One step emission tunable synthesis of PEG coated Ag 2 S NIR quantum dots and the development of receptor targeted drug delivery vehicles thereof

PEGylation of quantum dots (QDs) to decrease their toxicity, increase blood circulation time, reduce non-specific uptake and also to solubilize and stabilize hydrophobic QDs in aqueous medium is a widely used approach and many different methods were developed to achieve this. QDs that are luminescent in the near-infrared region (NIR) have recently emerged as the more appropriate materials for bio-imaging studies. In this work, we describe a single step emission tunable aqueous synthesis of PEGylated Ag2S NIRQDs. They are highly cytocompatible, not only due to the PEG coating but also due to the intrinsic biocompatibility of Ag2S, and prepared in a single step aqueous method using thiolated PEGs as the only coating material. Tuning the emission wavelength within the medical window (775–930 nm) with a quantum yield between 2 and 65% is achieved by changing the reaction variables such as PEG molecular weight, pH and precursor ratios. Ag2S–PEG NIRQDs prepared from 5 kDa MPEG-SH at acidic pH provided a dramatic enhancement in the luminescence intensity. These NIRQDs were also designed with surface functional groups to attach folic acid and loaded with doxorubicin (DOX) which dramatically enhanced the uptake and efficacy of DOX (50% cell death with 15 nM DOX) in FA-receptor overexpressed cancer cell lines (HeLa). They also showed a strong cytoplasmic NIR signal in the in vitro studies, demonstrating great theranostic potential

One-Step Aqueous Synthesis of Anionic and Cationic AgInS2 Quantum Dots and Their Utility in Improving the Efficacy of ALA-Based Photodynamic Therapy

Silver–indium–sulfide quantum dots (AIS QDs) have potential applications in many areas, including biomedicine. Their lack of regulated heavy metals, unlike many commercialized QDs, stands out as an advantage, but the necessity for alloyed or core–shell structures and related costly and sophisticated processes for the production of stable and high quantum yield aqueous AIS QDs are the current challenges. The present study demonstrates the one-step aqueous synthesis of simple AgInS2 QD compositions utilizing for the first time either a polyethyleneimine/2-mercaptopropionic acid (AIS-PEI/2MPA) mixture or only 2-mercaptopropionic acid (AIS-2MPA) as the stabilizing molecules, providing a AgInS2 portfolio consisting of cationic and anionic AIS QDs, respectively, and tuneable emission. Small AIS QDs with long-term stability and high quantum yields (19–23%) were achieved at a molar ratio of Ag/In/S 1/10/10 in water without any dopant or a semiconductor shell. The theranostic potential of these cationic and anionic AIS QDs was also evaluated in vitro. Non-toxic doses were determined, and fluorescence imaging potential was demonstrated. More importantly, these QDs were electrostatically loaded with zwitterionic 5-aminolevulinic acid (ALA) as a prodrug to enhance the tumor availability of ALA and to improve ALA-induced porphyrin photodynamic therapy (PDT). This is the first study investigating the influence of nanoparticle charge on ALA binding, release, and therapeutic efficacy. Surface charge was found to be more critical in cellular internalization and dark toxicity rather than drug loading and release. Both QDs provided enhanced ALA release at acidic pH but protected the prodrug at physiological pH, which is critical for tumor delivery of ALA, which suffers from low bioavailability. The PDT efficacy of the ALA-loaded AIS QDs was tested in 2D monolayers and 3D constructs of HT29 and SW480 human colon adenocarcinoma cancer cell lines. The incorporation of ALA delivery by the AIS QDs, which on their own do not cause phototoxicity, elicited significant cell death due to enhanced light-induced ROS generation and apoptotic/necrotic cell death, reducing the IC50 for ALA dramatically to about 0.1 and 0.01 mM in anionic and cationic AIS QDs, respectively. Combined with simple synthetic methods, the strong intracellular photoluminescence of AIS QDs, good biocompatibility of especially the anionic AIS QDs, and the ability to act as drug carriers for effective PDT signify that the AIS QDs, in particular AIS-2MPA, are highly promising theranostic QDs

Cetuximab-Ag₂S quantum dots for fluorescence imaging and highly effective combination of ALA-based photodynamic/chemo-therapy of colorectal cancer cells

