Biodistribution Research Articles

Using qPCR and ddPCR to study biodistribution of cell therapy products: a multi-site evaluation

Backgroud aimsRegenerative therapies employing cell therapy products (CTPs) have attracted considerable attention. Biodistribution (BD) evaluation of CTPs is mainly performed to clarify the cell survival time, engraftment, and distribution site. This evaluation is crucial for predicting the efficacy and safety profiles of clinical studies based on non-clinical BD study outcomes. However, no internationally unified method has been established for assessing cell BD after administration. Here, we aimed to standardize the BD assay method used for CTPs, conducting the following evaluations using the same protocol across multiple study facilities: (1) in vitro validation of quantitative polymerase chain reaction (qPCR) and droplet digital PCR (ddPCR) analyses using the primate-specific Alu gene, and (2) in vivo BD studies after the intravenous administration of human mesenchymal stem cells (hMSCs) to immunodeficient mice, commonly used in non-clinical tumorigenicity studies. MethodsQuality control samples were prepared and analyzed by adding a fixed number of human-derived cells to several mouse tissues. The respective quantitative performances of the qPCR and ddPCR methods were compared for accuracy and precision. hMSCs were intravenously administered to immunodeficient mice, and tissues were collected at 1, 4, and 24 h after administration. ResultsBoth methods demonstrated an accuracy (relative error) generally within ±50% and a precision (coefficient of variation) generally less than 50%. While differences in calibration curve ranges were observed between qPCR and ddPCR, no significant differences in quantification were found among the assay facilities. The BD of hMSCs in mice was evaluated at seven facilities (qPCR at three facilities; ddPCR at four facilities), revealing similar tissue distribution profiles in all facilities, with the lungs showing the highest cell distribution among the tissues tested. ConclusionsQuantitative evaluation of qPCR and ddPCR using Alu sequences was conducted, demonstrating that the test method can be adapted for BD evaluation.

Formulation and Evaluation of Liposomes containing Metformin Hydrochloride

The characterization and evaluation of metformin hydrochloride-loaded liposomal formulations are critical processes aimed at assessing their effectiveness and suitability for medical use. These formulations, composed of small synthetic vesicles called liposomes, are designed to enhance the delivery and efficacy of metformin, a widely used medication for managing type 2diabetes. Liposomes, with their unique blend of hydrophobic and hydrophilic properties, offer promising advantages in drug delivery. One key aspect of this process involves characterizing the liposomal formulations. This characterization entails examining various parameters such as size, surface charge, morphology, and encapsulation efficiency. Techniques like dynamic light scattering, zeta potential analysis, and microscopy are employed for this purpose, providing valuable insights into the physical properties of the liposomes. Additionally, the stability of the liposomal formulations is thoroughly assessed. This involves evaluating their physical and chemical stability under various storage conditions, including temperature and humidity variations, over a defined period. Ensuring the stability of the formulations is essential for maintaining their efficacy during storage and transportation. Finally, if feasible, preclinical pharmacokinetic studies are conducted in appropriate animal models to evaluate the bio distribution, systemic exposure, and pharmacokinetic parameters of metformin hydrochloride following administration of the liposomal formulations. These studies help determine the drug's behavior in living organisms and its potential therapeutic benefits

Revolutionizing Healthcare through Applications and Challenges of Nanomaterials in Targeted Drug Delivery and Therapeutics

This research investigates the cutting edge of healthcare advancement through the applications and challenges of nanomaterials focused on sedate conveyance and therapeutics. Gold nanoparticles (AuNPs) and liposomes were synthesized, characterized, and utilized as carriers for doxorubicin, illustrating remarkable medicate stacking capacities of 4.5% and 80.2%, individually. The discharge energy uncovered a Higuchi demonstration for AuNPs and first-order energy for liposomes, exhibiting custom-fitted medicate discharge profiles. In vitro studies illustrated critical cytotoxicity, with an IC50 of 12.3 µM for AuNPs in A549 cells and 8.7 µM for liposomes in MCF-7 cells. Cellular take-up rates of 35.6% and 50.2% advance asserted their adequacy. Moving to in vivo studies, the circulation half-life of AuNPs was 6.2 hours, whereas liposomes displayed a longer half-life of 8.5 hours. Bio distribution ponders illustrated particular aggregation within the tumor, coming to 4.8% ID/g for AuNPs and 6.2% ID/g for liposomes. Helpful results included tumor measure decrease and by and large survival rates of 75.4% for AuNPs and 82.7% for liposomes. Comparison with related works highlighted the competitive execution of the created nanomaterials, emphasizing their potential in progressing exactness medication. This research contributes to the advancing scene of nanomedicine, emphasizing personalized and maintainable healthcare arrangements.

