Non-target Organs Research Articles

Development and preliminary evaluation of an integrin α2β1-targeted PET probe as a supplement and alternative of PSMA imaging for prostate cancer

An integrin α2β1-targeted PET probe (68Ga-IABtP) was developed to serve as a supplement and alternative of PSMA imaging for prostate cancer. 68Ga-IABtP was synthesized by labeling the precursor peptide with 68Ga with 93% labeling yield and 4.14 MBq/μg specific radioactivity. 68Ga-IABtP showed no specific uptake in LNCaP prostate cancer cell with low integrin α2β1 expression but significantly increased uptake in PC-3 prostate cancer cell with high integrin α2β1 expression, which could be specifically blocked by the integrin α2β1 monoclonal antibody. The efflux experiments demonstrated that 68Ga-IABtP could rapidly penetrate into PC-3 cell after cell binding, thereby prolonging the residence time in the tumor and allow enough time for probe clearance from the circulation and non-specific organs. The biodistribution study indicated that 68Ga-IABtP showed no specific accumulation in non-target organs and was quickly cleared from the kidney. The in vivo PET-CT imaging demonstrated that 68Ga-IABtP showed no specific uptake in LNCaP tumor but could specifically accumulate in the PC-3 tumor, and was rapidly cleared from spleen, intestine, kidney and liver, resulting in excellent contrast effect with low background signal and high target to non-target ratios.

Extracts of Tagetes erecta exhibit potential cytotoxic and antitumor activity that could be employed as a promising therapeutic agent against cancer: A study involving in vitro and in vivo approach

Background and purposeGlobally, the burden of cancer is increasing consistently. Modern cancer therapies include lots of toxicity in the non-targeted organs reducing the life expectancy of the patients. Therefore, the development of safer alternative medicines with less toxicity and high efficacy is of immense importance. The present study was designed to evaluate the anticancer activity of a medicinal plant, “Tagetes erecta L.” (TE), in established cancer cell lines in vitro and in animal models in vivo. MethodsGC–MS analysis was performed to reveal the bioactive compounds present in the leaves of TE. To evaluate the antitumor potential of aqueous extract of TE (AETE), EAC (Ehrlich ascites carcinoma) induced solid tumor model was prepared in Swiss albino mice. The effect of AETE on body weight (BW), tumor weight (TW), and tumor volume (TV) was assessed in control and tumor-bearing animals. Further, the survival of the experimental animals was also monitored to assess the effect of AETE on life span. To determine the cytotoxicity induced by AETE, trypan blue dye exclusion assay, MTT assay, and LDH release assay was performed in EAC and HEp-2 cell lines by in vitro methods. Further, cell cycle assay and apoptosis assay was employed to ascertain the AETE-induced cytotoxicity is due to apoptosis or not. In addition, we have done a mitochondrial membrane potential assay using a flow cytometer to understand the mechanism of apoptosis. ResultsGC–MS analysis revealed the presence of hexadecanoic acid, Linolenic acid, Quinic acid, 2,3- dihydro benzofuran (Coumaran), and β-stigmasterol as major bioactive compounds in TE leaves. Results in animal studies showed that AETE treatment potentially reduced the TW and TV and increased the life span in EAC-induced tumor-bearing animals. Side effect analysis was also done in normal Swiss albino mice that confirmed the lack of toxicity of AETE. Studies in cancer cell lines indicated dose and time-dependent cytotoxicity in HEp-2 and EAC cells. Flow cytometric analysis established significant induction of apoptosis in EAC cells without arresting the cell cycle. In addition, AETE treatment led to a significant increase in cells with depolarised mitochondrial membrane potential. ConclusionThe present study indicated that AETE potentially inhibits tumor progression without disturbing normal body physiology. Thus, we conclude that AETE can be used as a potential therapeutic agent against cancer.

Antimicrobial Activity of Nanoconjugated Glycopeptide Antibiotics and Their Effect on Staphylococcus aureus Biofilm.

