Doxorubicin Loaded Poloxamer Thermosensitive Hydrogels: Chemical, Pharmacological and Biological Evaluation

(1) Background: doxorubicin is a potent chemotherapeutic agent, but it has limitations regarding its side effects and therapy resistance. Hydrogels potentially deal with these problems, but several characterizations need to be optimized to better understand how hydrogel assisted chemotherapy works. Poloxamer 407 (P407) hydrogels were mixed with doxorubicin and physico-chemical, biological, and pharmacological characterizations were considered. (2) Methods: hydrogels were prepared by mixing P407 in PBS at 4 °C. Doxorubicin was added upon solutions became clear. Time-to-gelation, hydrogel morphology, and micelles were studied first. The effects of P407-doxorubicin were evaluated on MC-38 colon cancer cells. Furthermore, doxorubicin release was assessed and contrasted with non-invasive in vivo whole body fluorescence imaging. (3) Results: 25% P407 had favorable gelation properties with pore sizes of 30–180 µm. P407 micelles were approximately 5 nm in size. Doxorubicin was fully released in vitro from 25% P407 hydrogel within 120 h. Furthermore, P407 micelles strongly enhanced the anti-neoplastic effects of doxorubicin on MC-38 cells. In vivo fluorescence imaging revealed that hydrogels retained fluorescence signals at the injection site for 168 h. (4) Conclusions: non-invasive imaging showed how P407 gels retained drug at the injection site. Doxorubicin P407 micelles strongly enhanced the anti-tumor effects.

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In vivo and in vitro tracking of erosion in biodegradable materials using non-invasive fluorescence imaging

Nature Materials ◽

10.1038/nmat3095 ◽

2011 ◽

Vol 10 (9) ◽

pp. 890-890 ◽

Cited By ~ 124

Author(s):

Natalie Artzi ◽

Nuria Oliva ◽

Cristina Puron ◽

Sagi Shitreet ◽

Shay Artzi ◽

...

Keyword(s):

Fluorescence Imaging ◽

Biodegradable Materials ◽

Non Invasive

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Erratum: In vivo and in vitro tracking of erosion in biodegradable materials using non-invasive fluorescence imaging

Nature Materials ◽

10.1038/nmat3147 ◽

2011 ◽

Vol 10 (11) ◽

pp. 896-896 ◽

Cited By ~ 6

Author(s):

Natalie Artzi ◽

Nuria Oliva ◽

Cristina Puron ◽

Sagi Shitreet ◽

Shay Artzi ◽

...

Keyword(s):

Fluorescence Imaging ◽

Biodegradable Materials ◽

Non Invasive

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Non-invasive synchronous monitoring of neutrophil migration using whole body near-infrared fluorescence-based imaging

Scientific Reports ◽

10.1038/s41598-021-81097-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jack Leslie ◽

Stuart M. Robinson ◽

Fiona Oakley ◽

Saimir Luli

Keyword(s):

Real Time ◽

Fluorescence Imaging ◽

Near Infrared ◽

Spectral Unmixing ◽

Whole Body ◽

Spectral Signature ◽

Cell Labelling ◽

Cellular Interactions ◽

Non Invasive

AbstractAdvances in fluorescence imaging coupled with the generation of near infrared probes have significantly improved the capabilities of non-invasive, real-time imaging in whole animals. In this study we were able to overcome a limitation of in vivo fluorescence imaging and have established a dual cell tracking method where two different cell types can be monitored according to the spectral signature of the cell labelling fluorophore. Using a mouse model of acute liver injury, we have characterised the in vivo migration patterns of wild type and transgenic neutrophils with impaired chemotaxis. Here, we were able to demonstrate that IVIS provides a sensitive multiplexing technology to differentiate two different cell populations based on the spectral signature of the cell labelling fluorophores. This spectral unmixing methodology has the potential to uncover multidimensional cellular interactions involved in many diseases such as fibrosis and cancer. In vivo spectral un-mixing provides a useful tool for monitoring multiple biological process in real-time in the same animal.

