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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.

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.

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.

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.

Simple Summary Currently, radiotherapy and chemotherapy are the most commonly used options, in addition to surgery, to treat cancer. There has been tremendous progress in interfacing nanotechnology to current cancer therapeutic protocols. For example, nanoparticles are used as drug carriers in chemotherapy and as radiation dose enhancers in radiotherapy. However, most of the work to date has been focused on tumor cells. To make significant progress in this field, we need to consider the tumor microenvironment, especially cancer-associated fibroblast cells that promote tumor growth. Our study shows the potential of targeting both tumor cells and cancer-associated fibroblasts to reap the full benefits of cancer nanomedicine. Abstract Due to recent advances in nanotechnology, the application of nanoparticles (NPs) in cancer therapy has become a leading area in cancer research. Despite the importance of cancer-associated fibroblasts (CAFs) in creating an optimal niche for tumor cells to grow extensively, most of the work has been focused on tumor cells. Therefore, to effectively use NPs for therapeutic purposes, it is important to elucidate the extent of NP uptake and retention in tumor cells and CAFs. Three tumor cell lines and three CAF cell lines were studied using gold NPs (GNPs) as a model NP system. We found a seven-fold increase in NP uptake in CAFs compared to tumor cells. The retention percentage of NPs was three-fold higher in tumor cells as compared to CAFs. Furthermore, NP uptake and retention were significantly enhanced using a 50 nM concentration of docetaxel (DTX). NP uptake was improved by a factor of three in tumor cells and a factor of two in CAFs, while the retention of NPs was two-fold higher in tumor cells compared to CAFs, 72 h post-treatment with DTX. However, the quantity of NPs in CAFs was still three-fold higher compared to tumor cells. Our quantitative data were supported by qualitative imaging data. We believe that targeting of NPs in the presence of DTX is a very promising approach to accumulate a higher percentage of NPs and maintain a longer retention in both tumor cells and CAFs for achieving the full therapeutic potential of cancer nanotechnology.

Optimizing the interface between nanoparticles (NPs) and the biological environment at various levels should be considered for improving delivery of NPs to the target tumor area. For NPs to be successfully delivered to cancer cells, NPs needs to be functionalized for circulation through the blood vessels. In this study, accumulation of Polyethylene Glycol (PEG) functionalized gold nanoparticles (GNPs) was first tested using in vitro monolayer cells and multilayer cell models prior to in vivo models. A diameter of 10 nm sized GNP was selected for this study for sufficient penetration through tumor tissue. The surfaces of the GNPs were modified with PEG molecules, to improve circulation time by reducing non-specific uptake by the reticuloendothelial system (RES) in animal models, and with a peptide containing integrin binding domain, RGD (arginyl-glycyl-aspartic acid), to improve internalization at the cellular level. A 10–12% accumulation of the injected GNP dose within the tumor was observed in vivo and the GNPs remained within the tumor tissue up to 72 h. This study suggests an in vitro platform for optimizing the accumulation of NP complexes in cells and tissue structures before testing them in animal models. Higher accumulation within the tumor in vivo upon surface modification is a promising outcome for future applications where GNPs can be used for drug delivery and radiation therapy.

Nanoparticles (NPs) can be used to overcome the side effects of poor distribution of anticancer drugs. Among other NPs, colloidal gold nanoparticles (GNPs) offer the possibility of transporting major quantities of drugs due to their large surface-to-volume ratio. This is while confining these anticancer drugs as closely as possible to their biological targets through passive and active targeting, thus ensuring limited harmful systemic distribution. In this study, we chose to use bleomycin (BLM) as the anticancer drug due to its limited therapeutic efficiency (harmful side effects). BLM was conjugated onto GNPs through a thiol bond. The effectiveness of the chemotherapeutic drug, BLM, is observed by visualizing DNA double strand breaks and by calculating the survival fraction. The action of the drug (where the drug takes effect) is known to be in the nucleus, and our experiments have shown that some of the GNPs carrying BLM were present in the nucleus. The use of GNPs to deliver BLM increased the delivery and therapeutic efficacy of the drug. Having a better control over delivery of anticancer drugs using GNPs will establish a more successful NP-based platform for a combined therapeutic approach. This is due to the fact that GNPs can also be used as radiation dose enhancers in cancer research.