In the era of antimicrobial resistance, the use of nanoconjugated antibiotics is regarded as a promising approach for preventing and fighting infections caused by resistant bacteria, including those exacerbated by the formation of difficult-to-treat bacterial biofilms. Thanks to their biocompatibility and magnetic properties, iron oxide nanoparticles (IONPs) are particularly attractive as antibiotic carriers for the targeting therapy. IONPs can direct conjugated antibiotics to infection sites by the use of an external magnet, facilitating tissue penetration and disturbing biofilm formation. As a consequence of antibiotic localization, a decrease in its administration dosage might be possible, reducing the side effects to non-targeted organs and the risk of antibiotic resistance spread in the commensal microbiota. Here, we prepared nanoformulations of the ‘last-resort’ glycopeptides teicoplanin and vancomycin by conjugating them to IONPs via surface functionalization with (3-aminopropyl) triethoxysilane (APTES). These superparamagnetic NP-TEICO and NP-VANCO were chemically stable and NP-TEICO (better than NP-VANCO) conserved the typical spectrum of antimicrobial activity of glycopeptide antibiotics, being effective against a panel of staphylococci and enterococci, including clinical isolates and resistant strains. By a combination of different methodological approaches, we proved that NP-TEICO and, although to a lesser extent, NP-VANCO were effective in reducing biofilm formation by three methicillin-sensitive or resistant Staphylococcus aureus strains. Moreover, when attracted and concentrated by the action of an external magnet, NP-TEICO exerted a localized inhibitory effect on S. aureus biofilm formation at low antibiotic concentration. Finally, we proved that the conjugation of glycopeptide antibiotics to IONPs reduced their intrinsic cytotoxicity toward a human cell line.

Ultrasound triggered topical delivery of Bmp7 mRNA for white fat browning induction via engineered smart exosomes

BackgroundEfficient and topical delivery of drugs is essential for maximized efficacy and minimized toxicity. In this study, we aimed to design an exosome-based drug delivery platform endowed with the ability of escaping from phagocytosis at non-target organs and controllably releasing drugs at targeted location.ResultsThe swtichable stealth coat CP05-TK-mPEG was synthesized and anchored onto exosomes through the interaction between peptide CP05 and exosomal surface marker CD63. Chlorin e6 (Ce6) was loaded into exosomes by direct incubation. Controllable removal of PEG could be achieved by breaking thioketal (TK) through reactive oxygen species (ROS), which was produced by Ce6 under ultrasound irradiation. The whole platform was called SmartExo. The stealth effects were analyzed in RAW264.7 cells and C57BL/6 mice via tracing the exosomes. To confirm the efficacy of the engineered smart exosomes, Bone morphogenetic protein 7 (Bmp7) mRNA was encapsulated into exosomes by transfection of overexpressing plasmid, followed by stealth coating, with the exosomes designated as SmartExo@Bmp7. Therapeutic advantages of SmartExo@Bmp7 were proved by targeted delivering Bmp7 mRNA to omental adipose tissue (OAT) of obese C57BL/6 mice for browning induction. SmartExo platform was successfully constructed without changing the basic characteristics of exosomes. The engineered exosomes effectively escaped from the phagocytosis by RAW264.7 and non-target organs. In addition, the SmartExo could be uptaken locally on-demand by ultrasound mediated removal of the stealth coat. Compared with control exosomes, SmartExo@Bmp7 effectively delivered Bmp7 mRNA into OAT upon ultrasound irradiation, and induced OAT browning, as evidenced by the histology of OAT and increased expression of uncoupling protein 1 (Ucp1).ConclusionsThe proposed SmartExo-based delivery platform, which minimizes side effects and maximizing drug efficacy, offers a novel safe and efficient approach for targeted drug delivery. As a proof, the SmartExo@Bmp7 induced local white adipose tissue browning, and it would be a promising strategy for anti-obesity therapy.Graphical

Epicatechin ameliorative effects on methotrexate-induced hepatotoxicity in mice.

