Search

Additional file 1: Figure S1. Zeta potential analysis of the crude, C1-C5, Resovist® and Sinerem® samples. Figure S2. Cell viability of NIH3T3 cells treated with the samples with various concentrations ofSPION for 4 h according to XTT assay. The data were normalized to control value (SPION-freemedia), which was set as 100% cell viability. Experiments were performed at different concentrationsof SPION in the range of 0.1 to 10.0 mM. Values represent means ± standard deviations of fiveidentical experiments made in three replicates. Figure S3. LDH leakage of NIH3T3 cells treated with the samples with various concentrations ofSPION for 4 h according to the manufacturer’s instructions. Experiments were done at differentconcentrations of SPION in the range of 0.1 to 10.0 mM. Values represent mean ± standard deviationof five identical experiments made in three replicates. Figure S4. ROS generated in NIH3T3 cells incubated with the samples with various concentrations ofSPION to the control cells (SPION-free media) after 24 h treatment. Experiments were done atdifferent concentrations of SPION in the range of 0.1 to 5 mM. Data represent mean ± standarddeviation of three identical experiments made in three replicates. Figure S5. Colloidal stability of the samples in undiluted FBS monitored by visual inspection andDLS. Visual inspection indicated no aggregation up until 24 h. In line with this, size and PDI obtainedby DLS also showed no significant changes at 24 h. The iron concentration for all the samples was 5mM. The FBS size according to DLS was 19.7±1.5 nm which is very close to hydrodynamic diameterof C1. Also, FBS is polydisperse and has PDI of 0.49±0.05. These two notions explain the high PDI forC1 in FBS. Figure S6. Colloidal stability of the samples in 4 wt% BSA in DI water. Visual inspection showed noaggregation at 24 h. Also, size and PDI obtained by DLS showed no important differences in theirvalues at 24 h. The iron concentration for all the samples was 5 mM. Figure S7. Temperature-dependent magnetization at 1000 Oe of the crude SPION mixture (C), thesize-isolated samples C1-C5, Resovist® (R) and Sinerem® (S). Results were normalized to Fe content. Figure S8. T1- and T2-weighted MR images of the crude, C1-C5, Resovist® and Sinerem® samples atdifferent concentrations from 0.005 to 0.05 mM. Figure S9. Longitudinal (1/T1; a) and transverse (1/T2; b) relaxation rates of the crude, C1-C5,Resovist® and Sinerem® samples as a function of concentration of Fe. The straight lines represent thelinear fit to the experimental data. The relaxivities r1 and r2 were calculated as the slope of the linesfitted to the experimental data. Values represent average of one experiment made in three replicates. Figure S10. Relaxivity ratios (r2/r1) for the crude, C1-C5, Resovist® and Sinerem® samples. Figure S11. Normalized SNR values of the samples from the 4th up to the 10th harmonic of the MPIdrive field. Figure S12. Magnetic particle imaging of size-isolated SPION. (a) MPI images reconstructed basedon “V” shaped phantoms filled with the crude sample, C2 and Resovist®. (b) The intensity line profilesof the red marked lines through the phantoms in panel (a) are shown. The line profiles show the voxelintensity along the marked line and demonstrate a doubling of signal intensity for C2 in comparison toResovist®. Table S1. Overview of the results obtained in the size analyses performed using TEM, DLS and NTA.The different SPION formulations were evaluated in different media and upon different storage times.

Combined therapy with penicillins and aminoglycosides has been proved beneficial to address many persistent bacterial infections with possible synergistic effects. However, the different pharmacokinetic profiles of these two antibiotic classes may not guarantee a concerted spatio-temporal delivery at the site of action, decreasing the efficacy of this combination and promoting resistance. Herein, we propose a multifunctional antibiotic-polymer conjugate, designed to colocalize ampicillin and gentamicin to tackle persistent biofilm infections. The two antibacterial molecules were grafted along with the amino acid l-arginine to a biocompatible polymer backbone with peptidomimetic hydrophilic structure, obtaining the antimicrobial poly(argilylaspartamide-co-aspartic) acid-ampicillin, gentamicin (PAA-AG) conjugate. The PAA-AG conjugate displayed excellent biocompatibility on human cell lines if compared with free drugs, potentially enlarging their therapeutic window and safety, and suitable mucoadhesive characteristics which may help local treatments of mucosal infections. Studies on planktonic cultures of clinical and reference strains of S. aureus, P. aeruginosa, and E. coli revealed that PAA-AG holds a broad-spectrum antibacterial efficacy, revealing high potency in inhibiting the growth of the tested strains. More interestingly, PAA-AG exhibited excellent antibiofilm activity on both Gram+ and Gram- communities, showing inhibition of their formation at subMIC concentrations as well as inducing the regression of mature biofilms. Given the high biocompatibility and broad antibiofilm efficacy, combined with the opportunity for synchronous co-delivery, the PAA-AG conjugate could be a valuable tool to increase the success of ampicillin/gentamicin-based antibiotic multitherapy.

