Novel gold nanoparticles coated with somatostatin as a potential delivery system for targeting somatostatin receptors

Targeting of G-protein coupled receptors (GPCRs) like somatostatin-14 (SST-14) could have a potential interest in delivery of anti-cancer agents to tumor cells. Attachment of SST to different nano-carriers e.g. polymeric nanoparticles is limited due to the difficulty of interaction between SST itself and those nano-carriers. Furthermore, the instability problems associated with the final formulation. Attaching of SST to gold nanoparticles (AuNPs) using the positive and negative charge of SST and citrate-AuNPs could be considered a new technique to get stable non-aggregated AuNPs coated with SST. Different analyses techniques have been performed to proof the principle of coating between AuNPs and SST. Furthermore, cellular uptake studies on HCC-1806, HELA and U-87 cell lines has been investigated to show the ability of AuNPs coated SST to enter the cells via SST receptors. Dynamic light scattering (DLS) indicated a successful coating of SST on the MUA-AuNPs surface. Furthermore, all the performed analysis including DLS, SDS-PAGE and UV-VIS absorption spectra indicated a successful coating of AuNPs with SST. Cellular uptake studies on HCC-1806, HELA and U-87 cell lines showed that the number of AuNPs-SST per cell is signiflcantly higher compared to citrate-AuNPs when quantified using inductively coupled plasma spectroscopy. Moreover, the binding of AuNPs-SST to cells can be suppressed by addition of antagonist, indicating that the binding of AuNPs-SST to cells is due to receptor-specific binding. In conclusion, AuNPs could be attached to SST via adsorption to get stable AuNPs coated SST. This new formulation has a potential to target SST receptors localized in many normal and tumor cells.     

Tumor Targeting Strategies of Smart Fluorescent Nanoparticles and Their Applications in Cancer Diagnosis and Treatment

Advantages such as strong signal strength, resistance to photobleaching, tunable fluorescence emissions, high sensitivity, and biocompatibility are the driving forces for the application of fluorescent nanoparticles (FNPs) in cancer diagnosis and therapy. In addition, the large surface area and easy modification of FNPs provide a platform for the design of multifunctional nanoparticles (MFNPs) for tumor targeting, diagnosis, and treatment. In order to obtain better targeting and therapeutic effects, it is necessary to understand the properties and targeting mechanisms of FNPs, which are the foundation and play a key role in the targeting design of nanoparticles (NPs). Widely accepted and applied targeting mechanisms such as enhanced permeability and retention (EPR) effect, active targeting, and tumor microenvironment (TME) targeting are summarized here. Additionally, a freshly discovered targeting mechanism is introduced, termed cell membrane permeability targeting (CMPT), which improves the tumor‐targeting rate from less than 5% of the EPR effect to more than 50%. A new design strategy is also summarized, which is promising for future clinical targeting NPs/nanomedicines design. The targeting mechanism and design strategy will inspire new insights and thoughts on targeting design and will speed up precision medicine and contribute to cancer therapy and early diagnosis.     

An anisotropic propagation technique for synthesizing hyperbranched polyvillic gold nanoparticles

Of late, many synthesis processes have been studied to develop irregular nano-morphologies of gold nanostructures for biomedical applications in order to increase the efficacy of nanoparticle theranostics, tune the plasmonic absorbance spectra, and increase the sensitivity of biomolecule detection through surface enhanced Raman spectroscopy. Here we report, a novel, non-seed mediated versatile single pot synthesis method capable of producing hyperbranched gold “nano-polyvilli” with more than 50–90 branching nanowires propagating from a single origin within each structure. The technique was capable of achieving precise tuning of the branch propagation where the branching could be controlled by varying the duration of incubation, temperature, and hydrogen ion concentration.

