scholarly journals Penetration Efficiency of Antitumor Agents in Ovarian Cancer Spheroids: The Case of Recombinant Targeted Toxin DARPin-LoPE and the Chemotherapy Drug, Doxorubicin

Pharmaceutics ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 219 ◽  
Author(s):  
Evgeniya Sokolova ◽  
Olga Kutova ◽  
Alena Grishina ◽  
Anton Pospelov ◽  
Evgeniy Guryev ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Antitumor Agents ◽  
Three Dimensional ◽  
Growth Factor Receptor ◽  
Ovarian Adenocarcinoma ◽  
Chemotherapy Drug ◽  
Molecular Weights ◽  
Epidermal Growth ◽  
Cancer Spheroids ◽  
Targeted Toxin

The efficiency of delivering a therapeutic agent into a tumor is among the crucial factors determining the prospects for its clinical use. This problem is particularly acute in the case of targeted antitumor agents since many of them are high-molecular-weight compounds. In this work, the penetration of therapeutic agents of two distinct molecular weights into the spheroids of ovarian adenocarcinoma overexpressing human epidermal growth factor receptor 2 (HER2) was studied. It was shown that the low-molecular-weight chemotherapy drug, doxorubicin (~0.5 kDa), effectively penetrates through almost the entire depth of a 300 to 400 μm spheroid, while the penetration depth of the HER2-specific recombinant targeted toxin, DARPin-LoPE (~42 kDa), is only a few surface layers of cells and does not exceed 70 μm. The low penetration of the targeted toxin into spheroid was shown along with a significant decrease in its efficiency against the three-dimensional tumor spheroid as compared with the two-dimensional monolayer culture. The approaches to increasing the accumulation of agents in the tumor are presented and prospects of their use in order to improve the effectiveness of therapy are discussed.

Physical Properties of Fractions of GR-S and Their Vulcanizates

1949 ◽  
Vol 22 (2) ◽  
pp. 494-517 ◽  
Author(s):  
John A. Yanko
Keyword(s):  
Molecular Weight ◽  
Intrinsic Viscosity ◽  
Large Scale ◽  
Average Molecular Weight ◽  
Three Dimensional ◽  
Reduced Pressure ◽  
Molecular Weights ◽  
Styrene Copolymers ◽  
Straight Line ◽  
The Relationship

Abstract A large-scale precise fractionation of GR-S (X-55) was carried out at 25° C, using a fractional precipitation technique. Nine fractions, each weighing approximately 150 grams and comprising about 11 per cent by weight of the original unfractionated sample, were obtained, with number-average molecular weights varying from 4000 to 1,650,000. High molecular fractions undergo gelation rapidly, even when dried in the absence of light at reduced pressure, and the higher the molecular weight of the fraction, the greater the amount of gel formed. Compared to unfractionated butadiene-styrene copolymers of similar gel contents, the gel portions of the higher molecular fractions had unusually high swelling indices, indicating qualitatively that the average molecular weights between points of effective cross-linking in the three-dimensional gel structure were higher than those found in the past in unfractionated samples of similar gel contents. Through the concentration range studied, the intrinsic viscosity values varied as a straight-line function of the concentration terms for all the fractions. However, the negative slopes of these lines increased as the molecular weight of the fraction increased, demonstrating the greater dependence of the intrinsic viscosity values of the higher molecular fractions on the concentration variable. The relationship between number-average molecular weight, as determined by osmometric measurements, and limiting intrinsic viscosity of the GR-S fractions is given by the equation: [η]0=5.4×10−4 M0.66, which is similar to that obtained by French and Ewart. The μi values calculated from the equation of Huggins were essentially the same (0.35) through the molecular range 12,400 to 723,000.

scholarly journals Association of the epidermal growth factor receptor kinase with the detergent-insoluble cytoskeleton of A431 cells.

1985 ◽  
Vol 101 (4) ◽  
pp. 1341-1350 ◽  
Author(s):  
G E Landreth ◽  
L K Williams ◽  
G D Rieser
Keyword(s):  
Molecular Weight ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Kinase Activity ◽  
Growth Factor Receptor ◽  
A431 Cells ◽  
Structural Association ◽  
Epidermal Growth ◽  
Cytoskeletal Elements

The epidermal growth factor receptor (EGF-R) on human epidermoid carcinoma cells, A431, was found to be predominantly associated with the detergent-insoluble cytoskeleton, where it retained both a functional ligand-binding domain and an intrinsic tyrosine kinase activity. The EGF-R was constitutively associated with the A431 cytoskeleton; this association was not a consequence of adventitious binding. The EGF-R was associated with cytoskeletal elements both at the cell surface, within intracellular vesicles mediating the internalization of the hormone-receptor complex, and within lysosomes. The EGF-R became more stably associated with cytoskeletal elements after its internalization. The cytoskeletal association of the EGF-R was partially disrupted on suspension of adherent cells, indicating that alteration of cellular morphology influences the structural association of the EGF-R, and that the EGF-R is not intrinsically insoluble. Cytoskeletons prepared from EGF-treated A431 cells, when incubated with gamma-32P-ATP, demonstrated enhanced autophosphorylation of the EGF-R in situ as well as the phosphorylation of several high molecular weight proteins. In this system, phosphorylation occurs between immobilized kinase and substrate. The EGF-R and several high molecular weight cytoskeletal proteins were phosphorylated on tyrosine residues; two of the latter proteins were phosphorylated transiently as a consequence of EGF action, suggesting that EGF caused the active redistribution of the protein substrates relative to protein kinases. The ability of EGF to stimulate protein phosphorylation in situ required treatment of intact cells at physiological temperatures; addition of EGF directly to cytoskeletons had no effect. These data suggest that the structural association of the EGF-R may play a role in cellular processing of the hormone, as well as in regulation of the EGF-R kinase activity and in specifying its cellular substrates.

