Design of a Platelet-Mediated Delivery System for Drug-Incorporated Nanospheres to Enhance Anti-Tumor Therapeutic Effect

The objective of this study is to construct a platelet-mediated delivery system for drug-incorporated nanospheres. Nanospheres of poly(lactic-co-glycolic acid) (PLGA-NS) with different sizes and surface properties were prepared by changing the preparation parameters, such as the type of polymer surfactant, the concentration of polymer surfactant and PLGA, and the stirring rate. When incubated with platelets, PLGA-NS prepared with poly(vinyl alcohol) suppressed the platelet activation. Scanning electron microscopic and flow cytometry examinations revealed that platelets associated with PLGA-NS (platelet hybrids, PH) had a similar appearance and biological properties to those of the original platelets. In addition, the PH with PLGA-NS specifically adhered onto the substrate pre-coated with fibrin to a significantly great extent compared with PLGA-NS alone. When applied in an in vitro model of tumor tissue which was composed of an upper chamber pre-coated with fibrin and a lower chamber culturing tumor cells, the PH with PLGA-NS incorporating an anti-tumor drug were delivered to the tumor cells through the specific adhesion onto the upper chamber and, consequently, drug release from the upper chamber took place, resulting in the growth suppression of tumor cells. It is concluded that the drug delivery system based on PH is promising for tumor treatment.

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Isobornylchalcones as Scaffold for the Synthesis of Diarylpyrazolines with Antioxidant Activity

Molecules ◽

10.3390/molecules26123579 ◽

2021 ◽

Vol 26 (12) ◽

pp. 3579

Author(s):

Svetlana A. Popova ◽

Evgenia V. Pavlova ◽

Oksana G. Shevchenko ◽

Irina Yu. Chukicheva ◽

Aleksandr V. Kutchin

Keyword(s):

Antioxidant Activity ◽

Antioxidant Properties ◽

Biological Properties ◽

High Reactivity ◽

Biologically Active ◽

Brain Lipids ◽

Wide Range ◽

Privileged Structure ◽

Vitro Model

The pyrazoline ring is defined as a “privileged structure” in medicinal chemistry. A variety of pharmacological properties of pyrazolines is associated with the nature and position of various substituents, which is especially evident in diarylpyrazolines. Compounds with a chalcone fragment show a wide range of biological properties as well as high reactivity which is primarily due to the presence of an α, β-unsaturated carbonyl system. At the same time, bicyclic monoterpenoids deserve special attention as a source of a key structural block or as one of the pharmacophore components of biologically active molecules. A series of new diarylpyrazoline derivatives based on isobornylchalcones with different substitutes (MeO, Hal, NO2, N(Me)2) was synthesized. Antioxidant properties of the obtained compounds were comparatively evaluated using in vitro model Fe2+/ascorbate-initiated lipid peroxidation in the substrate containing brain lipids of laboratory mice. It was demonstrated that the combination of the electron-donating group in the para-position of ring B and OH-group in the ring A in the structure of chalcone fragment provides significant antioxidant activity of synthesized diarylpyrazoline derivatives.

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The cancer glycocalyx mediates intravascular adhesion and extravasation during metastatic dissemination

Communications Biology ◽

10.1038/s42003-021-01774-2 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Giovanni S. Offeddu ◽

Cynthia Hajal ◽

Colleen R. Foley ◽

Zhengpeng Wan ◽

Lina Ibrahim ◽

...

Keyword(s):

Hyaluronic Acid ◽

Tumor Cells ◽

Cancer Progression ◽

Vascular System ◽

Migration And Invasion ◽

Improve Patient Survival ◽

Adhesive Interactions ◽

Vitro Model ◽

Metastatic Sites

AbstractThe glycocalyx on tumor cells has been recently identified as an important driver for cancer progression, possibly providing critical opportunities for treatment. Metastasis, in particular, is often the limiting step in the survival to cancer, yet our understanding of how tumor cells escape the vascular system to initiate metastatic sites remains limited. Using an in vitro model of the human microvasculature, we assess here the importance of the tumor and vascular glycocalyces during tumor cell extravasation. Through selective manipulation of individual components of the glycocalyx, we reveal a mechanism whereby tumor cells prepare an adhesive vascular niche by depositing components of the glycocalyx along the endothelium. Accumulated hyaluronic acid shed by tumor cells subsequently mediates adhesion to the endothelium via the glycoprotein CD44. Trans-endothelial migration and invasion into the stroma occurs through binding of the isoform CD44v to components of the sub-endothelial extra-cellular matrix. Targeting of the hyaluronic acid-CD44 glycocalyx complex results in significant reduction in the extravasation of tumor cells. These studies provide evidence of tumor cells repurposing the glycocalyx to promote adhesive interactions leading to cancer progression. Such glycocalyx-mediated mechanisms may be therapeutically targeted to hinder metastasis and improve patient survival.