In this paper, we propose a rational design of a hybrid nanosystem capable of locally delivering a high amount of hydrophobic anticancer drugs (sorafenib or lenvatinib) and heat (hyperthermia) in a remote-controlled manner. We combined in a unique nanosystem the excellent NIR photothermal conversion of gold nanorods (AuNRs) with the ability of a specially designed galactosylated amphiphilic graft copolymer (PHEA-g-BIB-pButMA-g-PEG-GAL) able to recognize hepatic cells overexpressing the asialoglycoprotein receptor (ASGPR) on their membranes, thus giving rise to a smart composite nanosystem for the NIR-triggered chemo-phototherapy of hepatocarcinoma. In order to allow the internalization of AuNRs in the hydrophobic core of polymeric nanoparticles, AuNRs were coated with a thiolated fatty acid (12-mercaptododecanoic acid). The drug-loaded hybrid nanoparticles were prepared by the nanoprecipitation method, obtaining nanoparticles of about 200 nm and drug loadings of 9.0 and 5.4% w/w for sorafenib and lenvatinib, respectively. These multifunctional nanosystems have shown to convert NIR radiation into heat and release charged drugs in a remote-controlled manner. Then, the biocompatibility and synergistic effects of a chemo-phototherapy combination, as well the receptor-mediated internalization, were evaluated by an in vitro test on HepG2, HuH7, and NHDF. The results indicate that the proposed nanoparticles can be considered to be virtuous candidates for an efficient and selective dual-mode therapy of hepatocarcinoma.

The high incidence of cancer recurrences and the frequent occurrence of multidrug resistance often stem from a poorly selective and inefficient antineoplastic therapy, responsible for the onset of undesired side effects as well. A combination of minimal-invasive approaches could thus be a useful strategy to surmount these shortcomings, achieving a safe and solid cancer therapy. Herein, a multi-therapeutic nanotool was designed by merging the photothermal properties of gold nanorods (AuNRs) with the photodynamic activity of the photosensitizer ver-teporfin. AuNRs were coated with the natural materials lipoic acid and gellan gum (AuNRs_LA,GG) and subse-quently loaded with verteporfin (AuNRs_LA,GG/Vert) producing stable colloidal dispersions. AuNRs_LA,GG/Vert were characterized in terms of stability, size and morphology. The hyperthermia exhibited after NIR excitation (810 nm) was also evaluated to highlight the effect on increasing the drug released profile in intra-tumoral mimicking media, as well as cytotoxicity on human colon cancer cell line (HCT116). In vivo studies on HCT116 murine xenograft models were carried out to prove the ability of AuNRs_LA,GG to arrest the tumor growth via NIR laser-triggered hyperthermia. Furthermore, the complete xenograft depletion was demonstrated upon AuNRs_LA,GG/Vert administration by combined photothermal (PTT) and photodynamic (PDT) effects.

HBDI-like chromophores represent a novel set of biomimetic switches mimicking the fluorophore of the green fluorescent protein that are currently studied with the hope to expand the molecular switch/motor toolbox. However, until now members capable of absorbing visible light in their neutral (i. e. non-anionic) form have not been reported. In this contribution we report the preparation of an HBDI-like chromophore based on a 3-phenylbenzofulvene scaffold capable of absorbing blue light and photoisomerizing on the picosecond timescale. More specifically, we show that double-bond photoisomerization occurs in both the E-to-Z and Z-to-E directions and that these can be controlled by irradiating with blue and UV light, respectively. Finally, as a preliminary applicative result, we report the incorporation of the chromophore in an amphiphilic molecule and demonstrate the formation of a visible-light-sensitive nanoaggregated state in water.

