Optical Fibre-Enabled Photoswitching for Localised Activation of an Anti-Cancer Therapeutic Drug

Local activation of an anti-cancer drug when and where needed can improve selectivity and reduce undesirable side effects. Photoswitchable drugs can be selectively switched between active and inactive states by illumination with light; however, the clinical development of these drugs has been restricted by the difficulty in delivering light deep into tissue where needed. Optical fibres have great potential for light delivery in vivo, but their use in facilitating photoswitching in anti-cancer compounds has not yet been explored. In this paper, a photoswitchable chemotherapeutic is switched using an optical fibre, and the cytotoxicity of each state is measured against HCT-116 colorectal cancer cells. The performance of optical-fibre-enabled photoswitching is characterised through its dose response. The UV–Vis spectra confirm light delivered by an optical fibre effectively enables photoswitching. The activated drug is shown to be twice as effective as the inactive drug in causing cancer cell death, characterised using an MTT assay and fluorescent microscopy. This is the first study in which a photoswitchable anti-cancer compound is switched using an optical fibre and demonstrates the feasibility of using optical fibres to activate photoswitchable drugs for potential future clinical applications.

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Controlled pharmacokinetic anti-cancer drug concentration profiles lead to growth inhibition of colorectal cancer cells in a microfluidic device

Lab on a Chip ◽

10.1039/d0lc00419g ◽

2020 ◽

Vol 20 (17) ◽

pp. 3167-3178

Author(s):

Job Komen ◽

Eiko Y. Westerbeek ◽

Ruben W. Kolkman ◽

Julia Roesthuis ◽

Caroline Lievens ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Microfluidic Device ◽

Concentration Profile ◽

Cancer Drug ◽

Concentration Profiles ◽

Anti Cancer ◽

Colorectal Cancer Cells ◽

On Chip

We present a microfluidic device to expose cancer cells to a dynamic, in vivo-like concentration profile of a drug, and quantify efficacy on-chip.

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The Encapsulation of Febuxostat into Emulsomes Strongly Enhances the Cytotoxic Potential of the Drug on HCT 116 Colon Cancer Cells

Pharmaceutics ◽

10.3390/pharmaceutics12100956 ◽

2020 ◽

Vol 12 (10) ◽

pp. 956 ◽

Cited By ~ 1

Author(s):

Usama A. Fahmy ◽

Hibah M. Aldawsari ◽

Shaimaa M. Badr-Eldin ◽

Osama A. A. Ahmed ◽

Nabil A. Alhakamy ◽

...

Keyword(s):

Cancer Cells ◽

Significant Inhibition ◽

Cancer Drug ◽

Cytotoxic Potential ◽

Anti Cancer ◽

Colorectal Cancer Cells ◽

Hct 116 ◽

Hct 116 Cells ◽

New Formulation ◽

Toxic Potential

Febuxostat (FBX) is a drug able to inhibit xanthine oxidase and reduce uric acid production commonly used for the treatment of hyperuricemia in subjects suffering from gout. Several studies have also been directed at its use as anti-cancer drug during the last years, opening a window for its off-label use. In the present study, an optimized formulation in terms of vesicle size and drug release, obtained by encapsulation of FBX into the emulsomes (FBX-EMLs), was evaluated for its cytotoxic potential in human colorectal carcinoma (HCT 116) cells. The optimized FBX-EMLs formula had an improved half maximal inhibitory concentration (IC50), about 4-fold lower, compared to the free drug. The cell cycle analysis showed a significant inhibition of the HCT 116 cells proliferation following FBX-EMLs treatment compared to all the other conditions, with a higher number of cells accumulating on G2/M and pre-G1 phases, paralleled by a significant reduction of cells in G0/G1 and S phases. The optimized formula was also able to significantly increase the percentage of cell population in both early and late stages of apoptosis, characterized by a higher intracellular caspase-3 concentration, as well as percentage of necrotic cells. Lastly, the FBX ability to decrease the mitochondrial membrane potential was enhanced when the drug was delivered into the EMLs. In conclusion, the new formulation of FBX into EMLs improved all the parameters related to the anti-proliferative activity and the toxic potential of the drug towards colorectal cancer cells.

