Celina Yang

Optimization of PEG coated nanoscale gold particles for enhanced radiation therapy

Nanoscale gold particles are being used as a radiation dose enhancer in cancer research. The purpose of this study was to optimize the uptake of polyethylene glycol (PEG) functionalized gold nanoparticles (GNPs) for an enhanced therapeutic effect during radiation therapy. PEG is widely used in providing NPs with stealth properties, thus prolonging blood circulation times. However, PEG minimizes PEG-GNP interaction with cell surface ligands resulting in significantly lower in vitro cellular uptake. As intracellular localization of GNPs maximizes its therapeutic enhancement, there is a need to improve the uptake of PEG-GNPs. To enhance uptake, RGD peptide containing an integrin binding domain was conjugated along with PEG. Spherical GNPs of diameters 14 and 50 nm and PEG chain lengths of 2 kDa were used for the study. Nanoparticles functionalized with both RGD peptide and PEG had higher uptake than NPs functionalized with PEG alone. The enhancement in uptake was higher for 14 nm NPs as compared to 50 nm NPs. Our radiation therapy results showed that smaller NPs conjugated with PEG and RGD peptides have a three-fold therapeutic enhancement as compared to larger NPs in MDA-MB-231 cells at clinically relevant 6 MV energy. This study will shed light on clinical use of GNPs in radiation therapy in the near future.

Size dependent gold nanoparticle interaction at nano-micro interface using both monolayer and multilayer (tissue-like) cell models

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.

Colloidal Gold-Mediated Delivery of Bleomycin for Improved Outcome in Chemotherapy

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.

Peptide Mediated In Vivo Tumor Targeting of Nanoparticles through Optimization in Single and Multilayer In Vitro Cell Models

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.

Optimizing the bio-nano interface for gold nanoparticles

Abstract: The interface between nanotechnology and biology needs to be well understood for improved outcome in medical applications. In other words, we need to know the interaction of nanoparticles (unit cells in nanotechnology) with cells (unit cells in biology) for improved outcome in diagnosis, imaging and therapeutic techniques. In this chapter, 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 as their size, shape and surface properties can be easily tailored. These findings provide useful information to tailor nanoparticle-based devices at the single cell level for effective applications in diagnosis, therapeutics and imaging.

Cancer nanomedicine: gold nanoparticle mediated combined cancer therapy

Recent developments in nanotechnology has provided new tools for cancer therapy and diagnosis. Among other nanomaterial systems, gold nanoparticles are being used as radiation dose enhancers and anticancer drug carriers in cancer therapy. Fate of gold nanoparticles within biological tissues can be probed using techniques such as TEM (transmission electron microscopy) and SEM (Scanning Electron Microscopy) due to their high electron density. We have shown for the first time that cancer drug loaded gold nanoparticles can reach the nucleus (or the brain) of cancer cells enhancing the therapeutic effect dramatically. Nucleus of the cancer cells are the most desirable target in cancer therapy. In chemotherapy, smart delivery of highly toxic anticancer drugs through packaging using nanoparticles will reduce the side effects and improve the quality and care of cancer patients. In radiation therapy, use of gold nanoparticles as radiation dose enhancer is very promising due to enhanced localized dose within the cancer tissue. Recent advancement in nanomaterial characterization techniques will facilitate mapping of nanomaterial distribution within biological specimens to correlate the radiobiological effects due to treatment. Hence, gold nanoparticle mediated combined chemoradiation would provide promising tools to achieve personalized and tailored cancer treatments in the near future.

Determining the Radiation Enhancement Effects of Gold Nanoparticles in Cells in a Combined Treatment with Cisplatin and Radiation at Therapeutic Megavoltage Energies

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.

Gold-mediated drug delivery for improved outcome in chemotherapy

Nanoparticles can be used to overcome the side effects due to 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 while confining anticancer drugs as closely as possible to their biological targets through passive and active targeting ensuring limited harmful systemic distribution. In this study, we chose bleomycin (BLM) as the anticancer drug since its therapeutic efficiency is severely limited because of its side effects. Bleomycin was conjugated to GNPs through a thiol bond. The effectiveness of the chemotherapeutic drug, bleomycin, is observed by visualizing DNA double strand breaks and calculating the survival fraction. The action of the drug is known to be in the nucleus and our experiments have shown GNPs in the nucleus along with bleomycin. Use of GNPs to deliver bleomycin increased the therapeutic efficacy of the drug. Having a better understanding of the interaction of GNPs and drugs will establish a more successful NP-based platform for combined therapeutic approach in cancer research since GNPs can be used as radiation dose enhancers.

Increase in uptake of peptide modified gold nanoparticles (GNPs)

The interactions of synthetically produced gold nanoparticles (GNPs) with living organisms are getting attention in the biomedical sciences. While non-viral carriers, like GNPs, are safer and more cost-efficient than viral vectors, the efficiency of cell penetration is lower. Unmodified GNPs enter the cell through a receptor-medicated endocytosis (RME) and is encapsulated inside a double membrane endosome, which leads to exocytosis. Increasing uptake of GNPs into the cell is a challenging task as the GNPs has to escape the regular endo-lyso pathway. In this paper, various modifications using peptide conjugates have been performed to the GNPs to increase the efficiency of cell penetration. Quantitative and qualitative data are obtained from a UV spectrometer, an Atomic Absorption spectrometer, and Transmission Electron Microscope.

Peptide-modified gold nanoparticles for improved cancer therapeutics

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 cancer therapeutics. Among other nanoparticle (NP) systems, there has been tremendous progress made in the use of spherical gold NPs (GNPs) in cancer therapeutics. In treating cancer, radiation therapy and chemotherapy remain the most widely used treatment options. These nanostructures further provide strategies for improving loading, targeting, and controlling the release of drugs to minimize the side effects of highly toxic anticancer drugs used in chemotherapy. Our recent results show enhancement of cell death during radiation therapy when GNPs are targeted to nucleus. In addition, we have seen enhanced therapeutic effects when GNPs are used as anticancer drug carriers. Hence, gold nanostructures provide a versatile platform to integrate many therapeutic options leading to effective combinational therapy in the fight against cancer. A multifunctional platform based on gold nanostructures with targeting ligands, therapeutic molecules, and imaging contrast agents will hold the possibility of promising directions in cancer research.