Design and synthesis of zinc protoporphyrin IX-adamantane/cyclodextrin/cellulose nanocrystals complexes for anticancer photodynamic therapy.

Two protoporphyrin IX (PpIX) adamantane derivatives were synthesized and then metallated with zinc. The Zn-PpIX derivatives, exhibiting a high singlet oxygen quantum yield, were tested for their photodynamic activity against the HT-29 cell line. In order to enhance their water-solubility and their cellular bioavailability, these photosensitizers were encapsulated into the hydrophobic cavity of cyclodextrins (CD) previously attached to cellulose nanocrystals (CNCs) via electrostatic interactions. Under illumination, the encapsulated adamantanyl-porphyrins exerted an enhanced in vitro cytotoxicity, as compared with the corresponding free photosensitizers.

Curcumin-cyclodextrin/cellulose nanocrystals improve the phenotype of Charcot-Marie-Tooth-1A transgenic rats through the reduction of oxidative stress.

The most prevalent form of Charcot-Marie-Tooth disease (CMT type 1A) is characterized by duplication of the PMP22 gene, peripheral dysmyelination and decreased nerve conduction velocities leading to muscle weakness. Recently, oxidative stress was reported as a feature in CMT1A patients. Curcumin exhibits antioxidant activities and has shown beneficial properties on peripheral nerves. However, curcumin presents unfavorable pharmacokinetics. We developed curcumin-cyclodextrin/cellulose nanocrystals (Nano-Cur) to bypass this limitation. The present study investigated the therapeutic potential of Nano-Cur in vitro in Schwann cells (SCs) and in vivo in the transgenic CMT1A rat model. In vitro, Nano-Cur treatment (0.01 µM for 8 h) reduced reactive oxygen species and improved mitochondrial membrane potential in CMT1A SCs. Moreover, Nano-Cur treatment (0.01 µM for 1 week) increased the expression of myelin basic protein in SC/neuron co-cultures. Preliminary in vivo experiments carried out in WT rats showed that intraperitoneal (i.p.) injection of Nano-Cur treatment containing 0.2 mg/kg of curcumin strongly enhanced the bioavailability of curcumin. Afterwards, in 1-month-old male CMT1A rats, Nano-Cur treatment (0.2 mg/kg/day, i.p. for 8 weeks) significantly improved sensori-motor functions (grip strength, balance performance, and mechanical and thermal sensitivities). Importantly, sensory and motor nerve conduction velocities were improved. Further histological and biochemical analyses indicated that myelin sheath thickness and myelin protein expression (myelin protein zero and PMP22) were increased. In addition, oxidative stress markers were decreased in the sciatic nerve and gastrocnemius muscle. Finally, Nrf2 expression and some major antioxidant enzymes were increased in sciatic nerve. Therefore, Nano-Cur significantly improved cellular, electrophysiological, and functional features of CMT1A rats.

Enhancement of hydrosolubility and in vitro antiproliferative properties of chalcones following encapsulation into ß-cyclodextrin/cellulose-nanocrystal complexes.

This paper describes the preparation of two chalcone/ß-cyclodextrin/cellulose-nanocrystals complexes and the study of their antiproliferative activities against two colorectal and two prostatic cancer cell lines. The aim of this work was to enhance hydrosolubility of chalcones thanks to the hydrophilic character of cellulose nanocrystals. These latter were linked, through ionic interactions, to a cationic derivative of ß-cyclodextrins whose lipophilic cavity allowed the encapsulation of hydrophobic chalcones: 3-hydroxy-3',4,4',5'-tetramethoxychalcone (1) and 3',4,4',5'-tetramethoxychalcone (2). First, we showed that encapsulation allowed hydrosolubilization of chalcones. Then, chalcone/ß-cyclodextrin/cellulose-nanocrystals complexes demonstrated enhanced in vitro antiproliferative activities, compared to the corresponding free-chalcones.

Enhanced cytotoxicity of gold porphyrin complexes after inclusion in cyclodextrin scaffolds adsorbed on polyethyleneimine-coated gold nanoparticles.

A new gold nanoparticle-based construct has been designed to hydrophobic drugs delivery into cancer cells. Cyclodextrin scaffolds adsorbed on polyethyleneimine-coated gold nanoparticles (AuNP@PEI@CD) have been used to encapsulate hydrophobic tetrapyrrolic compounds consisting of gold complexes of 5,10,15,20-tetraphenyl porphyrin (AuTPPCl) and 5-(4-acetoxyphenyl)-10,15,20-triphenyl porphyrin (AuTPPOAcCl). These two nanoparticles have been tested for their cytotoxic activities against the two colorectal cancer cell lines HT-29 and HCT-116 and have shown significant increases in toxicity when compared to the corresponding non-vectorized tetrapyrrolic macrocycles.

In vitro anticancer activity of new gold(III) porphyrin complexes in colon cancer cells.

Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide. The limitations of cisplatin-based chemotherapy have prompted intense interest among scientists to search for alternative metal-based anticancer medicines. Gold(III) complexes have been among the most widely investigated since they showed higher cytotoxicity than cisplatin and promising in vitro and in vivo anticancer activities in CRC but their clinical usefulness has been limited by their poor stability under physiological conditions. A novel gold(III) porphyrin complexes [gold(III) porphyrin-adamantane chloride (SN1) and gold(III) porphyrin mono-acetate chloride (SN2)] with improved aqueous stability were synthesized. SN1 and SN2 reduced the survival of human CRC HT-29 and HCT-116 cell lines, caused cell cycle arrest in G2/M phase, and we observed downregulation of the expression of cyclin B1 and cyclin-dependent kinase 1 (Cdk1) along with up-regulation of the active form of p53, p21 and Bcl-2-associated X (Bax). Furthermore, SN1 and SN2 induced apoptosis by the intrinsic pathway, since they lead to the cleavage of caspase 9, caspase 3 and poly(ADP-ribose) polymerase (PARP), and up-regulating Bax. Phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), nuclear factor-κB (NF-κB) and extracellular signal-regulated kinases (ERK) are important for cell survival and proliferation. SN1 and SN2 lead to decrease in the activity of Akt where the phosphorylated form decreased with time as well as they caused an important decrease in the phosphorylation of ERK and activity of NF-κB. Finally, SN1 and SN2 complexes affected p38/mitogen-activated protein kinase (MAPK) pathway then we recorded an increase in the cyclooxygenase-2 expression and its enzymatic product prostaglandin E2.

PEI-cellulose nanocrystal hybrids as efficient siRNA delivery agents-Synthesis, physicochemical characterization and in vitro evaluation.

We describe the synthesis of cellulose nanocrystals (CNCs) complexed to siRNA. PEI (600Da) was first covalently attached to CNCs by reductive amination reaction, then CNCs-PEI were loaded with siRNA, resulting in the formation of CNCs-PEI-siRNA particles, strongly stabilized by ionic interactions. Efficient cellular uptake of these particles was monitored by ethidium bromide staining. Not only did CNCs-PEI show no cytotoxicity at the studied concentrations, but they also protected siRNA from degradation and favored its delivery into the cells. This siRNA (siRNA killer) is able to silence the expression of cell cycle genes and to induce cell death by apoptosis. Therefore, this study suggests that these CNCs-PEI are promising non-viral nanovehicles for siRNA delivery and for efficient anti-tumor strategy.

Analysis of the in vitro and in vivo effects of photodynamic therapy on prostate cancer by using new photosensitizers, protoporphyrin IX-polyamine derivatives.

BACKGROUND: Photodynamic therapy, using porphyrins as photosensitizers (PS), has been approved in treatment of several solid tumors. However, commonly used PS induce death but also resistance pathways in cancer cells and an alteration of surrounding normal tissues. Because polyamines (PA) are actively accumulated in cancer cells by the Polyamine Transport System (PTS), they may enable PS to specifically target cancer cells. Here, we investigated whether new protoporphyrin IX-polyamine derivatives were effective PS against prostate cancer and whether PA increased PDT specificity after 630nm irradiation. METHODS: CHO and CHO-MG cells (differing in their PTS activity) were used to assess efficacy of polyamine vectorization. MTT assays were performed on human prostate non-malignant (RWPE-1) and malignant (PC-3, DU 145 and LNCaP) cell lines to test PS phototoxicity. ROS generation, DNA fragmentation and cell signalling were assessed by ELISA/EIA, western-blots and gel shift assays. Finally, PS effects were studied on tumor growth in nude mice. RESULTS: Our PS were more effective on cancer cells compared to non-malignant cells and more effective than PpIX alone. PpIX-PA generated ROS production involved in induction of apoptotic intrinsic pathways. Different pathways involved in apoptosis resistance were studied: PS inhibited Bcl-2, Akt, and NF-κB but activated p38/COX-2/PGE2 pathways which were not implicated in apoptosis resistance in our model. In vivo experiments showed PpIX-PA efficacy was greater than results obtained with PpIX. CONCLUSIONS: All together, our results showed that PpIX-PA exerted its maximum effects without activating resistance pathways and appears to be a good candidate for prostate cancer PDT treatment.

Delivery of tanshinone IIA and α-mangostin from gold/PEI/cyclodextrin nanoparticle platform designed for prostate cancer chemotherapy.

A new anti-cancer drug delivery system, based on gold nanoparticles, has been designed for hydrophobic active compounds. The system is a conjugate of gold/polyethyleneimine (AuNPs/PEI) nanoparticles and sulphated ß-cyclodextrin (CD). Anionic cyclodextrin was attached to the positively charged AuNPs/PEI nanoparticles by ionic bonds. Tanshinone IIA and α-mangostin were extracted, purified and encapsulated into the AuNPs/PEI/CD nanoparticles. In vitro preliminary cell viability assays against prostate cancer cell lines PC-3 and DU145 showed that encapsulation resulted in increased cytotoxicity.

