Geotemporal Fluorophore Biodistribution Mapping of Colorectal Cancer: Micro and Macroscopic Insights.

Fluorescence-guided oncology promises to improve both the detection and treatment of malignancy. We sought to investigate the temporal distribution of indocyanine green (ICG), an exogenous fluorophore in human colorectal cancer. This analysis aims to enhance our understanding of ICG's effectiveness in current tumour detection and inform potential future diagnostic and therapeutic enhancements. METHODS: Fifty consenting patients undergoing treatment for suspected/confirmed colorectal neoplasia provided near infrared (NIR) video and imagery of transanally recorded and ex vivo resected rectal lesions following intravenous ICG administration (0.25 mg/kg), with a subgroup providing tissue samples for microscopic (including near infrared) analysis. Computer vision techniques detailed macroscopic 'early' (<15 min post ICG administration) and 'late' (>2 h) tissue fluorescence appearances from surgical imagery with digital NIR scanning (Licor, Lincoln, NE, USA) and from microscopic analysis (Nikon, Tokyo, Japan) undertaken by a consultant pathologist detailing tissue-level fluorescence distribution over the same time. RESULTS: Significant intra-tumoural fluorescence heterogeneity was seen 'early' in malignant versus benign lesions. In all 'early' samples, fluorescence was predominantly within the tissue stroma, with uptake within plasma cells, blood vessels and lymphatics, but not within malignant or healthy glands. At 'late' stage observation, fluorescence was visualised non-uniformly within the intracellular cytoplasm of malignant tissue but not retained in benign glands. Fluorescence also accumulated within any present peritumoural inflammatory tissue. CONCLUSION: This study demonstrates the time course diffusion patterns of ICG through both benign and malignant tumours in vivo in human patients at both macroscopic and microscopic levels, demonstrating important cellular drivers and features of geolocalisation and how they differ longitudinally after exposure to ICG.

Antihormonal-Treatment Status Affects 68Ga-PSMA-HBED-CC PET Biodistribution in Patients with Prostate Cancer.

Androgen deprivation therapy (ADT) is known to influence the prostate-specific membrane antigen (PSMA) expression of prostate cancer, potentially complicating the interpretation of PSMA ligand PET findings and affecting PSMA radioligand therapy. However, the impact of ADT on PSMA ligand biodistribution in nontumorous organs is not well understood. Methods: Men (n = 112) with histologically proven prostate cancer who underwent 68Ga-PSMA-HBED-CC (68Ga-PSMA-11) PET/CT between November 2015 and July 2021 at the Medical University Vienna with known ADT status were retrospectively recruited. Fifty-six patients were on gonadotropin-releasing hormone-interfering ADT at the time of imaging (ADT group), whereas 56 patients with no history of ADT served as a control group. Physiologically PSMA-expressing organs (salivary glands, kidneys, liver, and spleen) were delineated, and their uptake was compared according to their data distributions. Multivariate regression analysis assessed the relationship between renal, hepatic, splenic, and salivary gland uptake and the explanatory variables metabolic tumor volume, glomerular filtration rate, and ADT status. Results: ADT was associated with lower levels of PSMA uptake in the kidneys (SUVmean: Δ[ADT - control] = -7.89; 95% CI, -10.73 to -5.04; P < 0.001), liver (SUVpeak: Δ[ADT - control] = -2.3; 95% CI, -5.72 to -0.93; P = 0.003), spleen (SUVpeak: Δ[ADT - control] = -1.27; 95% CI, -3.61 to -0.16; P = 0.033), and salivary glands (SUVmean: Δ[ADT - control] = -1.04; 95% CI, -2.48 to -0.13; P = 0.027). In a multivariate analysis, ADT was found to be associated with lower renal (SUVmean: ß = -7.95; 95% CI, -11.06 to -4.84; P < 0.0001), hepatic (SUVpeak: ß = -7.85; 95% CI, -11.78 to -3.91; P < 0.0001), splenic (SUVpeak: ß = -5.83; 95% CI, -9.95 to -1.7; P = 0.006), and salivary gland (SUVmean: ß = -1.47; 95% CI, -2.76 to -0.17; P = 0.027) uptake. A higher glomerular filtration rate was associated with a higher renal SUVmean (ß = 0.16; 95% CI, 0.05 to 0.26; P = 0.0034). Conclusion: These findings suggest that ADT systemically modulates PSMA expression, which may have implications for treatment-optimizing and side-effect-minimizing strategies for PSMA radioligand therapies, particularly those using more potent 225Ac-labeled PSMA conjugates.

