Asymmetric Core-Shell Gold Nanoparticles and Controllable Assemblies for SERS Ratiometric Detection of MicroRNA.

Janus nanogap gold nanoparticles (JAuNNPs) with varying proportions of Au shell coverage of (ca. 100/75/50/25 %) are presented. The internal nanogap between the partial Au shell and core caused asymmetric optical behavior; tunability depends on the degree of Au shell coverage and structural asymmetry. The shell-to-shell or core-to-core JAuNNDs(50 %) were self-assembled from amphiphilic JAuNNPs(50 %) by tuning the hydrophilic and hydrophobic polymer brushes on the Au core or shell. The positions of electromagnetic field enhancement of JAuNNDs varied with geometrical configurations because of hybridized plasmonic coupling effects. Furthermore, DNA linkers were utilized to form JAuNND12 (50 %). By combining with Raman molecules, ratiometric SERS signals could be generated, enabling JAuNND12 (50 %) to image the distribution of miR-21 in living cells and tumors. Asymmetric JAuNNPs allowed facile conjugation of various linkage molecules to fabricate dimeric nanostructures.

siRNA-Based Carrier-Free System for Synergistic Chemo/Chemodynamic/RNAi Therapy of Drug-Resistant Tumors.

Multiple drug-resistance mechanisms originate from defensive pathways in cancer and are associated with the unsatisfied efficacy of chemotherapy. The combination of small interfering RNA (siRNA) and chemotherapeutics provides a strategy for reducing drug efflux but requires more delivery options for clinical translation. Herein, multidrug resistance protein 1 (MDR1) siRNA is used as the skeleton to assemble chemotherapeutic cisplatin (CDDP) and divalent copper ion (Cu2+) for constructing a carrier-free Cu-siMDR-CDDP system. Cu-siMDR-CDDP specifically responds and disassembles in the acidic tumor microenvironment (TME). The released CDDP activates cascade bioreactions of NADPH oxidases and superoxide dismutase to generate hydrogen peroxide (H2O2). Then a Cu2+-catalyzed Fenton-like reaction transforms H2O2 to hydroxyl radicals (HO•) and causes glutathione (GSH) depletion to disrupt the redox adaptation mechanism of drug-resistant cancer cells. Besides, delivery of MDR1 siRNA is facilitated by HO•-triggered lysosome destruction, thus inhibiting P-glycoprotein (P-gp) expression and CDDP efflux. The unique design of Cu-siMDR-CDDP is to exploit siRNA as building blocks in regulating the self-assembly behavior, and integration of functional units simultaneously alleviates limitations caused by drug-resistance mechanisms. Such a carrier-free system shows synergistic chemo/chemodynamic/RNA interference therapy in suppressing tumor growth in vivo and has the reference value for overcoming drug resistance.

Site-Specific Biomimicry of Antioxidative Melanin Formation and Its Application for Acute Liver Injury Therapy and Imaging.

Biocompatible nano-antioxidants composed of natural molecules/materials, such as dopamine and melanin, are of great interest for diverse biomedical applications. However, the lack of understanding of the precise structure of these biomaterials and thus the actual dose of effective components impedes their advancement to translation. Herein, a strategy to mimic in situ melanin formation and explore its antioxidative applications is reported, by developing a PEGylated, phenylboronic-acid-protected L-DOPA precursor (PAD) that can self-assemble into well-defined nanoparticles (PADN). Exposure to oxidative species leads to deprotection of phenylboronic acids, transforming PADN to PEG-L-DOPA, which, similar to the biosynthetic pathway of melanin, can be oxidized and polymerized into an antioxidative melanin-like structure. With ultrahigh stability and superior antioxidative activity, the PADN shows remarkable efficacy in prevention and treatment of acute liver injury/failure. Moreover, the in situ structure transformation enables PADN to visualize damaged tissue noninvasively by photoacoustic imaging. Overall, a bioinspired antioxidant with precise structure and site-specific biological activity for theranostics of oxidative stress-related diseases is described.

Attachment of streptavidin-modified superparamagnetic iron oxide nanoparticles to the PC-12 cell membrane.

Efficient attachment of magnetic nanoparticles to cell membranes plays an important role in the activation of cell membrane channels. Streptavidin (SA) was successfully modified to Poly (ethylene imine) (PEI)-superparamagnetic iron oxide nanoparticles (SPIONs) to form SA/PEI-SPIONs, which have high colloidal stability and low cytotoxicity. The SA/PEI-SPIONs were incubated with PC-12 cells which had first been cultured in a Roswell Park Memorial Institute medium 1640 containing 0.2 mg l-1 biotin for 12 h. The cells were observed by transmission electron microscopy, and the nanoparticles were clearly attached on the cell membrane, which can be attributed to the specific binding between the SA and biotin sites on the cell surface. This work provides a simple way to attach SA-modified nanoparticles on the membranes of cells by only culturing cells in a biotin-containing medium. This work makes possible biomedical applications that require nanoparticles to target cell membranes.

Biologically Responsive Plasmonic Assemblies for Second Near-Infrared Window Photoacoustic Imaging-Guided Concurrent Chemo-Immunotherapy.

