PEGylated Gold Nanoparticles Research Articles

Targeted detection of the cancer cells using the anti-CD24 bio modified PEGylated gold nanoparticles: the application of CD24 as a vital cancer biomarker

Objective(s): The central role of molecular imaging modalities in cancer management is an undeniable fact that could help to diagnose cancer tumors in early stages. The main aim of this study is to prepare a novel targeted molecular imaging nanoprobe of CD24-PEGylated Au NPs to improve the ability of Computed tomography scanning (CT scan) outputs for both in vitro and in vivo detection of breast cancer (4T1) cells. Materials and methods: Gold nanoparticles (Au NPs) were synthesized and coated with polyethylene glycol (PEG) chains in order to improve the stability of the Au NPs and to provide bio modification points for antibody immobilization. The synthesized nanoprobe was used for both in vitro and in vivo targeted CT imaging breast cancer cells (4T1) and the xenograft tumor model. Results: Findings showed that the attenuation coefficient of 4T1 cells that were targeted by CD24-PEGylated Au NPs is calculated to be over two times higher than the untargeted 4T1 cells (15 HU vs 39 HU, respectively). Indeed, the results clearly reveal that the developed CD24-PEGylated Au NPs showed the tumor CT enhancement was higher than that of Omnipaqe which used as control. Also, the CT number values of the tumor area at different time points gradually increased after 60 min post injection and was significantly higher than before injection. Conclusions: Results showed the introduced CT imaging nanoprobe (Au NPs-PEGylated) could be useful for CT imaging of breast tumors under in vivo condition. Overall, it is concluded that Au NPs-PEGylated contrast media is able to detect breast cancer (4T1) cells and is more effective compared with other casual methods.

Abstract 670: Specific ROS generation and monitoring in cancer using radioactive gold nanoparticle

Abstract Radiotherapy is a key treatment and is beneficial in the treatment of about 50% of all cancer patients. Such treatment relies on the deposition of energy (the dose) in tumour cells, typically by irradiation with either high-energy gamma rays or X-rays (photons), or energetic beams of ions, sufficient to damage the cancer cells or their vasculature and thus induce tumour death or nutrient starvation. However, like chemotherapy, photon radiotherapy is non-specific, since a significant dose can be delivered to healthy tissue along the track of the photons, in front and behind the tumour. Therefore, recently several research groups have proposed the use of specifically targeted noble-metal nanoparticles irradiated by radiation as an effective therapeutic tool for treating various malignancies with minimum collateral damage to healthy tissue. In general, the photoelectric absorption cross sections of radiosensitive materials directly depend on atom radius, and thus their radiotherapy effects also depend on atom radius. This physical principle determines that gold (atomic-number Z=79) has a stronger radiation enhancement effect by photoelectric effect. Loading with gold nanoparticles (AuNPs) is one of the promising candidates in this area. Gold NPs have a larger atomic radius than gold atom (~0.17 nm), and thus should have a stronger radiation enhancement effect than gold atom. During irradiation, this results in an enhancement of the energy deposition in the vicinity of the gold particles generate the ROS on the surface due to the generation of photoelectrons, Auger electrons, and characteristic X-rays. ROS play important roles in various cellular process. In particularly, at sufficiently high concentrations, ROS could become an effect that is utilized for various therapeutic application such as apoptosis. Herein, we synthesized the radiosensitizer PEGylated gold nanoparticles (RPAuNPs) for generation and measuring of ROS on surface by radiation exposure. First, gold nanoparticles (AuNPs) was prepared by one-pot synthesis and the sharpness and size were efficiently controlled by adjusting the amount of reducing agent. Furthermore, they were replaced with heterobifunctional PEG (COOH-PEG-SH) not only to serve as a biocompatible stabilizer (PAuNPs) and but also to conjugate Dihydrorhodamine 123 (DHR 123) (RPAuNPs) as ROS sensor. Well-engineered formation of RPAuNPs was verified by transmission electron microscopy (TEM) showing their overall size of 50 nm. In addition, UV-Vis data strongly demonstrated successful synthesis. We evaluated their functional use in inducing ROS and the results showed that our radiosensitizing agents exhibited the feasibility of effective ROS generation under x-ray radiation. And we investigated there in vitro/in vivo imaging and therapeutic efficacies, optical properties, biocompatibility for tumor cell. Citation Format: Jihye Choi, Yoon Woo Koh, Hyung Kwon Byeon, Guillem Pratx, Jaemoon Yang. Specific ROS generation and monitoring in cancer using radioactive gold nanoparticle [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 670.