Chemometric assisted natural DES based VA-DLLME-LC-MS/MS method for the quantitative determination of Garcinol in biofluids/tissues: A practical application to pharmacokinetics and biodistribution studies.

Garcinol (GAR) is a polyisoprenylated benzophenone obtained from Garcinia indica used as anti-oxidant and anti-inflammatory in traditional medicine and due to these activities, it possesses anticancer properties. It is considered to be a next generation epigenetic drug. A green solvent based analytical method which is efficient, sophisticated, and highly enriched has been developed for the quantitative analysis of GAR in biological samples (plasma, liver, kidney and spleen) with the use of deep eutectic solvent (DES) for its extraction. A series of 23 DESs were synthesized and out of which, Thymol (Th)-Terpeniol (T), 2:1 molar ratio with a more hydrophobic environment and high interaction efficiency between GAR and DES was identified for the better extraction from mice plasma and tissue samples. The Design of Experiment approaches like placket-burmann design and central composite design were used to optimize the method conditions. The method validation characteristics, such as limit of detection (0.193-0.237 ng/mL), limit of quantification (0.644-0.697 ng/mL), lower limit of quantification (0.5 ng/mL), broad range of linearity with R2 (0.9994-0.9997) with a percent recovery not less than 87% was observed, which are well within the acceptance criteria for a bioanalytical method. The enrichment factor is upto 53-60 folds, with high extraction efficiency (89-97%). The measurement uncertainty was estimated with an expanded uncertainty ranged between 10.9%-19.0%. The method developed and validated was effectively applied to examine the pharmacokinetic and biodistribution patterns for GAR in mice.

Assessment of sub-chronic oral toxicity of Nityanand Rasa: An ayurvedic herbo-metallic formulation.

ETHNOPHARMACOLOGICAL RELEVANCE: Nityananda Rasa (NR) is an ayurvedic herbo-metallic formulation used to treat gout, obesity, hypothyroidism, elephantiasis, and other diseases. However, its safety is a concern owing to the use of heavy metals like mercury and arsenic. AIM OF THE STUDY: To study the sub-chronic oral toxicity of NR on albino wistar rats for safety evaluation. MATERIALS AND METHODS: The male and female albino wistar rats were administered a daily dose of 30 (low), 300 (medium) and 600 (high) mg/kg BW/day of NR for 90-day period. The body weight and feed consumption were monitored once a week. After 90 days, blood and vital organs were harvested for genotoxicity, hematology, biochemistry, histopathology, gene expression and the biodistribution analysis. RESULTS: There was no mortality or severe behavioural changes observed in rats. Significant changes in biochemical enzyme levels were seen at medium and high doses of NR i. e. 300 and 600 mg/kg BW/day respectively. No hematological changes were observed. Mild histopathological changes seen at high dose of NR which were found in concurrence with the biochemical alterations in liver and brain. There was mild genotoxicity and no detectable level of mercury but significant arsenic level in blood at high dose. Gene expression was mildly affected. CONCLUSIONS: NR induced moderate toxic effects at high dose but can be considered safe at therapeutic doses.

Fabrication of food grade zein-dispersed selenium dual-nanoparticles with controllable size, cell friendliness and oral bioavailability.

