scholarly journals Structure-to-Efficacy Relationship of HPMA-Based Nanomedicines: The Tumor Spheroid Penetration Study

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1242
Author(s):  
Júlia Kudláčová ◽  
Lenka Kotrchová ◽  
Libor Kostka ◽  
Eva Randárová ◽  
Marcela Filipová ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Drug Carrier ◽  
In Vitro Models ◽  
Hpma Copolymer ◽  
Polymer Carriers ◽  
Hydroxypropyl Methacrylamide ◽  
Tumor Accumulation ◽  
Structural Architecture ◽  
Relationship Of

Nanomedicines are a novel class of therapeutics that benefit from the nano dimensions of the drug carrier. These nanosystems are highly advantageous mainly within cancer treatment due to their enhanced tumor accumulation. Monolayer tumor cells frequently used in routine preclinical assessment of nanotherapeutics do not have a spatial structural architecture that allows the investigation of the penetration of nanomedicines to predict their behavior in real tumor tissue. Therefore, tumor spheroids from colon carcinoma C26 cells and glioblastoma U87-MG cells were used as 3D in vitro models to analyze the effect of the inner structure, hydrodynamic size, dispersity, and biodegradability of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based nanomedicines carrying anticancer drug pirarubicin (THP) on the penetration within spheroids. While almost identical penetration through spheroids of linear and star-like copolymers and also their conjugates with THP was observed, THP penetration after nanomedicines application was considerably deeper than for the free THP, thus proving the benefit of polymer carriers. The cytotoxicity of THP-polymer nanomedicines against tumor cell spheroids was almost identical as for the free THP, whereas the 2D cell cytotoxicity of these nanomedicines is usually lower. The nanomedicines thus proved the enhanced efficacy within the more realistic 3D tumor cell spheroid system.

Pinocytic capture and exocytosis of rat immunoglobulin IgG-N-(2-hydroxy-propyl)methacrylamide copolymer conjugates by rat visceral yolk sacs cultured in vitro

1986 ◽  
Vol 6 (10) ◽  
pp. 869-877 ◽  
Author(s):  
Ruth Duncan ◽  
Hazel C. Cable ◽  
Jiri Strohalm ◽  
Jindřich Kopeček
Keyword(s):  
Drug Carrier ◽  
Yolk Sac ◽  
Membrane Receptors ◽  
Cellular Transport ◽  
Hpma Copolymer ◽  
Intracellular Degradation ◽  
Hpma Copolymers ◽  
Hydroxypropyl Methacrylamide ◽  
Covalently Bound

Rat immunoglobulin (IgG) was covalently bound to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers via glycylglycyl spacer. The resultant conjugate, free IgG and HPMA copolymer (containing a low percentage of tyrosinamide to facilitate radiolabelling) were radioiodinated, and their rates of pinocytic uptake, intracellular degradation and exocytic release by rat visceral yolk sacs cultured in vitro were determined. Free IgG was pinocytosed rapidly by the yolk sac and some IgG was subject to intracellular proteolysis. In comparison the IgG-HPMA copolymer conjugate was captured more slowly, but faster than unmodified HPMA. IgG was also exocytosed rapidly by the yolk sac following pinocytic capture and similarly IgG-HPMA copolymer had a much higher rate of release than unmodified H PMA. Measurement of tissue accumulation of125I-labelled IgG-H PMA copolymer in the presence of increasing concentrations of non-radiolabelled IgG showed competition for membrane binding sites between the free, and polymer-bound immunoglobulin. These experiments indicate that immunoglobulins can be covalently bound to a soluble polymer developed as a drug-carrier in such a way that they can still interact with specific membrane receptors and they are subsequently subjected to specific cellular transport mechanisms.

scholarly journals Synthesis of Water-Soluble Star Polymers Based on Cyclodextrins

2018 ◽  
pp. S357-S365
Author(s):  
L. KOTRCHOVÁ ◽  
T. ETRYCH
Keyword(s):  
Star Polymers ◽  
Water Soluble ◽  
Hpma Copolymer ◽  
Polymer Carriers ◽  
Physico Chemical ◽  
Reversible Addition ◽  
Degradation Rates ◽  
Hpma Copolymers ◽  
Hydroxypropyl Methacrylamide ◽  
Chain Transfer Polymerization

