Dual Enhancement in the Radiosensitivity of Prostate Cancer Through Nanoparticles and Chemotherapeutics

BACKGROUND: Radiotherapy (RT) is an essential component in the treatment regimens for many cancer patients. However, the dose escalation required to improve curative results is hindered due to the normal tissue toxicity that is induced. The introduction of radiosensitizers to RT treatment is an avenue that is currently being explored to overcome this issue. By introducing radiosensitizers into tumor sites, it is possible to preferentially enhance the local dose deposited. Gold nanoparticles (GNPs) are a potential candidate that have shown great promise in increasing the radiosensitivity of cancer cells through an enhancement in DNA damage. Furthermore, docetaxel (DTX) is a chemotherapeutic agent that arrests cells in the G2/M phase of the cell cycle, the phase most sensitive to radiation damage. We hypothesized that by incorporating DTX to GNP-enhanced radiotherapy treatment, we could further improve the radiosensitization experienced by cancer cells. To assess this strategy, we analyzed the radiotherapeutic effects on monolayer cell cultures in vitro, as well as on a mice prostate xenograft model in vivo while using clinically feasible concentrations for both GNPs and DTX. RESULTS: The introduction of DTX to GNP-enhanced radiotherapy further increased the radiotherapeutic effects experienced by cancer cells. A 38% increase in DNA double-strand breaks was observed with the combination of GNP/DTX vs GNP alone after a dose of 2 Gy was administered. In vivo results displayed significant reduction in tumor growth over a 30-day observation period with the treatment of GNP/DTX/RT when compared to GNP/RT after a single 5 Gy dose was given to mice. The treatment strategy also resulted in 100% mice survival, which was not observed for other treatment conditions. CONCLUSIONS: Incorporating DTX to work in unison with GNPs and RT can increase the efficacy of RT treatment. Our study suggests that the treatment strategy could improve tumor control through local dose enhancement. As the concentrations used in this study are clinically feasible, there is potential for this strategy to be translated into clinical settings

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

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

Low-Dose Ionizing Radiation Solid Cancer Risk in Adults : Radiation Hormesis Study Design

Cancer risk at low-dose ionizing radiation has been the subject of great scientific controversy in the past century. The clear majority of national and international radiation protection regulators adopt the linear no-threshold (LNT) model based on the atomic-bomb survivors Life Span Study (LSS) for solid cancer risk assessment. The LNT model assumes a linear relationship between radiation dose and cancer risk including interpolation of high dose values down to zero dose with no ‘safe’ threshold. New scientific evidence in the fields of molecular biology and epidemiology challenge the validity of the LNT model suggesting beneficial effects at low doses of ionizing radiation in a process better known as ‘hormesis’. This paper investigates current evidence for radiation hormesis with respect to solid cancer risks in adults and proposes a modest study design to test the hormesis hypothesis in humans with the potential of using low dose ionizing radiation to reduce solid cancer incidence in a population, if hormesis is proven. Current evidence confirms that hormesis does occur at low dose and low dose rates of low LET ionizing radiation. Every effort should be made from scientists in related fields in order to make the best use of the hormesis phenomenon with the aim of benefiting and protecting the public as the main objectives

A Synergetic Approach Utilizing Nanotechnology, Chemotherapy, and Radiotherapy for Pancreatic Cancer Treatment

The objective of this study was to assess the anticancer effectiveness of gold nanoparticles (GNPs) and lipid-encapsulated docetaxel prodrug (LNPDTX-P) with radiotherapy (RT). The study utilized a co-culture spheroid model comprising MIA PaCa-2 cancer cells and patient-derived cancer-associated fibroblasts (CAF-98) to mimic pancreatic cancer conditions. The spheroids underwent treatment with GNPs (7.5 μg/mL), LNPDTX-P (99 nM of DTX pro-drug), and 2 Gy of RT. Cell viability of the spheroids was evaluated using the CellTiter-Glo 3D assay. At the same time, DNA double-strand breaks (DSBs) were assessed by examining the expression of the DNA damage marker 53BP1 through an immunofluorescence assay. Alt-hough GNPs/RT and RT/LNPDTX-P showed a reduction in spheroid size and an apparent in-crease in DNA DSB damage, the combination of the two nanoparticles, GNPs, and LNPDTX-P, with RT, significantly enhanced the anticancer efficacy, resulting in a 28% decrease in spheroid size and an estimated 39% increase in DNA DSB. The combination of GNPs and LNPDTX-P with RT showed a synergetic effect due to their radiosensitizing properties, improving the ther-apeutic efficacy of each treatment modality alone. This triple modality offers a hopeful strategy to enhance cancer treatment efficacy while reducing adverse effects

