Gemini imidazolium gels enhance the photodynamic performance of porphyrins

Photodynamic therapy (PDT) successful clinical use has led to an emerging interest in the development of improved delivery systems for photosensitizers. Amongst different formulations, gels have the advantage of being easier to apply, providing greater adhesion to the affected region and allowing light penetration. Importantly, we have previously reported that by incorporating porphyrin into a bisimidazolium gelator matrix there is an increased reactive oxygen species (ROS) generation compared to the photosensitizer in solution [1]. Motivated by this, we report further assessment on the photosensitizing capabilities of porphyrins in a gel structure. In this work, we evaluated effect of varying the chemical structures of porphyrins on their photosensitizing capabilities whilst embedded within a supramolecular hydrogel based on gemini imidazolium amphiphiles. The investigated porphyrins presented enhanced singlet oxygen (1O2) within the hydrogel matrix compared to solution and showed negligent release in relevant biological media. Rheological measurements revealed that porphyrin hydrogels presented desirable viscoelastic properties as a functional delivery system for PDT

Antimicrobial and Photoantimicrobial Activities of Chitosan/CNPPV Nanocomposites

Multidrug-resistant bacteria represent a global health and economic burden that urgently calls for new technologies to combat bacterial antimicrobial resistance. Here, we developed novel nanocomposites (NCPs) based on chitosan that display different degrees of acetylation (DAs), and conjugated polymer cyano-substituted poly(p-phenylene vinylene) (CNPPV) as an alternative approach to inactivate Gram-negative (E. coli) and Gram-positive (S. aureus) bacteria. Chitosan's structure was confirmed through FT-Raman spectroscopy. Bactericidal and photobactericidal activities of NCPs were tested under dark and blue-light irradiation conditions, respectively. Hydrodynamic size and aqueous stability were determined by DLS, zeta potential (ZP) and time-domain NMR. TEM micrographs of NCPs were obtained, and their capacity of generating reactive oxygen species (ROS) under blue illumination was also characterized. Meaningful variations on ZP and relaxation time T2 confirmed successful physical attachment of chitosan/CNPPV. All NCPs exhibited a similar and shrunken spherical shape according to TEM. A lower DA is responsible for driving higher bactericidal performance alongside the synergistic effect from CNPPV, lower nanosized distribution profile and higher positive charged surface. ROS production was proportionally found in NCPs with and without CNPPV by decreasing the DA, leading to a remarkable photobactericidal effect under blue-light irradiation. Overall, our findings indicate that chitosan/CNPPV NCPs may constitute a valuable asset for the development of innovative strategies for inactivation and/or photoinactivation of bacteria. Keywords: photoantimicrobial activity; blue-light irradiation; chitosan; CNPPV; nanocomposites; E. coli; S. aureu

Functionalized block co-polymer pro-drug nanoparticles with anti-cancer efficacy in 3D spheroids and in an orthotopic triple negative breast cancer model

Amphiphilic block co-polymers composed of poly(ethylene glycol)-co-poly(lactide)-co-poly(2-((tert-butoxycarbonyl)amino)-3-propyl carbonate) (PEG-pLA-pTBPC) are synthesized in monomer ratios and arrangements to enable assembly into nanoparticles with different sizes and architectures. These materials are based on components in clinical use, or known to be biodegradable, and retain the same fundamental chemistry across 'AB' and 'BAB' block architectures. In MCF7 and MDA-MB-231 breast cancer cells, nanoparticles of < 100 nm are internalized most rapidly, by both clathrin-and caveolin-mediated pathways. In THP-1 cells, polymer architecture and length of the hydrophilic block is the most important factor in the rate of internalization. The organ distributions of systemically injected nanoparticles in healthy mice indicate highest accumulation of the BAB-blocks in lungs and liver and the lowest accumulation in these organs of a methoxyPEG5000-pLA-pTBPC polymer. Conjugation of doxorubicin via a serum-stable urea linker to the carbonate regions of PEG5000-pLA-pTBPC generates self-assembling nanoparticles which are more cytotoxic in 2D, and penetrate further in 3D spheroids of triple negative breast cancer cells, than the free drug. In an aggressive orthotopic triple negative breast cancer mouse model, the methoxyPEG5000-pLA-pTBPC is of similar potency to free doxorubicin but with no evidence of adverse effects in terms of body weight

Metal-Free g-C3N4/Nanodiamond Heterostructures for Enhanced Photocatalytic Pollutant Removal and Bacteria Photoinactivation

Heterogeneous photocatalysis has emerged as a promising alternative for both micropollutant removal and bacterial inactivation under solar irradiation. Among a variety of photocatalysts explored in the literature, graphite carbon nitride (g-C3N4) is a metal-free semiconductor with acceptable chemical stability, low toxicity, and excellent cost-effectiveness. To minimize its high charge recombination rate and increase the photocatalyst adsorption capacity whilst keeping the metal-free photocatalyst system idea, we proposed the heterojunction formation of g-C3N4 with diamond nanocrystals (DNCs), also known as nanodiamonds. Samples containing different amounts of DNCs were assessed as photocatalysts for pollutant removal from water and as light-activated antibacterial agents against Staphylococcus sureus. The sample containing 28.3 wt.% of DNCs presented the best photocatalytic efficiency against methylene blue, removing 71% of the initial dye concentration after 120 min, with a pseudo-first-order kinetic and a constant rate of 0.0104 min−1, which is nearly twice the value of pure g-C3N4 (0.0059 min−1). The best metal-free photocatalyst was able to promote an enhanced reduction in bacterial growth under illumination, demonstrating its capability of photocatalytic inactivation of Staphylococcus aureus. The enhanced photocatalytic activity was discussed and attributed to (i) the increased adsorption capacity promoted by the presence of DNCs; (ii) the reduced charge recombination rate due to a type-II heterojunction formation; (iii) the enhanced light absorption effectiveness; and (iv) the better charge transfer resistance. These results show that g-C3N4/DNC are low-cost and metal-free photoactive catalysts for wastewater treatment and inactivation of bacteria