International audience; This roadmap outlines the potential roles of metallic nanoparticles (MNPs) in the field of radiation therapy. MNPs made up of a wide range of materials (from Titanium, Z = 22, to Bismuth, Z = 83) and a similarly wide spectrum of potential clinical applications, including diagnostic, therapeutic (radiation dose enhancers, hyperthermia inducers, drug delivery vehicles, vaccine adjuvants, photosensitizers, enhancers of immunotherapy) and theranostic (combining both diagnostic and therapeutic), are being fabricated and evaluated. This roadmap covers contributions from experts in these topics summarizing their view of the current status and challenges, as well as expected advancements in technology to address these challenges.

Successful integration of nanotechnology into the current paradigm of cancer therapy requires proper understanding of the interface between nanoparticles (NPs) and cancer cells, as well as other key components within the tumor microenvironment (TME), such as normal fibroblasts (FBs) and cancer-associated FBs (CAFs). So far, much focus has been on cancer cells, but FBs and CAFs also play a critical role: FBs suppress the tumor growth while CAFs promote it. It is not yet known how NPs interact with FBs and CAFs compared to cancer cells. Hence, our goal was to elucidate the extent of NP uptake, retention, and toxicity in cancer cells, FBs, and CAFs to further understand the fate of NPs in a real tumor-like environment. The outcome of this would guide designing of NP-based delivery systems to fully exploit the TME for a better therapeutic outcome. We used gold nanoparticles as our model NP system due to their numerous applications in cancer therapy, including radiotherapy and chemotherapy. A cervical cancer cell line, HeLa, and a triple-negative breast cancer cell line, MDA-MB-231 were chosen as cancer cell lines. For this study, a clinically feasible 0.2 nM concentration of GNPs was employed. According to our results, the cancer cells and CAFs had over 25- and 10-fold higher NP uptake per unit cell volume compared to FBs, respectively. Further, the cancer cells and CAFs had over 30% higher NP retention compared to FBs. There was no observed significant toxicity due to GNPs in all the cell lines studied. Higher uptake and retention of NPs in cancer cells and CAFs vs FBs is very important in promoting NP-based applications in cancer therapy. Our results show potential in modulating uptake and retention of GNPs among key components of TME, in an effort to develop NP-based strategies to suppress the tumor growth. An ideal NP-based platform would eradicate tumor cells, protect FBs, and deactivate CAFs. Therefore, this study lays a road map to exploit the TME for the advancement of “smart” nanomedicines that would constitute the next generation of cancer therapeutics.

One of the major issues in cancer radiotherapy (RT) is normal tissue toxicity. Introduction of radiosensitizers like gold nanoparticles (GNPs) into cancer cells to enhance the local RT dose has been tested successfully. However, it is not known how GNPs interact with other stromal cells such as normal fibroblasts (FBs) and cancer associated fibroblasts (CAFs) within the tumour microenvironment. It is known that FBs turn into CAFs to promote tumour growth. Hence, we used FBs and CAFs along with HeLa (our cancer cell line) to evaluate the differences in GNP uptake and resulting radiation induced damage to elucidate the GNP-mediated therapeutic effect in RT. The CAFs had the largest uptake of the GNPs per cell, with on average 265% relative to HeLa while FBs had only 7.55% the uptake of HeLa and 2.87% the uptake of CAFs. This translated to increases in 53BP1-related DNA damage foci in CAFs (13.5%) and HeLa (9.8%) compared to FBs (8.8%) with RT treatment. This difference in DNA damage due to selective targeting of cancer associated cells over normal cells may allow GNPs to be an effective tool in future cancer RT to battle normal tissue toxicity while improving local RT dose to the tumour.