Tritiated stainless steel (nano)particle release following a nuclear dismantling incident scenario: Significant exposure of freshwater ecosystem benthic zone

Nuclear facilities continue to be developed to help meet global energy demands while reducing fossil fuel use. However, an incident during the dismantling of these facilities could accidentally release tritiated particles (e.g. stainless steel) into the environment. Herein, we investigated the environmental dosimetry, fate, and impact of tritiated stainless steel (nano)particles (1 mg.L−1 particles and 1 MBq.L−1 tritium) using indoor freshwater aquatic mesocosms to mimic a pond ecosystem. The tritium (bio)distribution and particle fate and (bio)transformation were monitored in the different environmental compartments over 4 weeks using beta counting and chemical analysis. Impacts on picoplanktonic and picobenthic communities, and the benthic freshwater snail, Anisus vortex, were assessed as indicators of environmental health. Following contamination, some tritium (∼16%) desorbed into the water column while the particles rapidly settled onto the sediment. After 4 weeks, the particles and the majority of the tritium (>80%) had accumulated in the sediment, indicating a high exposure of the benthic ecological niche. Indeed, the benthic grazers presented significant behavioral changes despite low steel uptake (<0.01%). These results provide knowledge on the potential environmental impacts of incidental tritiated (nano)particles, which will allow for improved hazard and risk management.

Formulation and Development of Nanoparticulate System containing Rutin from Leaves Extract of Aegle marmelos for effective Management of Diabetes

Current work aimed at the modified release of content from carrier system at predetermined rate and secondly, to decrease the use of synthetic drug on biological system. Successive solvent extraction of crude drug of Aegle marmelos plant was done. Active constituent of leaves that is rutin was isolated and identified through HPTLC and FTIR. SLN was selected as carrier system and fabricated by solvent diffusion method. Characterization and performance evaluation of particulate system loaded with herbal plant extract of the Aegle marmelos leaves was done. TEM, In-vitro drug release profile, entrapment efficiency and particle size was determined. Solid lipid nanoparticles have enormous effect in loading high amount or loading dose concentration in body and also maintain the same over prolonged interlude of time. SLN was formulated and characterized for the particle size, shape and its distribution, percentage drug entrapment and In-vitro drug release profile along with the stability studies. In-vivo bio distribution studies on animals suggested the accumulation of formulations in the different organs. Solid lipid nanoparticles also show good stability as compared to other novel carrier systems. Prolonged release of natural drug from carrier system, decrease the dosing frequency and also decrease the dose size. Better results than marketed synthetic anti-diabetic drugs.

Abstract LB245: ONM-501, a dual-activating polyvalent STING agonist, enhances tumor retention and demonstrates favorable preclinical safety profile