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Specific Photothermal Ablation Therapy of Endometriosis by Targeting Delivery of Gold Nanospheres

Endometriosis is difficult to treat since the side effects of the current therapeutic method and the high recurrence rate; thus, newer and safer therapeutic approaches are urgently needed. This work investigates the enhanced permeability and retention effect of CdTe quantum dots (QDs) and hollow gold nanospheres (HAuNS) in endometriosis to increase the delivery of HAuNS into lesion cells. The surface of HAuNS is successfully conjugated with a TNYL peptide that has specific affinity for the EphB4 receptor, which is a member of the Eph family of receptor tyrosine kinases. It is found that the EphB4 receptor is overexpressed in endometriosis lesions. The data indicate that both QDs and HAuNS can efficiently accumulate in endometriotic lesions through permeable vessels and the TNYL‐conjugated HAuNS (TNYL‐HAuNS) accumulate more via the interaction with EphB4. The specific photothermal ablation therapy based on TNYL‐HAuNS significantly inhibits the growth of the endometriotic volume and induces the atrophy and degeneration of ectopic endometrium with no detectable toxicity to the normal organs. The level of TNF‐α and estradiol also significantly decreases in the endometriotic lesions, indicating that the treatment enables a recovery from hormonal imbalance and inflammatory injury. This work can be a valuable reference for future endometriosis therapy.     

Nanosphere molecularly imprinted polymers doped with gold nanoparticles for high selectivity molecular sensors

We report the first attempt of using molecularly imprinted polymers (MIPs) in the shape of nanoparticles that were doped with gold nanoparticles (AuNPs) for surface enhanced Raman scattering (SERS)-based sensing of molecular species.Specifically,AuNPs doped molecularly imprinted nano-spheres (AuNPs@nanoMIPs) were synthesized by one-pot precipitation polymerization using Sudan Ⅳ as the template for the SERS sensing.The AuNPs@nanoMIPs were characterized by various modes of scanning transmission electron microscopy (STEM) that showed the exact location of the AuNPs inside the MIP particles.The effects of Au concentration and solution stirring on the shape and the polydispersity of the particles were studied.Significant enhancement of the Raman signals was observed only when the MIP particles were doped with the AuNPs.The SERS signal improved significantly with increase in the Au concentration inside the AuNPs@nanoMIPs.Selectivity measurements of the Sudan Ⅳ imprinted AuNPs@nanoMIPs carried out with different Sudan derivatives showed high selectivity of the AuNPs-doped MIP particles.     

Interaction of gold nanoparticles with proteins and cells

Abstract

Gold nanoparticles (Au NPs) possess many advantages such as facile synthesis, controllable size and shape, good biocompatibility, and unique optical properties. Au NPs have been widely used in biomedical fields, such as hyperthermia, biocatalysis, imaging, and drug delivery. The broad application range may result in hazards to the environment and human health. Therefore, it is important to predict safety and evaluate therapeutic efficiency of Au NPs. It is necessary to establish proper approaches for the study of toxicity and biomedical effects. In this review, we first focus on the recent progress in biological effects of Au NPs at the molecular and cellular levels, and then introduce key techniques to study the interaction between Au NPs and proteins. Knowledge of the biomedical effects of Au NPs is significant for the rational design of functional nanomaterials and will help predict their safety and potential applications.     

HDL‐Mimicking Peptide–Lipid Nanoparticles with Improved Tumor Targeting

Targeted delivery of intracellularly active diagnostics and therapeutics in vivo is a major challenge in cancer nanomedicine. A nanocarrier should possess long circulation time yet be small and stable enough to freely navigate through interstitial space to deliver its cargo to targeted cells. Herein, it is shown that by adding targeting ligands to nanoparticles that mimic high‐density lipoprotein (HDL), tumor‐targeted sub‐30‐nm peptide–lipid nanocarriers are created with controllable size, cargo loading, and shielding properties. The size of the nanocarrier is tunable between 10 and 30 nm, which correlates with a payload of 15–100 molecules of fluorescent dye. Ligand‐directed nanocarriers targeting epidermal growth factor receptor (EGFR) are confirmed both in vitro and in vivo. The nanocarriers show favorable circulation time, tumor accumulation, and biodistribution with or without the targeting ligand. The EGFR targeting ligand is proved to be essential for the EGFR‐mediated tumor cell uptake of the nanocarriers, a prerequisite of intracellular delivery. The results demonstrate that targeted HDL‐mimetic nanocarriers are useful delivery vehicles that could open new avenues for the development of clinically viable targeted nanomedicine.     