Nanoparticles (NPs) have shown promise in both radiotherapy and chemotherapy. NPs are mainly transported along cellular microtubules (MTs). Docetaxel (DTX) is a commonly used chemotherapeutic drug that can manipulate the cellular MT network to maximize its clinical benefit. However, the effect of DTX on NP behaviour has not yet been fully elucidated. We used gold NPs of diameters 15 and 50 nm at a concentration of 0.2 nM to investigate the size dependence of NP behaviour. Meanwhile, DTX concentrations of 0, 10 and 50 nM were used to uphold clinical relevance. Our study reveals that a concentration of 50 nM DTX increased NP uptake by ~50% and their retention by ~90% compared to cells treated with 0 and 10 nM DTX. Smaller NPs had a 20-fold higher uptake in cells treated with 50 nM DTX vs. 0 and 10 nM DTX. With the treatment of 50 nm DTX, the cells became more spherical in shape, and NPs were redistributed closer to the nucleus. A significant increase in NP uptake and retention along with their intracellular distribution closer to the nucleus with 50 nM DTX could be exploited to target a higher dose to the most important target, the nucleus in both radiotherapy and chemotherapy.

Background The combined use of radiation therapy and chemotherapy is commonly being used in cancer treatment. The side effects of the treatment can be further minimized through targeted delivery of anticancer drugs and local enhancement of the radiation dose. Gold nanoparticles (GNPs) can play a significant role in this regard since GNPs can be used as radiation dose enhancers and anticancer drug carriers. Anticancer drug, bleomycin, was chosen as the model drug, since it could be easily conjugated onto GNPs through the gold–thiol bond. Methods Gold nanoparticles of size 10 nm were synthesized using the citrate reduction method. The surface of The GNPs was modified with a peptide sequence (CKKKKKKGGRGDMFG) containing the RGD domain and anticancer drug, bleomycin. Human breast cancer cells (MDA-MB-231) were incubated with 0.3 nM concentration of GNP–drug complex for 16 h prior to irradiation with a 2 Gy single fraction of 6 MV X-rays. After the treatment, cells were trypsinized and seeded in 60 mm dishes for clonogenic assay. Damage to DNA was probed using immunofluorescence assay. Results Cancer cells internalized with the GNP–drug complex had a 32 ± 9% decrease in cell survival and statistically significant enhancement in DNA (deoxyribonucleic acid) damage as compared to control cells (irradiated with no GNPs) after receiving a radiation dose of 2 Gy with 6 MV photons. Conclusions The experimental results demonstrate that GNP-mediated chemoradiation has the potential to improve cancer care in the near future through enhancement of the local radiation dose and controlled delivery of anticancer drugs.

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.

Background Radiotherapy is commonly used for treating cancer. Novel sensitizers, such as gold nanoparticles (GNPs), are being used to enhance the local radiation dose. It is not known how the uptake and radiation dose enhancement of GNPs vary in synchronized vs unsynchronized (control) tumor cell populations. Successful application of GNPs in radiation therapy requires NPs to be accumulated within individual tumor cells at clinically feasible NP concentrations. Use of small GNPs as a radiation dose enhancer in the past required very high NP concentration, since the driving force for the uptake of smaller GNPs is low. We used a novel lipid-based NP of 50 nm diameter system as a Trojan horse to deliver smaller GNPs of size 5 nm (LNP–GNP) at 0.2 nM concentration. We investigated the changes in GNP uptake and survival fraction with the LNP delivery at different cell stages using human breast cancer as our tumor model and choosing the triple-negative MDA-MB-231 cell line. Results Using the LNP–GNP system resulted in a 39- and 73-fold enhancement in uptake of 5 nm GNPs in unsynchronized and synchronized tumor cell populations, respectively. The NP uptake per cell increased from 800 to 1200 and from 30,841 to 88,477 for individual 5 nm GNPs and 5 nm GNPs incorporated in LNPs, respectively. After a radiation dose of 2 Gy with 6 MeV photons, synchronized tumor cell populations incorporated with LNP–GNPs produced a 27% enhancement in tumor cell death compared to the control (unsynchronized; no GNPs; 2 Gy). The findings of our experimental results were supported by modeling predictions based on Monte Carlo calculations. Conclusions This study clearly shows that the cell cycle, GNPs, and radiation therapy can be combined to improve outcome of cancer therapy. Using the experimental data, we estimated the predicted improvement for a clinical treatment plan where 30 fractions of 2 Gy radiation dose were given over a period of time. Enhanced uptake and radiation sensitivity of a synchronous tumor cell population would produce a significant improvement in cell killing. For example, synchronizing cells and the addition of LNP–GNPs into tumor cells produced a 1000-fold enhancement in cell killing. Because the agents used for cell synchronization are in clinical practice, this approach may be a simple and cost-effective way to further enhance local radiation dose. Finally, this study provides a novel lipid-based NP platform to further improve GNP-mediated radiation therapy through synchronization of breast cancer cell population.

