Can intracellular drug delivery using hyaluronic acid functionalised pH-sensitive liposomes overcome gemcitabine resistance in pancreatic cancer?

Tang, Mingtan; Svirskis, Darren; Leung, Euphemia; Kanamala, Manju; Wang, Hongbo; Wu, Zimei

doi:10.1016/j.jconrel.2019.05.018

Cited by 56 publications

(19 citation statements)

References 58 publications

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“…All animal experiments were approved by the department of laboratory animals of Central South University. MDA-MB-231 cells (6 × 10 6 /mouse) with or without silencing eEF-2K were injected subcutaneously into the right flank of 6-week-old female nude mice 46 . There were six mice in each group.…”

Section: Methodsmentioning

confidence: 99%

Combined treatment of mitoxantrone sensitizes breast cancer cells to rapalogs through blocking eEF-2K-mediated activation of Akt and autophagy

Guan

Jiang

et al. 2020

Cell Death Dis

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Oncogenic activation of the mTOR signaling pathway occurs frequently in tumor cells and contributes to the devastating features of cancer, including breast cancer. mTOR inhibitors rapalogs are promising anticancer agents in clinical trials; however, rapalogs resistance remains an unresolved clinical challenge. Therefore, understanding the mechanisms by which cells become resistant to rapalogs may guide the development of successful mTOR-targeted cancer therapy. In this study, we found that eEF-2K, which is overexpressed in cancer cells and is required for survival of stressed cells, was involved in the negative-feedback activation of Akt and cytoprotective autophagy induction in breast cancer cells in response to mTOR inhibitors. Therefore, disruption of eEF-2K simultaneously abrogates the two critical resistance signaling pathways, sensitizing breast cancer cells to rapalogs. Importantly, we identified mitoxantrone, an admitted anticancer drug for a wide range of tumors, as a potential inhibitor of eEF-2K via a structure-based virtual screening strategy. We further demonstrated that mitoxantrone binds to eEF-2K and inhibits its activity, and the combination treatment of mitoxantrone and mTOR inhibitor resulted in significant synergistic cytotoxicity in breast cancer. In conclusion, we report that eEF-2K contributes to the activation of resistance signaling pathways of mTOR inhibitor, suggesting a novel strategy to enhance mTOR-targeted cancer therapy through combining mitoxantrone, an eEF-2K inhibitor.

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Section: Methodsmentioning

confidence: 99%

Combined treatment of mitoxantrone sensitizes breast cancer cells to rapalogs through blocking eEF-2K-mediated activation of Akt and autophagy

Guan

Jiang

et al. 2020

Cell Death Dis

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“…[177,178] Whilst the pH, temperature, and enzyme alterations at the tumor microenvironment act as initiators for the drug release from liposomes, internally induced release only, might not circumvent drug resistance. [179] Externally induced drug release from liposomes includes light and heat producing methods, known as photodynamic therapy (PDT). [180] PDT in combination with magnetic particles presents imaging applications.…”

Section: Tumor Targeted Liposomesmentioning

confidence: 99%

Section: Drug Delivery Systems and Droplet‐based Technologymentioning

confidence: 99%

Droplet Microfluidics for Tumor Drug‐Related Studies and Programmable Artificial Cells

Dimitriou

Tornillo

et al. 2021

Global Challenges

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(1 of 17)www.global-challenges.com robotics, have promoted the use of in vitro tumor models in high-throughput drug screenings. [2,3] High-throughput screens for anticancer drugs have been, for a long time, limited to 2D culture of tumor cells, grown as a monolayer on the bottom of a well of a microtiter plate. Compared to 2D cell cultures, 3D culture systems can more faithfully model cell-cell interactions, matrix deposition and tumor microenvironments, including more physiological flow conditions, oxygen and nutrient gradients. [4] Therefore, 3D cultures have recently begun to be incorporated into high-throughput drug screenings, with the aim of better predicting drug efficacy and improving the prioritization of candidate drugs for further in vivo testing in animals.Because of the relatively simple, reproducible, amenable to automation and scalable culture methods, single-cell type and mixed-cell tumor spheroids, known as multicellular tumor spheroids (MCTSs), are used as 3D models. [5] There exists a broad range of natural hydrogels that are compatible with microfluidics, and which provide cancer cells with mechanical cues and adhesion sites to proliferate and grow into MCTSs. [6] With the aid of microfluidics and development of more complex 3D tumor models, [7,8] and the large-scale production of tumor spheroids in hydrogels, the number of compounds that could progress to in vivo testing could be restricted, thus reducing the number of animals needed for preclinical studies.Tumor-targeted drug delivery using microparticles and liposomes is beneficial compared to conventional drug administration. This is because encapsulated drug dosages can be controlled, healthy tissues can remain unharmed during treatment and drug resistance of cancer cells may be reduced/ prevented. [9,10] Microparticles and liposomes can be tailored to specifically target tumor sites using molecular conjugates, while avoiding toxic effects. [9] This review discusses the application of droplet-based microfluidic technologies for the development of accurate in vitro tumor models and improved cancer treatment strategies. The first part of the review centers around the generation of MCTSs in natural hydrogels for a better recapitulation of the in vivo tumor microenvironment. The second section is focused on microparticle and liposomal production for tumor-targeted drug delivery. Emphases is given to microfluidic methodologies for the production of these systems, and the potential of compartmentalized artificial cells as anticancer drug screening platforms.