scholarly journals Synthesis, cytotoxicity, and molecular docking of methylated (–)-epigallocatechin-3-gallate-4β-triazolopodophyllotoxin derivatives as novel antitumor agents

2021 ◽  
pp. 174751982110273
Author(s):  
Cheng-Ting Zi ◽  
Ze-Hao Wang ◽  
Jing Shi ◽  
Bo-Ya Shi ◽  
Ning Zhang ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Anticancer Agents ◽  
Antitumor Agents ◽  
Click Reaction ◽  
Human Cancer ◽  
Growth Factor Receptor ◽  
Human Cancer Cell Lines ◽  
Epidermal Growth ◽  
Further Development ◽  
Mcf 7

A series of novel methylated (–)-epigallocatechin-3-gallate-4β-triazolopodophyllotoxin derivatives is synthesized by utilizing the click reaction. Evaluation of their cytotoxicity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480) using the MTT assay shows that most of these compounds exhibit weak cytotoxicity. It is observed that compound 12 shows the highest activity against A-549 cells with an IC50 value of 10.27 ± 0.90 μM. Molecular docking results suggested that this compound 12 has a higher binding affinity for epidermal growth factor receptor than for tubulin. Our findings support the utility of compound 12 as a novel compound for the further development of anticancer agents.

Synthesis and Evaluation of Some Novel 6-Substituted Quinazoline Derivatives as Antitumor Agents

2019 ◽  
Vol 41 (1) ◽  
pp. 186-186
Author(s):  
Hai guan Ding Hai guan Ding ◽  
Zhi qiang Cai Zhi qiang Cai ◽  
Ling Hou Ling Hou ◽  
Zhi quan Hu Zhi quan Hu ◽  
Zheng sheng Jin Zheng sheng Jin ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Antitumor Agents ◽  
Mcf7 Cell ◽  
Growth Factor Receptor ◽  
The Novel ◽  
Mcf7 Cell Line ◽  
Epidermal Growth ◽  
Quinazoline Derivatives

A series of novel 6-substituted quinazoline derivatives were synthesised as epidermal growth factor receptor(EGFR) and Human epidermal growth factor receptor 2 (HER2)inhibitors in our lab. The novel compounds were measured for their dual enzyme inhibition as well as their cytotoxic activity on MCF7 cell line. The results revealed that all the compounds showed inhibition of both enzymes. Compound 5c showed the best inhibitory activity against both enzymes and IC50 of its was 2.6 nM against EGFR kinases and 4.3 nM against HER2 kinases, respectively. Most of the measured compounds showed to antitumor activity on MCF7.

Effect of Initial Molecular Weight of a Rubber on the Strength and Fatigue of Its Vulcanizates

1957 ◽  
Vol 30 (1) ◽  
pp. 54-60
Author(s):  
G. M. Bartenev ◽  
A. S. Novikov ◽  
F. A. Galil-Ogly
Keyword(s):  
Molecular Weight ◽  
Dynamic Testing ◽  
Three Dimensional ◽  
Maximum Load ◽  
Testing Conditions ◽  
Maximum Deformation ◽  
Molecular Weights ◽  
Permanent Set ◽  
Dimensional Network ◽  
Equilibrium Modulus

Abstract (1) With decrease of the original molecular weight of rubber, there is a parallel decrease of the durability of its vulcanizates when they contain the same percentage of combined sulfur. On the other hand, this decrease of durability with decrease of the original molecular weight is only slight for vulcanizates having the same equilibrium modulus, i.e., the same density of crosslinks in the three-dimensional network. (2) In dynamic testing which involves repeated stretching, the durability depends on the testing conditions when the vulcanizates contain the same percentage of combined sulfur and at the same time when either the original molecular weight of the rubber is low or the equilibrium modulus is small. On the contrary, when the original molecular weight or the modulus is high, the durability does not depend on the testing conditions. When vulcanizates have the same equilibrium modulus, their durability depends on the original molecular weight. In this latter case the durability increases with increase of the molecular weight, independent of the testing conditions (given maximum load, given maximum deformation, etc.), and reaches a practically constant value at high molecular weights. (3) The fundamental influence of the original molecular weight on the strength and dynamic durability of vulcanizates containing the same percentage of combined sulfur is manifest in the retardation of the formation of a spatial network in low-molecular rubbers when vulcanized. With rubber of low original molecular weight, vulcanization leads to the formation of a thin space network and consequently a large number of molecular chain ends outside the network. For this reason, vulcanizates of low-molecular rubbers when tested are characterized by high permanent set.

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