Long-Term Accumulation, Biological Effects and Toxicity of BSA-Coated Gold Nanoparticles in the Mouse Liver, Spleen, and Kidneys.

Introduction: Gold nanoparticles are promising candidates as vehicles for drug delivery systems and could be developed into effective anticancer treatments. However, concerns about their safety need to be identified, addressed, and satisfactorily answered. Although gold nanoparticles are considered biocompatible and nontoxic, most of the toxicology evidence originates from in vitro studies, which may not reflect the responses in complex living organisms. Methods: We used an animal model to study the long-term effects of 20 nm spherical AuNPs coated with bovine serum albumin. Mice received a 1 mg/kg single intravenous dose of nanoparticles, and the biodistribution and accumulation, as well as the organ changes caused by the nanoparticles, were characterized in the liver, spleen, and kidneys during 120 days. Results: The amount of nanoparticles in the organs remained high at 120 days compared with day 1, showing a 39% reduction in the liver, a 53% increase in the spleen, and a 150% increase in the kidneys. The biological effects of chronic nanoparticle exposure were associated with early inflammatory and fibrotic responses in the organs and were more pronounced in the kidneys, despite a negligible amount of nanoparticles found in renal tissues. Conclusion: Our data suggest, that although AuNPs belong to the safest nanomaterial platforms nowadays, due to their slow tissue elimination leading to long-term accumulation in the biological systems, they may induce toxic responses in the vital organs, and so understanding of their long-term biological impact is important to consider their potential therapeutic applications.

Clinical translation of gold nanoparticles.

Gold nanoparticles display unique physicochemical features, which can be useful for therapeutic purposes. After two decades of preclinical progress, gold nanoconstructs are slowly but steadily transitioning into clinical trials. Although initially thought to be "magic golden bullets" that could be used to treat a wide range of diseases, current consensus has moved toward a more realistic approach, where gold nanoformulations are being investigated to treat specific disorders. These therapeutic applications are dictated by the pharmacokinetics and biodistribution profiles of gold nanoparticles. Here, we analyze the current clinical landscape of therapeutic gold nanoconstructs, discuss the shared characteristics that allowed for their transition from bench to bedside, and examine existing hurdles that need to be overcome before they can be approved for clinical use.

Interactions of Nanoparticles with Macrophages and Feasibility of Drug Delivery for Asthma.

Understanding the interaction between nanoparticles and immune cells is essential for the evaluation of nanotoxicity and development of nanomedicines. However, to date, there is little data on the membrane microstructure and biochemical changes in nanoparticle-loaded immune cells. In this study, we observed the microstructure of nanoparticle-loaded macrophages and changes in lipid droplets using holotomography analysis. Quantitatively analyzing the refractive index distribution of nanoparticle-loaded macrophages, we identified the interactions between nanoparticles and macrophages. The results showed that, when nanoparticles were phagocytized by macrophages, the number of lipid droplets and cell volume increased. The volume and mass of the lipid droplets slightly increased, owing to the absorption of nanoparticles. Meanwhile, the number of lipid droplets increased more conspicuously than the other factors. Furthermore, alveolar macrophages are involved in the development and progression of asthma. Studies have shown that macrophages play an essential role in the maintenance of asthma-related inflammation and tissue damage, suggesting that macrophage cells may be applied to asthma target delivery strategies. Therefore, we investigated the target delivery efficiency of gold nanoparticle-loaded macrophages at the biodistribution level, using an ovalbumin-induced asthma mouse model. Normal and severe asthma models were selected to determine the difference in the level of inflammation in the lung. Consequently, macrophages had increased mobility in models of severe asthma, compared to those of normal asthma disease. In this regard, the detection of observable differences in nanoparticle-loaded macrophages may be of primary interest, as an essential endpoint analysis for investigating nanomedical applications and immunotheragnostic strategies.

Emerging trends in the application of gold nanoformulations in colon cancer diagnosis and treatment.