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The chinchilla as a novel animal model of pregnancy

Royal Society Open Science ◽

10.1098/rsos.161098 ◽

2017 ◽

Vol 4 (4) ◽

pp. 161098 ◽

Cited By ~ 6

Author(s):

Emmeli Mikkelsen ◽

Henrik Lauridsen ◽

Per Mose Nielsen ◽

Haiyun Qi ◽

Thomas Nørlinger ◽

...

Keyword(s):

Animal Model ◽

Ex Vivo ◽

Gestation Period ◽

Whole Body ◽

Non Invasive ◽

Whole Body Ct ◽

Contrast Enhanced Ct ◽

Hyperpolarized Mri

Several parameters are important when choosing the most appropriate animal to model human obstetrics, including gestation period, number of fetuses per gestation and placental structure. The domesticated long-tailed chinchilla ( Chinchilla lanigera ) is a well-suited and appropriate animal model of pregnancy that often will carry only one offspring and has a long gestation period of 105–115 days. Furthermore, the chinchilla placenta is of the haemomonochorial labyrinthine type and is therefore comparable to the human villous haemomonochorial placenta. This proof-of-concept study demonstrated the feasibility in laboratory settings, and demonstrated the potential of the pregnant chinchilla as an animal model for obstetric research and its potential usefulness for non-invasive measurements in the placenta. We demonstrate measurements of the placental and fetal metabolism (demonstrated in vivo by hyperpolarized MRI and in vitro by qPCR analyses), placental vessels (demonstrated ex vivo by contrast-enhanced CT angiography) and overall anatomy (demonstrated in vivo by whole-body CT).

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Non-invasive skin sampling of tryptophan/kynurenine ratio in vitro towards a skin cancer biomarker

Scientific Reports ◽

10.1038/s41598-020-79903-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Skaidre Jankovskaja ◽

Johan Engblom ◽

Melinda Rezeli ◽

György Marko-Varga ◽

Tautgirdas Ruzgas ◽

...

Keyword(s):

Skin Cancer ◽

Relative Increase ◽

Cancer Biomarker ◽

Cancer Diagnostics ◽

Sampling Time ◽

Skin Permeability ◽

Experimental Conditions ◽

Non Invasive

AbstractThe tryptophan to kynurenine ratio (Trp/Kyn) has been proposed as a cancer biomarker. Non-invasive topical sampling of Trp/Kyn can therefore serve as a promising concept for skin cancer diagnostics. By performing in vitro pig skin permeability studies, we conclude that non-invasive topical sampling of Trp and Kyn is feasible. We explore the influence of different experimental conditions, which are relevant for the clinical in vivo setting, such as pH variations, sampling time, and microbial degradation of Trp and Kyn. The permeabilities of Trp and Kyn are overall similar. However, the permeated Trp/Kyn ratio is generally higher than unity due to endogenous Trp, which should be taken into account to obtain a non-biased Trp/Kyn ratio accurately reflecting systemic concentrations. Additionally, prolonged sampling time is associated with bacterial Trp and Kyn degradation and should be considered in a clinical setting. Finally, the experimental results are supported by the four permeation pathways model, predicting that the hydrophilic Trp and Kyn molecules mainly permeate through lipid defects (i.e., the porous pathway). However, the hydrophobic indole ring of Trp is suggested to result in a small but noticeable relative increase of Trp diffusion via pathways across the SC lipid lamellae, while the shunt pathway is proposed to slightly favor permeation of Kyn relative to Trp.