Due to the fact that methotrexate is widely used both as an immunosuppressive drug and as a chemotherapy agent, many studies are needed to reduce the side effects of this drug on non-target organs. This study was designed to investigate the effects of epicatechin (Epi) on MTX (methotrexate)-induced hepatotoxicity in mice. After 1 week for adaptation, we randomly divided 42 male Naval Medical Research Institute mice into six groups: (I) control; (II) Epi (100 mg/kg, po); (III) MTX (20 mg/kg, i.p.) on the fifth day; and (IV, V, and VI) Epi (25, 50, and 100 mg/kg, po) + MTX (20 mg/kg, i.p.) on the fifth day. At day 10, the mice were sacrificed and serum factors, oxidative stress markers, and inflammatory cytokines were measured. MTX increased activity level of serum enzymes (alanine aminotransferase and aspartate aminotransferase), lipid peroxidation marker (malondialdehyde), and inflammatory factors including interleukin-1 beta, tumor necrosis factor-alpha, and nitric oxide. Furthermore, MTX decreased glutathione level and activity level of catalase, superoxide dismutase, and glutathione peroxidase. Epi was able to reduce the destructive effects of oxidative/antioxidant system imbalance and inflammatory reactions and also histopathological damage in MTX intoxicated mice. Epi pretreatment reduced liver dysfunction by improving the antioxidant defense system, anti-inflammatory effects, and alleviation of histopathological damage in MTX hepatotoxicity. Accordingly, Epi can be used as a therapeutic agent in hepatotoxicity associated with MTX chemotherapy.

Advances in Injectable In Situ-Forming Hydrogels for Intratumoral Treatment.

Chemotherapy has been linked to a variety of severe side effects, and the bioavailability of current chemotherapeutic agents is generally low, which decreases their effectiveness. Therefore, there is an ongoing effort to develop drug delivery systems to increase the bioavailability of these agents and minimize their side effects. Among these, intratumoral injections using in situ-forming hydrogels can improve drugs’ bioavailability and minimize drugs’ accumulation in non-target organs or tissues. This review describes different types of injectable in situ-forming hydrogels and their intratumoral injection for cancer treatment, after which we discuss the antitumor effects of intratumoral injection of drug-loaded hydrogels. This review concludes with perspectives on the future applicability of, and challenges for, the adoption of this drug delivery technology.

Impact of metallic coating on the retention of 225Ac and its daugthers within core–shell nanocarriers

Currently, alpha-emitting radionuclide 225Ac is one of the most promising isotopes in alpha therapy due to its high linear energy transfer during four sequential alpha decays. However, the main obstacle preventing the full introduction of 225Ac into clinical practice is the lack of stable retention of radionuclides, leading to free circulation of toxic isotopes in the body. In this work, the surface of silica nanoparticles (SiO2 NPs) has been modified with metallic shells composed of titanium dioxide (TiO2) and gold (Au) nanostructures to improve the retention of 225Ac and its decay products within the developed nanocarriers. In vitro and in vivo studies in healthy mice show that the metallic surface coating of SiO2 NPs promotes an enhanced sequestering of radionuclides (225Ac and its daughter isotopes) compared to non-modified SiO2 NPs for a prolonged period of time. Histological analysis reveals that for the period of 3–10 d after the injections, the developed nanocarriers have no significant toxic effects in mice. At the same time, almost no accumulation of leaked radionuclides can be detected in non-target organs (e.g., in the kidneys). In contrast, non-modified carriers (SiO2 NPs) demonstrate the release of free radionuclides, which are distributed over the whole animal body with the consequent morphological changes in the lung, liver and kidney tissues. These results highlight the potential of the developed nanocarriers to be utilized as radionuclide delivery systems and offer an insight into design rules for the fabrication of new nanotherapeutic agents.

Impact of Eye and Breast Shielding on Organ Doses During Cervical Spine Radiography: Design and Validation of MIRD Computational Phantom.

Purpose: The study aimed to design and validate computational phantoms (MIRD) using the MCNPX code to assess the impact of shielding on organ doses.Method: To validate the optimized phantom, the obtained results were compared with experimental results. The validation of the optimized MIRD phantom was provided by using the results of a previous anthropomorphic phantom study. MIRD phantom was designed by considering the parameters used in the anthropomorphic phantom study. A test simulation was performed to compare the dose reduction percentages (%) between the experimental anthropomorphic phantom study and the MCNPX-MIRD phantom. The simulation was performed twice, with and without shielding materials, using the same number and locations of the detector.Results: The absorbed dose amounts were directly extracted from the required organ and tissue cell parts of output files. Dose reduction percentages between the simulation with shielding and simulation without shielding were compared. The highest dose reduction was noted in the thymus (95%) and breasts (88%). The obtained dose reduction percentages between the anthropomorphic phantom study and the MCNPX-MIRD phantom were highly consistent and correlated values with experimental anthropomorphic data. Both methods showed Relative Difference (%) ranges between 0.88 and 2.22. Moreover, the MCNPX-MIRD optimized phantom provides detailed dose analysis for target and non-target organs and can be used to assess the efficiency of shielding in radiological examination.Conclusion: Shielding breasts and eyes during cervical radiography reduced the radiation dose to many organs. The decision to not shield patients should be based on research evidence as this approach does not apply to all cases.