In this study, novel bioavailable selenium nanoparticles with controllable particle size and low toxicity were developed. With selenium modified zein nanoparticles (zein NPs) in-situ, dispersed nano-selenium particles with different structure were formed simultaneously. The particle size, zeta potential, morphology and binding mechanism of synthesized zein-selenium nanoparticles (zein-Se NPs) were systematically discussed. Selenium was considered to be combined with OH and -CO-NH- groups of zein. The selenium in the complex particles presented an amorphous structure with zero valence. The cytotoxicity of zein-Se NPs was significantly lower than that of sodium selenite, even exhibited a growth-promoting effect on normal liver cells (L-02), and were proven to be orally absorbed by organisms in vivo experiments. The difference in particle structure had certain effects on cytotoxicity and oral targeting. The complex particles obtained by this method were anticipated be further used as food fortifiers or medicines.

Multiscale Multimodal Investigation of the Intratissural Biodistribution of Iron Nanotherapeutics with Single Cell Resolution Reveals Co-Localization with Endogenous Iron in Splenic Macrophages.

Imaging of iron-based nanoparticles (NPs) remains challenging because of the presence of endogenous iron in tissues that is difficult to distinguish from exogenous iron originating from the NPs. Here, an analytical cascade for characterizing the biodistribution of biomedically relevant iron-based NPs from the organ scale to the cellular and subcellular scales is introduced. The biodistribution on an organ level is assessed by elemental analysis and quantification of magnetic iron by electron paramagnetic resonance, which allowed differentiation of exogenous and endogenous iron. Complementary to these bulk analysis techniques, correlative whole-slide optical and electron microscopy provided spatially resolved insight into the biodistribution of endo- and exogenous iron accumulation in macrophages, with single-cell and single-particle resolution, revealing coaccumulation of iron NPs with endogenous iron in splenic macrophages. Subsequent transmission electron microscopy revealed two types of morphologically distinct iron-containing structures (exogenous nanoparticles and endogenous ferritin) within membrane-bound vesicles in the cytoplasm, hinting at an attempt of splenic macrophages to extract and recycle iron from exogenous nanoparticles. Overall, this strategy enables the distinction of endo- and exogenous iron across scales (from cm to nm, based on the analysis of thousands of cells) and illustrates distribution on organ, cell, and organelle levels.

Age-dependent assessment of selenium nanoparticles: biodistribution and toxicity study in young and adult rats.

Aim: To study the biodistribution and toxicology of selenium nanoparticles (SeNPs) versus their bulk counterpart in young and adult male rats in a 28-day study. Methods: SeNPs were synthesized and conjugated with indocyanine green to assess comparative biodistribution by in vivo imaging and further characterized by transmission electron microscopy, Fourier transform infrared, scanning electron microscopy/energy dispersive x-ray spectroscopy, UV and ζ-analysis. The toxicity of bulk selenium was evaluated relative to its nano form by hematology indices, redox, inflammatory markers and histopathology. Results: Indocyanine green-conjugated nanoparticles showed preferential accumulation in the liver, followed by testis and kidney. The protective effect of SeNPs was more significantly observed in young livers than in adults compared with the bulk counterpart. Conclusion: Age-dependent monitoring and diagnosis of toxicity may need different biomarkers of selenium and may also provide better understanding of SeNPs as therapeutics.

Selenium is an essential element in the body. Its bioactive properties can protect against neurological conditions, diabetes, cancer and other chronic disorders. However, selenium in various biological forms (bulk) can be toxic. Selenium nanoparticles (SeNPs) have unique properties which might prevent this toxicity, providing a potential alternative for selenium supplementation and therapy. However, more studies are needed to see where SeNPs localize in the body, as well as comparing their toxicology with conventional forms of selenium in different age groups. We synthesized and characterized SeNPs of 70­90 nm, then injected them into young and adult rats to see where they distributed in the body. This was compared with rats injected with bulk selenium. SeNPs showed preferential accumulation in the liver, followed by the testes and kidneys. Next, the toxicity profiles of SeNPs and bulk selenium were established by measuring a series of health markers in the liver. It was found that the protection against toxicity provided by SeNPs was more significant in younger rats. Our results demonstrate that the same dose may behave differently in different age groups and that bulk selenium induces different toxicities in young and adult rats compared with SeNPs, highlighting the importance of different indicators of health for the monitoring of selenium-related toxicity when designing selenium-based therapeutics.