Colorectal cancer (CRC) has a poor prognosis and urgently needs better therapeutic approaches. 5-Aminolevulinic acid (ALA) induced protoprophyrin IX (PpIX) based photodynamic therapy (PDT) is already approved in the clinic for several cancers but not yet well investigated for CRC. Currently, systemic administration of ALA offers a limited degree of tumour selectivity, except for intracranial tumours, limiting its wider use in the clinic. Combination of effective ALA-PDT with chemotherapy may provide a promising alternative approach for CRC treatment. Herein, theranostic Ag2S quantum dots (AS-2MPA) optically trackable in near-infrared (NIR), conjugated with endothelial growth factor receptor (EGFR) targeting Cetuximab (Cet) and loaded with ALA for PDT monotherapy or ALA/5-fluorouracil (5FU) for the combination therapy is proposed for enhanced treatment of EGFR(+) CRC. AS-2MPA-Cet endowed excellent targeting of the high EGFR expressing cells and showed a strong intracellular signal for NIR optical detection in a comparative study performed on SW480, HCT116, and HT29 cells, which are high, medium and low EGFR expressers. Targeting provided enhanced uptake of the ALA loaded nanoparticles by strong EGFR expressing cells and formation of higher levels of PpIX. Cells also differ in their efficiency to convert ALA to PpIX, and SW480 was the best, followed by HT29, while HCT116 were determined as unsuitable for ALA-PDT. The therapeutic efficacy was evaluated in 2D cell cultures and 3D spheroids of SW480 and HT29 cells using AS-2MPA with either electrostatically loaded, hydrazone or amide linked ALA to achieve different levels of pH or enzyme sensitive release. Most effective phototoxicity was observed in SW480 cells using AS-2MPA-ALA-electrostatic-Cet due enhanced uptake of the particles, fast ALA release and effective ALA-to-PpIX conversion. Targeted delivery reduced the effective ALA concentration significantly which was further reduced with codelivery of 5FU. Delivery of ALA via covalent linkage was also effective for PDT, but required longer incubation time for the release of ALA in therapeutic doses. Phototoxicity was correlated with high levels of reactive oxygen species (ROS) and apoptotic/necrotic cell death. Hence, both AS-2MPA-ALA-Cet based PDT and AS-2MPA-ALA-Cet-5FU based Chemo/PDT combination therapy coupled with strong NIR tracking of the nanoparticles demonstrate an exceptional therapeutic effect on CRC cells and an excellent potential for synergistic multistage tumour targeting therapy

pH and molecular weight dependence of auric acid reduction by polyethylenimine and the gene transfection efficiency of cationic gold nanoparticles thereof

Small, cationic gold nanoparticles (GNP) are produced by the direct reduction of auric acid in a non-reducing solvent, water, with branched polyethylenimine (bPEI) in a broad pH range (3.0–9.0). Basic pH, which is studied for the first time, emerged as a favorable condition to achieve good reducing power and surface passivation simultaneously, providing smaller particles (hydrodynamic size ca. 6 nm) with enhanced long-term stability and a sharper surface plasmon peak (SPP). This synthetic method produces colloidal GNPs with bPEI in a broad molecular weight range (0.6, 1.8, 10 and 25 kDa). The molecular weight did not influence the crystal size much but did affect the hydrodynamic size and the stability. 0.6 kDa bPEI provides the largest GNPs (ca. 100 nm aggregates) which lack long term stability. 1.8 kDa bPEI provides small particles (hydrodynamic size ca. 7 nm) with the sharpest SPP. The GNPs prepared with 25 and 1.8 kDa bPEI show no significant cytotoxicity in HEK 293T cells and PEI25–Au transfects green fluorescent protein (GFP) into HEK 293T cells more efficiently (82%) than FuGENE® (50%). This simple one pot synthesis of cationic GNPs in water is a valuable, simple alternative for the generation of new cationic GNPs in water with even low molecular weight PEI

MAGNETIC ACTUATION OF NANOFLUIDS WITH FERROMAGNETIC PARTICLES

ABSTRACT Electromagnetically actuated microflows are generated by using ferromagnetic nanofluids containing Fe 2 O 3 based nanoparticles. Because of their magnetic properties these nanoparticles are able to response to a magnetic field imposed along a microchannel so that a microflow could be driven. Nanofluid samples were located inside a minichannel and were directed with a magnetic field, which was induced by a solenoid wrapped around the minichannel, to drive the flow inside the minichannel, where its flow rate was also recorded. The flow rate was measured as a function of the imposed magnetic field. The corresponding pressure drop to deliver the same flow rate with an ordinary pump along the same minichannel was estimated so that the potential of this system for acting as a micropump in microfluidic applications was revealed