Combined use of chemotherapy and radiation therapy is commonly used in cancer treatment, but the toxic effects on normal tissue are a major limitation. This study assesses the potential to improve radiation therapy when combining gold nanoparticle (GNP) mediated radiation sensitization with chemoradiation compared to chemoradiation alone. Incorporation of GNPs with 2 Gy, 6 MV (megavoltage) radiation resulted in a 19 ± 6% decrease in survival of MDA-MB-231 cells. Monte-Carlo simulations were performed to assess dosimetric differences in the presence of GNPs in radiation. The results show that physics dosimetry represents a small fraction of the observed effect. The survival fraction of the cells exposed to GNPs, cisplatin, and radiation was 0.16 ± 0.007, while cells treated with cisplatin and radiation only was 0.23 ± 0.011. The presence of GNPs resulted in a 30 ± 6% decrease in the survival, having an additive effect. The concentration of the GNPs and free drug used for this study was 0.3 and 435 nM, respectively. These concentrations are relatively lower and achievable in an in vivo setting. Hence, the results of our study would accelerate the incorporation of GNP-mediated chemoradiation into current cancer therapeutic protocols in the near future.

Nanomedicine is an exponentially growing field, and gold nanoparticles (GNPs) in particular are extensively used in research due to their abilities as anti-cancer drug carriers for chemotherapy and as dose enhancers in radiotherapy. Most GNP research in the past involved a system where GNP localization was in the cytoplasm of the cell. However, it is predicted that therapy response can be enhanced if GNPs can be effectively targeted into the nucleus. With nuclear targeting, there is a possibility in producing additional free radicals in response to irradiation within the nucleus. This can cause more damage to the DNA of cancer cells. In this review article, we discuss the successful NP-based platforms available for nuclear targeting. In addition, we also present the possible mechanisms of nuclear targeting in detail followed by its applications in cancer therapy.

Gold nanoparticles (GNPs) are emerging as a novel tool to improve existing cancer therapeutics. GNPs are being used as radiation dose enhancers in radiation therapy as well as anticancer drugs carriers in chemotherapy. However, the success of GNP-based therapeutics depends on their ability to penetrate tumor tissue. GNPs of 20 and 50 nm diameters were used to elucidate the effects of size on the GNP interaction with tumor cells at monolayer and multilayer level. At monolayer cell level, smaller NPs had a lower uptake compared to larger NPs at monolayer cell level. However, the order was reversed at tissue-like multilayer level. The smaller NPs penetrated better compared to larger NPs in tissue-like materials. Based on our study using tissue-like materials, we can predict that the smaller NPs are better for future therapeutics due to their greater penetration in tumor tissue once leaving the leaky blood vessels. In this study, tissue-like multilayer cellular structures (MLCs) were grown to model the post-vascular tumor environment. The MLCs exhibited a much more extensive extracellular matrix than monolayer cell cultures. The MLC model can be used to optimize the nano–micro interface at tissue level before moving into animal models. This would accelerate the use of NPs in future cancer therapeutics. Electronic supplementary material The online version of this article (doi:10.1007/s40820-015-0060-6) contains supplementary material, which is available to authorized users.

The nucleus is the desired intracellular target in cancer therapeutics. The most efficient nuclear targeting is achieved by using viruses, which commonly utilize different peptides for crossing cellular and nuclear membrane barrier. However, nonviral systems such as gold nanoparticles (GNPs) currently appear to be safer and more cost-effective than viral systems. The challenge of using nonviral systems is that they are less efficient at nuclear delivery. In this book chapter, we will discuss how we can overcome the challenges in nuclear delivery of GNPs through a combination of multiple peptides assembled on a single nanoparticle (NP) surface. GNPs also play a bigger role in cancer therapy because they can enhance the radiation dose in radiation therapy and deliver anticancer drug effectively to cancer cells in chemotherapy. Hence, targeting of GNPs into the nucleus would further enhance the damage to DNA resulting in a better outcome in cancer therapy. This book chapter will cover the latest strategies for nuclear targeting of NPs followed by their applications in cancer therapy.