Novel star polymers based on the water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer and cyclodextrin were synthesized and the physico-chemical behavior of these precursors was studied. Semitelechelic HPMA copolymers were grafted onto the cyclodextrin core, thus forming star-like structure. Both prepared systems were designed as possible polymer carriers for the controlled release of cytostatic drugs, which after the drug release and degradation will be eliminated from the organism. Two synthesis approaches were used to obtain similar polymer carriers with different degradation rates. All the polymers were prepared by reversible addition-fragmentation chain-transfer polymerization, which guarantees low dispersity of the prepared systems.

Augmented tumor accumulation and photothermal ablation using gold nanoparticles with a particular cellular entry orientation

2018 ◽  
Vol 33 (6) ◽  
pp. 660-675
Author(s):  
Gwang Jin Noh ◽  
Hongsuk Park ◽  
Eun Seong Lee
Keyword(s):  
Gold Nanoparticles ◽  
Tumor Cell ◽  
Gold Nanoparticle ◽  
Cellular Internalization ◽  
Tat Peptide ◽  
Peptide Expression ◽  
Cellular Entry ◽  
Tumor Accumulation

Gold nanoparticles with various functionalities have served as potential tools in nanotechnology for tumor ablation. In this work, we seek to design and develop gold nanoparticle with poly(ethylene glycol)-containing dopamine (hereafter termed as AuND), and to synthesize the AuND with one-sided Tat peptide expression (OT@AuND). We demonstrate the tumor cell-targeting ability on the basis of anti-nonspecific cell binding of OT@AuND and determine how the chemically modified gold nanoparticle–based product affects photothermal tumor therapy in vitro and in vivo. The OT@AuND with a particular cellular entry orientation–induced delayed endocytosis, which is advantageous for enhanced permeability and retention effect-based tumor accumulation. This is because the slower cellular interaction of OT@AuND allows it to have the time to be transported to and bind to the tumor site. In tumor cell lines, OT@AuND showed a lower cellular uptake than gold nanoparticles with full-sided Tat peptide expression (FT@AuND) in the early period (after its in vitro and in vivo administration), but the cellular internalization rate of OT@AuND caught up with that of FT@AuND in the late period. Importantly, the delayed cellular internalization feature of OT@AuND resulted in efficient tumor accumulation in tumor-bearing mice, because the time interval provided OT@AuND more chances not to bind to any cells, but to enter tumor cells, leading to selective photothermal tumor ablation. These data suggest that gold nanoparticles with a particular cellular entry orientation can be further explored as a potential photothermal therapeutic agent and as a strategy to treat tumors.

scholarly journals Doxorubicin-Loaded Mixed Micelles Using Degradable Graft and Diblock Copolymers to Enhance Anticancer Sensitivity

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3816
Author(s):  
Yi-Chun Chen ◽  
Chang-Jung Chang ◽  
Ging-Ho Hsiue ◽  
Yi-Ting Chiang
Keyword(s):  
Cancer Cells ◽  
Graft Copolymer ◽  
Diblock Copolymers ◽  
Mixed Micelles ◽  
High Rate ◽  
Micellar System ◽  
Hydroxypropyl Methacrylamide ◽  
Tumor Accumulation

In this study, a graft copolymer, poly(N-(2-hydroxypropyl) methacrylamide dilactate)-co-(N-(2-hydroxypropyl) methacrylamide-co-histidine)-graft-poly(d,l-lactide), and a diblock copolymer, methoxy poly(ethylene glycol)-b-poly(d,l-lactide), were assembled into a mixed micellar system to encapsulate the anticancer drug doxorubicin (Dox). This mixed micellar system possesses the hydrophobic lactide segment of both copolymers, which reinforces its stability in physiological milieus; the histidine molecules appended on the graft copolymer provide the desired pH-responsive behavior to release Dox during internalization in cancer cells. The results demonstrate that the two copolymers were successfully prepared, and their ratios in the mixed micelles were optimized on the basis of the results of the stability tests. Under acidic conditions, the mixed micelles swell and are able to release their payloads. Therefore, the in vitro results indicate that the Dox in the mixed micelles is released effectively in response to the environmental pH of the mimetic internalization process, increasing cancer cells’ sensitivity toward Dox. The mixed micelles display low cytotoxicity due to the degradability of the polymers. The in vivo images show that the high stability of the mixed micelles ensures a high tumor accumulation. This selective tumor accumulation results in an excellent inhibition of in vivo tumor growth and a high rate of apoptosis in cancerous tissues, with low toxicity. This highly stable, mixed micellar system with a pH-dependent drug release, which enables the precise delivery of drugs to the tumor lesions, is feasible to employ clinically in cancer therapy.