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Use of Toxicokinetics in Risk Assessment Based on In Vitro Data

Alternatives to Laboratory Animals ◽

10.1177/026119299302100209 ◽

1993 ◽

Vol 21 (2) ◽

pp. 173-180

Author(s):

Gunnar Johanson

Keyword(s):

Risk Assessment ◽

Whole Body ◽

External Exposure ◽

Target Dose ◽

Toxic Response ◽

Route Of Exposure ◽

Vitro Data ◽

In Vitro Data

This presentation addresses some aspects of the methodology, advantages and problems associated with toxicokinetic modelling based on in vitro data. By using toxicokinetic models, particularly physiologically-based ones, it is possible, in principle, to describe whole body toxicokinetics, target doses and toxic effects from in vitro data. Modelling can be divided into three major steps: 1) to relate external exposure (applied dose) of xenobiotic to target dose; 2) to establish the relationship between target dose and effect (in vitro data, e.g. metabolism in microsomes, partitioning in tissue homogenates, and toxicity in cell cultures, are useful in both steps); and 3) to relate external exposure to toxic effect by combining the first two steps. Extrapolations from in vitro to in vivo, between animal and man, and between high and low doses, can easily be carried out by toxicokinetic simulations. In addition, several factors that may affect the toxic response by changing the target dose, such as route of exposure and physical activity, can be studied. New insights concerning the processes involved in toxicity often emerge during the design, refinement and validation of the model. The modelling approach is illustrated by two examples: 1) the carcinogenicity of 1,3-butadiene; and 2) the haematotoxicity of 2-butoxyethanol. Toxicokinetic modelling is an important tool in toxicological risk assessment based on in vitro data. Many factors, some of which can, and should be, studied in vitro, are involved in the expression of toxicity. Successful modelling depends on the identification and quantification of these factors.

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Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver

Nature Communications ◽

10.1038/s41467-021-22106-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

KyeongJin Kim ◽

Jin Ku Kang ◽

Young Hoon Jung ◽

Sang Bae Lee ◽

Raffaela Rametta ◽

...

Keyword(s):

Fatty Liver ◽

Whole Body ◽

Acid Oxidation ◽

Chow Diet ◽

Peroxisome Proliferator ◽

Obese Mice ◽

Ph Domain ◽

Peroxisome Proliferator Activated Receptor

AbstractIncreased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

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Zingiber zerumbet(L.) Smith: A Review of Its Ethnomedicinal, Chemical, and Pharmacological Uses

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2011/543216 ◽

2011 ◽

Vol 2011 ◽

pp. 1-12 ◽

Cited By ~ 80

Author(s):

N. J. Yob ◽

S. Mohd. Jofrry ◽

M. M. R. Meor. Mohd. Affandi ◽

L. K. Teh ◽

M. Z. Salleh ◽

...

Keyword(s):

Medicinal Plant ◽

Traditional Medicine ◽

Biological Evaluation ◽

Perennial Herb ◽

Zingiber Zerumbet ◽

Tropical Countries ◽

Traditional Uses ◽

Worm Infestation

Zingiber zerumbetSm., locally known to the Malay as “Lempoyang,” is a perennial herb found in many tropical countries, including Malaysia. The rhizomes ofZ. zerumbet, particularly, have been regularly used as food flavouring and appetizer in various Malays' cuisines while the rhizomes extracts have been used in Malay traditional medicine to treat various types of ailments (e.g., inflammatory- and pain-mediated diseases, worm infestation and diarrhea). Research carried out using differentin vitroandin vivoassays of biological evaluation support most of these claims. The active pharmacological component ofZ. zerumbetrhizomes most widely studied is zerumbone. This paper presents the botany, traditional uses, chemistry, and pharmacology of this medicinal plant.

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Photoelectric Dye, NK-5962, as a Potential Drug for Preventing Retinal Neurons from Apoptosis: Pharmacokinetic Studies Based on Review of the Evidence

Life ◽

10.3390/life11060591 ◽

2021 ◽

Vol 11 (6) ◽

pp. 591

Author(s):

Toshihiko Matsuo ◽

Shihui Liu ◽

Tetsuya Uchida ◽

Satomi Onoue ◽

Shinsaku Nakagawa ◽

...