Abstract Background: The Stimulator of Interferon Genes (STING) plays a crucial role in the innate immune response. Several previous STING agonist development compounds have shown limited therapeutic efficacy in oncology clinical trials. ONM-501 is a novel STING agonist: the endogenous STING agonist 2’,3’-cyclic GMP-AMP (cGAMP) is encapsulated within PC7A micelles. PC7A induces polyvalent STING condensation and prolongs immune activation. cGAMP-PC7A nanoparticles offer a dual ‘burst’ and ‘sustained’ STING activation. The anti-tumor efficacy and pharmacodynamic analysis of ONM-501 in multiple tumor models have been demonstrated previously. Here we report the pharmacokinetic (PK) and biodistribution (BD) analysis of ONM-501 in mice and safety evaluation in mice, rats and primates. Methods: PC7A polymers conjugated with LiCOR 800CW were mixed with unlabeled PC7A in 1:9 ratio and cGAMP was encapsulated into micelles to generate an “always-on” fluorescently labelled ONM-501-CW800. Naïve or tumor-bearing mice were injected subcutaneously (SC) or intratumorally (IT) with ONM-501-CW800, respectively, and plasma and multiple organ samples were collected; the whole tissue specimens were first imaged ex vivo using LiCOR Pearl Imaging system, and then homogenized and the fluorescence quantified against standard curves prepared by spiking ONM-501-CW800 into a homogenate of the relevant matrix. PK parameters were calculated using non-compartmental methods. Safety and tolerability were evaluated by single- and multiple-dose SC injections in naïve animals up to the highest feasible doses. Results: The BD pattern of ONM-501-CW800 was similar after IT and SC injections. The highest concentrations were observed at the injection sites and draining lymph nodes at all timepoints for both routes of administration. The concentrations in the injection site were much higher in tumors following IT than in dermal tissue following SC injection. After a 50 µg dose, systemic exposure to ONM-501-CW800 was ~1.8- and 2.4-fold lower after IT than SC injection based on Cmax and AUC(inf), respectively. The plasma t½ after IT injection, 17.4 hours, was ~1.3-fold longer than after SC injection, 12.9 hours. The Cmax and AUC (inf) in tumors were ~144- and 120-fold higher than in plasma after IT injection, with a t½ of 25.2 hours in tumors. In single-dose toxicology studies, ONM-501 was well tolerated in mice, rats and monkeys without severe or irreversible systemic toxicities up to the maximum feasible SC doses at 74, 45 and 30 mg/kg, respectively. In the 4-week repeat-dose GLP toxicology studies, the highest non-severely toxic SC dose (HNSTD) was 30 and 7.5 mg/kg in rats and monkeys, respectively. Conclusions: Systemic exposure to ONM-501 was lower after IT than SC administration, which is consistent with increased ONM-501 retention in tumors. Combined with preclinical toxicology studies, ONM-501 showed a favorable pharmacokinetic, tolerability and safety profile that support its continued development in cancer patients. Citation Format: Zirong Chen, Gang Huang, Katy Torres, Fiona Stavros, Alessandra Ahmed, Jason Miller, Tian Zhao, Jinming Gao, Ruolan Han. ONM-501, a dual-activating polyvalent STING agonist, enhances tumor retention and demonstrates favorable preclinical safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB245.

Liposomal Antibiotics for the Treatment of Infectious Diseases

Liposomal delivery systems have been utilized in developing effective therapeutics against cancer and targeting microorganisms in and out of host cells and within biofilm community. The most attractive feature of liposome-based drugs are enhancing therapeutic index of the new or existing drugs while minimizing their adverse effects. This communication provides an overview on several aspects of liposomal antibiotics including the most widely used preparation techniques for encapsulating different agents and the most important characteristic parameters applied for examining shape, size and stability of the spherical vesicles. In addition, the routes of administration, liposome--cell interactions and host parameters affecting the bio distribution of liposomes are highlighted. Liposomes are safe and suitable for delivery of variety of molecules and drugs in biomedical research and medicine. They are known to improve the therapeutic index of encapsulated agents and reduce drug toxic- ity. Recent studies on liposomal formulation of chemotherapeutic and bioac- tive agents and their targeted delivery show liposomal antibiotics potential in the treatment of microbial infections.

Soft X-ray and susceptibility based magnetic resonance imaging to map iron distribution in apples: initial results to model iron storage in water-deficient or dehydrated biological tissue