scholarly journals Cancer-Associated Fibroblasts Modulate Transcriptional Signatures Involved in Proliferation, Differentiation and Metastasis in Head and Neck Squamous Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3361
Author(s):  
Emilia Wiechec ◽  
Mustafa Magan ◽  
Natasa Matic ◽  
Anna Ansell-Schultz ◽  
Matti Kankainen ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
In Vitro Models ◽  
Cancer Associated Fibroblasts ◽  
Mesenchymal Transition ◽  
2D And 3D

Cancer-associated fibroblasts (CAFs) are known to increase tumor growth and to stimulate invasion and metastasis. Increasing evidence suggests that CAFs mediate response to various treatments. HNSCC cell lines were co-cultured with their patient-matched CAFs in 2D and 3D in vitro models, and the tumor cell gene expression profiles were investigated by cDNA microarray and qRT-PCR. The mRNA expression of eight candidate genes was examined in tumor biopsies from 32 HNSCC patients and in five biopsies from normal oral tissue. Differences in overall survival (OS) were tested with Kaplan–Meier long-rank analysis. Thirteen protein coding genes were found to be differentially expressed in tumor cells co-cultured with CAFs in 2D and 81 in 3D when compared to tumor cells cultured without CAFs. Six of these genes were upregulated both in 2D and 3D (POSTN, GREM1, BGN, COL1A2, COL6A3, and COL1A1). Moreover, two genes upregulated in 3D, MMP9 and FMOD, were significantly associated with the OS. In conclusion, we demonstrated in vitro that CAF-derived signals alter the tumor cell expression of multiple genes, several of which are associated with differentiation, epithelial-to-mesenchymal transition (EMT) phenotype, and metastasis. Moreover, six of the most highly upregulated genes were found to be overexpressed in tumor tissue compared to normal tissue.

scholarly journals Modeling of the Human Bone Environment: Mechanical Stimuli Guide Mesenchymal Stem Cell–Extracellular Matrix Interactions

Materials ◽  
2021 ◽  
Vol 14 (16) ◽  
pp. 4431
Author(s):  
Ana Rita Pereira ◽  
Andreas Lipphaus ◽  
Mert Ergin ◽  
Sahar Salehi ◽  
Dominic Gehweiler ◽  
...  
Keyword(s):  
Shear Stress ◽  
Bone Development ◽  
Early Response ◽  
In Vitro Models ◽  
Human Bone ◽  
Mechanical Stimuli ◽  
Bone Scaffolds ◽  
The Matrix ◽  
Structural Architecture

In bone tissue engineering, the design of in vitro models able to recreate both the chemical composition, the structural architecture, and the overall mechanical environment of the native tissue is still often neglected. In this study, we apply a bioreactor system where human bone-marrow hMSCs are seeded in human femoral head-derived decellularized bone scaffolds and subjected to dynamic culture, i.e., shear stress induced by continuous cell culture medium perfusion at 1.7 mL/min flow rate and compressive stress by 10% uniaxial load at 1 Hz for 1 h per day. In silico modeling revealed that continuous medium flow generates a mean shear stress of 8.5 mPa sensed by hMSCs seeded on 3D bone scaffolds. Experimentally, both dynamic conditions improved cell repopulation within the scaffold and boosted ECM production compared with static controls. Early response of hMSCs to mechanical stimuli comprises evident cell shape changes and stronger integrin-mediated adhesion to the matrix. Stress-induced Col6 and SPP1 gene expression suggests an early hMSC commitment towards osteogenic lineage independent of Runx2 signaling. This study provides a foundation for exploring the early effects of external mechanical stimuli on hMSC behavior in a biologically meaningful in vitro environment, opening new opportunities to study bone development, remodeling, and pathologies.