Colorectal cancer is one of the most aggressive types of cancer with about two million new cases and one million deaths in 2020. The side effects of the available chemotherapies and the possibility of developing resistance against treatment highlight the importance of developing new therapeutic options. The development in the field of nanotechnology have introduced the application of nanoparticles (NPs) as a promising approach in the diagnosis and treatments of colorectal cancer and other types of cancer. Gold nanoparticles (AuNPs) are currently one of the most studied materials as they possess unique tunable properties allowing them to play a role in colorectal cancer bioimaging, diagnosis, and therapy. The high surface-to-volume ratio of AuNPs mediates their utilization in drug delivery as well as functionalization to provide specific targeting. Moreover, depending on their physical properties (size, shape), AuNPs can be modified to fit the intended application. However, there are contradictory results around the pharmacokinetics of AuNPs including their biodistribution, clearance, and toxicity. This variation of opinions is most likely due to the development of different AuNPs that vary in shape, size, and surface chemistry, in addition to the conditions under which each research was carried out. The conflicting data represent a challenge in the clinical use of AuNPs suggesting the need to understand the toxicity, fate, and long-term exposure of AuNPs in vivo. Thus, there is an unmet need for the establishment of a publicly available data base for extensive analysis. In this review, we discuss the recent advances in AuNP applications in the treatment and diagnosis of colorectal cancer, mechanisms of action, and clinical challenges.

Computational Studies of Au(I) and Au(III) Anticancer MetalLodrugs: A Survey.

Owing to the growing hardware capabilities and the enhancing efficacy of computational methodologies, computational chemistry approaches have constantly become more important in the development of novel anticancer metallodrugs. Besides traditional Pt-based drugs, inorganic and organometallic complexes of other transition metals are showing increasing potential in the treatment of cancer. Among them, Au(I)- and Au(III)-based compounds are promising candidates due to the strong affinity of Au(I) cations to cysteine and selenocysteine side chains of the protein residues and to Au(III) complexes being more labile and prone to the reduction to either Au(I) or Au(0) in the physiological milieu. A correct prediction of metal complexes' properties and of their bonding interactions with potential ligands requires QM computations, usually at the ab initio or DFT level. However, MM, MD, and docking approaches can also give useful information on their binding site on large biomolecular targets, such as proteins or DNA, provided a careful parametrization of the metal force field is employed. In this review, we provide an overview of the recent computational studies of Au(I) and Au(III) antitumor compounds and of their interactions with biomolecular targets, such as sulfur- and selenium-containing enzymes, like glutathione reductases, glutathione peroxidase, glutathione-S-transferase, cysteine protease, thioredoxin reductase and poly (ADP-ribose) polymerase 1.

Prostate Cancer Targeted X-Ray Fluorescence Imaging via Gold Nanoparticles Functionalized With Prostate-Specific Membrane Antigen (PSMA).

PURPOSE: The gold nanoparticle (GNP) as a promising theranostic probe has been increasingly studied. The tumor-targeting efficiency of GNPs is crucial to increase the therapeutic ratio. In this study, we developed PSMA-targeted GNPs to enhance GNP uptake in prostate cancer and developed an x-ray fluorescence imaging system to noninvasively monitor and assess GNP delivery. METHODS AND MATERIALS: For targeted therapy of prostate cancer, anti-prostate-specific membrane antigen (PSMA) antibodies were conjugated onto PEGylated GNPs through 1-ethyl-3-(-3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) (EDC/NHS) chemistry. In vivo imaging was implemented using an in-house-developed dual-modality computed tomography (CT) and x-ray fluorescence CT (XFCT) system on mice bearing subcutaneous LNCaP prostate tumors. After intravenous administration of GNPs (15 mg/mL, 200 µL), the x-ray fluorescence signals from the tumor were collected at various time points (5 minutes to approximately 30 hours) for GNP pharmacokinetics analysis. At 24 hours after administration, x-ray fluorescence projection (XRFproj) and XFCT imaging were conducted to evaluate the prostate tumor uptake of active- and passive-targeting GNPs. Inductively coupled plasma mass spectrometry analysis was adopted as a benchmark to verify the quantification accuracy of XRFproj/XFCT imaging. RESULTS: Fluorescence microscopic imaging confirmed the enhanced (approximately 4 times) targeting efficiency of PSMA-targeted GNPs in vitro. The pharmacokinetics analysis showed enhanced tumor uptake/retention of PSMA-targeted GNPs and revealed that the peak tumor accumulation appeared at approximately 24 hours after intravenous administration. Both XRFproj and XFCT imaging presented their accuracy in quantifying GNPs within tumors noninvasively. Moreover, XFCT imaging verified its unique capabilities to simultaneously determine the heterogeneous spatial distribution and the concentration of GNPs within tumors in vivo. CONCLUSIONS: In conjunction with PSMA-targeted GNPs, XRFproj/XFCT would be a highly sensitive tool for targeted imaging of prostate cancer, benefiting the elucidation of mechanisms of GNP-assisted prostate-cancer therapy.