Design and preparation of proline, tryptophan and poly-l-lysine functionalized magnetic nanoparticles and their radiolabeling with 131I and 177Lu for potential theranostic use.

Surface modification of magnetic nanoparticles with poly-l-lysine, proline, and tryptophan was used to design potential theranostic agents for the application in cancer diagnosis and radionuclide-hyperthermia therapy. Characterization of bare and functionalized magnetic nanoparticles was performed in detail. The transparency of the examined magnetic nanoparticles was measured in the non-alternating magnetic field for a complete and better understanding of hyperthermia. For the first time amino acid-functionalized magnetic nanoparticles were labeled with theranostic radionuclides 131I and 177Lu. The specific absorption rate (SAR) procured for poly-l-lysine functionalized magnetic nanoparticles (SAR values of 99.7 W/g at H0 = 15.9 kA/m and resonant frequency of 252 kHz) demonstrated their possible application in magnetic hyperthermia. Poly-l-lysine functionalized magnetic nanoparticles labeled with 177Lu showed the highest radiochemical purity (>99.00 %) and in vitro stability in saline and serum (>98.00 % up to 96 h). The in vivo analysis performed after their intravenous administration in healthy Wistar rats presented good in vivo stability for several days. Encouraging results as well as magnetic and radiochemical properties of 177Lu-PLL-MNPs (80 °C) justify their further testing toward the potential use as theranostic agents for diagnostic and combined radionuclide-hyperthermia therapeutic applications.

Self-regulating novel iron oxide nanoparticle-based magnetic hyperthermia in swine: biocompatibility, biodistribution, and safety assessments.

Studies demonstrating the successful and safe application of magnetic hyperthermia in large animals are scarce. A therapeutic approach for advanced cancer comprising multicore encapsulated iron oxide (IO) Sarah Nanoparticles (SaNPs), that uniquely self-regulate their temperature, was developed thus overcoming the safety challenges of hyperthermia. SaNPs are intravenously injected and accumulate in tumor tissue, leading to selective heating upon exposure to an external alternating magnetic field (AMF). A series of studies were conducted in healthy swine to assess SaNPs' safety, alone or combined with AMF application. Administration of single high (up to 22 mg IO/kg) or low (3.6 mg IO/kg) SaNP doses had no adverse effects, including no infusion reactions. Vital signs remained stable with no significant clinical pathology changes, and no treatment-associated toxicities. Biodistribution analysis indicated that SaNPs predominantly accumulate in the lungs and clear in a dose- and time-dependent manner. In minipigs that received a single SaNP no-observed-adverse-effect-level (NOAEL)-based dose (3.6 mg IO/kg) with AMF, the average percentage remaining in vital organs after 90 days was 13.7%. No noticeable clinical signs were noted during the 87 to 92-day observation period following irradiation, and no inflammation, necrosis, nor thermal damage were found in the histopathology evaluation. In another minipig, ~ 90 days after three recurrent high doses (14 mg IO/kg), without AMF, almost half of the injected SaNPs were cleared with no residual detrimental effects. We demonstrate that the approach is safe and well tolerated in swine, opening potential avenues as a novel therapeutic modality for cancer patients.

Macrophage blockade using nature-inspired ferrihydrite for enhanced nanoparticle delivery to tumor.