P-315 - Cytodiagnosis of hypersialylated metastatic cancers by phenylboronic acid-installed PEGylated gold nanoparticle and their management by nitroxide radical-containing nanoparticles

Correlation between metastatic incidence and aberrantly high surface expression of reactive oxygen species (ROS) regulated sialic acid (hypersialylation) on tumors accentuates the sialyation signaling pathways as venerable targets for cytodiagnosis and redox therapeutics of hypersialyated metastatic cancers. Hence, in this line, we herein report on the diagnosis of hypersialylated tumors by surface-enhanced Raman spectroscopy (SERS) by phenylboronic acid-installed PEGylated gold nanoparticles coupled with Toluidine blue O (T/BA-GNPs) and redox cancer therapeutics by our original ROS scavenging polymeric micelle, nitroxide-radical containing nanoparticles (RNPs). In this study, we confirmed specific high SERS signal to noise ratio from metastatic cancer cell lines (MDA-MB-231 and Colon-26) and tumors in contrast to non-metastatic cancer cells (MCF-7) and healthy tissues. Furthermore, we also confirmed reduction in sialic acid-associated SERS signals from MDA-MB-231 surface upon treatment with RNPs, which was mediated by attenuation of ROS sensitive NF-κB-sialyltransferase signaling cascade. The aforementioned findings thus establish T/BA-GNPs based SERS as a potential cytodiagnostic system and RNPs as a promising antioxidant nanotherapeutics for hypersialylated metastatic tumors.

Complement Activation by PEGylated Gold Nanoparticles.

Gold nanoparticles (AuNPs) are widely used in biomedical applications, but much less is known about their immunological properties, particularly their interaction with the complement system, a key component of innate immunity serving as an indicator of their biocompatibility. Using a library of different-sized AuNPs (10, 20, 40, and 80 nm) passivated with polyethylene glycol (PEG) of different molecular weight ( Mw = 1, 2, 5, and 10 kDa), we demonstrated that citrate-capped AuNPs activated the whole complement system in a size-dependent manner, characterized by the formation of the end-point activation product, SC5b-9, in human serum. Although PEGylation of AuNPs mitigated, but did not abolish, the activation level, complement activation by PEGylated AuNPs was independent of both the core size of AuNPs and the molecular weight of PEG. The cellular uptake of both citrate-capped and PEGylated AuNPs by human U937 promonocytic cells which expresses complement receptors were highly correlated to the level of complement activation. Taken together, our results provided new insights on the innate complement activation by PEGylated AuNPs that are widely considered to be inert biocompatible nanomaterials.

Separation of PEGylated Gold Nanoparticles by Micellar Enhanced Electrospun Fiber Based Ultrathin Layer Chromatography.

Gold nanoparticles (AuNPs) are of great interest in many fields, especially in biomedical applications. Thiol terminated polyethylene glycol (PEG) is the most widely used polymer to increase the biocompatibility of nanoparticle therapeutics. Herein, a rapid method for separation and characterization of PEGylated AuNPs on an ultrathin layer chromatographic (UTLC) plate using electrospun polyacrylonitrile (PAN) nanofibers as the stationary phase is described. AuNPs with sizes ranging from 10 to 80 and 30 nm AuNPs coated with various molecular weight of PEG (2, 5, 10, and 20 kDa) were all successfully separated by UTLC using optimized conditions. The fabrication of electrospun UTLC is simple, fast, and inexpensive. The UTLC, with much thinner sorbent layer (10× thinner than traditional TLC) and small fiber size (∼300 nm), requires minimal mobile phase solvent and provides faster separation and higher resolution compared to other separation methods for AuNPs. AuNPs with different sizes and different PEG molecular weights were well separated within 5 min with lowest plate height <2 μm and resolution value >1.5. As an example of this method, the size transformation of AuNPs in serum protein was determined quantitatively.