Dosimetric Predictors of Toxicity in Patients With Early-Stage Prostate Cancer Treated With Moderately Hypofractionated IMRT or PBT: A Multi-Institutional Analysis

<h3>Purpose/Objective(s)</h3> Limited published data address modifiable risk factors for significant toxicity complicating moderately hypofractionated schedules of intensity-modulated radiation therapy (IMRT) and proton-beam therapy (PBT) in patients with early-stage prostate cancer (PC). This study explored dosimetric predictors of Grade 3+ gastrointestinal (GI) and genitourinary (GU) toxicity following IMRT or PBT in this patient population. <h3>Materials/Methods</h3> The study population included patients from five tertiary referral centers treated from 2002-2018 for low- or intermediate-risk biopsy-proven prostate adenocarcinoma. All patients were treated with moderately hypofractionated radiation defined as 250–300 cGY per daily fraction given over 4-6 weeks. Primary outcomes were late GI and GU toxicity as defined by CTCAE v4.0. Dosimetric variables included PTV max dose, PTV volume, bladder V31 Gy, bladder V50 Gy, bladder V70 Gy, bladder max dose, rectum V31 Gy, rectum V50 Gy, rectum V70 Gy, rectum max dose, penile bulb V10 Gy, penile bulb V15 Gy, and the left and right femoral head V40 Gy. The association of dosimetric variables with treatment toxicity was assessed with the Wilcoxon signed-rank test. <h3>Results</h3> Dosimetric data were obtained for 1139 patients, including 667 treated with IMRT and 472 treated with PBT. Median follow-up for the two groups was 46.0 and 48.5 months, respectively. Late toxicity rates for the total population were 4.7% for Grade 3+ GU toxicity and 1.5% for Grade 3+ GI toxicity. Grade 3+ GU toxicity was associated with prostate volume, bladder V31 Gy and bladder V50 Gy (<i>P</i> = 0.016, <i>P</i> = 0.018, <i>P</i> = 0.028), but not with bladder V70 Gy or maximum dose to the bladder. Grade 3+ GI toxicity was not associated with any of the dosimetric variables. When analyzed by treatment group, Grade 3+ GU toxicity was observed in 3% of the IMRT cohort and 1.7% of the PBT cohort. Grade 3+ GI toxicity was seen only in PBT and was observed in 1.5% of patients. Proton plans were associated with less radiation exposure of rectum and bladder at lower doses (rectum V31 Gy: 13% vs 16%, <i>P</i> < 0.001; bladder V31 Gy: 18% vs 26%, <i>P</i> < 0.001), while IMRT was associated with less radiation exposure of rectum and bladder at higher doses (rectum V70 Gy: 0.4% vs 2%, <i>P</i> < 0.001; bladder V70 Gy: 1% vs 3%, <i>P</i> < 0.001). Photon plans yielded superior V40 Gy to the femoral heads, and superior V10 Gy and V15 Gy to the penile bulb (<i>P</i> < 0.001, <i>P</i> < 0.003, <i>P</i> < 0.002). <h3>Conclusion</h3> In this multi-institutional analysis of 1139 early-stage PC patients treated with moderately hypofractionated IMRT or PBT, risk of serious late GU and GI complications was low for both treatment groups. Analysis of the dosimetric variables identified an association of Grade 3+ GU toxicity with low-dose radiation exposure of the bladder. Grade 3+ GI toxicity was unrelated to dosimetric variables. PBT plans yielded less exposure of non-target organs to lower-dose radiation while IMRT plans yielded less exposure of non-target organs to higher-dose radiation.