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CAFs affect the proliferation and treatment response of head and neck cancer spheroids during co-culturing in a unique in vitro model

Cancer Cell International ◽

10.1186/s12935-020-01718-6 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Mustafa Magan ◽

Emilia Wiechec ◽

Karin Roberg

Keyword(s):

Cell Proliferation ◽

Tumor Cell ◽

Head And Neck ◽

Treatment Response ◽

Tumor Cells ◽

In Vitro Model ◽

Tumor Spheroids ◽

Vitro Model ◽

The Impact

Abstract Background Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors for which the overall survival rate worldwide is around 60%. The tumor microenvironment, including cancer-associated fibroblasts (CAFs), is believed to affect the treatment response and migration of HNSCC. The aim of this study was to create a biologically relevant HNSCC in vitro model consisting of both tumor cells and CAFs cultured in 3D to establish predictive biomarkers for treatment response, as well as to investigate the impact of CAFs on phenotype, proliferation and treatment response in HNSCC cells. Methods Three different HNSCC patient-derived tumor cell lines were cultured with and without CAFs in a 3D model. Immunohistochemistry of the proliferation marker Ki67, epidermal growth factor receptor (EGFR) and fibronectin and a TUNEL-assay were performed to analyze the effect of CAFs on both tumor cell proliferation and response to cisplatin and cetuximab treatment in tumor spheroids (3D). mRNA expression of epithelial-mesenchymal transition (EMT) and cancer stem cells markers were analyzed using qRT-PCR. Results The results demonstrated increased cell proliferation within the tumor spheroids in the presence of CAFs, correlating with increased expression of EGFR. In spheroids with increased expression of EGFR, a potentiated response to cetuximab treatment was observed. Surprisingly, an increase in Ki67 expressing tumor cells were observed in spheroids treated with cisplatin for 3 days, correlating with increased expression of EGFR. Furthermore, tumor cells co-cultured with CAFs presented an increased EMT phenotype compared to tumor cells cultured alone in 3D. Conclusion Taken together, our results reveal increased cell proliferation and elevated expression of EGFR in HNSCC tumor spheroids in the presence of CAFs. These results, together with the altered EMT phenotype, may influence the response to cetuximab or cisplatin treatment.

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Involvement of leukocyte function-associated antigen-1 (LFA-1) in the invasion of hepatocyte cultures by lymphoma and T-cell hybridoma cells.

The Journal of Cell Biology ◽

10.1083/jcb.105.1.553 ◽

1987 ◽

Vol 105 (1) ◽

pp. 553-559 ◽

Cited By ~ 33

Author(s):

E Roos ◽

F F Roossien

Keyword(s):

T Cell ◽

Tumor Cells ◽

Cell Types ◽

Hybridoma Cells ◽

Lymphoma Cells ◽

Hepatocyte Cultures ◽

Leukocyte Function ◽

Vitro Model

We studied the interaction of MB6A lymphoma and TAM2D2 T cell hybridoma cells with hepatocyte cultures as an in vitro model for in vivo liver invasion by these tumor cells. A monoclonal antibody against leukocyte function-associated antigen-1 (LFA-1) inhibited adhesion of the tumor cells to the surface of hepatocytes and consequently strongly reduced invasion. This effect was specific since control antibodies, directed against Thy.1 and against T200, of the same isotype, similar affinity, and comparable binding to these cells, did not inhibit adhesion. This suggests that LFA-1 is involved in the formation of liver metastases by lymphoma cells. TAM2D2 T cell hybridoma cells were agglutinated by anti-LFA-1, but not by control antibodies. Reduction of adhesion was not due to this agglutination since monovalent Fab fragments inhibited adhesion as well, inhibition was also seen under conditions where agglutination was minimal, and anti-LFA-1 similarly affected adhesion of MB6A lymphoma cells that were not agglutinated. The two cell types differed in LFA-1 surface density. TAM2D2 cells exhibited 400,000 surface LFA-1 molecules, 10 times more than MB6A cells. Nevertheless, the level of adhesion and the extent of inhibition by the anti-LFA-1 antibody were only slightly larger for the TAM2D2 cells.