Efforts in the field of anticancer therapy are increasingly focusing on the development of localized and selective treatments. Photothermal therapy (PTT) can lead to a spatially confined death of cancer cells, exploiting an increasing in temperature generated after UV-NIR irradiation of peculiar materials. Herein, a new actively targeted gold-based drug delivery system, named PHEA-LA-Fol-AuNRs/Iri, was explored for hyperthermia and chemotherapy colon cancer treatment. Gold nanorods were stabilized using a folate-derivative of α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA-LA-PEG-FA) as coating agent and then loaded with the antineoplastic drug irinotecan (Iri). The efficacy of empty and irinotecan-bearing systems was investigated in vitro on human colon cancer (HCT116) cell line, as well as in vivo, employing a xenograft mouse model of colon cancer. After laser treatment, both nanostructures tested induced a considerable deceleration in tumor growth overtime, achieving the total eradication of the cancer when the nanosystems produced were intratumorally administered. Biodistribution data showed that the polymer coated nanorods were able to preferentially accumulate in the tumor site. Considering the excellent stability in aqueous media, the capacity to reach the tumor site and, finally, the in vivo efficacy, PHEA-LA-Fol-AuNRs/Iri might be recommended as an effective tool in the chemotherapy and PTT of colon cancer.

Gold nanorods (AuNRs) can combine therapeutic hyperthermia with diagnostic features, representing a smart choice to address personalized cancer treatments. In this regard, a crucial quest is the selection of the right biocompatible coating agent able to stabilize them in the physiological environment, further endowing the possibility to load bioactive molecules and/or targeting moieties. Therefore, AuNRs optical properties can be successfully merged with advantageous materials features to obtain selective photothermal therapy (PTT) systems. Here, the natural materials lipoic acid (LA) and the polysaccharide gellan gum (GG) were chosen to prepare three types of stabilized gold nanorods, using LA (AuNRs/LA), a layered coating of LA and GG (AuNRs/LA,GG) or a newly synthesized covalent derivative of LA and GG (AuNRs/GG-LA). The samples displayed diverse stability and dispersibility. Hydrodynamic diameters and surface potential analyses confirmed the nanometric size (100&ndash, 200 nm) and showed surface charges ranging from +19.5 to &minus, 25.6 mV. Particular attention was thus paid to analyze the differences between hyperthermia properties exhibited after near-infrared (NIR) laser irradiation. Furthermore, the cytocompatibility and photothermal effect were tested on HCT116 human colon cancer cell line. Collected data have finally allowed selecting AuNRs/LA,GG as the best candidate for possible use in PTT of cancer.

Chitosan oligosaccharide (C) was functionalized with L-arginine (A) and short hydrocarbon chains (C-8) to design an amphiphilic copolymer, henceforth CAC(8), leading to microparticles (MPs) consisting of an arginine-decorated hydrophilic shell and inner hydrophobic domains allowing the encapsulation of high amount hydrophobic drugs such as sorafenib tosylate (>10% w/w). L-arginine side chains were selected in order to impart the final MPs enhanced transcorneal penetration properties, thus overcoming the typical biological barriers which hamper the absorption of drugs upon topical ocular administration. The mucoadhesive properties and drug release profile of the CAC(8) MPs (CAC(8)-MPs) were studied, showing that CAC(8)-MPs can strongly interact with mucin, and thus gradually release their payload in situ to potentially improve the bioavailability of the drug after topical administration. In vitro transcorneal studies also showed that CAC(8)-MPs are endowed with effective permeation enhancer ability combined with negligible toxicity. (c) 2019 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.

The extremely complex tumor microenvironment (TME) in humans is the major responsible for the therapeutic failure in cancer nanomedicine. A new concept of disease-driven nanomedicine, henceforth named “Theranomics”, which attempts to target cancer cells and TME on the whole, represents an attractive alternative. Herein, a nanomedicine able to co-deliver doxorubicin and a tumor suppressive proteolytic protein such as collagenase-2 was developed. We successfully obtained superparamagnetic nanogels (SPIONs/Doco@Col) via the intermolecular azide-alkyne Huisgen cycloaddition. We demonstrated that a local ECM degradation and remodeling in solid tumors by means of collagenase-2 could enhance tumor penetration of nanomedicines and the in situ sustained release of the drug payload throughout 3-D tumor spheroids up to the core (parenchyma), thus enabling a synergistic and efficient anticancer effect toward highly invasive breast tumors. We illustrate that SPIONs/Doxo@Col is also capable of reducing the invasivity of cancer cells.