Metastatic and non-metastatic melanoma imaging using Sgc8-c aptamer PTK7-recognizer

Melanoma is one of the most aggressive and deadly skin cancers, and although histopathological criteria are used for its prognosis, biomarkers are necessary to identify the different evolution stages. The applications of molecular imaging include the in vivo diagnosis of cancer with probes that recognize the tumor-biomarkers specific expression allowing external image acquisitions and evaluation of the biological process in quali-quantitative ways. Aptamers are oligonucleotides that recognize targets with high affinity and specificity presenting advantages that make them interesting molecular imaging probes. Sgc8-c (DNA-aptamer) selectively recognizes PTK7-receptor overexpressed in various types of tumors. Herein, Sgc8-c was evaluated, for the first time, in a metastatic melanoma model as molecular imaging probe for in vivo diagnostic, as well as in a non-metastatic melanoma model. Firstly, two probes, radio- and fluorescent-probe, were in vitro evaluated verifying the high specific PTK7 recognition and its internalization in tumor cells by the endosomal route. Secondly, in vivo proof of concept was performed in animal tumor models. In addition, they have rapid clearance from blood exhibiting excellent target (tumor)/non-target organ ratios. Furthermore, optimal biodistribution was observed 24 h after probes injections accumulating almost exclusively in the tumor tissue. Sgc8-c is a potential tool for their specific use in the early detection of melanoma.

A food-ingested sublethal concentration of thiamethoxam has harmful effects on the stingless bee Melipona scutellaris

In recent years, the importance of bee's biodiversity in the Neotropical region has been evidencing the relevance of including native bees in risk assessments. Therefore, the sublethal effects of the insecticide thiamethoxam on the survival and morphological parameters of the stingless bee Melipona scutellaris were investigated in the present study. Cells from both non-target organs (Malpighian tubules and midgut) and target organs (brain) were analyzed for morphological alterations using light microscopy and transmission electron microscopy. The findings showed that when M. scutellaris foragers were exposed to a sublethal concentration of thiamethoxam (LC50/100 = 0.000543 ng a. i./μL), longevity was not reduced but brain function was affected, even with the non-target organs attempting to detoxify. The cellular damage in all the organs was mostly reflected in irregular nuclei shape and condensed chromatin, indicating cell death. The most frequent impairments in the Malpighian tubules were loss of microvilli, disorganization of the basal labyrinth, and cytoplasmic loss. These characteristics are related to an attempt by the cells to increase the excretion process, probably because of the high number of toxic molecules that reach the Malpighian tubules and need to be secreted. In general, damages that compromise the absorption of nutrients, excretion, memory, and learning processes, which are essential for the survival of M. scutellaris, were found. The present results also fill in gaps on how these bees respond to thiamethoxam exposure and will be useful in future risk assessments for the conservation of bee biodiversity.

Bruceae Fructus Oil Inhibits Triple-Negative Breast Cancer by Restraining Autophagy: Dependence on the Gut Microbiota-Mediated Amino Acid Regulation.

Triple-negative breast cancer (TNBC) has been acknowledged as an aggressive disease with worst prognosis, which requires endeavor to develop novel therapeutic agents. Bruceae fructus oil (BO), a vegetable oil derived from the fruit of Brucea javanica (L.) Merr., is an approved marketable drug for the treatment of cancer in China for several decades. Despite that the anti–breast cancer activity of several quassinoids derived from B. javanica has been found, it was the first time that the potential of BO against TNBC was revealed. Although BO had no cytotoxicity on TNBC cell lines in vitro, the oral administration of BO exhibited a gut microbiota–dependent tumor suppression without toxicity on the non-targeted organs in vivo. By metagenomics and untargeted metabolomics, it was found that BO not only altered the composition and amino acid metabolism function of gut microbiota but also regulated the host’s amino acid profile, which was in accordance with the metabolism alternation in gut microbiota. Moreover, the activity of mTOR in tumor was promoted by BO treatment as indicated by the phosphorylation of 4E-binding protein 1 (4E-BP1) and ribosomal protein S6, and hyper-autophagy was consequently restrained. By contrast, the failure of tumor suppression by BO under pseudo germ-free (PGF) condition came with indistinctive changes in autophagy and mTOR activity, implying the critical role of the gut microbiota in BO’s anticancer activity. The present study highlighted a promising application of BO against breast cancer with novel efficacy and safety.

