Biomaterials and emerging anticancer therapeutics: engineering the microenvironment

Gu, Luo; Mooney, David J.

doi:10.1038/nrc.2015.3

Cited by 367 publications

(297 citation statements)

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“…Transwell ®), as well as immunofluorescent or immunohistochemical staining and imaging [4,19,20]. However, the inability of 2D culture to accurately predict therapeutic response and the complexity of animal models has paved the way for the development of 3D in vitro models, which utilize materials such as hydrogels to recapitulate elements of the tumor microenvironment [21][22][23]. To date, 3D in vitro models for GBM primarily incorporate only tumor cells, despite the demonstrated contributions of additional cell types to in vivo GBM behavior [6,[24][25][26][27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel

Harley

Ngo

2018

Preprint

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Glioblastoma (GBM) is the most common primary malignant brain tumor, with patients exhibiting poor survival (median survival time: 15 months). Difficulties in treating GBM include not only the inability to resect the diffusively-invading tumor cells but also therapeutic resistance. The perivascular niche within the GBM tumor microenvironment contributes significantly to tumor cell invasion, cancer stem cell maintenance, and has been shown to protect tumor cells from radiation and chemotherapy. In this study, we describe the development of an in vitro artificial perivascular niche (PVN), culturing endothelial and stromal cells along with GBM cells within a methacrylamide-functionalized gelatin hydrogel, in order to examine howthe presence of the PVN alters global genomic expression profiles. Using RNA-seq, we demonstrate that the inclusion of perivascular niche cells with GBM cells upregulates genes related to angiogenesis and remodeling, while downregulated genes are related to cell cycle and DNA damage repair.Signaling pathways and genes commonly implicated in GBM malignancy, such as MGMT, EGFR, PI3K-Akt signaling, and Ras/MAPK signaling are also upregulated in the presence of perivascular niche cells. We describe the kinetics of gene expression within the PVN hydrogels over a course of 14 days, observing the patterns associated with previously-observed GBMmediated endothelial network co-option and regression that are altered in the presence of covalently-bound hyaluronic acid. We finally examine the effect of PVN culture on GBM cell responsiveness to temozolomide, a frontline chemotherapy used clinically against GBM.Notably, the presence of a PVN leads to significantly increased TMZ resistance compared to hydrogels containing only GBM cells. Overall, these results demonstrate that inclusion of cellular and matrix-associated elements of the PVN within in vitro models of GBM provide critical signals to regulate the phenotype and therapeutic responsiveness of GBM cells.

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Section: Introductionmentioning

confidence: 99%

Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel

Harley

Ngo

2018

Preprint

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“…With this combinatory approach, it will be possible to gain a more complete picture of the cancer microenvironment and ascertain potential avenues of treatment. Additionally, non-cell factors such as chemotaxis, 130 3D culture 94,[131][132][133][134][135][136] , and hypoxia 137 should be considered for future investigations, in conjunction with mechanical cues to create a microenvironment that can more fully recapitulate in vivo conditions. The study of ovarian cancer mechanotransduction promises to improve patient treatment through future investigations that utilize designs pertinent to the specific microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Review: Mechanotransduction in ovarian cancer: Shearing into the unknown

2018

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Perspective: The role of mechanobiology in the etiology of brain metastasis APL Bioengineering 2, 031801 (2018) Ovarian cancer remains a deadly diagnosis with an 85% recurrence rate and a 5-year survival rate of only 46%. The poor outlook of this disease has improved little over the past 50 years owing to the lack of early detection, chemoresistance and the complex tumor microenvironment. Within the peritoneal cavity, the presence of ascites stimulates ovarian tumors with shear stresses. The stiff environment found within the tumor extracellular matrix and the peritoneal membrane are also implicated in the metastatic potential and epithelial to mesenchymal transition (EMT) of ovarian cancer. Though these mechanical cues remain highly relevant to the understanding and treatment of ovarian cancers, our current knowledge of their biological processes and their clinical relevance is deeply lacking. Seminal studies on ovarian cancer mechanotransduction have demonstrated close ties between mechanotransduction and ovarian cancer chemoresistance, EMT, enhanced cancer stem cell populations, and metastasis. This review summarizes our current understanding of ovarian cancer mechanotransduction and the gaps in knowledge that exist. Future investigations on ovarian cancer mechanotransduction will greatly improve clinical outcomes via systematic studies that determine shear stress magnitude and its influence on ovarian cancer progression, metastasis, and treatment.