A Highly Efficient Tumor‐Targeting Nanoprobe with a Novel Cell Membrane Permeability Mechanism

Efficient tumor targeting has been a great challenge in the clinic for a very long time. The traditional targeting methods based on enhanced permeability and retention (EPR) effects show only an ≈5% targeting rate. To solve this problem, a new graphene‐based tumor cell nuclear targeting fluorescent nanoprobe (GTTN), with a new tumor‐targeting mechanism, is developed. GTTN is a graphene‐like single‐crystalline structure amphiphilic fluorescent probe with a periphery that is functionalized by sulfonic and hydroxyl groups. This probe has the characteristic of specific tumor cell targeting, as it can directly cross the cell membrane and specifically target to the tumor cell nucleus by the changed permeability of the tumor cell membranes in the tumor tissue. This new targeting mechanism is named the cell membrane permeability targeting (CMPT) mechanism, which is very different from the EPR effect. These probes can recognize tumor tissue at a very early stage and track the invasion and metastasis of tumor cells at the single cell level. The tumor‐targeting rate is improved from less than 5% to more than 50%. This achievement in efficient and accurate tumor cell targeting will speed up the arrival of a new era of tumor diagnosis and treatment.     

Interactions of human endothelial cells with gold nanoparticles of different morphologies

The interactions between noncancerous, primary endothelial cells and gold nanoparticles with different morphologies but the same ligand capping are investigated. The endothelial cells are incubated with gold nanospheres, nanorods, hollow gold spheres, and core/shell silica/gold nanocrystals, which are coated with monocarboxy (1-mercaptoundec-11-yl) hexaethylene glycol (OEG). Cell viability studies show that all types of gold particles are noncytotoxic. The number of particles taken up by the cells is estimated using inductively coupled plasma (ICP), and are found to differ depending on particle morphology. The above results are discussed with respect to heating efficiency. Using experimental data reported earlier and theoretical model calculations which take into account the physical properties and distribution of particles in the cellular microenvironment, it is found that collective heating effects of several cells loaded with nanoparticles must be included to explain the observed viability of the endothelial cells.     

Interactions of gold nanoparticles with the interior of hollow graphitized carbon nanofibers

Interactions of free-standing gold nanoparticles and hollow graphitized nanofibers in colloidal suspension are investigated, revealing the first example of the controlled arrangement of nanoparticles inside nano-containers, as directed by their internal structure. The ordering is highly effective for small gold nanoparticles whose sizes are commensurate with the height of graphitic step-edges in the graphitized carbon nanofibers and is less effective for larger gold nanoparticles. Studies aimed at understanding the role of the organic-solvent surface tension, employed for the filling experiments, demonstrate that gold nanoparticles become preferentially anchored into the hollow graphitized carbon nanofibers under a mixture of pentane/CO(2) in supercritical conditions. It is shown that a three-step cleaning procedure enables effective removal of gold nanoparticles adsorbed on the exterior surface of graphitized carbon nanofibers, while ordered arrays of encapsulated nanoparticles are retained.     

Salinomycin nanoparticles interfere with tumor cell growth and the tumor microenvironment in an orthotopic model of pancreatic cancer

Aims: Recently, salinomycin (SAL) has been reported to inhibit proliferation and induce apoptosis in various tumors. The aim of this study was to deliver SAL to orthotopic model of pancreatic cancer by the aid of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs).

