Phase I/II docetaxel plus concurrent hyperfractionated radiotherapy in locally advanced unresectable head and neck cancer (TAX.ES1.102 study)

Barnadas, Agustí; Mesı́a, Ricard; Majem, Margarita; Galiana, R.; López‐Pousa, Antonio; Vega, José M.; Margelı́, Mireia; Valentí, V.; Anglada, Lluís; Lloansí, Ariadna; Arellano, Antonio

doi:10.1007/s12094-011-0650-9

Cited by 4 publications

(2 citation statements)

References 26 publications

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“…[40][41][42][43] It has also been investigated as a radiosensitizer in several Phase II clinical trials. [44][45][46][47][48] (Figure 8b(ii)). For example, 50nM DTX is sufficient to cause a 'mitotic catastrophe': the cell cannot enter anaphase and remains locked in mitosis or becomes multinucleate as the nuclear envelope reforms around the multiple asters (Figure 8b(iii)).…”

Section: 1 Radiosensitization Mechanisms Of Gold Nanoparticlesmentioning

confidence: 99%

Modulation of nanoparticle uptake, intracellular distribution, and retention with docetaxel to enhance radiotherapy

Bannister

Bromma

Sung

et al. 2019

The British Journal of Radiology

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Objective: One of the major issues in current radiotherapy (RT) is the normal tissue toxicity. A smart combination of agents within the tumor would allow lowering the RT dose required while minimizing the damage to healthy tissue surrounding the tumor. We chose gold nanoparticles (GNPs) and docetaxel (DTX) as our choice of two radiosensitizing agents. They have a different mechanism of action which could lead to a synergistic effect. Our first goal was to assess the variation in GNP uptake, distribution, and retention in the presence of DTX. Our second goal was to assess the therapeutic results of the triple combination, RT/GNPs/DTX. Methods: We used HeLa and MDA-MB-231 cells for our study. Cells were incubated with GNPs (0.2 nM) in the absence and presence of DTX (50 nM) for 24 h to determine uptake, distribution, and retention of NPs. For RT experiments, treated cells were given a 2 Gy dose of 6 MV photons using a linear accelerator. Results: Concurrent treatment of DTX and GNPs resulted in over 85% retention of GNPs in tumor cells. DTX treatment also forced GNPs to be closer to the most important target, the nucleus, resulting in a decrease in cell survival and increase in DNA damage with the triple combination of RT/ GNPs/DTX vs RT/DTX. Our experimental therapeutic results were supported by Monte Carlo simulations. Conclusion: The ability to not only trap GNPs at clinically feasible doses but also to retain them within the cells could lead to meaningful fractionated treatments in future combined cancer therapy. Furthermore, the suggested triple combination of RT/GNPs/DTX may allow lowering the RT dose to spare surrounding healthy tissue. Advances in knowledge: This is the first study to show intracellular GNP transport disruption by DTX, and its advantage in radiosensitization.

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Section: 1 Radiosensitization Mechanisms Of Gold Nanoparticlesmentioning

confidence: 99%

Modulation of nanoparticle uptake, intracellular distribution, and retention with docetaxel to enhance radiotherapy

Bannister

Bromma

Sung

et al. 2019

The British Journal of Radiology

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“…Despite its toxicity, free DTX has already shown remarkable radiosensitization effects in several clinical trials [ 44 , 45 , 46 , 47 , 48 , 49 ]. Hence, our results are very promising, as they show the potential of using the LNP DTX-1 and LNP DTX-2 formulations instead of free DTX as potential radiosensitizers, as they deliver similar synchronizations of cancer cells in the radiosensitive G2/M phases and similar GNP uptake and retention.…”

Section: Resultsmentioning

confidence: 99%

Lipid-Nanoparticle-Mediated Delivery of Docetaxel Prodrug for Exploiting Full Potential of Gold Nanoparticles in the Treatment of Pancreatic Cancer