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“…Molecular metaphors can have a broad range of applications, from synthetic organic chemistry to nanotechnology platforms [36] and including biomaterials [37]. Consequently, this review provides a valuable contribution to the interest of drug discovery and molecular imaging groups.…”

Section: Kitsonmentioning

confidence: 99%

“…Admittedly, it is hard to stay on top of a still rapidly developing synthetic methodology and move to systems of biological complexity at the same time. Some opinions signify that we have a complete array of methods available with which to probe and investigate living systems, for example the use of computational methods applied to rational drug design [35].Molecular metaphors can have a broad range of applications, from synthetic organic chemistry to nanotechnology platforms [36] and including biomaterials [37]. Consequently, this review provides a valuable contribution to the interest of drug discovery and molecular imaging groups.…”

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confidence: 99%

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

Kitson¹

2017

J Diagn Imaging Ther

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Molecular Metaphors is the application of squaryl building blocks towards creative functional group chemistry to produce lead compounds and imaging agents. This strategy is applied to rational drug design and to various imaging agents that would normally contain conventional functional group chemistry. These, include carboxylic acids, α-amino acids, peptide bonds and phosphonates. Moreover, the squaryl metaphor is a precursor to complex organic molecules involving functional group interchange (FGI) and rearrangements. This article discusses the application of these metaphors in the area of neurochemistry, especially NMDA receptors. An important area of drug design is the inhibition of angiotensin II enzyme by the use of losartan. This commercial drug contains a tetrazole moiety that can be modified using the squaryl group to give a semisquarate derivative. These concepts can extend to the semisquarate of ibuprofen. Moreover, a discussion on peptidomimetics regarding the substitution of the peptide bond for squaramide allows for a change in the biological properties due to modification at the peptide bond. Furthermore, the topic on how squaryl metaphors can be exploited primarily by the central 1,3-hydroxyamide sequence to the generation of a novel class of HIV protease inhibitors. Also, squaryl metaphors can be used to develop potential inhibitors of glutathione and novel anti-migraine drugs. The discussion continues on the design of anticancer drugs: in particular, a novel class of metalloproteases, including phosphonates for semisquaramides, leading to squaryl nucleosides. This review concludes with the application of squaryl metaphors in the design of positron emission tomography (PET) and magnetic resonance imaging (MRI) agents towards theranostics. describe the ability of individual functional chemical groups to mimic other moieties [2,3]. KeywordsErlenmeyer rationalised these concepts and categorised isosteres into atoms, ions and molecules based on the valence level of electrons [4]. A further understanding by Friedman led to the term bioisosterism to include all atoms and molecules that fit the broadest definition of isosteres [5]. This approach was independent of whether the drug was an agonist or an antagonist towards biological activity.Moreover, Thornber applied the term bioisosterism to include subunits, groups or molecules that possess physicochemical properties of similar biological effects [6]. Finally, in 1991 Burger widened the definition of bioisosteres to include compounds or groups that possess similar molecular shapes and volumes independent of agonists or antagonists [7]. REVIEW ARTICLE Squaryl KitsonThese bioisosteres would require approximately the same distribution of electrons and give a high probability of generating comparable physical properties such as hydrophobicity [8]. Currently, bioisosterism is one of the most useful tools to the medicinal chemist in rational drug design and in particular regarding the carboxylic acid bioisosteres [9]. The carboxylic acid functional ...

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Biomaterials and emerging anticancer therapeutics: engineering the microenvironment

Cited by 367 publications

References 182 publications

Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel

Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel

Review: Mechanotransduction in ovarian cancer: Shearing into the unknown

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

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