Methods: The NPs were physico-chemically characterized and evaluated for cytotoxicity on luciferase-transduced AsPC-1 cells in vitro as well as implanted orthotopically into the pancreas of nude mice.

Results: SAL (3.5 mg/kg every other day) blocked tumor growth by 52% compared to the control group after 3 weeks of therapy. Western blotting of tumor protein extracts indicated that SAL treatment leads to up-regulation of E-cadherin, β-catenin, and transforming growth factor beta receptor (TGFβR) expressions in AsPC-1 orthotopic tumor. Noteworthy, immunofluorescence staining of adjacent tumor sections showed that treatment with SAL NPs cause significant apoptosis in the tumor cells rather than the stroma. Further investigations also revealed that TGFβR2 over-expression was induced in stroma cells after treatment with SAL NPs.

Conclusion: These results highlight SAL-loaded PLGA NPs as a promising system for pancreatic cancer treatment, while the mechanistic questions need to be subsequently tested.     

Plasmonic-coupling-based sensing by the assembly and disassembly of dipycolylamine-tagged gold nanoparticles induced by complexing with cations and anions

A surface-plasmon-coupling-mediated sensor system is developed based on Au nanoparticles tagged with a coordinative dipycolylamine and lipoyl-anchored naphthalimide derivative (AuNP@DPA). The AuNPs with tailored ligands exhibit distinct sensing activity via sequential assembly into nanoparticle aggregates induced by metal ion complexing, and disassembly in the presence of pyrophosphate (PPi) anions, which is accompanied by a swift, reversible color change due to a surface plasmon resonance coupling effect. It is found that divalent metal ions are more effective than mono- or tri-valent ions in the aggregate formation process, Mn(2+)-induced aggregates are more sensitive to the capture of PPi anions than other AuNP aggregates, and the disassembly upon anion complexation exhibits a highly selective response. The AuNP@DPA-based molecular recognition system also demonstrates a viable performance for the detection of total selective metal ions present in different types of water analytes.     

Albumin as a carrier for NO delivery: preparation,physicochemical characterization,and interaction with gold nanoparticles

Background: Nitric oxide (NO) is a gaseous transmitter playing numerous physiological roles and characterized by a short half-life. Its binding to endogenous thiols increases its stability, facilitating its storage and transport. The purpose of this study was to investigate the nitrosated serum albumin (SA-SNO) and to provide a reference for its easy preparation for further use in in vitro studies.

Methods: Serum albumin (SA) was S-nitrosated by reacting with (i) NaNO₂ in acidic medium; (ii) different low-molecular weight S-nitrosothiols (RSNO) (S-nitrosocysteine (CysNO), S-nitrosoglutathione (GSNO), and S,S'-dinitrosobucillamine (Buc(NO)₂)); and (iii) diethylamine NONOate (DEA/NO). SA-SNO was purified by size exclusion chromatography and the S-nitrosation site and the rate were studied by mass spectrometry and Griess–Saville assay, respectively. Then, SA-SNO was characterized by spectrofluorimetry, dynamic light scattering, and circular dichroism. Finally, SA-SNO reactivity with citrate stabilized gold nanoparticles (AuNP-citrate) was investigated via determination of NO release.

Results: S-nitrosation rates of SA were 90.1?±?3.3, 76.8?±?2.7, 80.3?±?3.2, 84.8?±?5.0, and 15.4?±?1.9% (n?=?5), when SA was reacted with acidified NaNO₂, CysNO, GSNO, Buc(NO)₂, and DEA/NO, respectively. The physicochemical characterization indicated that the resulting product corresponded to a mono-S-nitrosothiol (on cysteine-34), and the conformational construction remained unchanged. Stability studies showed that the NO content was preserved over 1 week. AuNP-citrate reacted with SA-SNO with increase of its hydrodynamic diameter but preservation of SNO bond.

Conclusions: SA-SNO prepared and stored under the reported conditions affords a well-defined reference suitable for in vitro studies.     