The cancer therapy materialization by theranostic nanoparticles based on gold doped iron oxide under electromagnetic field amplification.

The harnessing of the cancer X-ray radiation therapy by gold-decorated Fe3O4 theranostic nanoparticles (Au-Fe3O4 NPs) under electromagnetic field was articulated. The applied electromagnetic field could assemble the NPs inside cell in oriented field direction and enhance the local irradiation dose inside cell. By materializing NPs, the absorption of the energy exposed by X-ray radiation under electromagnetic field was restricted. The cytotoxic properties of the Au-Fe3O4 NPs were assessed using MTT assay in L929, HeLa and PC3 cell lines under radiation and dark conditions. The efficiency of the Au-Fe3O4 NPs under 2 Gy dose radiations was higher than 6 Gy radiations in untreated cells. The in vitro measurements showed that under electromagnetic field and X-ray radiation therapy with Au-Fe3O4 NPs, around 90% of the cancer cells population was annihilated. The in vivo measurements indicated that the tumor shape and size under X-ray with Au-Fe3O4 NPs after 3 weeks were efficiently deteriorated.

Superparamagnetic iron oxide-gold nanoparticles conjugated with porous coordination cages: Towards controlled drug release for non-invasive neuroregeneration.

This paper reports a smart intracellular nanocarrier for sustainable and controlled drug release in non-invasive neuroregeneration. The nanocarrier is composed by superparamagnetic iron oxide-gold (SPIO-Au) core-shell nanoparticles (NPs) conjugated with porous coordination cages (PCCs) through the thiol-containing molecules as bridges. The negatively charged PCC-2 and positively charged PCC-3 are compared for intracellular targeting. Both types result in intracellular targeting via direct penetration across cellular membranes. However, the pyrene (Py)-PEG-SH bridge enabled functionalization of SPIO-Au NPs with PCC-3 exhibits higher interaction with PC-12 neuron-like cells, compared with the rhodamine B (RhB)-PEG-SH bridge enabled case and the stand-alone SPIO-Au NPs. With neglectable toxicities to PC-12 cells, the proposed SPIO-Au-RhB(Py)-PCC-2(3) nanocarriers exhibit effective drug loading capacity of retinoic acid (RA) at 13.505 µg/mg of RA/NPs within 24 h. A controlled release of RA is achieved by using a low-intensity 525 nm LED light (100% compared to 40% for control group within 96 h).

Reversing the Chirality of Surface Ligands Can Improve the Biosafety and Pharmacokinetics of Cationic Gold Nanoclusters.

Severe toxicity and rapid in vivo clearance of cationic nanomaterials seriously hinder their clinical translation. Present strategies to improve the biosafety and in vivo performance of cationic nanomaterials require neutralization of positive charge, which often compromises their efficacy. Herein, we report that substituting L-glutathione (L-GSH) on cationic gold nanoclusters (GNCs) with its D-counterpart can effectively improve the biosafety and pharmacokinetics. Compared with L-GNCs, D-GNCs do not exhibit cellular cytotoxicity, hemolysis, or acute damage to organs. Cationic D-GNCs show less cell internalization than L-GNCs, and do not induce cellular apoptosis. In vivo, the chirality of surface ligands distinctly affects the pharmacokinetics and tumor targeting abilities of D-/L-GNCs. D-GNCs show higher extended circulation time in blood plasma compared to similarly-sized and poly (ethylene glycol)-modified gold nanoparticles. This work demonstrates that the choice of chirality of surface ligands can determine toxicities and pharmacokinetics of cationic nanomaterials.