Junction opener protein increases nanoparticle accumulation in solid tumors

Carcinomas contain tight junctions that can limit the penetration and therefore therapeutic efficacy of anticancer agents, especially those delivered by nano-carrier systems. The junction opener (JO) protein is a virus-derived protein that can transiently open intercellular junctions in epithelial tumors by cleaving the junction protein desmoglein-2 (DSG2). Co-administration of JO was previously shown to significantly increase the efficacy of various monoclonal antibodies and chemotherapy drugs in murine tumor models by allowing for increased intratumoral penetration of the drugs. To investigate the size-dependent effect of JO on nanocarriers, we used PEGylated gold nanoparticles (AuNPs) of two different sizes as model drugs and investigated their biodistribution following JO protein treatment. By inductively coupled plasma mass spectrometry (ICP-MS), JO was found to significantly increase bulk tumor accumulation of AuNPs of 35nm but not 120nm particles in both medium (200–300mm3) and large (500–600mm3) tumors. Image analysis of tumor sections corroborates this JO-mediated increase in tumor accumulation of AuNPs. Quantitative intratumoral distribution analyses show that most nanoparticles were found within 100μm of the vasculature, and that the penetration profiles of AuNPs are not significantly affected by JO treatment at the 6h timepoint.

Aptamer Grafting onto (on) and into (in) Pegylated Gold Nanoparticles: Physicochemical Characterization and In vitro Cytotoxicity Investigation in Renal Cells

Gold Nanoparticles (AuNPs) have already a remarkable interest as viable biomedical materials. Additionally, the strategy of using biomolecules to modify their surface properties is a very attractive as it leads to the generation of new nanometric hybrid materials. In this respect, aptamers, functional small single-strand oligonucleotides (DNA or RNA), are ideal candidates for molecular targeting applications since the high affinity to their target molecules. Thus, the urge of new and effective methodologies to graft aptamers on AuNPs is rapidly increasing especially for applications in bioanalysis and biomedicine, including early diagnosis and drug delivery. Here we used two chemical methodologies to conjugate the aptamer (APT) onto pegylated gold nanoparticles (PEG-AuNPs): the carbodiimide chemistry (EDC/NHS) (methodology ON) and the chelation-bond (R-Au bond) (methodology IN). The aptamer's conjugations with the PEGAuNPs were characterized by UV-Vis absorption, Raman Spectroscopy and transmission electron microscopy (TEM). In addition, the potential nanotoxicity of the two aptamer-conjugated AuNPs was evaluated on two different renal cell lines, being the kidneys one of the most important site of bioaccumulation upon systemic circulation. Interestingly, the two aptamer-conjugated AuNPs showed different cytotoxicity when exposed to human embryonic kidney (HEK293) and mouse collecting duct cells (M-1), indicating that cell viability has to be taken into account when choosing the proper strategy for NPs production. In conclusion this study provides two effective methods to graft aptamers on NPs and important insights regarding NPs conformation and the relative cell viability.