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In Situ Vitrification of Lung Cancer Organoids on a Microwell Array

Micromachines ◽

10.3390/mi12060624 ◽

2021 ◽

Vol 12 (6) ◽

pp. 624

Author(s):

Qiang Liu ◽

Tian Zhao ◽

Xianning Wang ◽

Zhongyao Chen ◽

Yawei Hu ◽

...

Keyword(s):

Lung Cancer ◽

Drug Sensitivity ◽

Simple Procedure ◽

Three Dimensional ◽

Cancer Drug ◽

Microwell Array ◽

Sensitivity Tests ◽

Anti Cancer

Three-dimensional cultured patient-derived cancer organoids (PDOs) represent a powerful tool for anti-cancer drug development due to their similarity to the in vivo tumor tissues. However, the culture and manipulation of PDOs is more difficult than 2D cultured cell lines due to the presence of the culture matrix and the 3D feature of the organoids. In our other study, we established a method for lung cancer organoid (LCO)-based drug sensitivity tests on the superhydrophobic microwell array chip (SMAR-chip). Here, we describe a novel in situ cryopreservation technology on the SMAR-chip to preserve the viability of the organoids for future drug sensitivity tests. We compared two cryopreservation approaches (slow freezing and vitrification) and demonstrated that vitrification performed better at preserving the viability of LCOs. Next, we developed a simple procedure for in situ cryopreservation and thawing of the LCOs on the SMAR-chip. We proved that the on-chip cryopreserved organoids can be recovered successfully and, more importantly, showing similar responses to anti-cancer drugs as the unfrozen controls. This in situ vitrification technology eliminated the harvesting and centrifugation steps in conventional cryopreservation, making the whole freeze–thaw process easier to perform and the preserved LCOs ready to be used for the subsequent drug sensitivity test.

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Prevascularized, Co-Culture Model for Breast Cancer Drug Development

ASME 2012 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2012-80409 ◽

2012 ◽

Author(s):

Lauren Marshall ◽

Isabel Löwstedt ◽

Paul Gatenholm ◽

Joel Berry

Keyword(s):

Breast Cancer ◽

Drug Development ◽

Three Dimensional ◽

Human Tumor ◽

3D Models ◽

Cancer Drug ◽

Cancer Therapies ◽

Anti Cancer

The objective of this study was to create 3D engineered tissue models to accelerate identification of safe and efficacious breast cancer drug therapies. It is expected that this platform will dramatically reduce the time and costs associated with development and regulatory approval of anti-cancer therapies, currently a multi-billion dollar endeavor [1]. Existing two-dimensional (2D) in vitro and in vivo animal studies required for identification of effective cancer therapies account for much of the high costs of anti-cancer medications and health insurance premiums borne by patients, many of whom cannot afford it. An emerging paradigm in pharmaceutical drug development is the use of three-dimensional (3D) cell/biomaterial models that will accurately screen novel therapeutic compounds, repurpose existing compounds and terminate ineffective ones. In particular, identification of effective chemotherapies for breast cancer are anticipated to occur more quickly in 3D in vitro models than 2D in vitro environments and in vivo animal models, neither of which accurately mimic natural human tumor environments [2]. Moreover, these 3D models can be multi-cellular and designed with extracellular matrix (ECM) function and mechanical properties similar to that of natural in vivo cancer environments [3].

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The relevance of therapeutic drug monitoring in plasma and erythrocytes in anti-cancer drug treatment

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm.2004.244 ◽

2004 ◽

Vol 42 (11) ◽

Cited By ~ 8

Author(s):

Herlinde Dumez ◽

Gunther Guetens ◽

Gert De Boeck ◽

Martin S. Highley ◽

Robert A. A. Maes ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Drug Transport ◽