The improved killing of both androgen-dependent and independent prostate cancer cells by etoposide loaded SPIONs coupled with NIR irradiation

Etoposide (Eto) is a toxic drug that shows promise in treating prostate cancer (PCa) but confers significant side effects, and has poor solubility and bioavailability. Nanoparticles are quite successful in overcoming such problems. Multifunctional nanoparticles that provide an opportunity to perform combination therapy have attracted great interest in recent years. Superparamagnetic iron oxide nanoparticles (SPIONs) are popular in various biomedical applications, including magnetic resonance imaging, drug delivery, magnetic hyperthermia and recently in photothermal therapy, combining imaging with therapy. Here, for the enhanced killing of PCa cells that are either androgen-dependent or not, the combination of SPION based Eto delivery and mild hyperthermia triggered by laser irradiation is proposed for the first time in the literature. For the encapsulation of Eto, highly stable, small, polyacrylic acid coated SPIONs were conjugated with bovine serum albumin (BSA) (Eto-BSA@PAA@SPION). Eto-BSA@PAA@SPION with 9% drug content produced better chemotherapeutic outcomes than free Eto on both androgen-dependent/castration sensitive LNCaP and androgen-independent/castration-resistant PC3 and DU145 PCa cells by enhancing drug internalization. Single and short irradiation of Eto-BSA@PAA@SPION treated cells at 808 nm improved the drug release and sensitized cells for Eto, hence, increasing the toxicity dramatically in all studied PCa cell lines. Caspase-mediated apoptosis, DNA damage, and ROS generation were detected in the treated cells, increasing with the Eto dose and laser treatment. The IC50 for Eto is reduced to 0.08 mu g mL(-1), 0.13 mu g mL(-1) and 2.8 mu g mL(-1) with laser/Eto-BSA@PAA@SPION for LNCaP, DU145 and PC3 cells, respectively. These are the lowest IC50 values seen in the literature for Eto on these cell lines so far, suggesting that the demonstrated nanoparticles and treatment approaches have great potential to treat various PCa cells at low doses of the drug under mild laser treatment conditions

Autoxidized Oleic Acid Bifunctional Macro Peroxide Initiators for Free Radical and Condensation Polymerization. Synthesis and Characterization of Multiblock Copolymers

Secilmis Canbay, Hale/0000-0002-3783-8064; Hazer, Baki/0000-0001-8770-805XWOS: 000491549500023TARAMASCOPUSIndex: SCI-E, WOS, ScopusTARAMAWOSAutoxidation of unsaturated fatty acids gives fatty acid macroperoxide initiators containing two functionalities which can lead to free radical and condensation polymerizations in a single pot. The oleic acid macroperoxide initiator obtained by ecofriendly autoxidation (Pole4m) was used in both the free radical polymerization of styrene and the condensation polymerization with amine-terminated polyethylene glycol (PEGNH2) to obtain triblock branched graft copolymers. The narrow molar masses of the poly oleic acid-g-styrene (PoleS) and poly oleic acid-g-styrene-g-PEG (PoSG) graft copolymers were successfully obtained. The inclusion of oleic acid decreased the glass transition temperature of the polystyrene segment because of the plasticizing effect of oleic acid. In addition, a mechanical property of the copolymer was improved when compared with the pure PS. Structural characterization, morphology of the fracture surface, micelle formation, thermal analysis and molar masses of the obtained products were also evaluated.Kapadokya University Research Fund [KUN.2018-BAGP-001]; Bulent Ecevit University Research FundBulent Ecevit University [BEU-2017-72118496-01]This work was supported by the Kapadokya University Research Fund (KUN.2018-BAGP-001) and Bulent Ecevit University Research Fund (#BEU-2017-72118496-01). The Authors thank to Koray Alper and Fatih Pekdemir for taking SEM and FTIR spectra, respectively. The Authors thank to Serdar Coban, Sidika Sarac Tabakli and Gulsen Darici (Cilas Kaucuk, Devrek, Zonguldak, Turkey) for taking stress-strain measurements