The rapid elimination of systemically administered drug nanocarriers by the mononuclear phagocyte system (MPS) compromises nanomedicine delivery efficacy. To mitigate this problem, an approach to block the MPS has been introduced and implemented by intravenous pre-administering blocker nanoparticles. The required large doses of blocker nanoparticles appeared to burden the MPS, raising toxicity concerns. To alleviate the toxicity issues in MPS blockade, we propose an intrinsically biocompatible blocker, ferrihydrite - a metabolite ubiquitous in a biological organism. Ferrihydrite particles were synthesized to mimic endogenous ferritin-bound iron. Ferrihydrite surface coating with carboxymethyl-dextran was found to improve MPS blockade dramatically with a 9-fold prolongation of magnetic nanoparticle circulation in the bloodstream and a 24-fold increase in the tumor targeted delivery. The administration of high doses of ferrihydrite caused low toxicity with a rapid recovery of toxicological parameters after 3 days. We believe that ferrihydrite particles coated with carboxymethyl-dextran represent superior blocking biomaterial with enviable biocompatibility.

Sub-chronic oral toxicity evaluation of herbo-metallic formulation Arshakuthar rasa in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Arshakuthar rasa (AR) is a mercury based Ayurvedic herbo-metallic formulation. The concerns are being raised about the probable toxicity of mercury after prolonged use of AR. Hence, there is need for a long-term repeated in vivo toxicity study. The study will provide data with scientific evidence to enable safe use of the drug. Moreover, lack of toxicity study with AR incited us to perform sub-chronic study on rats. AIM OF THE STUDY: The aim of the study is to generate data by performing a sub-chronic study to assess the toxicity of AR after its prolonged oral intake. MATERIALS AND METHODS: The female and male rats were administered with 30 (low), 300 (medium) and 600 mg/kg BW/day (high) dose of AR for 90 consecutive days. The body weight, feed consumption and water intake were monitored weekly. On 91st day, blood was collected from retro-orbital plexus of rats and then sacrificed to harvest the vital organs for biochemical, haematological, histopathological, genotoxicity along with the expression study of oxidative stress related genes and the biodistribution of elements in the blood. RESULTS: Significant alterations in serum biochemical parameters were observed at the medium and high doses. The histopathological changes were in corroboration with biochemical changes at high dose in liver. There was no detectable level of mercury in blood, less to moderate biochemical changes, no haematological changes, moderate regulation of stress-related genes, and low genotoxicity. These results indicated that AR can be considered as moderately toxic above 600 mg/kg BW and mildly toxic at 300 mg/kg BW. CONCLUSIONS: It may be interpreted that AR may not induce grave toxic response in human after long-duration of oral administration at therapeutic doses.

Effects of 1α,25-dihydroxyvitamin D3 on the pharmacokinetics and biodistribution of ergothioneine, an endogenous organic cation/carnitine transporter 1 substrate, in rats.

Purpose: This study aimed to investigate the effects of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the expression levels of organic cation/carnitine transporter 1 (OCTN1) as well as the pharmacokinetics and biodistribution of ergothioneine, an OCTN1 substrate, in rats. Methods: Rats pretreated with 1,25(OH)2D3 (2.56 nmol/kg/day) for four days were administered ergothioneine (2 mg/kg) intravenously. The expression levels of rat OCTN1 (rOCTN1) in organs were determined using real-time quantitative polymerase chain reaction. Ergothioneine levels in plasma, urine, and organs (with and without intravenous injection of exogenous ergothioneine) were determined using liquid chromatography-tandem mass spectrometry. Results: 1,25(OH)2D3 pretreatment resulted in a significant decrease in rOCTN1 mRNA expression levels in the kidney and brain, a significant increase in basal plasma levels of ergothioneine (from 48 h), and a significant decrease in the tissue-plasma partition coefficient (Kp) in all tissues (except the heart and lungs) and the basal urine levels of ergothioneine. After intravenous administration, the pharmacokinetic profiles of ergothioneine were consistent with the basal levels of endogenous ergothioneine, with an increase in AUC∞ by 85%, a significant decrease in total clearance by 49%, and a decrease in Vss by 32% in 1,25(OH)2D3-treated rats. The Kp value and urinary recovery of ergothioneine also decreased in the 1,25(OH)2D3-treated group. Conclusion: This study showed the effects of 1,25(OH)2D3 on the expression and function of rOCTN1 by investigating the interaction between 1,25(OH)2D3 and ergothioneine. Dose adjustment and possible changes in bioavailability should be considered before the co-administration of vitamin D or its active forms and OCTN1 substrates. Supplementary Information: The online version contains supplementary material available at 10.1007/s40005-022-00563-1.