Alhussan

Jackson

Eaton

et al. 2022

Cancers

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Current chemoradiation therapy suffers from normal tissue toxicity. Thus, we are proposing incorporating gold nanoparticles (GNPs) and docetaxel (DTX), as they have shown very promising synergetic radiosensitization effects. Here, we explored the effect of a DTX prodrug encapsulated in lipid nanoparticles (LNPDTX-P) on GNP uptake in pancreatic cancer models in vitro and in vivo. For the in vitro experiment, a pancreatic cancer cell line, MIA PaCa-2, was cultured and dosed with 1 nM GNPs and 45 nM free DTX or an equivalent dose of LNPDTX-P. For the in vivo experiment, MIA PaCa-2 cells were implanted subcutaneously in NRG mice, and the mice were dosed with 2 mg/kg of GNPs and 6 mg/kg of DTX or an equivalent dose of LNPDTX-P. The results show that LNPDTX-P-treated tumour samples had double the amount GNPs compared to control samples, both in vitro and in vivo. The results are very promising, as LNPDTX-P have superior targeting of tumour tissues compared to free DTX due to their nanosize and their ability to be functionalized. Because of their minimal toxicity to normal tissues, both GNPs and LNPDTX-P could be ideal radiosensitization candidates in radiotherapy and would produce very promising synergistic therapeutic outcomes.

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Lipid Nanoparticle Mediated Delivery of Docetaxel Prodrug for Exploiting Full Potential of Gold Radiosensitizers in the Treatment of Pancreatic Cancer.

Alhussan

Jackson

Eaton

et al. 2022

Preprint

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Background Pancreatic cancer is one of the leading causes of cancer deaths worldwide. Current chemoradiation therapy suffers from normal tissue toxicity. To overcome this problem, we are proposing incorporating nanoparticles as radiosensitizers and as drug delivery vehicles into current chemoradiation regimes. Gold nanoparticles (GNPs) and Docetaxel (DTX) have shown very promising synergetic radiosensitization effects despite DTX toxicity to normal tissues. Here, we explored the effect of DTX prodrug encapsulated in lipid nanoparticles (LNPDTX−P) on GNP uptake in pancreatic cancer models in vitro and in vivo. Methods For the in vitro experiment, pancreatic cancer cell line, MIA PaCa-2, were cultured and dosed with 7.5 µg/mL of GNPs (of ~ 11 nm in diameter functionalized with PEG and RGD peptide) and with 45 nM of free DTX or equivalent dose of LNPDTX−P. For the in vivo experiment, MIA PaCa-2 were implanted subcutaneously in NRG mice and the mice were dosed with 2 mg/kg of GNPs and 6 mg/kg of DTX or equivalent dose of LNPDTX−P. GNPs content in mice and in cells were measured using Inductively Coupled Plasma–Mass Spectrometry (ICP–MS). Results The results show that LNPDTX−P treated tumour samples have no less than 191% increase in GNPs uptake compared to control samples in both in vitro and in vivo. The results also show that LNPDTX−P treated tumour samples have retained over 160% of GNPs compared to control samples in both in vitro and in vivo. No significant difference was found in GNP uptake or retention between free DTX and LNPDTX−P in tumour treated samples in vivo. Conclusions The results are very promising as LNPDTX−P have superior targeting of tumour tissues compared to free DTX due to their nano size and their ability to be functionalized. Because of their minimal toxicity to normal tissues, both GNPs and LNPDTX−P can be ideal radiosensitization candidates in radiotherapy and would produce very promising synergistic therapeutic outcome. Current radiotherapy treatments can hugely benefit from the effects of these two radiosensitizers boosting the radiation dose to the tumour while reducing the normal tissue dose. This in return will improve patient outcome and quality of life.

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Phase I/II docetaxel plus concurrent hyperfractionated radiotherapy in locally advanced unresectable head and neck cancer (TAX.ES1.102 study)

Abstract: Weekly docetaxel+hyperfractionation radiotherapy is active but with high toxicity rates and, hence, this treatment regimen would be difficult to justify.

Cited by 4 publications

References 26 publications

Modulation of nanoparticle uptake, intracellular distribution, and retention with docetaxel to enhance radiotherapy

Modulation of nanoparticle uptake, intracellular distribution, and retention with docetaxel to enhance radiotherapy

Lipid-Nanoparticle-Mediated Delivery of Docetaxel Prodrug for Exploiting Full Potential of Gold Nanoparticles in the Treatment of Pancreatic Cancer

Lipid Nanoparticle Mediated Delivery of Docetaxel Prodrug for Exploiting Full Potential of Gold Radiosensitizers in the Treatment of Pancreatic Cancer.

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