Radiology departments have contributed significantly to greenhouse gases including release of toxic imaging contrast media to environment. We feel Radiology also has several spectroscopy and imaging tools that may apply to monitor and support cleaner environmental goals. The current manuscript is one of the firsts to prompt Radiology to move in that direction by non-invasive imaging of bio metals that are less abundant in biological tissues but play key roles as co-factors in tissue structure and function. Conventional analytical tools are mostly invasive and cannot characterize the native oxidation states of bio metals. We chose carbohydrate matrix of metal-rich fruits and optimized two non-invasive imaging methods to detect changes in bio metal distribution as the samples were allowed to dry over time. It complements our prior work in Tomography Journal that demonstrated breakdown of specific radiological contrast media causing inflow of lanthanides and iodinated compounds to agricultural products and alter homeostasis by chelation and transmetallation. We observed that in the 20–30 keV range, that is at low end of clinical X-ray, commercial mammography detectors can detect alkali, alkaline earth, and transition metals in fruit samples irrespective of their oxidation states with appropriate X-ray filters utilizing preferential photoelectric absorption while high field magnetic resonance imagers (MRI) can localize paramagnetic states of certain minerals due to their ability to accelerate proton T2* decay and was used here to study biological tissues at different stages of dehydration. We also observed a central, radial shift of iron distribution from cortex toward the core for partially dried Apples indicative of porosity changes with de-moisturization. However, at this time our approach is unable to convincingly separate the susceptibility effects of paramagnetic bio metals from susceptibility effects of porosity changes during dehydration. We believe this work has two novel aspects: first, that MRI and X-ray could be used for complementary roles to map distribution of paramagnetics rich species, and secondly, ionic transport during heat processing of agricultural products or crops grown in arid land can be monitored for altered bio metal distribution by low energy X-ray as well as by high field MRI. In vivo applications may be possible to exploit MR susceptibility of native bio metals to localize abnormal iron distribution in neurodegeneration.

Nonclinical pharmacokinetics and biodistribution of VSV-GP using methods to decouple input drug disposition and viral replication

Viral replication places oncolytic viruses (OVs) in a unique niche in the field of drug pharmacokinetics (PK) as their self-amplification obscures exposure-response relationships. Moreover, standard bioanalytical techniques are unable to distinguish the input from replicated drug products. Here, we combine two novel approaches to characterize PK and biodistribution (BD) after systemic administration of vesicular stomatitis virus pseudotyped with lymphocytic choriomeningitis virus glycoprotein (VSV-GP) in healthy mice. First: to decouple input drug PK/BD versus replication PK/BD, we developed and fully characterized a replication-incompetent tool virus that retained all other critical attributes of the drug. We used this approach to quantify replication in blood and tissues and to determine its impact on PK and BD. Second: to discriminate the genomic and antigenomic viral RNA strands contributing to replication dynamics in tissues, we developed an in situ hybridization method using strand-specific probes and assessed their spatiotemporal distribution in tissues. This latter approach demonstrated that distribution, transcription, and replication localized to tissue-resident macrophages, indicating their role in PK and BD. Ultimately, our study results in a refined PK/BD profile for a replicating OV, new proposed PK parameters, and deeper understanding of OV PK/BD using unique approaches that could be applied to other replicating vectors.

A Predictive Pharmacokinetic Model for Immune Cell-Mediated Uptake and Retention of Nanoparticles in Tumors.

A promise of cancer nanomedicine is the "targeted" delivery of therapeutic agents to tumors by the rational design of nanostructured materials. During the past several decades, a realization that in vitro and in vivo preclinical data are unreliable predictors of successful clinical translation has motivated a reexamination of this approach. Mathematical models of drug pharmacokinetics (PK) and biodistribution (BD) are essential tools for small-molecule drugs development. A key assumption underlying these models is that drug-target binding kinetics dominate blood clearance, hence recognition by host innate immune cells is not explicitly included. Nanoparticles circulating in the blood are conspicuous to phagocytes, and inevitable interactions typically trigger active biological responses to sequester and remove them from circulation. Our recent findings suggest that, instead of referring to nanoparticles as designed for active or passive "tumor targeting", we ought rather to refer to immune cells residing in the tumor microenvironment (TME) as active or passive actors in an essentially "cell-mediated tumor retention" process that competes with active removal by other phagocytes. Indeed, following intravenous injection, nanoparticles induce changes in the immune compartment of the TME because of nanoparticle uptake, irrespective of the nature of tumor targeting moieties. In this study, we propose a 6-compartment PK model as an initial mathematical framework for modeling this tumor-associated immune cell-mediated retention. Published in vivo PK and BD results obtained with bionized nanoferrite® (BNF®) nanoparticles were combined with results from in vitro internalization experiments with murine macrophages to guide simulations. As a preliminary approximation, we assumed that tumor-associated macrophages (TAMs) are solely responsible for active retention in the TME. We model the TAM approximation by relating in vitro macrophage uptake to an effective macrophage avidity term for the BNF® nanoparticles under consideration.