Clove Oil-Nanostructured Lipid Carriers: A Platform of Herbal Anesthetics in Whiteleg Shrimp (Penaeus vannamei).

Whiteleg shrimp (Penaeus vannamei) have been vulnerable to the stress induced by different aquaculture operations such as capture, handling, and transportation. In this study, we developed a novel clove oil-nanostructured lipid carrier (CO-NLC) to enhance the water-soluble capability and improve its anesthetic potential in whiteleg shrimp. The physicochemical characteristics, stability, and drug release capacity were assessed in vitro. The anesthetic effect and biodistribution were fully investigated in the shrimp body as well as the acute multiple-dose toxicity study. The average particle size, polydispersity index, and zeta potential value of the CO-NLCs were 175 nm, 0.12, and -48.37 mV, respectively, with a spherical shape that was stable for up to 3 months of storage. The average encapsulation efficiency of the CO-NLCs was 88.55%. In addition, the CO-NLCs were able to release 20% of eugenol after 2 h, which was lower than the standard (STD)-CO. The CO-NLC at 50 ppm observed the lowest anesthesia (2.2 min), the fastest recovery time (3.3 min), and the most rapid clearance (30 min) in shrimp body biodistribution. The results suggest that the CO-NLC could be a potent alternative nanodelivery platform for increasing the anesthetic activity of clove oil in whiteleg shrimp (P. vannamei).

A comparative study of optimized naringenin nanoformulations using nano-carriers (PLA/PVA and zein/pectin) for improvement of bioavailability.

Naringenin, a lipophilic flavanone of citrus fruits, was encapsulated for enhanced bioavailability using biodegradable polymers of polylactic acid/polyvinyl alcohol (PLA/PVA) as well as zein/pectin as P/P-Nar-NPs and Z/P-Nar-NPs, respectively. The formulation variables were optimized using response surface methodology to achieve smaller particle size with higher surface charge and encapsulation efficiencies. The optimized formulations were physically characterized by SEM, FTIR, TGA and XRD techniques. Compared to Z/P-Nar-NPs, the P/P-Nar-NPs had better encapsulation efficiency and sustained release of naringenin under simulated gastrointestinal conditions. Furthermore, the oral administration of single dose of free and nanoforms of naringenin in rats (90 mg/kg b.wt) showed higher efficacy of PLA/PVA in improving the relative bioavailability of naringenin (4.7-fold) as compared to the zein/pectin polymer (1.9-fold). Overall, the present study provides insights into the formulation performance of the encapsulated bioactive compound under different polymeric matrices.

Preclinical and clinical studies to evaluate cutaneous biodistribution, safety and efficacy of UV filters encapsulated in mesoporous silica SBA-15.

Innovative technologies have been designed to improve efficacy and safety of chemical UV filters. Encapsulation can enhance efficacy and reduce transdermal permeation and systemic exposure. The aims of this work were (i) to determine the cutaneous biodistribution of avobenzone (AVO), oxybenzone (OXY), and octyl methoxycinnamate (OMC) incorporated in mesoporous silica SBA-15 and (ii) to perform preclinical (in vitro) and (iii) clinical safety studies to demonstrate their innocuity and to evaluate sun protection factor (SPF) in humans. Skin penetration studies showed that deposition of OXY and AVO in porcine and human skin after application of stick formulation with incorporated filters (stick incorporated filters) was significantly lower than from a marketed (non-encapsulated) stick. Cutaneous deposition and transdermal permeation of OXY in and across human skin were 3.8-and 13.4- fold lower, respectively, after application of stick entrapped filters. Biodistribution results showed that encapsulation in SBA-15 decreased AVO and OXY penetration reaching porcine and human dermis. Greater deposition (and permeation) of OXY in porcine skin than in human skin, pointed to the role of follicular transport. Stick incorporated filters had good biocompatibility in vivo and safety profiles, even under sun-exposed conditions. Entrapment of UV filters improved the SPF by 26% and produced the same SPF profile as a marketed stick. Overall, the results showed that SBA-15 enabled safety and efficacy of UV filters to be increased.