Synthesis, Characterization and Biocompatibility of a Multifunctional Gold Nanoparticle System for the Delivery of Single-Stranded RNA to Lymphocytes

The use of RNA macromolecules as therapeutic agents for HIV and other infectious diseases is promising but limited by suboptimal delivery to the target site. With HIV infection, this is particularly challenging since lymphocytes are particularly difficult to transfect. This paper describes an innovative strategy for the intracellular delivery of a novel single-stranded RNA (oligoribonucleotide) with putative anti-HIV activity. This strategy is based on a PEGylated gold nanoparticle scaffold covalently linked to the thiol-modified oligoribonucleotide via a cleavable N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP) linker molecule. The nanoparticle was then coated with a cationic polymer (polyethyleneimine) to facilitate cell entry and endosomal escape. A synthetic anti-CD4 cyclic targeting peptide was attached to the polyethyleneimine-coated nanoparticle via an SPDP linker molecule, in an attempt to enhance uptake and selectivity. Synthesis, characterization, SPDP and RNA loading, cytotoxicity and antiviral activity of the nanoparticle are described. Approximately 45 000 strands of RNA were taken up per lymphocyte. Uptake was limited by relatively inefficient loading ofRNAonto the gold nanoparticle surface (1 strand per 4.8 nm 2 of nanoparticle surface area) and significant aggregation of the nanoparticle in physiological solutions. No antiviral activity was demonstrated, possibly due to insufficient intracytoplasmic delivery of the RNA. Keywords: Gold nanoparticle, polyethyleneimine, transfection, RNA delivery

Atomic structural details of a protein grafted onto gold nanoparticles

The development of a methodology for the structural characterization at atomic detail of proteins conjugated to nanoparticles would be a breakthrough in nanotechnology. Solution and solid-state NMR spectroscopies are currently used to investigate molecules and peptides grafted onto nanoparticles, but the strategies used so far fall short in the application to proteins, which represent a thrilling development in theranostics. We here demonstrate the feasibility of highly-resolved multidimensional heteronuclear spectra of a large protein assembly conjugated to PEGylated gold nanoparticles. The spectra have been obtained by direct proton detection under fast MAS and allow for both a fast fingerprinting for the assessment of the preservation of the native fold and for resonance assignment. We thus demonstrate that the structural characterization and the application of the structure-based methodologies to proteins bound to gold nanoparticles is feasible and potentially extensible to other hybrid protein-nanomaterials.

A simple assay for direct colorimetric detection of prostatic acid phosphatase (PAP) at fg levels using biphosphonated loaded PEGylated gold nanoparticles

A fast and sensitive colorimetric assay for the determination of prostatic acid phosphatase (PAP) levels using biphosphonates-PEG-coated gold nanoparticles (BP-PEG-AuNPs) has been developed. Addition of different amounts of PAP to the AuNPs results in a significant change of color, from a red-wine color to purple, and finally to blue. The PAP should bind onto the AuNPs surface and crosslink the AuNPs inducing their aggregation and as a consequence a color change of the solution from wine red to purple/blue. The color change was monitored by UV–vis spectrophotometry or with the naked eye. The ensuing concentration-dependent red-shift of surface plasmon resonance absorption allows the determination concentration within the fg range in 10 min. Importantly, the visual detection limit (1 ng/mL) allows the rapid differential diagnosis with naked eye or image analyzer. This demonstrates that the color modification observed with BP-PEG-AuNP is effectively due to an interaction between PAP and BP.

Increased cellular uptake of peptide-modified PEGylated gold nanoparticles

Gold nanoparticles are promising drug delivery vehicles for nucleic acids, small molecules, and proteins, allowing various modifications on the particle surface. However, the instability and low bioavailability of gold nanoparticles compromise their clinical application. Here, we functionalized gold nanoparticles with CPP fragments (CALNNPFVYLI, CALRRRRRRRR) through sulfhydryl PEG to increase their stability and bioavailability. The resulting gold nanoparticles were characterized with transmission electron microscopy (TEM), dynamic light scattering (DLS), UV-visible spectrometry and X-ray photoelectron spectroscopy (XPS), and the stability in biological solutions was evaluated. Comparing to PEGylated gold nanoparticles, CPP (CALNNPFVYLI, CALRRRRRRRR)-modified gold nanoparticles showed 46 folds increase in cellular uptake in A549 and B16 cell lines, as evidenced by the inductively coupled plasma atomic emission spectroscopy (ICP-AES). The interactions between gold nanoparticles and liposomes indicated CPP-modified gold nanoparticles bind to cell membrane more effectively than PEGylated gold nanoparticles. Surface plasmon resonance (SPR) was used to measure interactions between nanoparticles and the membrane. TEM and uptake inhibitor experiments indicated that the cellular entry of gold nanoparticles was mediated by clathrin and macropinocytosis. Other energy independent endocytosis pathways were also identified. Our work revealed a new strategy to modify gold nanoparticles with CPP and illustrated the cellular uptake pathway of CPP-modified gold nanoparticles.