The applications of nanoparticles (NPs) for improved therapeutics are at the forefront of cancer nanotechnology. Gold nanoparticles (GNPs) have been extensively used due to their ability to act as both an anticancer drug carrier in chemotherapy and as a dose enhancer in radiotherapy. GNPs used in the studies were predominantly localized in the cell cytoplasm. However, the therapeutic response can be further enhanced if NPs can be effectively targeted into the nucleus. Here, we present an effective strategy for designing a GNP-peptide complex for nuclear targeting. Two peptides were conjugated onto a NP: One peptide enhanced the uptake while the other peptide enhanced the nuclear delivery. The nuclear targeted cells displayed a four-fold increase in the therapeutic response when treated with radiation as compared to untargeted ones. There was a modest increase in the DNA damage for radiated cells with nuclear targeted GNPs. This research will establish a more successful NP-based platform for combining more than one treatment modality, such as chemotherapy and radiotherapy, and creates a more aggressive approach in eradicating cancer.

Objective: The incorporation of high atomic number materials such as gold nanoparticles (GNPs) into tumor cells is being tested to enhance the local radiotherapy (RT) dose. It is also known that the radiosensitivity of tumor cells depends on the phase of their cell cycle. Triple combination of GNPs, phase of tumor cell population, and RT for improved outcomes in cancer treatment. Methods: We used a double-thymidine block method for synchronization of the tumor cell population. GNPs of diameters 17 and 46 nm were used to capture the size dependent effects. A radiation dose of 2 Gy with 6 MV linear accelerator was used to assess the efficacy of this proposed combined treatment. A triple negative breast cancer cell line, MDA-MB-231 was chosen as the model cell line. Monte Carlo (MC) calculations were done to predict the GNP-mediated cell death using the experimental GNP uptake data. Results: There was a 1.5- and 2- fold increase in uptake of 17 and 46 nm GNPs in the synchronized cell population, respectively. A radiation dose of 2 Gy with clinically relevant 6 MV photons resulted in a 62 and 38 % enhancement in cell death in the synchronized cell population with the incorporation of 17 and 46 nm GNPs, respectively. MC data supported the experimental data, but to a lesser extent. Conclusion: A triple combination of GNPs, cell cycle synchronization, and RT could pave the way to enhance the local radiation dose while minimizing side effects to the surrounding healthy tissue. Advances in knowledge: This is the first study to show that the combined use of GNPs, phase of tumor cell population, and RT could enhance tumor cell death.

Gold nanoparticles (GNPs) can be used as a model NP system to improve the interface between nanotechnology and medicine since their size and surface properties can be tailored easily. GNPs are being used as radiation dose enhancers and as drug carriers in cancer research. Hence, it is important to know the optimum NP size for uptake not only at monolayer level but also at tissue level. Once GNPs leave tumor vasculature, they enter the tumor tissue. Success of any therapeutic technique using NPs depends on how well NPs penetrate the tumor tissue and reach individual tumor cells. In this work, multicellular layers (MCLs) were grown to model the post-vascular tumor environment. GNPs of 20 nm and 50 nm diameters were used to elucidate the effects of size on the GNP penetration and distribution dynamics. Larger NPs (50 nm) were better at monolayer level, but smaller NPs (20 nm) were at tissue level. The MCLs exhibited a much more extensive extracellular matrix (ECM) than monolayer cell cultures. This increased ECM created a barrier for NP transport and ECM was also dependent on the tumor cell lines. Smaller NPs penetrated better compared to larger NPs. Transport of NPs was better in MDA-MB231 vs MCF-7. This MCL model tissue structures are better tools to optimize NP transport through tissue before using them in animal models. Based on our study, we believe that smaller NPs are better for improved outcome in future cancer therapeutics.