Synchrotron-Based Imaging Reveals the Fate of Selenium in Striped Marsh Frog Tadpoles.

Synchrotron-based X-ray fluorescence microscopy (XFM) coupled with X-ray absorption near-edge structure (XANES) imaging was used to study selenium (Se) biodistribution and speciation in Limnodynastes peronii tadpoles. Tadpoles were exposed to dissolved Se (30 µg/L) as selenite (SeIV) or selenate (SeVI) for 7 days followed by 3 days of depuration. High-resolution elemental maps revealed that Se partitioned primarily in the eyes (specifically the eye lens, iris, and retinal pigmented epithelium), digestive and excretory organs of SeIV-exposed tadpoles. Speciation analysis confirmed that the majority of accumulated Se was converted to organo-Se. Multielement analyses provided new information on Se colocalization and its impact on trace element homeostasis. New insights into the fate of Se on a whole organism scale contribute to our understanding of the mechanisms and risks associated with Se pollution.

Iron biodistribution profile changes in the rat spleen after administration of high-fat diet or iron supplementation and the role of curcumin.

Curcumin as active metal chelating and antioxidant agent has a potential role in metal reduction and free radicals' neutralization in tissues. Of note, long-term administration of high fat diet (HFD) is considered as a main factor of blood serum iron deficiency. This study aimed to investigate the biodistribution profiles of iron in the spleen after long-term administration of HFD along with iron supplementation. Furthermore, the ameliorative role of curcumin to reduce iron accumulation level and improve the histological abnormalities produced by iron in spleen will be evaluated in the rats. Treated albino rats of this experiment were divided into six groups. Group I was a control group where group II was treated with HFD. Group III and group IV were treated with combination of HFD and curcumin or HFD and iron supplement respectively. Additionally, group V and group VI were treated with combination of HFD, iron supplement and curcumin or curcumin only respectively. Mainly histological analysis was used to investigate iron biodistribution and induced abnormalities in spleen under light microscope. The histochemical specific staining of iron in the spleen showed different biodistribution profiles of iron in the spleen. Administration of the HFD or HFD and iron supplementation increased the iron accumulation in the spleen. Where, curcumin administration with HFD (Group III) or with HFD and iron supplementation (Group V) significantly reduced the iron levels in the spleen. The splenic tissue inflammation, cellular apoptosis and fibrosis produced by higher iron accumulation was ameliorated after administration of curcumin supplementation as shown in the animals treated with HFD/curcumin (Group III) or HFD/iron supplement/curcumin (Group V). This study recommended that, it is preferable to use iron supplementation along with curcumin supplement for less than 4 months to avoid additional iron accumulation in the healthy organs.

Critical Parameters to Improve Pancreatic Cancer Treatment Using Magnetic Hyperthermia: Field Conditions, Immune Response, and Particle Biodistribution.