Effect of Alkylation on the Cellular Uptake of Polyethylene Glycol-Coated Gold Nanoparticles.

Alkyl groups (CnH2n+1) are prevalent in engineered bionanomaterials used for many intracellular applications, yet how alkyl groups dictate the interactions between nanoparticles and mammalian cells remains incomprehensively investigated. In this work, we report the effect of alkylation on the cellular uptake of densely polyethylene glycol-coated nanoparticles, which are characterized by their limited entry into mammalian cells. Specifically, we prepare densely PEGylated gold nanoparticles that bear alkyl chains of varying carbon chain lengths (n) and loading densities (termed "alkyl-PEG-AuNPs"), followed by investigating their uptake by Kera-308 keratinocytes. Strikingly, provided a modest alkyl mass percentage of 0.2% (2 orders of magnitude lower than that of conventional lipid-based NPs) in their PEG shells, dodecyl-PEG-AuNPs (n = 12) and octadecyl-PEG-AuNPs (n = 18) can enter Kera-308 cells 30-fold more than methoxy-PEG-AuNPs (no alkyl groups) and hexyl-PEG-AuNPs (n = 6) after 24 h of incubation. Such strong dependence on n is valid for all serum concentrations considered (even under serum-free conditions), although enhanced serum levels can trigger the agglomeration of alkyl-PEG-AuNPs (without permanent aggregation of the AuNP cores) and can attenuate their cellular uptake. Additionally, alkyl-PEG-AuNPs can rapidly enter Kera-308 cells via the filipodia-mediated pathway, engaging the tips of membrane protrusions and accumulating within interdigital folds. Most alkyl-PEG-AuNPs adopt the "endo-lysosomal" route of trafficking, but ∼15% of them accumulate in the cytosol. Regardless of intracellular location, alkyl-PEG-AuNPs predominantly appear as individual entities after 24 h of incubation. Our work offers insights into the incorporation of alkyl groups for designing bionanomaterials for cellular uptake and cytosolic accumulation with intracellular stability.

Hesperetin conjugated PEGylated gold nanoparticles exploring the potential role in anti-inflammation and anti-proliferation during diethylnitrosamine-induced hepatocarcinogenesis in rats

Liver cancer is the fifth most common cancer and one of the leading causes of death in the world, and second most common cause of death in men. Natural products emerge as the most enduring approaches in the development of anticancer targeting drug. Hesperetin (HP), one of the abundant flavonoids found naturally in citrus fruits, has received considerable attention in anti-cancer promotion and progression. The present study was conducted to decipher the role of 0.5 ml hesperetin conjugated gold nanoparticles (Au-mPEG(5000)-S-HP NPs) during diethylnitrosamine (DEN)-induced hepatocarcinogenesis in male Wistar albino rats and shows the better antioxidant that possesses anti-inflammatory, anti-proliferation and anticarcinogenic properties and may modulate signaling pathways. The confirmation of polymer functionalized gold nanoparticles and drug loaded polymer gold nanoparticles were characterized by HR-TEM with EDAX, and DLS with Zeta potential techniques. The drug encapsulation efficiency and release properties were carried out in PBS at pH 7.4 for Au- mPEG(5000)-S-HP and compared with the control pure hesperetin (HP). Here, we review the role of mast cell counts, tumor necrosis factor alpha (TNF-α), transcription factor nuclear factor-κB (NF-κB), levels of glycoconjugates, proliferating cell nuclear antigen (PCNA) and argyrophilic nucleolar organizing regions, are the master regulator of inflammation and proliferation, in the development of hepatocellular injury, liver fibrosis and HCC. DEN-administered animals showed increased mast cell counts, tumor necrosis factor alpha, transcription factor nuclear factor-κB, glycoconjugates, proliferating cell nuclear antigen, and argyrophilic nucleolar organizing regions. Whereas Au-mPEG(5000)-S-HP NPs supplementation considerably suppressed all the above abnormalities. These results suggest that the Au-mPEG(5000)-S-HP NPs exhibited the better potential anticancer activity by inhibiting cell inflammation and proliferation in DEN-induced hepatocellular carcinogenesis.