Quercetin Nanoparticles- A Promising Approach to Cancer Treatment: A Review

Quercetin, a naturally occurring polyphenolic element, has rapidly received attention as an anticancer agent. Although quercetin has demonstrated potent medical value, its application as an antitumor drug is limited because of poor solubility, low absorption, and fat metabolism. Nanoparticles are effective and versatile drug delivery devices because they can improve the solubility, pharmacokinetics, bio distribution, and in vivo stability of the free drug. The utilization of Nano-carrier scanning increases the bioavailability of the drug. Quercetin nanoparticles have shown high encapsulation efficiency, stability, sustained release, extended circulation time, improved accumulation at tumor sites, and therapeutic efficacy. This review article aims to estimate the anticancer efficiency of polymeric nanoparticles of quercetin. The majority of research is based on the preclinical anticancer activities of quercetin nanoparticles. MCF cells of breast cancer (BC), A 549 cells of lung cancer, cells of HepG2 liver malignancy, and cells of malignance are the primary targets for possible anticancer activity. Furthermore, combining quercetin with other diagnostic or therapeutic agents in a single Nano carrier has resulted in improvements in tumor detection or treatment. The antitumor outcome of drugs that are used in cancer therapy can also be supported by quercetin nanoparticles by increasing the anti-tumor development or decreasing the systemic toxicity level of the drug. Keywords: , , ,

Novel methylcellulose based thermosenstive in situ nano liposomes of docetaxel for improved pharmacokinetics and pharmacodynamics with reduced toxicity

The utility of Docetaxel (DTX) in different cancers is highly compromised due to reported side effects from its commercial injectable formulation. In this work, novel methylcellulose (MC) based thermosenstive in situ nano liposomes of anti-cancer drug docetaxel (DTX) was developed for its locoregional delivery in treatment of cancer. An array of biodegradable polymers; Hydroxy propyl methyl cellulose (HPMC), Poloxamer-407 and MC for development of in situ nano liposomes (NL) were utilized alone and in combinations of one another for different sets of formulations. Optimized formulation ISNL-MC-2 exhibited in situ gelation at 36.2 ± 0.5 ºC, ideal syringeability, and sustained drug release (at 37 ± 0.5 ºC) up to 6 days with immediate in vitro gelation (5.5 ± 0.3 min). Further, a significantly higher biological half-life (23 ± 0.2 h) was detected in vivo in comparison to the commercial DTX injectable formulation (1.7 ± 0.1 h). Bio distribution study revealed almost 3 fold higher drug localization from the optimized formulation. When evaluated pharmaco dynamically in Ehrlich Ascites Carcinoma (EAC) induced mice, better tumor inhibition (87.7 ± 2.5%) was seen with the optimized formulation compared to the commercial DTX formulation (76.5 ± 2.1%). The detailed characterization and optimization brought in situ behavior of the optimized formulation close to physiological temperature using suitable concentration of MC and sodium chloride.

Pharmacokinetics, Bio Distribution and Therapeutic Applications of Recently-Developed siRNA and DNA Repair Genes Recurrence

Up regulation of cell cycle-regulating and DNA repair genes appears to have a negative impact on recurrence-free survival in patients with papillary thyroid cancer. Furthermore, recurrence is associated with thyroid dedifferentiation. Most cases address local applications or diseases in the filtering organs, reflecting remaining challenges in systemic delivery of siRNA. Small Interfering RNA (siRNA) is a promising drug candidate, expected to have broad therapeutic potentials toward various diseases including viral infections and cancer. With recent advances in bio conjugate chemistry and carrier technology, several siRNA-based drugs have advanced to clinical trials. The difficulty in siRNA delivery is in large part due to poor circulation stability and unfavorable pharmacokinetics and bio distribution profiles of siRNA. In this research we describe the pharmacokinetics and bio distribution of siRNA Nano medicines, focusing on those reported in the past 5 years, and their pharmacological effects in selected disease models such as hepatocellular carcinoma, liver infections, and respiratory diseases. The examples discussed here will provide an insight into the current status of the art and unmet needs in siRNA delivery.