Nanoparticles have been used as a platform to improve therapeutic results in medical research. Gold nanoparticles (GNPs) have been extensively studied among other nanoparticles in cancer research due to its property being radio-sensitizing by producing more secondary electrons in response to irradiation. It is predicted that closer the GNPs can get to the DNA, the extra secondary electrons will cause more breaks in the DNA.However, the regular uptake pathway of GNPs into the cell is known to be through receptor mediated endocytosis, where GNPs follow the endo-lyso pathway. An effective design of GNP-peptide complex for nuclear targeting will be presented, where three different peptide sequences are conjugated onto 10 nm sized spherical GNPs.An effective design of a GNP-peptide complex for nuclear targeting will be presented, where three different peptide sequences are conjugated onto 10 nm sized spherical GNPs. Each of the peptides is used for enhancing intracellular retention, inducing nuclear delivery and stabilization. When in vitro cells were irradiated with 2 Gy of radiation, the cells incubated with peptide-modified GNPs had an improved therapeutic result, not only compared to the control sample (no incubation of GNP) but to cells incubated with unmodified GNPs.This research will provide insight to a more successful NP-based platform for combining treatment modalities that could eventually lead to a more effective approach in the treatment of cancer.

Better knowledge of interface between nanotechnology and biology will lead to advanced biomedical tools f or imaging and therapeutics. In this review, recent progress in the understanding of how size, shape, and surface properties of nanoparticles (NPs) affect intracellular uptake, transport, and processing of NPs will be discussed. Gold NPs are used as a model system in this regard since their size, shape, and surface properties can be easily manipulated. Recent experimental and theoretical studies have shown that NP -uptake is dependent upon size and shape of the NPs. Within the size range of 2 -100 nm, Gold nanoparticles (GNPs) of diameter 50 nm demonstrate the highest uptake. Cellular uptake studies of rod -shaped gold nanoparticles (GNRs) show that there is a decrease in uptake as the aspect ratio of GNRs increases. The surface ligand and charge of NPs play an important role in their uptake process as well. Different proteins on the surface of the NPs can be coated for effective targeting of NPs into specific organelles. Once in the cell, most of the NPs are trafficked via an endo -lysosomal path followed by a r eceptor mediated endocytosis process at the cell membrane. Exocytosis of NPs is also dependent on the size and shape of the NPs, however, the trend was different to endocytosis process. These findings provide useful information to tailor nano -scale devicesat single cell level for effective applications in diagnosis, therapeutics, and imaging.

The interactions of synthetically produced colloidal gold nanoparticles (GNPs) with living organisms are gaining much attention in the biomedical sciences. While non-viral carriers, such as GNPs, are safer and more cost-efficient as compared to viral vectors, the probability of cell internalization is lower. In this paper, we discussed a method to increase cell internalization of GNPs using a specific peptide known as “RME-Peptide”. Our results showed an enhancement in cell uptake of peptide-capped GNPs. Furthermore, we investigated the exocytosis process of peptide-capped GNPs. Our results showed that the peptide-modified GNPs had a lower number of NPs exocytosed as compared to citrate-capped or as-made colloidal GNPs. Our study shows that bio-nano interface can be improved using specially designed peptides on colloidal GNPs. The outcome of this research will be beneficial for their applications in therapeutics and imaging.

Nanotechnology involves creation and utilization of materials, devices or systems on the nanometer scale. The field of nanotechnology is currently undergoing explosive development on many fronts. The technology is expected to generate innovations and play a critical role in drug delivery and imaging. There has been tremendous progress made in the use of polymer and lipid based nanoparticles (NPs) for drug delivery and imaging. Recently, more attention has been given to incorporating inorganic NPs such as gold and magnetic NPs with both imaging and therapeutic capabilities into polymer and lipid based NPs for improved therapy and imaging in cancer treatment. In this review article, the recent progress in the development of multiplex polymer, lipid, and inorganic NPs towards optimizing techniques for drug delivery and multimodal imaging will be discussed along with the relevant patents.

The past decade has seen a dramatic increase in interest in the use of gold nanoparticles (GNPs) as radiation sensitizers for radiation therapy. This interest was initially driven by their strong absorption of ionizing radiation and the resulting ability to increase dose deposited within target volumes even at relatively low concentrations. These early observations are supported by extensive experimental validation, showing GNPs' efficacy at sensitizing tumors in both in vitro and in vivo systems to a range of types of ionizing radiation, including kilovoltage and megavoltage X rays as well as charged particles. Despite this experimental validation, there has been limited translation of GNP-mediated radiation sensitization to a clinical setting. One of the key challenges in this area is the wide range of experimental systems that have been investigated, spanning a range of particle sizes, shapes, and preparations. As a result, mechanisms of uptake and radiation sensitization have remained difficult to clearly identify. This has proven a significant impediment to the identification of optimal GNP formulations which strike a balance among their radiation sensitizing properties, their specificity to the tumors, their biocompatibility, and their imageability in vivo. This white paper reviews the current state of knowledge in each of the areas concerning the use of GNPs as radiosensitizers, and outlines the steps which will be required to advance GNP-enhanced radiation therapy from their current pre-clinical setting to clinical trials and eventual routine usage.

