Docetaxel-Mediated Uptake and Retention of Gold Nanoparticles in Tumor Cells and in Cancer-Associated Fibroblasts

Alhussan, Abdulaziz; Bromma, Kyle; Monica, Mesa; Beckham, Wayne; Alexander, Abraham; Howard, Perry L.; Chithrani, Devika B.

doi:10.3390/cancers13133157

Cited by 18 publications

(23 citation statements)

References 49 publications

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“…Labelled cell lines were assessed by flow cytometry to measure percent expression and median fluorescent intensity of the FITC signal in monocultures of MIA PaCa-2 and CAF98, vs. in co-cultures of MIA PaCa-2 and CAF98, Figure 3 D, which shows no effect of the co-culture on the GNP uptake of either cell lines. However, the results show that the uptake of GNPs in CAFs is over three times higher than that of cancer cells in both monoculture and co-culture, which is in agreement with our previous experiments that were done in monoculture [ 21 , 22 ]. This is an important observation that might open the door for targeting not only cancer cells but also CAFs using GNPs.…”

Section: Resultssupporting

confidence: 92%

“…Furthermore, GNPs were added to the RT protocol since GNPs are successful radiosensitizing agents. There is evidence that GNPs and low concentrations of anticancer drugs can sensitize cancer cells to radiotherapy in an in vitro monoculture environment [ 18 , 19 , 20 , 21 , 22 ]. GNPs enter cells primarily via receptor-mediated endocytosis (RME) [ 23 , 24 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

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Potential of Gold Nanoparticles in Current Radiotherapy Using a Co-Culture Model of Cancer Cells and Cancer Associated Fibroblasts

Alhussan

Palmerley

Smazynski³

et al. 2022

Cancers

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Many cancer therapeutics are tested in vitro using only tumour cells. However, the tumour promoting effect of cancer associated fibroblasts (CAFs) within the tumour microenvironment (TME) is thought to reduce cancer therapeutics’ efficacy. We have chosen pancreatic ductal adenocarcinoma (PDAC) as our tumor model. Our goal is to create a co-culture of CAFs and tumour cells to model the interaction between cancer and stromal cells in the TME and allow for better testing of therapeutic combinations. To test the proposed co-culture model, a gold nanoparticle (GNP) mediated-radiation response was used. Cells were grown in co-culture with different ratios of CAFs to cancer cells. MIA PaCa-2 was used as our PDAC cancer cell line. Co-cultured cells were treated with 2 Gy of radiation following GNP incubation. DNA damage and cell proliferation were examined to assess the combined effect of radiation and GNPs. Cancer cells in co-culture exhibited up to a 23% decrease in DNA double strand breaks (DSB) and up to a 35% increase in proliferation compared to monocultures. GNP/Radiotherapy (RT) induced up to a 25% increase in DNA DSBs and up to a 15% decrease in proliferation compared to RT alone in both monocultured and co-cultured cells. The observed resistance in the co-culture system may be attributed to the role of CAFs in supporting cancer cells. Moreover, we were able to reduce the activity of CAFs using GNPs during radiation treatment. Indeed, CAFs internalize a significantly higher number of GNPs, which may have led to the reduction in their activity. One reason experimental therapeutics fail in clinical trials relates to limitations in the pre-clinical models that lack a true representation of the TME. We have demonstrated a co-culture platform to test GNP/RT in a clinically relevant environment.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Potential of Gold Nanoparticles in Current Radiotherapy Using a Co-Culture Model of Cancer Cells and Cancer Associated Fibroblasts

Alhussan

Palmerley

Smazynski³

et al. 2022

Cancers

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“…These treated cells cannot enter anaphase and remain locked in mitosis and become multinucleate as the nuclear envelope reforms around the multiple asters with DTX dose under 50 nM 39 . These results are consistent with other studies that reported a signi cant increase in GNP uptake with the treatment of DTX in multiple different cell lines 19,39 .…”

Section: Docetaxel Prodrug Lipid Nanoparticles Effects In Vitrosupporting

confidence: 93%

“…Because of this, DTX has been used as a radiosensitizer in several clinical trials [17][18] . Moreover, the defect in the function of MTs leads to signi cant accumulation of GNPs within cells over time 19 . Hence, the coupling of these two radiosensitizers with RT could result in a synergistic therapeutic outcome due to their complementary mechanism of action.…”

mentioning

confidence: 99%

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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“…As a result, the combination of low dose DTX and GNPs has been explored as an option for combined therapy in two-dimensional (2D) monolayers and in three-dimensional (3D) spheroids, like those found in Fig. 1 26 , 27 . It has been shown that non-toxic doses of DTX can increase the uptake of GNPs, and that the addition of DTX to a GNP treatment leads to a synergistic effect when combined with RT, in monolayer 28 .…”

Section: Introductionmentioning

confidence: 99%

Enhancing nanoparticle accumulation in two dimensional, three dimensional, and xenograft mouse cancer cell models in the presence of docetaxel

Bromma

Santos²,

Barta

et al. 2022

Sci Rep

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Recent clinical trials show docetaxel (DTX), given in conjunction with radiation therapy (RT) and androgen suppression, improves survival in high-risk prostate cancer. Addition of gold nanoparticles (GNPs) to this current DTX/RT protocol is expected to further improve therapeutic benefits remarkably. However, the foundation for the triple combination of RT, DTX, and GNPs must be elucidated to ensure quicker facilitation to the clinic. In this study, we explored the use of low concentrations of DTX combined with GNPs in two prostate cancer cell lines in a two-dimensional monolayer, a three-dimensional spheroid, and a mouse xenograft model. When used together, DTX and GNPs induced a nearly identical relative increase in uptake of gold in both the spheroid model and the mouse xenograft, which saw a 130% and 126% increase respectively after 24 h, showcasing the benefit of using spheroids as an in vitro model to better optimize in vivo experiments. Further, the benefits of using low concentrations of DTX combined with GNPs extended for over 72 h, allowing for less frequency in dosing when translating to the clinic. Overall, these results highlight the benefits of using DTX combined with GNPs and lays the groundwork for the translation of the triple combination of RT, GNPs, and DTX to the clinic.

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Docetaxel-Mediated Uptake and Retention of Gold Nanoparticles in Tumor Cells and in Cancer-Associated Fibroblasts

Cited by 18 publications

References 49 publications

Potential of Gold Nanoparticles in Current Radiotherapy Using a Co-Culture Model of Cancer Cells and Cancer Associated Fibroblasts

Potential of Gold Nanoparticles in Current Radiotherapy Using a Co-Culture Model of Cancer Cells and Cancer Associated Fibroblasts

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

Enhancing nanoparticle accumulation in two dimensional, three dimensional, and xenograft mouse cancer cell models in the presence of docetaxel

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