Application of surface enhanced Raman spectroscopy as a diagnostic system for hypersialylated metastatic cancers.

Early diagnosis of metastatic cancers could greatly limit the number of cancer-associated deaths. Aberrant surface expression of sialic acid (hypersialylation) on tumors correlating with metastatic incidence and its involvement in tumorigenesis and progression is widely reported; hence detection of hypersialylated tumors may be an effective strategy to identify metastatic cancers. We herein report on the application of phenylboronic acid-installed PEGylated gold nanoparticles coupled with Toluidine blue O (T/BA-GNPs) as SERS probes to target surface sialic acid (N-acetylneuraminic acid, Neu5Ac). Strong SERS signals from metastatic cancer cell lines (breast cancer; MDA-MB231 and colon cancer; Colon-26) were observed, contrary to non-metastatic MCF-7cells (breast cancer). The detected SERS signals from various cancer cell lines correlated with their reported metastatic potential, implying that our T/BA-GNP based SERS system was capable of distinguishing the metastaticity of cells based on the surface Neu5Ac density. T/BA-GNP based SERS system could also significantly differentiate between hypersialylated tumor tissues and healthy tissues with high SERS signal to noise ratio, due to plasmon coupling between the specifically aggregated functionalized GNPs. Furthermore, we also confirmed reduction in SERS signals from MDA-MB231 surface upon treatment with our original reactive oxygen species (ROS)-scavenging polymeric micelle, nitroxide-radical containing nanoparticles (RNPs). The ROS-mediated abrogation of sialylation by impairing the activation of NF-κB-sialyltransferase signaling cascade upon RNP treatment was confirmed by expression studies and the T/BA-GNPs based SERS system. The aforementioned findings thus, establish T/BA-GNPs based SERS as a potential cytodiagnostic system to detect hypersialylated metastatic tumors and RNPs as anti-metastatic cancer drug candidates.

Preparation, aging and temperature stability of PEGylated gold nanoparticles

This work is aimed on preparation and characterization of gold nanoparticles (AuNPs) by direct deposition into polyethylene glycol (PEG) and thiolated polyethylene glycols (PEG-SH; PEG-S2H2). Furthermore, this work investigates temperature stability and aging of the prepared PEGylated AuNPs. The prepared colloidal nanoparticles were characterized by several analytical techniques. Transmission electron microscopy and UV–vis spectroscopy revealed the shape of AuNPs is spherical in all PEG solutions. The size of the prepared AuNPs was between 2.1 and 5.9nm, depending on the capturing medium. The particle size was confirmed by dynamic light scattering measurement, which provided additional information on monodispersity of the samples. Atomic absorption spectroscopy showed the concentration of AuNPs increases linearly with deposition time which also corresponds with the optical absorption and color of the prepared PEGylated AuNPs. For AuNPs smaller than 3nm the absence of surface plasmon resonance peak was observed, which is caused by both the small size of the nanoparticles and/or attachment of thiolated PEG to the surface of the AuNPs. AuNPs stabilized by PEG-SH were more stable and resistant to increased temperature than AuNPs stabilized by PEG-S2H2. These AuNPs subjected more easily to aggregation which resulted in decrease of absorption in the UV–vis spectra. The highest stability was observed for the Au core of 2.9nm in size protected by PEG-SH. The prepared materials can find applications in medicine and catalysis.