Immunolocalization of Steroidogenic Enzymes (3β-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase, and P450scc) in Rats with Testicular Dysfunction Treated with Mesenchymal Stem Cells-conditioned Medium

About 60-80 million couples in the world are suffering from infertility disease. Infertility is a major problem in patients coping with chemotherapy. The chemotherapy process can degenerate non-target organs, especially in testes. Infertility in male or testicular dysfunction is caused by the failure of proliferation and differentiation of the spermatogenic cells. Many studies reported that mesenchymal stem cells-conditioned medium promoted regenerative processes. The present study aimed to investigate the effect of mesenchymal stem cells-conditioned medium on the cisplatin-induced testicular dysfunction by examining the immunolocalization of steroidogenic enzymes, such as 3β-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase, and P450scc which are considered as markers of steroid production. All experimental animals were divided into three groups, namely the control group, mesenchymal stem cells-conditioned medium treated group with an injection dose of 0.2 ml/kg body weight (BW, P1), and mesenchymal stem cells-conditioned medium treated group with an injection dose of 0.5 ml/kg BW (P2). Cisplatin was injected into both treated groups to induce testicular dysfunction. The testicular tissues were processed by the paraffin method, then cut to a thickness of 5 µm, followed by immunohistochemical staining. The HSD3B1 immunoreactivities were found only in Leydig cells, and the intensity increased every week after the injection of mesenchymal stem cells-conditioned medium. The variety of weeks and groups was significantly different in the number of immunoreactive cells of HSD3B1. The results indicated a significant difference between one week after the first injection and the one week after the third and fourth injection. The findings showed a significant difference between the treated group with an injection dose of 0.2 ml/kg BW and the control group. The number of immunoreactive cells of HSD3B1 with an injection dose of 0.5 ml/kg BW was greater compared to the group that received an injection dose of 0.2 ml/kg BW. The intensity of HSD3B1 and HSD17B1 increased every week. The p450scc immunoreactive cells were only found in Leydig cells. The intensity of positive cells of p450scc in the treated group with an injection dose of 0.5 ml/kg BW was more intense, compared to the treated group with an injection dose of 0.2 ml/kg BW. The results of the current study showed that the injection of mesenchymal stem cells-conditioned medium can improve the regeneration of spermatogenic cells, and recover spermatogenesis proved by positive cells of HSD3B1, HSD17B1, and p450scc as markers of steroid production.

Behavioral and ultrastructural effects of novaluron on Aedes aegypti larvae.

Chitin synthesis inhibitors (CSI) are supposed to inhibit formation of chitin microfibrils in newly synthesized cuticle during molting process. Conversely, there has been comparatively few data on morphological effects of CSI on non-target insect organs. In this work, the effects of the CSI novaluron on behavior and midgut of A. aegypti were evaluated. Toxicity bioassays revealed that novaluron is toxic to A. aegypti larva with LC50=18.57mgL-1 when exposed in aqueous solution for 24h. Novaluron treated larvae were less active and spent more time resting compared to the control group. Histopathology showed that midguts of novaluron-treated larvae had cytoplasm vacuolization and damaged brush border. Cytotoxic effects in midguts of treated larvae induced necrosis, autophagy and damage to mitochondria. Despite being chitin synthesis inhibitor, novaluron did not induce alterations in the integument of A. aegypti larvae. Fluorescence microscopy revealed that the number of digestive cells were higher in novaluron-treated larvae than in control, in response to digestive cell apoptosis. The present study highlights the importance of novaluron against A. aegypti larvae by causing injuries to non-target organs, altering behaviors, inducing cell death and inhibiting cell proliferation.

Assessment of 177 Lu-labeled carboxyl-terminated polyamidoamine (PAMAM) dendrimer-RGD peptide conjugate.

Structurally unique polyamidoamine (PAMAM) dendrimers implanted with targeting biological moiety along with complexed radiometal constitute a favorable nano-system for diagnosis and therapy of targeted tumor sites. In the present study, carboxyl functionalities of PAMAM- generation 4 dendrimer (PAMAM-G4-COOH) were conjugated with ε-amino group of lysine of cRGDfK peptide to impart integrin αv β3 targeting capability. Reaction of p-NH2 -Bn-DOTA with PAMAM was accomplished via acid-amine coupling using EDC/NHS for 177 Lu-complexation. 177 Lu-labeled nano-system, 177 Lu-PAMAM-DOTA-cRGDfK demonstrated receptor-mediated uptake in murine melanoma B16F10 cells during in vitro cell uptake studies. In vivo biodistribution studies demonstrated low tumor uptake and retention of 177 Lu-PAMAM-DOTA-cRGDfK which may be attributed to rapid blood clearance. However, fast clearance from non-target organs resulted in higher target to background ratio. Tumor uptake of targeted nano-system, 177 Lu-PAMAM-DOTA-cRGDfK was observed to be significantly (p < 0.05) higher in comparison to 177 Lu-PAMAM-DOTA without the targeting peptide. Inhibition studies with unlabeled cRGDfK resulted in 60% reduction in tumor uptake of 177 Lu-PAMAM-DOTA-cRGDfK, indicating specificity of the developed nano-system towards integrin αv β3 receptors.