Nanocurcumin-Loaded UCNPs for Cancer Theranostics: Physicochemical Properties, In Vitro Toxicity, and In Vivo Imaging Studies.

Formulation of promising anticancer herbal drug curcumin as a nanoscale-sized curcumin (nanocurcumin) improved its delivery to cells and organisms both in vitro and in vivo. We report on coupling nanocurcumin with upconversion nanoparticles (UCNPs) using Poly (lactic-co-glycolic Acid) (PLGA) to endow visualisation in the near-infrared transparency window. Nanocurcumin was prepared by solvent-antisolvent method. NaYF4:Yb,Er (UCNP1) and NaYF4:Yb,Tm (UCNP2) nanoparticles were synthesised by reverse microemulsion method and then functionalized it with PLGA to form UCNP-PLGA nanocarrier followed up by loading with the solvent-antisolvent process synthesized herbal nanocurcumin. The UCNP samples were extensively characterised with XRD, Raman, FTIR, DSC, TGA, UV-VIS-NIR spectrophotometer, Upconversion spectrofluorometer, HRSEM, EDAX and Zeta Potential analyses. UCNP1-PLGA-nanocurcumin exhibited emission at 520, 540, 660 nm and UCNP2-PLGA-nanocurmin showed emission at 480 and 800 nm spectral bands. UCNP-PLGA-nanocurcumin incubated with rat glioblastoma cells demonstrated moderate cytotoxicity, 60–80% cell viability at 0.12–0.02 mg/mL marginally suitable for therapeutic applications. The cytotoxicity of UCNPs evaluated in tumour spheroids models confirmed UCNP-PLGA-nanocurcumin therapeutic potential. As-synthesised curcumin-loaded nanocomplexes were administered in tumour-bearing laboratory animals (Lewis lung cancer model) and showed adequate contrast to enable in vivo and ex vivo study of UCNP-PLGA-nanocurcumin bio distribution in organs, with dominant distribution in the liver and lungs. Our studies demonstrate promise of nanocurcumin-loaded upconversion nanoparticles for theranostics applications.

Dose predictions for [177Lu]Lu-DOTA-panitumumab F(ab\u2032)2 in NRG mice with HNSCC patient-derived tumour xenografts based on [64Cu]Cu-DOTA-panitumumab F(ab\u2032)2 \u2013 implications for a PET theranostic strategy