[Development of Drug Delivery Technology and Nanomedicine by Using Gold Nanoparticles].

Nanomedicine is a new medical field involving the use of nanoparticles. Early examples of biocompatible nanomedicines include liposomes (Doxil®) and albumin nanoparticles (Abraxane®), and promising new nanomedicines include nanocarriers such as nanomicelles and nanoemulsions. A new trend towards the use of metal-based nanoparticles, including gold nanoparticles, has led to global clinical trials. These particles exhibit novel properties compared to conventional nanomedicines such as liposomes and albumin nanoparticles. These properties hold promise for nanomedicines, and thus the biodistribution and pharmacokinetics of metal-based nanoparticles should be carefully investigated. This had led to an increasing number of clinical trials investigating metal nanoparticles and inorganic nanoparticles. The present review evaluates multi-functional gold nanoparticles described in recent articles and shows that the unique properties of gold nanoparticles are applicable for not only drug delivery, but also for imaging. The combined therapeutic modality between therapeutics and diagnostics is called "theranostics" and is promising for future personalized cancer therapy. This review also introduces recent research from our laboratory involving the use of various kinds of molecules [polyethylene glycol (PEG), drug/cyclodextrin inclusion complexes, biosimilars and small interfering (siRNAs)] loaded onto and/or conjugated with gold nanoparticles.

Gold Nanoparticles Perturb Drug-Metabolizing Enzymes and Antioxidants in the Livers of Male Rats: Potential Impact on Drug Interactions.

BACKGROUND AND AIM: With the wide applications of chitosan and gold nanoparticles in drug delivery and many consumer products, there is limited available information about their effects on drug-metabolizing enzymes (DMEs). Changes in DMEs could result in serious drug interactions. Therefore, this study aimed to investigate the effects of exposure to chitosan or gold nanoparticles on hepatic Phase I and II DMEs, liver function and integrity, oxidative damage and liver architecture in male rats. METHODS: Animals were divided into three equal groups: a control group, a group treated with chitosan nanoparticles (200 mg/kg, 50±5 nm) and a group treated with gold nanoparticles (4 mg/kg, 15±5 nm). Rats were orally administered their respective doses daily for 10 days. RESULTS: Both chitosan and gold nanoparticles decreased the body weights by more than 10%. Gold nanoparticles reduced the activities of antioxidants (superoxide dismutase and catalase), and reduced glutathione level and elevated the malondialdehyde level in the liver. Gold nanoparticles caused significant reductions in CYP1A1, CYP2E1, quinone oxidoreductase1, and glutathione S-transferase and elevated CYP2D6 and N-acetyl transferase2. Chitosan elevated CYP2E1 and CYP2D6 and reduced UDP-glucuronosyltransferase 1A1. Both nanoparticles disturbed the architecture of the liver, but the deleterious effects after gold nanoparticles treatment were more prominent. CONCLUSION: Taken together, gold nanoparticles severely perturbed the DMEs and would result in serious interactions with many drugs, herbs, and foods.

Redispersion of cryoaggregated gold nanoparticle by means of laser irradiation and effect on biological interactions.

Agglomeration/aggregation is an indispensable phenomenon observed by different nanoparticles. In the present study, commercial grade (50 nm) and chemically synthesized (40 nm) gold nanoparticles (AuNPs) were aggregated at sub-zero temperatures, followed by disruption of the AuNP aggregates via nanosecond laser-ablation and subsequent effect on biological interactions. AuNPs were characterized pre/post laser-ablation via UV-visible spectroscopy, transmission electron microscopy, atomic force microscopy, etc. The process of freezing (aggregation) and laser-ablation (dispersion) was performed multiple times, in order to compare the yield of nanoparticles after each cycle of laser-ablation. Further, AuNPs pre/post laser-ablation were assessed for cytotoxicity, protein-corona formation, and cell-uptake by in vitro studies using RAW264.7, Caco-2 and Neuro-2 a cell lines. Aggregates for both the types of AuNPs displayed fragmentation following first cycle of laser-ablation. In addition, AuNPs obtained after fragmentation of the aggregates showed reduction in diameter and reshaping, as compared to native AuNPs. The size and shape of the nanoparticles after second and third cycle of laser-ablation was same as that obtained after first cycle of ablation. Both laser-ablated and native AuNPs showed similar effects on viability of RAW 264.7 and Caco-2 cells, after 24 h and 48 h of exposure. Cell uptake of native and laser-ablated AuNPs was observed to be a size dependent phenomenon. Present findings showed that nanosecond laser ablation of cryoaggregated AuNPs lead to changes in the physical properties of AuNPs post ablation like size and shape, however, biological interaction with cells remained same. This work is first report on biological interactions of AuNPs generated via laser-ablation of cryoaggregated AuNPs.