Keyword(s):

Biological Evaluation ◽

Pharmacokinetic Studies ◽

Retinal Neurons ◽

Retinal Cells ◽

Intravitreous Injection ◽

Rcs Rats ◽

Photoelectric Dye ◽

Dark Conditions

NK-5962 is a key component of photoelectric dye-based retinal prosthesis (OUReP). In testing the safety and efficacy, NK-5962 was safe in all tests for the biological evaluation of medical devices (ISO 10993) and effective in preventing retinal cells from death even under dark conditions. The long-term implantation of the photoelectric dye-coupled polyethylene film in the subretinal space of hereditary retinal dystrophic (RCS) rats prevented neurons from apoptosis in the adjacent retinal tissue. The intravitreous injection of NK-5962 in the eyes of RCS rats, indeed, reduced the number of apoptotic cells in the retinal outer nuclear layer irrespective of light or dark conditions. In this study, we reviewed the in vitro and in vivo evidence of neuroprotective effect of NK-5962 and designed pharmacokinetic experiments. The in vitro IC50 of 1.7 μM, based on the protective effect on retinal cells in culture, could explain the in vivo EC50 of 3 μM that is calculated from concentrations of intravitreous injection to prevent retinal neurons from apoptosis. Pharmacokinetics of NK-5962 showed that intravenous administration, but not oral administration, led to the effective concentration in the eye of rats. NK-5962 would be a candidate drug for delaying the deterioration of retinal dystrophy, such as retinitis pigmentosa.

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Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2)

Cancers ◽

10.3390/cancers13163959 ◽

2021 ◽

Vol 13 (16) ◽

pp. 3959

Author(s):

Oluwaseun Adebayo Bamodu ◽

Yuan-Hung Wang ◽

Chen-Hsun Ho ◽

Su-Wei Hu ◽

Chia-Da Lin ◽

...

Keyword(s):

Prostate Cancer ◽

Disease Progression ◽

Therapy Resistance ◽

Calcium Signal ◽

Signal Transducer ◽

Castration Resistance ◽

Castration Resistant

Background: prostate cancer (PCa) is a principal cause of cancer-related morbidity and mortality. Castration resistance and metastasis are clinical challenges and continue to impede therapeutic success, despite diagnostic and therapeutic advances. There are reports of the oncogenic activity of genetic suppressor element (GSE)1 in breast and gastric cancers; however, its role in therapy resistance, metastasis, and susceptibility to disease recurrence in PCa patients remains unclear. Objective: this study investigated the role of aberrantly expressed GSE1 in the metastasis, therapy resistance, relapse, and poor prognosis of advanced PCa. Methods: we used a large cohort of multi-omics data and in vitro, ex vivo, and in vivo assays to investigate the potential effect of altered GSE1 expression on advanced/castration-resistant PCa (CRPC) treatment responses, disease progression, and prognosis. Results: using a multi-cohort approach, we showed that GSE1 is upregulated in PCa, while tumor-associated calcium signal transducer 2 (TACSTD2) is downregulated. Moreover, the direct, but inverse, correlation interaction between GSE1 and TACSTD2 drives metastatic disease, castration resistance, and disease progression and modulates the clinical and immune statuses of patients with PCa. Patients with GSE1highTACSTD2low expression are more prone to recurrence and disease-specific death than their GSE1lowTACSTD2high counterparts. Interestingly, we found that the GSE1–TACSTD2 expression profile is associated with the therapy responses and clinical outcomes in patients with PCa, especially those with metastatic/recurrent disease. Furthermore, we demonstrate that the shRNA-mediated targeting of GSE1 (shGSE1) significantly inhibits cell proliferation and attenuates cell migration and tumorsphere formation in metastatic PC3 and DU145 cell lines, with an associated suppression of VIM, SNAI2, and BCL2 and the concomitant upregulation of TACSTD2 and BAX. Moreover, shGSE1 enhances sensitivity to the antiandrogens abiraterone and enzalutamide in vitro and in vivo. Conclusion: these data provide preclinical evidence of the oncogenic role of dysregulated GSE1–TACSTD2 signaling and show that the molecular or pharmacological targeting of GSE1 is a workable therapeutic strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing CRPC to treatment, and repressing the metastatic/recurrent phenotypes of patients with PCa.

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