In Vitro and In Vivo Synergetic Radiotherapy with Gold Nanoparticles and Docetaxel for Pancreatic Cancer

This research underscores the potential of combining nanotechnology with conventional therapies in cancer treatment, particularly for challenging cases like pancreatic cancer. We aimed to enhance pancreatic cancer treatment by investigating the synergistic effects of gold nanoparticles (GNPs) and docetaxel (DTX) as potential radiosensitizers in radiotherapy (RT) both in vitro and in vivo, utilizing a MIA PaCa-2 monoculture spheroid model and NRG mice subcutaneously implanted with MIA PaCa-2 cells, respectively. Spheroids were treated with GNPs (7.5 μg/mL), DTX (100 nM), and 2 Gy of RT using a 6 MV linear accelerator. In parallel, mice received treatments of GNPs (2 mg/kg), DTX (6 mg/kg), and 5 Gy of RT (6 MV linear accelerator). In vitro results showed that though RT and DTX reduced spheroid size and increased DNA DSBs, the triple combination of DTX/RT/GNPs led to a significant 48% (p = 0.05) decrease in spheroid size and a 45% (p = 0.05) increase in DNA DSBs. In vivo results showed a 20% (p = 0.05) reduction in tumor growth 20 days post-treatment with (GNPs/RT/DTX) and an increase in mice median survival. The triple combination exhibited a synergistic effect, enhancing anticancer efficacy beyond individual treatments, and thus could be employed to improve radiotherapy and potentially reduce adverse effects

Repurposing Antimalarial Pyronaridine as a DNA Repair Inhibitor to Exploit the Full Potential of Gold-Nanoparticle-Mediated Radiation Response

Radiation therapy (RT) is frequently used to locally treat tumors. One of the major issues in RT is normal tissue toxicity; thus, it is necessary to limit dose escalation for enhanced local control in patients that have locally advanced tumors. Integrating radiosensitizing agents such as gold nanoparticles (GNPs) into RT has been shown to greatly increase the cure rate of solid tumors. The objective of this study was to explore the repurposing of an antimalarial drug, pyronaridine (PYD), as a DNA repair inhibitor to further enhance RT/GNP-induced DNA damage in cancerous cell lines. We were able to achieve inhibitory effects of DNA repair due to PYD at 500 nM concentration. Our results show a significant enhancement in DNA double-strand breaks of 42% in HeLa cells treated with PYD/GNP/RT in comparison to GNP/RT alone when irradiated with a dose of 2 Gy. Furthermore, there was a significant reduction in cellular proliferation for both HeLa and HCT-116 irradiated cells with the combined treatment of PYD/GNP/RT. Therefore, the emergence of promising novel concepts introduced in this study could lay the foundation for the transition of this treatment modality into clinical environments

Dual enhancement in the radiosensitivity of prostate cancer through nanoparticles and chemotherapeutics