Magnetic hyperthermia (MH) was used to treat a murine model of pancreatic cancer. This type of cancer is generally characterized by the presence of dense stroma that acts as a barrier for chemotherapeutic treatments. Several alternating magnetic field (AMF) conditions were evaluated using three-dimensional (3D) cell culture models loaded with magnetic nanoparticles (MNPs) to determine which conditions were producing a strong effect on the cell viability. Once the optimal AMF conditions were selected, in vivo experiments were carried out using similar frequency and field amplitude parameters. A marker of the immune response activation, calreticulin (CALR), was evaluated in cells from a xenograft tumor model after the MH treatment. Moreover, the distribution of nanoparticles within the tumor tissue was assessed by histological analysis of tumor sections, observing that the exposure to the alternating magnetic field resulted in the migration of particles toward the inner parts of the tumor. Finally, a relationship between an inadequate body biodistribution of the particles after their intratumoral injection and a significant decrease in the effectiveness of the MH treatment was found. Animals in which most of the particles remained in the tumor area after injection showed higher reductions in the tumor volume growth in comparison with those animals in which part of the particles were found also in the liver and spleen. Therefore, our results point out several factors that should be considered to improve the treatment effectiveness of pancreatic cancer by magnetic hyperthermia.

Laser-synthesized TiN nanoparticles for biomedical applications: Evaluation of safety, biodistribution and pharmacokinetics.

Having plasmonic absorption within the biological transparency window, titanium nitride (TiN) nanoparticles (NPs) can potentially outperform gold counterparts in phototheranostic applications, but characteristics of available TiN NPs are still far from required parameters. Recently emerged laser-ablative synthesis opens up opportunities to match these parameters as it makes possible the production of ultrapure low size-dispersed spherical TiN NPs, capable of generating a strong phototherapy effect under 750-800 nm excitation. This study presents the first assessment of toxicity, biodistribution and pharmacokinetics of laser-synthesized TiN NPs. Tests in vitro using 8 cell lines from different tissues evidenced safety of both as-synthesized and PEG-coated NPs (TiN-PEG NPs). After systemic administration in mice, they mainly accumulated in liver and spleen, but did not cause any sign of toxicity or organ damage up to concentration of 6 mg kg-1, which was confirmed by the invariability of blood biochemical parameters, weight and hemotoxicity examination. The NPs demonstrated efficient passive accumulation in EMT6/P mammary tumor, while concentration of TiN-PEG NPs was 2.2-fold higher due to "stealth" effect yielding 7-times longer circulation in blood. The obtained results evidence high safety of laser-synthesized TiN NPs for biological systems, which promises a major advancement of phototheranostic modalities on their basis.

A novel irinotecan-lipiodol nanoemulsion for intravascular administration: pharmacokinetics and biodistribution in the normal and tumor bearing rat liver.

Colorectal cancer is one of the most common cancers in the United States and treatment options are limited for patients who develop liver metastases. Several chemotherapeutic regimens have been used for transvascular liver-directed therapy in the treatment of colorectal liver metastases without clear evidence of superiority of one therapy over another. We describe the development of a novel nanoemulsion through combining irinotecan (IRI), a first line systemic agent used for the treatment of colon cancer, with lipiodol, an oily contrast medium derived from poppy seed oil, and evaluated its pharmacokinetic and biodistribution profile as a function of portal venous chemoembolization (PVCE) versus transarterial chemoembolization (TACE) delivery. The Tessari technique was used to create a stable emulsion (20 mg IRI mixed with 2 mL lipiodol) with resultant particle size ranging from 28.9 nm to 56.4 nm. Pharmacokinetic profile established through venous sampling in Buffalo rats demonstrate that the area under the curve (AUC0-∞) of IRI was significantly less after PVCE with IRI-lipiodol as compared to IRI alone (131 vs. 316 µg*min/mL, p-value = .023), suggesting significantly higher amounts of IRI retention in the liver with the IRI-lipiodol nanoemulsion via first-pass extraction. Subseqent biodistribution studies in tumor-bearing WAG/Rjj rats revealed more IRI present in the tumor following TACE versus PVCE (29.19 ± 12.33 µg/g versus 3.42 ± 1.62; p-value = .0033) or IV (29.19 ± 12.33 µg/g versus 1.05 ± 0.47; p-value = .0035). The IRI-lipiodol nanoemulsion demonstrated an acceptable hepatotoxicity profile in all routes of administration. In conclusion, the IRI-lipiodol nanoemulsion via TACE showed promise and warrants further investigation as an option for the treatment of metastatic colorectal cancer.