BackgroundEpidermal growth factor receptors (EGFR) are overexpressed on many head and neck squamous cell carcinoma (HNSCC). Radioimmunotherapy (RIT) with F(ab')2 of the anti-EGFR monoclonal antibody panitumumab labeled with the β-particle emitter, 177Lu may be a promising treatment for HNSCC. Our aim was to assess the feasibility of a theranostic strategy that combines positron emission tomography (PET) with [64Cu]Cu-DOTA-panitumumab F(ab')2 to image HNSCC and predict the radiation equivalent doses to the tumour and normal organs from RIT with [177Lu]Lu-DOTA-panitumumab F(ab')2.ResultsPanitumumab F(ab')2 were conjugated to DOTA and complexed to 64Cu or 177Lu in high radiochemical purity (95.6 ± 2.1% and 96.7 ± 3.5%, respectively) and exhibited high affinity EGFR binding (Kd = 2.9 ± 0.7 × 10− 9 mol/L). Biodistribution (BOD) studies at 6, 24 or 48 h post-injection (p.i.) of [64Cu]Cu-DOTA-panitumumab F(ab')2 (5.5–14.0 MBq; 50 μg) or [177Lu]Lu-DOTA-panitumumab F(ab')2 (6.5 MBq; 50 μg) in NRG mice with s.c. HNSCC patient-derived xenografts (PDX) overall showed no significant differences in tumour uptake but modest differences in normal organ uptake were noted at certain time points. Tumours were imaged by microPET/CT with [64Cu]Cu-DOTA-panitumumab F(ab')2 or microSPECT/CT with [177Lu]Lu-DOTA-panitumumab F(ab')2 but not with irrelevant [177Lu]Lu-DOTA-trastuzumab F(ab')2. Tumour uptake at 24 h p.i. of [64Cu]Cu-DOTA-panitumumab F(ab')2 [14.9 ± 1.1% injected dose/gram (%ID/g) and [177Lu]Lu-DOTA-panitumumab F(ab')2 (18.0 ± 0.4%ID/g) were significantly higher (P < 0.05) than [177Lu]Lu-DOTA-trastuzumab F(ab')2 (2.6 ± 0.5%ID/g), demonstrating EGFR-mediated tumour uptake. There were no significant differences in the radiation equivalent doses in the tumour and most normal organs estimated for [177Lu]Lu-DOTA-panitumumab F(ab')2 based on the BOD of [64Cu]Cu-DOTA-panitumumab F(ab')2 compared to those estimated directly from the BOD of [177Lu]Lu-DOTA-panitumumab F(ab')2 except for the liver and whole body which were modestly underestimated by [64Cu]Cu-DOTA-panitumumab F(ab')2. Region-of-interest (ROI) analysis of microPET/CT images provided dose estimates for the tumour and liver that were not significantly different for the two radioimmunoconjugates. Human doses from administration of [177Lu]Lu-DOTA-panitumumab F(ab')2 predicted that a 2 cm diameter HNSCC tumour in a patient would receive 1.1–1.5 mSv/MBq and the whole body dose would be 0.15–0.22 mSv/MBq.ConclusionA PET theranostic strategy combining [64Cu]Cu-DOTA-panitumumab F(ab')2 to image HNSCC tumours and predict the equivalent radiation doses in the tumour and normal organs from RIT with [177Lu]Lu-DOTA-panitumumab F(ab')2 is feasible. RIT with [177Lu]Lu-DOTA-panitumumab F(ab')2 may be a promising approach to treatment of HNSCC due to frequent overexpression of EGFR.

Biodistribution studies for cell therapy products: Current status and issues.

Information on the biodistribution (BD) of cell therapy products (CTPs) is essential for prediction and assessment of their efficacy and toxicity profiles in non-clinical and clinical studies. To conduct BD studies, it is necessary to understand regulatory requirements, implementation status, and analytical methods. This review aimed at surveying international and Japanese trends concerning the BD study for CTPs and the following subjects were investigated, which were considered particularly important: 1) comparison of guidelines to understand the regulatory status of BD studies in a global setting; 2) case studies of the BD study using databases to understand its current status in cell therapy; 3) case studies on quantitative polymerase chain reaction (qPCR) used primarily in non-clinical BD studies for CTPs; and 4) survey of imaging methods used for non-clinical and clinical BD studies. The results in this review will be a useful resource for implementing BD studies.

Innentitelbild: Implications of Quenching‐to‐Dequenching Switch in Quantitative Cell Uptake and Biodistribution of Dye‐Labeled Nanoparticles (Angew. Chem. 28/2021)

Innentitelbild: Implications of Quenching‐to‐Dequenching Switch in Quantitative Cell Uptake and Biodistribution of Dye‐Labeled Nanoparticles (Angew. Chem. 28/2021)

Preclinical evaluation of [225Ac]Ac-DOTA-TATE for treatment of lung neuroendocrine neoplasms.