A Systematic comparison of in vitro cell uptake and in vivo biodistribution for three classes of gold nanoparticles with saturated PEG coatings.

A great deal of attention has been focused on nanoparticles for cancer therapy, with the promise of tumor-selective delivery. However, despite intense work in the field over many years, the biggest obstacle to this vision remains extremely low delivery efficiency of nanoparticles into tumors. Due to the cost, time, and impact on the animals for in vivo studies, the nanoparticle field predominantly uses cellular uptake assays as a proxy to predict in vivo outcomes. Extensive research has focused on decreasing macrophage uptake in vitro as a proxy to delay nanoparticle accumulation in the mononuclear phagocytic system (MPS), mainly the liver and spleen, and thereby increase tumor accumulation. We have recently reported novel synthetic methods employing small molecule crosslinkers for the controlled assembly of small nanoparticles into larger aggregates and found that these nanoaggregates had remarkably high surface coverage and low cell uptake, even in macrophages. We further found that this extremely low cellular uptake could be recapitulated on solid gold nanoparticles by densely coating their surface with small molecules. Here we report our studies on the biodistribution and clearance of these materials in comparison to more conventional PEGylated gold nanoparticles. It was expected that the remarkably low macrophage uptake in vitro would translate to extended blood circulation time in vivo, but instead we found no correlation between either surface coverage or in vitro macrophage cell uptake and in vivo blood circulation. Gold nanoaggregates accumulate more rapidly and to a higher level in the liver compared to control gold nanoparticles. The lack of correlation between in vitro macrophage uptake and in vivo blood circulation suggests that the field must find other in vitro assays to use as a primary proxy for in vivo outcomes or use direct in vivo experimentation as a primary assay.

Preclinical Evaluation of NHS-Activated Gold Nanoparticles Functionalized with Bombesin or Neurotensin-Like Peptides for Targeting Colon and Prostate Tumours.

Recent advances and large-scale use of hybrid imaging modalities like PET-CT have led to the necessity of improving nano-drug carriers that can facilitate both functional and metabolic screening in nuclear medicine applications. In this study, we focused on the evaluation of four potential imaging nanoparticle structures labelled with the 68Ga positron emitter. For this purpose, we functionalized NHS-activated PEG-gold nanoparticles with 68Ga-DOTA-Neuromedin B, 68Ga-DOTA-PEG(4)-BBN(7-14), 68Ga-DOTA-NT and 68Ga-DOTA-Neuromedin N. In vitro binding kinetics and specific binding to human HT-29 colon carcinoma cells and DU-145 prostate carcinoma cells respectively were assessed, over 75% retention being obtained in the case of 68Ga-DOTA-PEG(4)-BBN(7-14)-AuNP in prostate tumour cells and over 50% in colon carcinoma cells. Biodistribution in NU/J mice highlighted a three-fold uptake increase in tumours at 30 min post-injection of 68Ga-DOTA-NT-AuNP and 68Ga-DOTA-PEG(4)-BBN(7-14)-AuNP compared to 68Ga-DOTA-NT and 68Ga-DOTA-PEG(4)-BBN(7-14) respectively, therewith fast distribution in prostate and colon tumours and minimum accumulation in non-targeted tissues.

Hybrid (2D/3D) Dosimetry of Radiolabeled Gold Nanoparticles for Sentinel Lymph Node Detection in Patients with Breast Cancer.