Free Fraction ◽

The Body ◽

Cancer Drug ◽

Therapeutic Drug ◽

Anti Cancer ◽

Plasma Compartment ◽

Made In

AbstractTherapeutic drug monitoring generally focuses on the plasma compartment only. Differentiation between the total plasma concentration and the free fraction (plasma water) has been described for a number of limited drugs. Besides the plasma compartment, blood has also a cellular fraction which has by far the largest theoretical surface and volume for drug transport. It is with anti-cancer drugs that major progress has been made in the study of partition between the largest cellular blood compartment, i.e., erythrocytes, and the plasma compartment. The aim of the present review is to detail the progress made in predicting what a drug does in the body, i.e., pharmacodynamics including toxicity and plasma and/or red blood cell concentration monitoring. Furthermore, techniques generally used in anti-cancer drug monitoring are highlighted. Data for complex Bayesian statistical approaches and population kinetics studies are beyond the scope of this review, since this is generally limited to the plasma compartment only.

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Frontiers in Anti-cancer Drug Discovery: Challenges and Perspectives of Metformin as Anti-angiogenic Add-on Therapy in Glioblastoma

10.20944/preprints202111.0531.v1 ◽

2021 ◽

Author(s):

Laura Guarnaccia ◽

Stefania Elena Navone ◽

Matteo Maria Masseroli ◽

Melissa Balsamo ◽

Manuela Caroli ◽

...

Keyword(s):

Target Therapy ◽

Cancer Drug ◽

Cancer Drug Discovery ◽

Average Survival ◽

Anti Cancer ◽

Tumor Neovascularization ◽

Novel Therapeutic Strategies

Glioblastoma (GBM) is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. GBM shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including GBM. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of the inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss the potential metformin’s antitumoral effects on GBM, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of GBM patients.

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Coherent Raman Scattering Microscopy in Oncology Pharmacokinetic Research

Frontiers in Pharmacology ◽

10.3389/fphar.2021.630167 ◽

2021 ◽

Vol 12 ◽

Author(s):

Junjie Zeng ◽

Wenying Zhao ◽

Shuhua Yue

Keyword(s):

Raman Scattering ◽

High Speed ◽

Cancer Drug ◽

Cancer Drugs ◽

High Speed Imaging ◽

Coherent Raman Scattering ◽

Anti Cancer ◽

Coherent Raman

The high attrition rates of anti-cancer drugs during clinical development remains a bottleneck problem in pharmaceutical industry. This is partially due to the lack of quantitative, selective, and rapid readouts of anti-cancer drug activity in situ with high resolution. Although fluorescence microscopy has been commonly used in oncology pharmacological research, fluorescent labels are often too large in size for small drug molecules, and thus may disturb the function or metabolism of these molecules. Such challenge can be overcome by coherent Raman scattering microscopy, which is capable of chemically selective, highly sensitive, high spatial resolution, and high-speed imaging, without the need of any labeling. Coherent Raman scattering microscopy has tremendously improved the understanding of pharmaceutical materials in the solid state, pharmacokinetics of anti-cancer drugs and nanocarriers in vitro and in vivo. This review focuses on the latest applications of coherent Raman scattering microscopy as a new emerging platform to facilitate oncology pharmacokinetic research.

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The Unique Pharmacometrics of Small Molecule Therapeutic Drug Tracer Imaging for Clinical Oncology

Cancers ◽

10.3390/cancers12092712 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2712

Author(s):

Mark P. S. Dunphy ◽

Nagavarakishore Pillarsetty

Keyword(s):

Small Molecule ◽

Response Assessment ◽

Imaging Biomarkers ◽

Cancer Drug ◽

Therapeutic Drug ◽

Therapeutic Drugs ◽

Tracer Imaging ◽

Tumor Pharmacokinetics ◽

Dosing Strategy

Translational development of radiolabeled analogues or isotopologues of small molecule therapeutic drugs as clinical imaging biomarkers for optimizing patient outcomes in targeted cancer therapy aims to address an urgent and recurring clinical need in therapeutic cancer drug development: drug- and target-specific biomarker assays that can optimize patient selection, dosing strategy, and response assessment. Imaging the in vivo tumor pharmacokinetics and biomolecular pharmacodynamics of small molecule cancer drugs offers patient- and tumor-specific data which are not available from other pharmacometric modalities. This review article examines clinical research with a growing pharmacopoeia of investigational small molecule cancer drug tracers.

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