Gold nanoparticles (GNPs) are emerging as promising novel agents for cancer therapy. However, the oxygen concentration in human tumors is highly heterogeneous, and there are many regions with very low levels of oxygen (hypoxia). A majority of solid tumors contain regions with oxygen pressure values of less than 0.7% in the gas phase. The purpose of this study was to investigate NP stability, toxicity, and cellular uptake under hypoxic conditions. GNPs 50 nm in diameter were used, and the experiment was performed under 0.2% (hypoxic) and 21% (normoxic) oxygen levels using MCF-7 and HeLa cells. Hypoxic cells with prolonged exposure (eighteen hours) to hypoxia had a higher NP uptake at both 6- and 24-hour NP incubation time points. No significant toxicity was introduced by NPs under hypoxic and normoxic conditions. These findings will play a vital role in the optimization of GNP-based therapeutics in cancer treatment.

This chapter addresses physicochemical properties that affect Nanoparticle (NP) intracellular behavior using Gold NPs (GNPs) as a model system. The main objective is to outline what is known about the effect of GNP size, shape, and surface properties on cellular uptake and intracellular pathway. The authors propose that the entry of GNPs into cells is related to its effectiveness in applications that favor intracellular localization of such GNPs. The authors also discuss how such properties are used to optimize GNP designs for medical applications. Finally, the authors discuss how GNPs may improve disease diagnosis and treatment. Furthermore, how they may be incorporated or used as alternatives to current treatment options is defined.

InAs/InP self-assembled quantum dots are deposited by chemical beam epitaxy on InP templates generated in situ during the growth process itself. By careful choice of nano-template geometry we produce linear arrays of site-selected, self-assembled quantum dots. The quantum dot density can be varied by nearly two orders of magnitude by choice of the nano-template dimensions. Preliminary optical measurements on these site-selected quantum dot structures are consistent with the evolution of the dot density with template dimension observed by electron microscopy.

The prospective cancer therapy applications of inorganic nanoparticles (NPs) have been encouraged by surface modifications with polyethylene glycol (PEG). When grafted at high densities, PEG reduces NP surface interaction with its environment, hence minimizing its detection by the immune system. The drawback of high density PEG surfaces is its reduced uptake by cancer cells. This is disadvantageous for applications that favor intracellular localization of such NPs. On the other hand, reduced PEG density leads to nonspecific adsorption of proteins on NP surface. Adsorbed proteins may either facilitate cancer cell entry or mark inorganic NPs for clearance from the body. This trade-off between intracellular localization and in vivo residency time was observed in this study. Two grafting densities of 1 PEG/nm 2 and 1 PEG/2 nm 2 for two PEG chain lengths with molecular weights of 2kDa and 5kDa were used to coat gold NPs (GNPs). Spherical GNPs with a diameter of 50 nm were used as a model system to investigate the effect of PEG characteristics on NP nonspecific protein adsorption and uptake by cancer cells in vitro in HeLa, MDA-MB-231 and MCF-7 cells. Higher grafting densities resulted into less protein adsorption and lower NP uptake by all cell lines. Longer PEG chain lengths also resulted into less cancer cell entry in all cell lines. Quantitative results were confirmed qualitatively via hyperspectral imaging of NPs in cancer cells. Hence, lower PEG grafting densities and shorter chain lengths lead to higher cellular uptake at the cost of greater nonspecific protein adsorption. Higher density grafting of shorter PEG chain lengths was found most favorable. This combination resulted into reduced nonspecific protein adsorption and higher uptake when compared to its lower density and longer chain length counterparts, respectively. To maximize cancer therapy improvement via inorganic NP platforms, using such PEG grafting characteristics may be beneficial.