Previously, we reported the preparation and preclinical studies of 99mTc-labeled gold nanoparticles-mannose (99mTc-AuNP-mannose) with potential for sentinel lymph node (SLN) detection by using nuclear medicine procedures. This study aimed to evaluate the biokinetics and hybrid (2D/3D) dosimetry of 99mTc-AuNP-mannose in five patients with breast cancer under a sentinel lymph node detection protocol. Anterior and posterior whole-body planar images (2D, at 0.5, 2, 6, and 24 h) and single-photon emission computed tomography (3D at 6.5 h)/computed tomography (SPECT/CT) images were acquired after 99mTc-AuNP-mannose administration (37 MBq). Through a hybrid quantification method, activity in tissues of interest at the different acquisition times was determined and integrated over time to obtain the total nuclear transformations (N), as well as the mean residence time, in each tissue. N values and the OLINDA code were used for estimating the internal radiation absorbed doses. Results demonstrated that 99mTc-AuNP-mannose successfully accumulates and remains up to 24 h in the sentinel lymph node without detectable migration to other lymph nodes and no side effects on patients. Negligible absorption of the radiolabeled nanoparticles into the circulatory system was observed, from which the radio-nanosystem is rapidly eliminated by kidneys. Hybrid (2D/3D) dosimetry evaluations showed equivalent doses to SLN, breast, and kidneys of 172.34, 5.32, and 0.08 mSv/37 MBq, respectively, with an effective dose of 2.05E - 03 mSv/MBq. The mean effective residence time in SLN was 0.92 h. This preliminary study indicates that the use of 99mTc-AuNP-mannose for successful SLN detection in patients is safe, producing an effective dose at the level recommended for diagnostic studies (<10 mSv).

Alginate mediated functional aggregation of gold nanoclusters for systemic photothermal therapy and efficient renal clearance.

For renal clearable nanoagents, it is challenging to delay the renal clearance to acquire efficient tumor accumulation. Herein, we report sodium alginate (SA) stabilized gold (Au) NCs. The Au NCs are of high biocompatibility and renal clearable. Contributed from the ligands of SA, the half-life (t1/2) of Au NCs is prolonged to ∼9.3 h, enhancing the tumor accumulation rate to 10.4 %ID/g. In tumor microenvironment (TME), the Au NCs are stimulated to functionally aggregate, which switches on the photothermal effect. Animal experiments prove that Au NCs aggregates are efficient photothermal therapy (PTT) agents for both local treatment of single tumors and systemic treatment of double-tumor models without causing noticeable side effects, confirming the biosecurity of Au NCs and systemic PTT. The switchable strategy of PTT may signify the establishment of a new systemic therapeutic methodology.

New organic/inorganic nanohybrids of targeted pullulan derivative/gold nanoparticles for effective drug delivery systems.

This study aimed to develop new organic/inorganic nanohybrids of targeted pullulan derivative/gold nanoparticles (FA-PABA-Q188-PUL@AuNPs) to improve the selectivity and efficacy of drugs. The chemical structure of targeted pullulan derivative, folic acid-decorated para-aminobenzoic acid-quat188-pullulan (FA-PABA-Q188-PUL), was designed for reducing, stabilizing, capping, and functionalizing AuNPs. Here, the key factors, including pH, temperature, and FA-PABA-Q188-PUL concentrations, were systematically optimized to control the morphology, size, and functionalization of multifunctional FA-PABA-Q188-PUL@AuNPs. Spherical FA-PABA-Q188-PUL@AuNPs obtained by a green, simple, and bio-inspired strategy under the optimum conditions were thoroughly characterized and had an average size of 12.6 ± 1.5 nm. The anticancer drug DOX was successfully loaded on monodispersed FA-PABA-Q188-PUL@AuNPs and the system exhibited excellent intracellular uptake, specificity, and physicochemical properties. The pH-responsive DOX release from FA-PABA-Q188-PUL@AuNPs-DOX showed fast release (85% after 72 h) under acidic conditions. Furthermore, FA-PABA-Q188-PUL@AuNPs-DOX enhanced the anticancer activity of DOX toward Chago-k1 cancer cells up to 4.8-fold and showed less cytotoxicity toward normal cells than free DOX. The FA-PABA-Q188-PUL@AuNPs-DOX induced the death of cells by increasing late apoptotic cells (26.4%) and arresting the cell cycle at S-G2/M phases. These results showed that innovative FA-PABA-Q188-PUL@AuNPs should be considered as new candidate platforms for anticancer drug delivery systems.