Lung Targeted Lipopolymeric Microspheres of Dexamethasone for the Treatment of ARDS.

Acute respiratory distress syndrome (ARDS), a catastrophic illness of multifactorial etiology, involves a rapid upsurge in inflammatory cytokines that leads to hypoxemic respiratory failure. Dexamethasone, a synthetic corticosteroid, mitigates the glucocorticoid-receptor-mediated inflammation and accelerates tissue homeostasis towards disease resolution. To minimize non-target organ side effects arising from frequent and chronic use of dexamethasone, we designed biodegradable, lung-targeted microspheres with sustained release profiles. Dexamethasone-loaded lipopolymeric microspheres of PLGA (Poly Lactic-co-Glycolic Acid) and DPPC (Dipalmitoylphosphatidylcholine) stabilized with vitamin E TPGS (D-α-tocopheryl polyethylene glycol succinate) were prepared by a single emulsion technique that had a mean diameter of 8.83 ± 0.32 μm and were spherical in shape as revealed from electron microscopy imaging. Pharmacokinetic and biodistribution patterns studied in the lungs, liver, and spleen of Wistar rats showed high selectivity and targeting efficiency for the lung tissue (re 13.98). As a proof-of-concept, in vivo efficacy of the microspheres was tested in the lipopolysaccharide-induced ARDS model in rats. Inflammation markers such as IL-1β, IL-6, and TNF-α, quantified in the bronchoalveolar lavage fluid indicated major improvement in rats treated with dexamethasone microspheres by intravenous route. Additionally, the microspheres substantially inhibited the protein infiltration, neutrophil accumulation and lipid peroxidation in the lungs of ARDS bearing rats, suggesting a reduction in oxidative stress. Histopathology showed decreased damage to the pulmonary tissue upon treatment with the dexamethasone-loaded microspheres. The multipronged formulation technology approach can thus serve as a potential treatment modality for reducing lung inflammation in ARDS. An improved therapeutic profile would help to reduce the dose, dosing frequency and, eventually, the toxicity.

The internal dosimetry user group position statement on molecular radiotherapy.

The Internal Dosimetry User Group (IDUG) is an independent, non-profit group of medical professionals dedicated to the promotion of dosimetry in molecular radiotherapy (www.IDUG.org.uk). The Ionising Radiation (Medical Exposure) Regulations 2017, IR(ME)R, stipulate a requirement for optimisation and verification of molecular radiotherapy treatments, ensuring doses to non-target organs are as low as reasonably practicable. For many molecular radiotherapy treatments currently undertaken within the UK, this requirement is not being fully met. The growth of this field is such that we risk digressing further from IR(ME)R compliance potentially delivering suboptimal therapies that are not in the best interest of our patients. For this purpose, IDUG proposes ten points of action to aid in the successful implementation of this legislation. We urge stakeholders to support these proposals and ensure national provision is sufficient to meet the criteria necessary for compliance, and for the future advancement of molecular radiotherapy within the UK.

Roles of Simvastatin and Sildenafil in Modulation of Cranial Irradiation-Induced Bystander Multiple Organs Injury in Rats.