Molecular dynamics simulations reveal how characteristics of surface and permeant affect permeation events at the surface of soft matter

Molecular dynamics simulations are particularly useful in providing details that permit understanding of phenomena occurring at surfaces, phenomena characterised by surface-sensitive experimental methods yielding average properties. The methods and examples that we consider here reveal how the characteristics of the surface and the permeant affect permeation events at the surface of soft matter, in particular, lipid bilayers. We choose permeation of lipid membranes as our example of the ability of molecular dynamics simulations to provide molecular-level mechanisms that are otherwise not available via other means. Molecular permeation through lipid membranes is a fundamental biological process that is important for small molecules such as therapeutics as well as nanoparticles that have become important modes of drug delivery. We describe methods applicable to such large systems and use examples where the permeants are uncharged particles: small molecules (Xe, O2, CO2), bare gold nanocrystals, gold-core nanoparticles with hydrophobic ligands (alkane thiols of various lengths) and gold-core nanoparticles with hydrophilic ligands (methyl-terminated polyethylene glycol of various lengths). In each example, we have previously validated our findings by comparisons with experimental data, using such information as is available from X-ray diffraction, electron paramagnetic resonance, nuclear magnetic resonance, atomic force microscopy, various imaging methods, diffusion measurements, dynamic light scattering. In addition to spherical core nanoparticles, we also examine the characteristic permeation mechanisms of gold nanorods with polyethylene glycol ligands, where the aspect ratio different from 1 makes the permeation event dependent on the angle of the rod axis relative to the membrane surface. This review examines the phenomena associated with the interaction of various permeants with the lipid bilayer that serves as our model membrane. We consider adsorption at the interface, the permeant within the top lipid leaflet, in the middle of the membrane within the lipid tail region, within the bottom lipid leaflet and finally exiting the membrane on the way to recovery, for various permeants: gas molecules, bare gold nanocrystal, gold nanoparticles with alkane thiol ligands, PEGylated gold nanoparticles and PEGylated gold nanorods. We observe formation of a water pore, occasional transport of ions, lipid flip-flops, lipid displacement from the membrane, and rotational behaviour of PEGylated nanorods during the permeation process. These events differ depending on the chemical nature (hydrophobic or hydrophilic) of the ligands, their length, the coverage density on the gold surface and the aspect ratio of the gold core. Direct comparisons across the board are possible by using identical interaction models (MARTINI coarse grain), molecular dynamics methods, simulation set-ups and analyses of MD results, thereby permitting generalisations to be made about mechanisms for the various events and how they are affected by these factors.

Correction: PEGylated gold nanoparticles: polymer quantification as a function of PEG lengths and nanoparticle dimensions

Correction for ‘PEGylated gold nanoparticles: polymer quantification as a function of PEG lengths and nanoparticle dimensions’ by Kamil Rahme et al., RSC Adv., 2013, 3, 6085–6094.

Gold nanoparticle interactions with endothelial cells cultured under physiological conditions.

PEGylated gold nanoparticles (AuNPs) have an extended circulation time after intravenous injection in vivo and exhibit favorable properties for biosensing, diagnostic imaging, and cancer treatment. No impact of PEGylated AuNPs on the barrier forming properties of endothelial cells (ECs) has been reported, but recent studies demonstrated that unexpected effects on erythrocytes are observed. Almost all studies to date have been with static-cultured ECs. Herein, ECs maintained under physiological cyclic stretch and flow conditions and used to generate a blood-brain barrier model were exposed to 20 nm PEGylated AuNPs. An evaluation of toxic effects, cell stress, the release profile of pro-inflammatory cytokines, and blood-brain barrier properties showed that even under physiological conditions no obvious effects of PEGylated AuNPs on ECs were observed. These findings suggest that 20 nm-sized, PEGylated AuNPs may be a useful tool for biomedical applications, as they do not affect the normal function of healthy ECs after entering the blood stream.