X-ray induced photodynamic therapy (PDT) with a mitochondria-targeted liposome delivery system.

In this study, we constructed multifunctional liposomes with preferentially mitochondria-targeted feature and gold nanoparticles-assisted synergistic photodynamic therapy. We systemically investigated the in vitro X-ray triggered PDT effect of these liposomes on HCT 116 cells including the levels of singlet oxygen, mitochondrial membrane potential, cell apoptosis/necrosis and the expression of apoptosis-related proteins. The results corroborated that synchronous action of PDT and X-ray radiation enhance the generation of cytotoxic reactive oxygen species produced from the engineered liposomes, causing mitochondrial dysfunction and increasing the levels of apoptosis.

Disulfiram-gold-nanorod integrate for effective tumor targeting and photothermal-chemical synergistic therapy.

Herein, we successfully constructed a combination therapeutic nanoplatform with high tumor targeting for cancer treatment by integrating gold nanorods with disulfiram (denoted Au-DSF). The Au-DSF integrates possess a uniform length (70 nm), excellent photothermal conversion ability and a high DSF loading content (23.2%), and the loaded DSFs show glutathione-, acid-, and laser-responsive release properties. The Au-DSF integrates show significantly enhanced cellular uptake efficiency in breast cancer cells due to the ability of DSF to chelate to the intracellular copper (Cu) which is present at high concentrations. Furthermore, the Au-DSF exhibits improved circulation time (mean residence time = 28.4 h) and increased tumor accumulation (12.0%), due to the targeting of DSF to the abundant Cu ions at the tumor site. Moreover, the DSF/Cu complexes potently elevate reactive oxygen species, which effectively induce cancer cell apoptosis. In vivo experiments show that the Au-DSF integrates dramatically decrease tumor size via photothermal therapy and chemotherapy. Hematoxylin-eosin and TUNEL staining show that the Au-DSF integrates induce necrosis and apoptosis in cancer cells. The high therapeutic efficiency of the Au-DSF integrates for breast cancer is further demonstrated by the reduced elasticity seen in ultrasound elastography, and the absence of perfusion of the contrast agent in contrast-enhanced ultrasound imaging in tumors.

Endosomal Confinement of Gold Nanospheres, Nanorods, and Nanoraspberries Governs Their Photothermal Identity and Is Beneficial for Cancer Cell Therapy.

Gold nanoparticles can act as photothermal agents to generate local tumor heating and subsequent depletion upon laser exposure. Herein, photothermal heating of four gold nanoparticles and the resulting induced cancer cell death are systematically assessed, within extra- or intracellular localizations. Two state-of-the-art gold nanorods are compared with small nanospheres (single-core) and nanoraspberries (multicore). Heat generation is measured in water dispersion and in cancer cells, using lasers at wavelengths of 680, 808, and 1064 nm, covering the entire range used in photothermal therapy, defined as near infrared first (NIR-I) and second (NIR-II) windows, with NIR-II offering more tissue penetration. When dispersed in water, gold nanospheres provide no significant heating, gold nanorods are efficient in NIR-I, and only gold nanoraspberries are still heating in NIR-II. However, in cells, due to endosomal confinement, all nanoparticles present an absorption red-shift translating visible and NIR-I absorbing nanoparticles into effective NIR-I and NIR-II nanoheaters, respectively. The gold nanorods then become competitive with the multicore nanoparticles (nanoraspberries) in NIR-II. Similarly, once in cells, gold nanospheres can be envisaged for NIR-I heating. Remarkably, nanoraspberries are efficient nanoheaters, whatever the laser applied, and the extra- versus intra-cellular localization demonstrates treatment versatility.