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“…This coating layer not only serves the purpose of enhancing their biocompatibility but also provides an opportunity to augment these particles with additional theranostic substances 20 or exclusively therapeutic substances such as chemotherapeutics like gemcitabine, which has been shown to be eminently augmented in efficiency by intracellular delivery. 21 In experimental settings, this beneficial synergistic effect has shown a particularly promising perspective in pancreatic cancer therapy regarding precise tumor targeting of chemotherapeutic agents in terms of augmented accumulation of the tumor site 9 and, thereby, inevitably reducing chemotherapeutic dosage by increasing treatment efficiency. 22 Extensive research on the applicability of MFH treatment on various cancer types led to the attribution of MFH with promising properties in terms of efficiency and applicability.…”

Section: Introductionmentioning

confidence: 99%

“…delivery. 21,57 Based on this, a favorable synergistic antitumor characteristic of intracellular MFH combined with intracellular drug delivery can be expected as MFH has already demonstrated a promising perspective when combined with a therapeutic agent in the experimental treatment of triple-negative breast cancer. 58 Future investigations exploiting this synergistic effect need to be employed to improve treatment efficiency.…”

mentioning

confidence: 99%

Magnetic Fluid Hyperthermia as Treatment Option for Pancreatic Cancer Cells and Pancreatic Cancer Organoids

Palzer

Mues

Goerg

et al. 2021

IJN

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Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a cancer with a meager prognosis due to its chemotherapy resistance. A new treatment method may be magnetic fluid hyperthermia (MFH). Magnetoliposomes (ML), consisting of superparamagnetic iron oxide nanoparticles (SPION) stabilized with a phospholipid-bilayer, are exposed to an alternating magnetic field (AMF) to generate heat. To optimize this therapy, we investigated the effects of MFH on human PDAC cell lines and 3D organoid cultures. Material and Methods: ML cytotoxicity was tested on Mia PaCa-2 and PANC-1 cells and on PDAC 3D organoid cultures, generated from resected tissue of patients. The MFH was achieved by AMF application with an amplitude of 40-47 kA/m and a frequency of 270 kHz. The MFH effect on the cell viability of the cell lines and the organoid cultures was investigated at two different time points. Clonogenic assays evaluated the impairment of colony formation. Altering ML set-ups addressed differences arising from intra-vs extracellular ML locations. Results: Mia PaCa-2 and PANC-1 cells showed no cytotoxic effects at ML concentrations up to 300 µg(Fe)/mL and 225 µg(Fe)/mL, respectively. ML at a concentration of 225 µg(Fe)/mL were also non-toxic for PDAC organoid cultures. MFH treatment using exclusively extracellular ML presented the highest impact on cell viability. Clonogenic assays demonstrated remarkable impairment as long-term outcome in MFH-treated PDAC cell lines. Additionally, we successfully treated PDAC organoids with extracellular ML-derived MFH, resulting in notably reduced cell viabilities 2h and 24 h post treatment. Still, PDAC organoids seem to partly recover from MFH after 24 h as opposed to conventional 2D-cultures. Conclusion:Treatment with MFH strongly diminished pancreatic cancer cell viability in vitro, making it a promising treatment strategy. As organoids resemble the more advanced in vivo conditions better than conventional 2D cell lines, our organoid model holds great potential for further investigations.

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Can intracellular drug delivery using hyaluronic acid functionalised pH-sensitive liposomes overcome gemcitabine resistance in pancreatic cancer?

Cited by 56 publications

References 58 publications

Combined treatment of mitoxantrone sensitizes breast cancer cells to rapalogs through blocking eEF-2K-mediated activation of Akt and autophagy

Combined treatment of mitoxantrone sensitizes breast cancer cells to rapalogs through blocking eEF-2K-mediated activation of Akt and autophagy

Droplet Microfluidics for Tumor Drug‐Related Studies and Programmable Artificial Cells

Magnetic Fluid Hyperthermia as Treatment Option for Pancreatic Cancer Cells and Pancreatic Cancer Organoids

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