Abstract Background Radiotherapy (RT) is an essential component in the treatment regimens for many cancer patients. However, the dose escalation required to improve curative results is hindered due to the normal tissue toxicity that is induced. The introduction of radiosensitizers to RT treatment is an avenue that is currently being explored to overcome this issue. By introducing radiosensitizers into tumor sites, it is possible to preferentially enhance the local dose deposited. Gold nanoparticles (GNPs) are a potential candidate that have shown great promise in increasing the radiosensitivity of cancer cells through an enhancement in DNA damage. Furthermore, docetaxel (DTX) is a chemotherapeutic agent that arrests cells in the G2/M phase of the cell cycle, the phase most sensitive to radiation damage. We hypothesized that by incorporating DTX to GNP-enhanced radiotherapy treatment, we could further improve the radiosensitization experienced by cancer cells. To assess this strategy, we analyzed the radiotherapeutic effects on monolayer cell cultures in vitro, as well as on a mice prostate xenograft model in vivo while using clinically feasible concentrations for both GNPs and DTX. Results The introduction of DTX to GNP-enhanced radiotherapy further increased the radiotherapeutic effects experienced by cancer cells. A 38% increase in DNA double-strand breaks was observed with the combination of GNP/DTX vs GNP alone after a dose of 2 Gy was administered. In vivo results displayed significant reduction in tumor growth over a 30-day observation period with the treatment of GNP/DTX/RT when compared to GNP/RT after a single 5 Gy dose was given to mice. The treatment strategy also resulted in 100% mice survival, which was not observed for other treatment conditions. Conclusions Incorporating DTX to work in unison with GNPs and RT can increase the efficacy of RT treatment. Our study suggests that the treatment strategy could improve tumor control through local dose enhancement. As the concentrations used in this study are clinically feasible, there is potential for this strategy to be translated into clinical settings

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

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

Investigation of Nano-Bio Interactions within a Pancreatic Tumor Microenvironment for the Advancement of Nanomedicine in Cancer Treatment

Pancreatic cancer is one of the deadliest types of cancer, with a five-year survival rate of only 10%. Nanotechnology offers a novel perspective to treat such deadly cancers through their incorporation into radiotherapy and chemotherapy. However, the interaction of nanoparticles (NPs) with cancer cells and with other major cell types within the pancreatic tumor microenvironment (TME) is yet to be understood. Therefore, our goal is to shed light on the dynamics of NPs within a TME of pancreatic origin. In addition to cancer cells, normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) were examined in this study due to their important yet opposite roles of suppressing tumor growth and promoting tumor growth, respectively. Gold nanoparticles were used as the model NP system due to their biocompatibility and physical and chemical proprieties, and their dynamics were studied both quantitatively and qualitatively in vitro and in vivo. The in vitro studies revealed that both cancer cells and CAFs take up 50% more NPs compared to NFs. Most importantly, they all managed to retain 70–80% of NPs over a 24-h time period. Uptake and retention of NPs within an in vivo environment was also consistent with in vitro results. This study shows the paradigm-changing potential of NPs to combat the disease.Medicine, Faculty ofScience, Irving K. Barber Faculty of (Okanagan)Non UBCComputer Science, Mathematics, Physics and Statistics, Department of (Okanagan)Pathology and Laboratory Medicine, Department ofReviewedFacultyResearche

Nanotechnology Driven Cancer Chemoradiation: Exploiting the Full Potential of Radiotherapy with a Unique Combination of Gold Nanoparticles and Bleomycin

One of the major issues in current radiotherapy (RT) is the associated normal tissue toxicity. Enhancement of the RT effect with novel radiosensitizers can address this need. In this study, gold nanoparticles (GNPs) and bleomycin (BLM) were used as a unique combination of radiosensitizers. GNPs offer a two-fold promise as a delivery vehicle for BLM and as a radiosensitizing agent. In this study, GNPs were functionalized and complexed with BLM using a gold-thiol bond (denoted GNP-BLM). Our results show that there was a 40% and 10% decrease in cell growth with GNP-BLM vs. free BLM for the MIA PaCa-2 and PC-3 cell lines, respectively. Testing the GNP-BLM platform with RT showed an 84% and 13% reduction in cell growth in MIA PaCa-2 cells treated with GNP-BLM and GNPs, respectively. Similar results were seen with PC-3 cells. The efficacy of this approach was verified by mapping DNA double-strand breaks (DSBs) as well. Therefore, this proposed incorporation of nanomedicine with RT is promising in achieving a significantly higher therapeutic ratio which is necessary to make a paradigm change to the current clinical approach