We developed dual biologically responsive nanogapped gold nanoparticle vesicles loaded with immune inhibitor and carrying an anticancer polymeric prodrug for synergistic concurrent chemo-immunotherapy against primary and metastatic tumors, along with guided cargo release by photoacoustic (PA) imaging in the second near-infrared (NIR-II) window. The responsive vesicle was prepared by self-assembly of nanogapped gold nanoparticles (AuNNPs) grafted with poly(ethylene glycol) (PEG) and dual pH/GSH-responsive polyprodug poly(SN38-co-4-vinylpyridine) (termed AuNNP@PEG/PSN38VP), showing intense PA signal in the NIR-II window. The effect of the rigidity of hydrophobic polymer PSN38VP on the assembled structures and the formation mechanism of AuNNP@SN38 Ve were elucidated by computational simulations. The immune inhibitor BLZ-945 was encapsulated into the vesicles, resulting in pH-responsive release of BLZ-945 for targeted immunotherapy, followed by the dissociation of the vesicles into single AuNNP@PEG/PSN38VP. The hydrophilic AuNNP@PEG/PSN38VP nanoparticles could penetrate deep into the tumor tissues and release the anticancer drug SN38 under the reductive environment. A PA signal in the NIR-II window in the deep tumor region was obtained. The BLZ-945-loaded vesicle enabled enhanced PA imaging-guided concurrent chemo-immunotherapy efficacy, inhibiting the growth of both primary tumors and metastatic tumors.

Light-activated gold nanorod vesicles with NIR-II fluorescence and photoacoustic imaging performances for cancer theranostics.

Fluorescence (FL) and photoacoustic (PA) imaging in the second near infrared window (NIR-II FL and NIR-II PA) hold great promise for biomedical applications because of their non-invasive nature and excellent spatial resolution properties. Methods: We develop a NIR-II PA and NIR-II FL dual-mode imaging gold nanorod vesicles (AuNR Ves) by self-assembly of amphiphilic AuNR coated with light responsive polyprodrug of Ru-complex and PEG, and NIR-II cyanine dye (IR 1061). The AuNR Ves showed strong ligh absorption property and PA imaging performance in the NIR-II windows. Moreover, the NIR-II fluorescence signal of IR 1061 loaded in the AuNR Ve is quenched. Results: The AuNR Ves can release photosensitizer Ru-complex and IR 1061 sequentially triggered by NIR light irradiation, leading to a corresponding NIR-II PA signal decrease and NIR-II FL signal recovery. Meanwhile, Ru-complex can not only serve as a chemotherapeutic drug but also generate singlet oxygen (1O2) under NIR light irradiation. The release of Ru-complex and photodynamic therapy are guided by the responsive variation of NIR-II PA and NIR-II FL signals. Conclusions: The AuNR Ve possessing not only precisely control 1O2/drug release but also the intrinsic ability to monitor therapy process offers a new strategy for the development of smart theranostic nanoplatform.

Subcellular distributions of iron oxide nanoparticles in rat brains affected by different surface modifications.

The impact of the surface modification on the subcellular distribution of nanoparticles in the brain remains elusive. The nanoparticles prepared by conjugating polyethylene glycol and maleic anhydride-coated superparamagnetic iron oxide nanoparticles (Mal-SPIONs) with bovine serum albumin (BSA/Mal-SPIONs) and with Arg-Gly-Asp peptide (RGD/Mal-SPIONs) were injected into the rat substantia nigra. Observation of transmission electron microscopy (TEM) samples obtained 24 h after perfusion showed that abundant RGD/Mal-SPIONs accumulated in the myelin sheath, dendrites, axon terminals and mitochondria, and on cell membranes in the brain tissue near the injection site. For rats injected with BSA/Mal-SPIONs, a few nanoparticles accumulated in the myelin sheath, axon terminals, endoplasmic reticulum, mitochondria, Golgi, and lysosomes of neurons and glial cells while least SPIONs in rats injected with Mal-SPIONs were found. TEM pictures showed some Mal-SPIONs were expelled out of the brain. RGD/Mal-SPIONs diffused extensively to the thalamus, frontal cortex, temporal lobe, olfactory bulb, and brain stem after injection. Only a few BSA/Mal-SPIONs diffused to the afore-mentioned brain areas. This work reveals different surface modifications on the iron oxide nanoparticles play crucial roles in their distribution and diffusion in the rat brains.

Superparamagnetic iron oxide nanoparticles modified with dimyristoylphosphatidylcholine and their distribution in the brain after injection in the rat substantia nigra.

The subcellular distributions of nanoparticles in the brain are important for their biological application. We synthesized and characterized the superparamagnetic iron oxide nanoparticles (SPIONs) modified with poly (ethylene glycol) (PEG) and polyethylenimine (PEI) (PEG/PEI-SPIONs), and with dimyristoylphosphatidylcholine (DMPC) (DMPC-SPIONs). The nanoparticles were unilaterally injected into the left substantia nigra of rat brains. The distributions of the nanoparticles in the left brains of the rats were examined by ICP-OES (inductively coupled plasma optical emission spectrometer) and TEM (transmission electron microscopy) at 24h after the injection. Iron was found in the olfactory bulb, temporal lobe, frontal cortex, thalamus and brain stem at 24h after the injection of DMPC-SPIONs and PEG/PEI-SPIONs. In the rat substantia nigra, most DMPC-SPIONs were distributed in and on the myelin sheath around axons or on cell membranes, some were in cells. As a comparison, less iron was found in the rat brains at 24h after the injection of PEG/PEI-SPIONs. Our experiments suggest DMPC modification on SPIONs be a safe and effective method for increasing SPIONs distribution on the cell membranes. This work is encouraging for further study on using DMPC-SPIONs for efficient drug delivery or for deep brain stimulation of neurons in a magnetic field.