombinase under a ubiquitous promoter in healthy adult Ai9 reporter mice. Following retro-orbital administration, we quantified tdTomato-positive labeling across 25 targets at multiple time points over six months and observed durable reporter activation in several nonvascular parenchymal populations relevant to systemic gene-delivery applications. We also identify a set of parenchymal cell types that are consistently labeled in both this vascularly initiated reporter system and our prior adult VE-cadherin-driven reporter paradigm, supporting a connection to vascular exposure without asserting lineage relationships. These results nominate mechanistic routes for future disambiguation, including viral transcytosis across endothelium, endothelial cell transdifferentiation and extracellular-vesicle-mediated transfer. The dataset and methods provide a reference framework for investigators optimizing systemic delivery and interpreting downstream labeling in vivo. Full article

Rationale: Radium-223 dichloride (²²³RaCl₂) is an FDA-approved alpha-emitting radiopharmaceutical that targets bone metastases in metastatic castration-resistant prostate cancer (mCRPC). This study investigates the therapeutic and immunological effects of combining ²²³RaCl₂ with immune checkpoint inhibitors (ICIs) in a clinically relevant, immunocompetent murine model of prostate cancer bone metastasis. Methods: Luciferase-expressing MyC-CaP prostate cancer cells were implanted intratibially into FVB mice to establish bone metastases. Mice were treated with escalating doses of ²²³RaCl₂ (0.04–0.27 µCi) alone or a single dose combined with anti-CTLA-4 and anti-PD-L1 ICIs. Tumor growth was monitored using bioluminescence imaging. Micro-CT, alpha camera imaging, histology, and qPCR were used to assess bone remodeling, radiopharmaceutical distribution, immune infiltration, and gene expression. Ex vivo biodistribution and blood analyses quantified tissue uptake and toxicity. Results: Escalating doses of ²²³RaCl₂ did not significantly inhibit tumor growth or improve survival. Biodistribution and imaging showed preferential localization of ²²³RaCl₂ to tumor-adjacent bone, with minimal signal in isolated tumor tissue. Immunohistochemistry revealed increased CD4⁺ and CD8α⁺ T-cell infiltration in regions of high γH2AX expression, indicating localized immune modulation. However, combination therapy with ICIs did not enhance tumor control or immune infiltration beyond monotherapy. qPCR demonstrated significant upregulation of Mhc1 only in the combination group, suggesting localized immune activation. Toxicity profiles remained acceptable. Conclusions: ²²³RaCl₂ localizes primarily to bone surfaces, limiting direct cytotoxic and immunomodulatory effects within the tumor microenvironment. While combination with ICIs did not improve efficacy, these findings provide a platform for studying spatial dose distribution and support future development of tumor-targeted alpha therapies to potentiate immunotherapy in mCRPC. Full article

Background: Bone-seeking radiopharmaceuticals based on bisphosphonates enable targeted therapy of skeletal metastases. They are suitable carriers for therapeutic radionuclides such as terbium-161 (¹⁶¹Tb), a β⁻ emitter that additionally releases short-range conversion and Auger electrons, which may enhance radiation dose delivery to small lesions. This study explored the potential of the well-established DOTA conjugated bisphosphonate BPAMD (4-{[(bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10 tetraazacyclododec-1-yl)acetic acid) radiolabeled with ¹⁶¹Tb as a bone-targeted radiopharmaceutical, focusing on the theranostic and radiophysical advantages conferred by the radionuclide. Methods: BPAMD was radiolabeled with ¹⁶¹Tb and ¹⁷⁷Lu under mild conditions (pH 4.5, 95 °C, 30 min); subsequently, the radiochemical purity was assessed by radio-TLC. Physicochemical properties (charge, lipophilicity, protein binding), in vitro stability (saline and human serum, 48 h), and hydroxyapatite (HAP) binding were evaluated for [¹⁶¹Tb]Tb-BPAMD. Biodistribution was investigated in healthy Wistar rats (n = 3 per time point) at 2 h, 24 h, and 7 days post-injection. Computational density functional theory (DFT) analyses were performed to explore the coordination chemistry of Tb³⁺ and Lu³⁺ with BPAMD. Results: Both complexes achieved a radiochemical yield of greater than 98%. [¹⁶¹Tb]Tb-BPAMD exhibited negative charge, high hydrophilicity (logP = −3.92 ± 0.13), low protein binding (19.07 ± 1.01%), excellent radiochemical stability under simulated physiological conditions (>97% at 48 h), and strong hydroxyapatite affinity (>98% with ≥10 mg HAP). Biodistribution showed high, stable bone uptake (8.06% ID/g at 2 h; 6.70% ID/g at 24 h; 5.31% ID/g at 7 d) with rapid blood clearance (<0.001% ID/g at 24 h) and low non-target retention. To contextualize its performance, [¹⁶¹Tb]Tb-BPAMD was compared with [¹⁷⁷Lu]Lu-BPAMD, which demonstrated similarly strong skeletal retention (8.74% ID/g at 2 h; 8.08% ID/g at 24 h; 5.25% ID/g at 7 d) but comparatively higher non-target organ uptake. DFT calculations indicate that both Tb³⁺ and Lu³⁺ favor octa-coordinated BPAMD complexes. Conclusions: [¹⁶¹Tb]Tb-BPAMD exhibits excellent radiochemical and pharmacokinetic properties, with enhanced biodistribution selectivity over [¹⁷⁷Lu]Lu-BPAMD. Combined with the radiobiological advantages of ¹⁶¹Tb, it represents a promising theranostic candidate for targeted therapy of bone metastases. Full article