scholarly journals A Hybrid in Silico and Tumor-on-a-Chip Approach to Model Targeted Protein Behavior in 3D Microenvironments

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2461
Author(s):  
Valentina Palacio-Castañeda ◽  
Simon Dumas ◽  
Philipp Albrecht ◽  
Thijmen J. Wijgers ◽  
Stéphanie Descroix ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Tumor Cell ◽  
Tumor Cells ◽  
In Silico ◽  
Growth Factor Receptor ◽  
In Vitro Models ◽  
Protein Activity ◽  
Apparent Diffusion Coefficients ◽  
Ankyrin Repeat Proteins

To rationally improve targeted drug delivery to tumor cells, new methods combining in silico and physiologically relevant in vitro models are needed. This study combines mathematical modeling with 3D in vitro co-culture models to study the delivery of engineered proteins, called designed ankyrin repeat proteins (DARPins), in biomimetic tumor microenvironments containing fibroblasts and tumor cells overexpressing epithelial cell adhesion molecule (EpCAM) or human epithelial growth factor receptor (HER2). In multicellular tumor spheroids, we observed strong binding-site barriers in combination with low apparent diffusion coefficients of 1 µm2·s-1 and 2 µm2 ·s-1 for EpCAM- and HER2-binding DARPin, respectively. Contrasting this, in a tumor-on-a-chip model for investigating delivery in real-time, transport was characterized by hindered diffusion as a consequence of the lower local tumor cell density. Finally, simulations of the diffusion of an EpCAM-targeting DARPin fused to a fragment of Pseudomonas aeruginosa exotoxin A, which specifically kills tumor cells while leaving fibroblasts untouched, correctly predicted the need for concentrations of 10 nM or higher for extensive tumor cell killing on-chip, whereas in 2D models picomolar concentrations were sufficient. These results illustrate the power of combining in vitro models with mathematical modeling to study and predict the protein activity in complex 3D models.

scholarly journals Metabolic Switching of Tumor Cells under Hypoxic Conditions in a Tumor-on-a-chip Model

Micromachines ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 382 ◽  
Author(s):  
Valentina Palacio-Castañeda ◽  
Lucas Kooijman ◽  
Bastien Venzac ◽  
Wouter Verdurmen ◽  
Séverine Le Gac
Keyword(s):  
Cell Culture ◽  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Tumor Cells ◽  
In Vitro Models ◽  
Cancer Therapies ◽  
Metabolic Switch ◽  
Hypoxic Conditions ◽  
Tumor Cell Culture

Hypoxia switches the metabolism of tumor cells and induces drug resistance. Currently, no therapeutic exists that effectively and specifically targets hypoxic cells in tumors. Development of such therapeutics critically depends on the availability of in vitro models that accurately recapitulate hypoxia as found in the tumor microenvironment. Here, we report on the design and validation of an easy-to-fabricate tumor-on-a-chip microfluidic platform that robustly emulates the hypoxic tumor microenvironment. The tumor-on-a-chip model consists of a central chamber for 3D tumor cell culture and two side channels for medium perfusion. The microfluidic device is fabricated from polydimethylsiloxane (PDMS), and oxygen diffusion in the device is blocked by an embedded sheet of polymethyl methacrylate (PMMA). Hypoxia was confirmed using oxygen-sensitive probes and the effect on the 3D tumor cell culture investigated by a pH-sensitive dual-labeled fluorescent dextran and a fluorescently labeled glucose analogue. In contrast to control devices without PMMA, PMMA-containing devices gave rise to decreases in oxygen and pH levels as well as an increased consumption of glucose after two days of culture, indicating a rapid metabolic switch of the tumor cells under hypoxic conditions towards increased glycolysis. This platform will open new avenues for testing anti-cancer therapies targeting hypoxic areas.

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