There is significant interest in the development of targeted alpha-particle therapies (TATs) for treatment of solid tumors. The metal chelator-peptide conjugate, DOTA-TATE, loaded with the β-particle emitting radionuclide 177Lu ([177Lu]Lu-DOTA-TATE) is now standard care for neuroendocrine tumors that express the somatostatin receptor 2 (SSTR2) target. A recent clinical study demonstrated efficacy of the corresponding [225Ac]Ac-DOTA-TATE in patients that were refractory to [177Lu]Lu-DOTA-TATE. Herein, we report the radiosynthesis, toxicity, biodistribution (BD), radiation dosimetry (RD), and efficacy of [225Ac]Ac-DOTA-TATE in small animal models of lung neuroendocrine neoplasms (NENs). [225Ac]Ac-DOTA-TATE was synthesized and characterized for radiochemical yield, purity and stability. Non-tumor-bearing BALB/c mice were tested for toxicity and BD. Efficacy was determined by single intravenous injection of [225Ac]Ac-DOTA-TATE into SCID mice-bearing human SSTR2 positive H727 and H69 lung NENs. RD was calculated using the BD data. [225Ac]Ac-DOTA-TATE was synthesized with 98% yield, 99.8% purity, and displayed 97% stability after 2days incubation in human serum at 37°C. All animals in the toxicity study appeared healthy 5months post injection with no indications of toxicity, except that animals that received ≥111kBq of [225Ac]Ac-DOTA-TATE had chronic progressive nephropathy. BD studies revealed that the primary route of elimination is by the renal route. RD calculations determined pharmacokinetics parameters and absorbed α-emission dosages from 225Ac and its daughters. For both tumor models, a significant tumor growth delay and time to experimental endpoint were observed following a single administration of [225Ac]Ac-DOTA-TATE relative to controls. These results suggest significant potential for the clinical translation of [225Ac]Ac-DOTA-TATE for lung NENs.

Lipophilicity Determines Routes of Uptake and Clearance, and Toxicity of an Alpha-Particle-Emitting Peptide Receptor Radiotherapy.

Lipophilicity is explored in the biodistribution (BD), pharmacokinetics (PK), radiation dosimetry (RD), and toxicity of an internally administered targeted alpha-particle therapy (TAT) under development for the treatment of metastatic melanoma. The TAT conjugate is comprised of the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), conjugated to melanocortin receptor 1 specific peptidic ligand (MC1RL) using a linker moiety and chelation of the 225Ac radiometal. A set of conjugates were prepared with a range of lipophilicities (log D 7.4 values) by varying the chemical properties of the linker. Reported are the observations that higher log D 7.4 values are associated with decreased kidney uptake, decreased absorbed radiation dose, and decreased kidney toxicity of the TAT, and the inverse is observed for lower log D 7.4 values. Animals administered TATs with lower lipophilicities exhibited acute nephropathy and death, whereas animals administered the highest activity TATs with higher lipophilicities lived for the duration of the 7 month study and exhibited chronic progressive nephropathy. Changes in TAT lipophilicity were not associated with changes in liver uptake, dose, or toxicity. Significant observations include that lipophilicity correlates with kidney BD, the kidney-to-liver BD ratio, and weight loss and that blood urea nitrogen (BUN) levels correlated with kidney uptake. Furthermore, BUN was identified as having higher sensitivity and specificity of detection of kidney pathology, and the liver enzyme alkaline phosphatase (ALKP) had high sensitivity and specificity for detection of liver damage associated with the TAT. These findings suggest that tuning radiopharmaceutical lipophilicity can effectively modulate the level of kidney uptake to reduce morbidity and improve both safety and efficacy.

Preparation of Technetium Labeled-Graphene Quantum Dots and Investigation of Their Bio Distribution

The novel radiotracer has been studied with the title of Graphene quantum dots (GQDs) and decorated by the usage of selenium (Se), while surface modification has been carried out in the following through the utilization of Polyethylene glycol (PEG) and labeled with 99mTechnetium (99mTc). Moreover, 99mTc has been eluted from a 99Mo/99mTc producer, and Graphene quantum dots have been synthesized with high photoluminescence (PL) intensity throughout the range of 600 to 900 nm. We have also evaluated the labeling stability percentages of GQDs and 99mTc in double-distilled water and human serum through the application of the Instant Thin Layer Chromatography (ITLC) method in different time intervals; it should be noted that methanol and acetone have been applied as the mobile phase. Radioactivity of 99mTc-GQDs have been injected into nine designated rats through their tail, while the bio distribution of radioactivity was being surveyed through a Gamma counter and had the percent of Injected Dose per gram (%ID/g) calculated for each organ. In addition, the process of capturing static posterior and anterior images by the application of a gamma camera has been done in vivo. In accordance with the observations, there has been a higher GQDs (Se-PEG) distribution throughout the kidneys when compared to the other organs. There is the possibility of exerting these quantum dots for the labeling of kidneys since they can almost completely escape the body within 24 h.