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Curcumin-Loaded Nanoparticles Based on Amphiphilic Hyaluronan-Conjugate Explored as Targeting Delivery System for Neurodegenerative Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms21228846 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8846

Author(s):

Giuseppe Pepe ◽

Enrica Calce ◽

Valentina Verdoliva ◽

Michele Saviano ◽

Vittorio Maglione ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Delivery System ◽

Neurodegenerative Disorders ◽

Natural Polysaccharide ◽

Promising Therapeutic Approach ◽

Targeting Delivery ◽

Effective Delivery ◽

Vitro Model

Identification of molecules able to promote neuroprotective mechanisms can represent a promising therapeutic approach to neurodegenerative disorders including Huntington’s disease. Curcumin is an antioxidant and neuroprotective agent, even though its efficacy is limited by its poor absorption, rapid metabolism, systemic elimination, and limited blood–brain barrier (BBB) permeability. Herein, we report on novel biodegradable curcumin-containing nanoparticles to favor the compound delivery and potentially enhance its brain bioavailability. The prepared hyaluronan-based materials able to self-assemble in stable spherical nanoparticles, consist of natural fatty acids chemically conjugated to the natural polysaccharide. The aim of this study is to provide a possible effective delivery system for curcumin with the expectation that, after having released the drug at the specific site, the biopolymer can degrade to nontoxic fragments before renal excretion, since all the starting materials are provided by natural resource. Our findings demonstrate that curcumin-encapsulated nanoparticles enter the cells and reduce their susceptibility to apoptosis in an in vitro model of Huntington’s disease.

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Liposomes-In-Hydrogel Delivery System Enhances the Potential of Resveratrol in Combating Vaginal Chlamydia Infection

Pharmaceutics ◽

10.3390/pharmaceutics12121203 ◽

2020 ◽

Vol 12 (12) ◽

pp. 1203

Author(s):

May Wenche Jøraholmen ◽

Mona Johannessen ◽

Kirsten Gravningen ◽

Mirja Puolakkainen ◽

Ganesh Acharya ◽

...

Keyword(s):

Delivery System ◽

Reproductive Tract ◽

Treatment Options ◽

Chlamydia Infection ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Sexually Transmitted ◽

Vitro Model ◽

Localized Treatment

Chlamydia trachomatis is the most common cause of bacterial sexually transmitted infections and causes serious reproductive tract complications among women. The limitations of existing oral antibiotics and treatment of antimicrobial resistance require alternative treatment options. We are proposing, for the first time, the natural polyphenol resveratrol (RES) in an advanced delivery system comprising liposomes incorporated in chitosan hydrogel, for the localized treatment of C. trachomatis infection. Both free RES and RES liposomes-in-hydrogel inhibited the propagation of C. trachomatis in a concentration-dependent manner, assessed by the commonly used in vitro model comprising McCoy cells. However, for lower concentrations, the anti-chlamydial effect of RES was enhanced when incorporated into a liposomes-in-hydrogel delivery system, with inhibition of 78% and 94% for 1.5 and 3 µg/mL RES, respectively for RES liposomes-in-hydrogel, compared to 43% and 72%, respectively, for free RES. Furthermore, RES liposomes-in-hydrogel exhibited strong anti-inflammatory activity in vitro, in a concentration-dependent inhibition of nitric oxide production in the LPS-induced macrophages (RAW 264.7). The combination of a natural substance exhibiting multi-targeted pharmacological properties, and a delivery system that provides enhanced activity as well as applicability for vaginal administration, could be a promising option for the localized treatment of C. trachomatis infection.

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STUDY OF EFFECTS OF CIRCADIAN RHYTHMS ON SOLID TUMOR CELLS PROLIFERATION AND CHEMORESISTANCE

Problems in oncology ◽

10.37469/0507-3758-2020-66-5-563-571 ◽

2020 ◽

Vol 66 (5) ◽

pp. 563-571

Author(s):

Anna Danilova ◽

N. Avdonkina ◽

Ye. Gubareva ◽

I. Baldueva ◽

Anton Zozulya ◽

...

Keyword(s):