Photosensitized and Photothermal Stimulation of Cellular Membranes by Organic Thin Films and Nanoparticles.

Conjugated polymers are increasingly exploited for biomedical applications. In this work, we explored the optical characteristics of conjugated polymers of variable chemical structures at multiple levels relevant to biological interfacing, from fluorescence yield to their influence on cellular membrane potential. We systematically compared the performance of conjugated polymer as cast thin films and as nanoparticles stabilized with amphiphilic polyethylene glycol-poly lactic acid-co-glycolic acid (PEG-PLGA). We assessed in both the dark and under illumination the stability of key optoelectronic properties in various environments, including air and biologically relevant physiological saline solutions. We found that photoreduction of oxygen correlates with nanoparticle and film degradation in physiologically relevant media. Using patch-clamp recordings in cell lines and primary neurons, we identified two broad classes of membrane potential response, which correspond to photosensitizer- and photothermal-mediated effects. Last, we introduced a metric named OED50 (optical energy for 50% depolarization), which conveys the phototoxic potency of a given agent and thereby its operational photo-safety profile

Supramolecular and base-induced singlet oxygen generation enhancement of a water-soluble phthalocyanine

Investigation into the reactive oxygen species (ROS) generating abilities of photosensitizers outside of in-vitro/vivo conditions is a crucial element in the wider study of photodynamic therapy (PDT) in clinical settings. Zinc (II) phthalocyanine tetrasulfonic acid (ZnPcTS) is a water-soluble photosensitizer that can generate ROS as singlet oxygen (SO) under irradiation in the red and far-red region of the electromagnetic spectrum. The incorporation of ZnPcTS into nano-fibers of a bis-imidazolium hydrogel was demonstrated and the material was characterized with photophysical, rheological, and microscopy techniques. This supramolecular material containing ZnPcTS (named ZnPcTS_nEqBase@ Gels) was found to significantly enhance the SO generation rate with respect to that of ZnPcTS in an aqueous solution. The effect is attributed mainly to reduced aggregation within the gel microenvironment compared with

Synthesis of micellar-like terpolymer nanoparticles with reductively-cleavable cross-links and evaluation of efficacy in 2D and 3D models of triple negative breast cancer

Triple negative or basal-like breast cancer (TNBC) is characterised by aggressive progression, lack of standard therapies and poorer overall survival rates for patients. The bad prognosis, high rate of relapse and resistance against anticancer drugs have been associated with a highly abnormal loss of redox control in TNBC cells. Here, we developed docetaxel (DTX)-loaded micellar-like nanoparticles (MLNPs), designed to address the aberrant TNBC biology through the placement of redox responsive cross-links designed into a terpolymer. The MLNPs were derived from poly(ethyleneglycol)-b-poly(lactide)-co-poly(N3-α-ε-caprolactone) with a disulfide linker pendant from the caprolactone regions in order to cross-link adjacent chains. The terpolymer contained both polylactide and polycaprolactone to provide a balance of accessibility to reductive agents necessary to ensure stability in transit, but rapid micellar breakdown and concomitant drug release, when in breast cancer cells with increased levels of reducing agents. The empty MLNPs did not show any cytotoxicity in vitro in 2D monolayers of MDA-MB-231 (triple negative breast cancer), MCF7 (breast cancer) and MCF10A (normal breast epithelial cell line), whereas DTX-loaded reducible crosslinked MLNPs exhibited higher cytotoxicity against TNBC and breast cancer cells which present high intracellular levels of glutathione. Crosslinked and non-crosslinked MLNPs showed high and concentration-dependent cellular uptake in monolayers and tumour spheroids, including when assessed in co-cultures of TNBC cells and cancer-associated fibroblasts. DTX loaded crosslinked MLNPs showed the highest efficacy against 3D spheroids of TNBC, in addition the MLNPs also induced higher levels of apoptosis, as assessed by annexin V/PI assays and increased caspase 3/7 activity in MDA-MB-231 cells in comparison to cells treated with DTX-loaded un-crosslinked MLNP (used as a control) and free DTX. Taken together these data demonstrate that the terpolymer micellar-like nanoparticles with reducible crosslinks have high efficacy in both 2D and 3D in vitro cancer models by targeting the aberrant biology, i.e. loss of redox control of this type of tumour, thus may be promising and effective carrier systems for future clinical applications in TNBC. © 2020 Elsevier B.V.EPSRC Programme Grant for Next Generation Biomaterials Discoveryand [Grants EP/H005625/1, EP/N03371X/1]; The Erasmus Mundus Joint Doctoral Program; NanoFarJointDoctoralProgra