Importance of nanoparticle size in colorimetric and SERS-based multimodal trace detection of Ni(II) ions with functional gold nanoparticles

Colorimetric detection of analytes using gold nanoparticles along with surface-enhanced Raman spectroscopy (SERS) are areas of intense research activity since they both offer sensing of very low concentrations of target species. Multimodal detection promotes the simultaneous detection of a sample by a combination of different techniques; consequently, surface chemistry design in the development of multimodal nanosensors is important for rapid and sensitive evaluation of the analytes by diverse analytical methods. Herein it is shown that nanoparticle size plays an important role in the design of functional nanoparticles for colorimetric and SERS-based sensing applications, allowing controlled nanoparticle assembly and tunable sensor response. The design and preparation of robust nanoparticle systems and their assembly is reported for trace detection of Ni(II) ions as a model system in an aqueous solution. The combination of covalently attached nitrilotriacetic acid moieties along with the L-carnosine dipeptide on the nanoparticle surface represents a highly sensitive platform for rapid and selective detection of Ni(II) ions. This systematic study demonstrates that significantly lower detection limits can be achieved by finely tuning the assembly of gold nanoparticles of different core sizes. The results clearly demonstrate the feasibility and usefulness of a multimodal approach.     

Comparative enhancement of curcumin cytotoxic photodynamic activity by nanoliposomes and gold nanoparticles with pharmacological appraisal in HepG2 cancer cells and Erlich solid tumor model

Curcumin is a natural pigment that generates singlet oxygen upon light excitation, hence it can be used as a photosensitizer in photodynamic therapy. The extremely low water solubility and poor systemic bioavailability make curcumin a challenging molecule to be used clinically. In this study, two nanocarrier systems for curcumin were prepared and characterized; nanoliposomes and polyvinyl pyrrolidone-capped gold nanoparticles. The dark and photocytotoxicity were investigated as a function of light fluence rate (100 and 200?mW/cm²) on HepG2 cancer cells. In vivo Erlich tumor model was developed and comparison of the tumor volume, survival rate, and histopathological alterations was made for the two nanocarriers. Results showed that both curcumin nanocarriers were successfully prepared and characterized. Light irradiation was able to augment the cytotoxicity of both curcumin liposomes and gold nanoparticles, with the former being superior in cytotoxicity compared to the latter. The tumor size was almost diminished 1 month post-photodynamic treatment for both systems with regression in the number of tumor cells upon histopathological evaluation, with curcumin liposomes producing better tumor regression than gold nanoparticles with comparable survival rate. Liposomes were confirmed to be superior to gold nanoparticles as a photodynamic treatment modality for cancer.     

X-ray computed tomography imaging of a tumor with high sensitivity using gold nanoparticles conjugated to a cancer-specific antibody via polyethylene glycol chains on their surface

Contrast agents are often used to enhance the contrast of X-ray computed tomography (CT) imaging of tumors to improve diagnostic accuracy. However, because the iodine-based contrast agents currently used in hospitals are of low molecular weight, the agent is rapidly excreted from the kidney or moves to extravascular tissues through the capillary vessels, depending on its concentration gradient. This leads to nonspecific enhancement of contrast images for tissues. Here, we created gold (Au) nanoparticles as a new contrast agent to specifically image tumors with CT using an enhanced permeability and retention (EPR) effect. Au has a higher X-ray absorption coefficient than does iodine. Au nanoparticles were supported with polyethylene glycol (PEG) chains on their surface to increase the blood retention and were conjugated with a cancer-specific antibody via terminal PEG chains. The developed Au nanoparticles were injected into tumor-bearing mice, and the distribution of Au was examined with CT imaging, transmission electron microscopy, and elemental analysis using inductively coupled plasma optical emission spectrometry. The results show that specific localization of the developed Au nanoparticles in the tumor is affected by a slight difference in particle size and enhanced by the conjugation of a specific antibody against the tumor.