Circadian Rhythms ◽

Tumor Cell ◽

Tumor Cells ◽

Cell Lines ◽

Solid Tumor ◽

Lung Tumor ◽

Morphological Characteristics ◽

Biological Properties ◽

Physiological Processes

Circadian clock is a complex mechanism regulating many different physiological processes. Preclinical, epidemiological and clinical studies demonstrate association between circadian rhythms disruption and tumor initiation. Study of modulation of solid tumor cells biological properties through enhancement of clock mechanisms could attribute to the development of more effective chemo- and hormone therapy approaches. Aim: Evaluate the effects of ovarian and lung tumor cells synchronization with dexamethasone in vitro on cells sensitivity to cisplatin. Materials and methods: Metastatic ovarian cancer (n=3) and lung cancer (n=3) cell lines were obtained from patients tumors. Tumor cell cultivation was performed in accordance with the protocol. Artificial synchronization was performed with dexamethasone 200 nM introduction to the cell cultures. Doses of cisplatin used were 1.5 and 3.0 mg/ml. xCELLigence Real-Time Cell Analysis and Cell-IQ was used to measure proliferation and chemoresistance of tumor cells. Results: Each cell-line had individual morphological characteristics and proliferation parameters. Preliminary incubation with dexamethasone (2 h) had a stimulating effect on proliferation of all tumor cell lines (Slope min -4.3(0.3)хЕ ‘х10-3 - max 36.8(0.6)хЫх10'3, min 2.2(0.2)хЕ1х10'3- max 50.4(0.8)хЕ1х10'3), and increased their sensitivity to cisplatin (min -43(2.6)хЕ1х10-3 - max 57.5(0.6)хЕ1х10-3 и min -217,3(2,2) -1,9(0,1)хч-1х10-3 - max -1,9(0,1)хч'1х10'3, respectively. Conclusion: These results should be the platform for future studies of the interaction of clock mechanisms, cell cycle regulation and viability of tumor cells.

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Encapsulated multicellular tumor spheroids as a novel in vitro model to study small size tumors

Hemijska industrija ◽

10.2298/hemind0312585m ◽

2003 ◽

Vol 57 (12) ◽

pp. 585-588 ◽

Cited By ~ 4

Author(s):

Elena Markvicheva ◽

Lina Bezdetnaya ◽

Artur Bartkowiak ◽

Annie Marc ◽

Jean-Louis Gorgen ◽

...

Keyword(s):

Tumor Cells ◽

Tumor Biology ◽

Cell Encapsulation ◽

Large Cell ◽

In Vitro Models ◽

Multicellular Tumor Spheroids ◽

Tumor Spheroids ◽

Vitro Model

Presently multicellular tumor spheroids (MTS) are being widely used in various aspects of tumor biology, including studies in biology and photodynamic therapy. The cellular organization of spheroids allows the recreation of in vivo small tumors much better than all common two-dimensional in vitro models. The cell encapsulation method could be proposed as a novel technique to quickly and easily prepare a large number of spheroids with narrow size distribution within a desirable diameter range. Moreover, the proposed technique for spheroid generation using encapsulated growing tumor cells could provide entirely new avenues to develop a novel spheroid co-culture model (for instance, the in vitro co-cultvation of tumor cells and monocytes, or epithelial cells, or fibroblasts etc). The current research was aimed at developing a simple and reliable method to encapsulate tumor cells and to cultivate them in vitro. In order to generate spheroids, MCF-7 cells were encapsulated and cultivated in 200 ml T-flasks in a 5% CO2 atmosphere at 37?C for 4-5 weeks. The cell proliferation was easily observed using a light microscope. The cells grew in aggregates increasing in size with time. The cell growth resulted in the formation of large cell clusters (spheroids) which filled the whole microcapsule volume in 4-5 weeks.

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Charge-conversion and ultrasound-responsive O-carboxymethyl chitosan nanodroplets for controlled drug delivery

Nanomedicine ◽

10.2217/nnm-2019-0217 ◽

2019 ◽

Vol 14 (19) ◽

pp. 2549-2565 ◽

Cited By ~ 5

Author(s):

Dong Meng ◽

Lu Guo ◽

Dandan Shi ◽

Xiao Sun ◽

Mengmeng Shang ◽

...

Keyword(s):

Drug Delivery ◽

Tumor Cells ◽

Drug Delivery System ◽

Ultrasound Imaging ◽

Delivery System ◽

Cell Interaction ◽

Carboxymethyl Chitosan ◽

Ultrasound Exposure ◽

Interaction Efficiency

Aim: O-carboxymethyl chitosan/perfluorohexane nanodroplets (O-CS NDs) and doxorubicin-loading O-carboxymethyl chitosan nanodroplets were synthesized and functionally tested as drug delivery system in vitro. Materials & methods: The characteristics, charge conversion, stability, cytotoxicity, ultrasound imaging ability, interaction with tumor cells of the nanodroplets and eradication on tumor cells of the doxorubicin-loaded nanodroplets were investigated. Results: O-CS NDs (below 200 nm) achieved higher tumor cellular associations at acidic pH, with great serum stability, pH-dependent charge conversion and good ultrasound imaging ability. Doxorubicin-loading O-carboxymethyl chitosan nanodroplets exhibited strong cytotoxicity on PC-3 cells with ultrasound exposure. Conclusion: These stable, safe and smart O-CS NDs may be a promising approach to improve cell interaction efficiency as an ultrasound imaging and cancer-targeting drug delivery system.

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