In radiobiology and radiation oncology fields, the observation of a phenomenon called radiation-induced bystander effect (RIBE) has introduced the prospect of remotely located tissues' affection. This phenomenon has been broadly developed to involve the concept of RIBE, which are relevant to the radiation-induced response of a distant tissue other than the irradiated one. The current study aimed at investigating each of the RIBE of cranial irradiation on oxidative and inflammatory status in different organs such as liver, kidney, heart, lung, and spleen. Being a vital target of the cholinergic anti-inflammatory response to an inflammatory stimulus, the splenic α-7-nicotinic acetylcholine receptor (α-7nAchR) was evaluated and the hepatic contents of thioredoxin, peroxisome proliferator-activated receptor-alpha and paraoxinase-1 (Trx/PPAR-α/PON) were also assessed as indicators for the liver oxidative stress and inflammatory responses. Being reported to act as antioxidant and anti-inflammatory agents, simvastatin (SV) and/or sildenafil (SD) were investigated for their effects against RIBE on these organs. These objectives were achieved via the biochemical assessments and the histopathological tissues examinations. Five experimental groups, one sham irradiated and four irradiated groups, were exposed to cranial irradiation at dose level of 25Gy using an experimental irradiator with a Cobalt (Co60) source, RIBE, RIBE + SV (20mg.(kg.bw)-1day-1), RIBE + SD (75mg.(kg.bw)-1day-1), and RIBE + SV + SD. Cranial irradiation induced structural, biochemical, and functional dys-regulations in non-targeted organs. RIBE-induced organs' injuries have been significantly corrected by the administration of SV and/or SD. Our results suggest the possibility of a potentiated interaction between SV and SD in the modulation of the RIBE associated with head and neck radiotherapy.

A Review on Tablet Dosage Form: Recent Advancements with Special Emphasis on Rapid Disintegrating Tablet

Tablets are the most commonly prescribed dosage form as offer a convenient form of drug administration provides dosage uniformity from tablet to tablet, stable over extended and diverse storage conditions, can be produced on high-speed compression, labelling, and packaging equipment. Advancements in technology and modification in standard compressed tablet are to achieve better acceptability as well as bioavailability. Various types of newer and more efficient tablets are developed to create a delivery system that is relatively simple to administration. In one sense osmotic pump systems are another type of membrane-controlled release drug delivery system and work in the following way. Drug is incorporated in a tablet core which is water soluble, and which will solubilize or suspend the drug in the presence of water. Also, a multi-layer tablet dosage form over a more conventional mono-layer tablet is useful. In FDDS Gastro retentive dosage form improves bioavailability, therapeutic efficacy and allows a reduction in the dose because of steady therapeutic levels of drug. The another system is MADDS Mucoadhesion is commonly used to describe an interaction between the mucin layer, which lines the entire GI tract, and a bio adhesive polymer, which could be natural or synthetic in origin. An ideal controlled drug delivery system is one which delivers the drugs at a predetermined rate, locally or systematically, for a specified period of time and an ideal targeted drug delivery system is the one which delivers the drugs only to its sites of action and not to the non-targeted organs or tissues. So, in this review article we will study the basic fundamentals of tablets their technologies, and types of systems with available marketed products of various dosage forms.

Topical Drug Delivery Therapeutics, Drug Absorption and Penetration Enhancement Techniques

The delivery of medications through the skin has long been a fascinating as well as difficult subject of study. For different medications, topical drug administration has brought substantial benefits over the systemic route, one of the most important of which is reduced toxicity due to minimal or no exposure to non-target organs. Because of its simplicity and affordability, topical administration is the preferred method for delivering medicinal substances locally. Topical drug delivery system includes solid powders, semisolids, liquid preparations, and sprays, among other pharmaceutical dose forms. Gels, creams, and ointments are the most often used semisolid preparations for topical medication delivery. Topical medication delivery methods allow a medicine to enter the systemic circulation at a controlled rate by penetrating the epidermal layer. New drugs are being developed utilizing the transdermal approach in addition to the existing formulations due to the inherent benefits of delivery via this route. Although low skin permeability limits its applicability, it does provide a non-invasive route of medication administration. Innovative research using penetration-enhancing technologies such iontophoresis, electroporation, microneedles, sonophoresis, and others offers promise for successful implementation of these drugs in clinical practice as consumer-friendly, transdermal dosage forms. This paper examines some of the most promising new strategies for enhancing transdermal permeability, as well as providing a scientific update on recent improvements in the topical drug delivery system. The current study focuses on the most modern methods and techniques for administering local treatment to the skin. This data can be used as a foundation for further research and development of existing methodologies and technologies.&#x0D; Keywords: Topical drug delivery, Recent techniques, TDDS, Advances in skin delivery