Evaluation of spectral photon counting computed tomography K-edge imaging for determination of gold nanoparticle biodistribution in vivo.

Spectral photon counting computed tomography (SPCCT) is an emerging medical imaging technology. SPCCT scanners record the energy of incident photons, which allows specific detection of contrast agents due to measurement of their characteristic X-ray attenuation profiles. This approach is known as K-edge imaging. Nanoparticles formed from elements such as gold, bismuth or ytterbium have been reported as potential contrast agents for SPCCT imaging. Furthermore, gold nanoparticles have many applications in medicine, such as adjuvants for radiotherapy and photothermal ablation. In particular, longitudinal imaging of the biodistribution of nanoparticles would be highly attractive for their clinical translation. We therefore studied the capabilities of a novel SPCCT scanner to quantify the biodistribution of gold nanoparticles in vivo. PEGylated gold nanoparticles were used. Phantom imaging showed that concentrations measured on gold images correlated well with known concentrations (slope = 0.94, intercept = 0.18, RMSE = 0.18, R2 = 0.99). The SPCCT system allowed repetitive and quick acquisitions in vivo, and follow-up of changes in the AuNP biodistribution over time. Measurements performed on gold images correlated with the inductively coupled plasma-optical emission spectrometry (ICP-OES) measurements in the organs of interest (slope = 0.77, intercept = 0.47, RMSE = 0.72, R2 = 0.93). TEM results were in agreement with the imaging and ICP-OES in that much higher concentrations of AuNPs were observed in the liver, spleen, bone marrow and lymph nodes (mainly in macrophages). In conclusion, we found that SPCCT can be used for repetitive and non-invasive determination of the biodistribution of gold nanoparticles in vivo.

Conjugation of Antibodies with Radiogold Nanoparticles, as an Effector Targeting Agents in Radiobioconjugate Cancer Therapy: Optimized Labeling and Biodistribution Results.

Purpose of the Study:Drug accessibility to the tumor cells is an important area of concern with an anticipation of increasing the efficacy of the drug to be delivered to a specific site. The biogenesis of gold nanoparticles using plant-mediated phytochemical extracts and their possible linkage to cancer antibodies with an aim at delivering the conjugate specifically to the tumor-associated antigen is the basic objective of the research.Materials and Methodology:Radiolabeling of antibodies with gold nanoparticles was carried out by a protocol, and the labeling extent of antibodies was compared with that of a radiogold solution to ordinary particulate size (AuNO-Ab). The amount of radiolabeling was estimated by subjecting the reaction mixtures to thin layer chromatography (ITLC-Silica-gel) in different solvent mediums, both by visual inspection of images of the Siemens Orbitor Gamma Camera ZLC-7500 and also by in vitro counting of the radioactive counts in different quarters of the chromatographic strips. Biodistribution relating to the deposition of injected dose in nontargeting sites (reticuloendothelial system [RES]-localization) was studied and efforts were made for reducing the same.Results:Much improved gold incorporation was confirmed at various molar ratios of gold to immunoglobulin (antibody) using nanogold solution (>85%). The RES uptake in the liver, spleen etc., was observed as a problem and the prior administration of unlabeled nonspecific gammaglobulin (before the actual radiolabeled product) was identified as the suitable blocking agent for this purpose.Conclusion:The study signifies the potential for PEGylated gold nanoparticles of a precise size range, suitable to use as a delivery vehicle for targeting small biomolecules (antibody etc.) to the tumor site. The stability of this labeled immunoconjugate and other toxicity effects under physiological conditions needs further evaluation. If successful, this could be a role model for attaining high tumor/nontumor ratio.