Development of curcumin-cyclodextrin/cellulose nanocrystals complexes: New anticancer drug delivery systems.

The synthesis of curcumin-cyclodextrin/cellulose nanocrystals (CNCx) nano complexes was performed. CNCx were functionalized by ionic association with cationic ß-cyclodextrin (CD) and CD/CNCx complexes were used to encapsulate curcumin. Preliminary in vitro results showed that the resulting curcumin-CD/CNCx complexes exerted antiproliferative effect on colorectal and prostatic cancer cell lines, with IC50s lower than that of curcumin alone.

Magnetic Dextran Nanoparticles That Bear Hydrophilic Porphyrin Derivatives: Bimodal Agents for Potential Application in Photodynamic Therapy.

Invited for this month's cover is the group of Prof. Vincent Sol from the University of Limoges, France. This study is a collaboration between the Universities of Limoges, Reims, Pierre et Marie Curie (UPMC, Paris), and Paris Sud (Orsay). The cover picture shows a magnetic dextran nanoparticle bearing hydrophilic porphyrin derivatives; the illustration shows bimodal nanoplatforms that could be used as contrast agents in magnetic resonance imaging as well as photosensitizers in photodynamic therapy. Read the full text of the article at 10.1002/cplu.201500087.

Magnetic Dextran Nanoparticles That Bear Hydrophilic Porphyrin Derivatives: Bimodal Agents for Potential Application in Photodynamic Therapy.

This study reports the chemical synthesis of a class of dextran superparamagnetic nanoparticles that bear hydrophilic porphyrin units covalently grafted by a click chemistry reaction in aqueous solution. Magnetic nanoparticles are used in magnetic resonance imaging (MRI) and hyperthermia, and the grafting of hydrophilic photosensitizers (PS) leads to elaborate new multifunctional platforms for potential diagnostic and targeted photodynamic therapy (PDT). The therapeutic potential for PDT of these nanoparticles is evaluated in vitro against the HaCaT cell line. The results show that these new multicharged nanomagnets-in particular, those that bear cationic porphyrins-show a significant uptake and an interesting photocytotoxic activity toward HaCaT cells. The whole series of these synthesized PS are massively incorporated inside HaCat cells and associated with mitochondria.

Hydrophilic chlorin-conjugated magnetic nanoparticles--potential anticancer agent for the treatment of melanoma by PDT.

This Letter reports the synthesis and the characterization of two new water-stable and soluble photosensitizer-conjugated magnetic nanoparticles (PS-MNPs) composed of an iron oxide magnetic core coated with a biocompatible dextran shell bearing polyaminated chlorin p6. Designed to improve cancer cell targeting, these photosensitizers were assayed for their antitumour activity against two variants of B16 mouse melanoma cell line (B16F10 and B16G4F, with or without melanin, respectively). Cell viability measurements demonstrated that PS-MNPs were more phototoxic than PEI-chlorin p6 making these photosensitizers promising for further in vitro and in vivo investigations.

Synthesis and photobiocidal properties of cationic porphyrin-grafted paper.

We report on the synthesis of cellulose paper bearing a cationic porphyrin, designed for antimicrobial applications. Tricationic porphyrin has been covalently grafted on paper, without previous chemical modification of the cellulosic support, using 1,3,5-triazine derivative as linker. The obtained porphyrin-grafted paper was characterized by infrared (ATR-FTIR), UV-visible and diffuse reflectance UV-vis (DRUV) spectroscopies to confirm the triazine linkage. Thermogravimetric analysis (TGA) was used to investigate thermal properties of grafted paper. Antimicrobial activity of porphyrin-cellulose material was tested under visible light irradiation against Staphylococcus aureus and Escherichia coli. The two bacterial strains deposited on the resulting photosensitizing filter paper are efficiently killed after illumination.

Chlorin-PEI-labeled cellulose nanocrystals: synthesis, characterization and potential application in PDT.

This Letter reports the synthesis and characterization of a new series of water-stable and soluble photosensitizers (PS-CNCs) composed of cellulose nanocrystals (CNCs) bearing polyaminated chlorin p6. With a view to improve cancer cell targeting, these photosensitizers were assayed for their antitumor activity against HaCat cell line. IC(50) values fell within the nanomolar-range, making these photosensitizers promising for further in vitro and in vivo investigations.

Photodynamic effects of porphyrin-polyamine conjugates in human breast cancer and keratinocyte cell lines.

Porphyrin-polyamine conjugates bearing two (cis or trans position) or four spermidine or spermine units were synthesized. We studied the photostability, the hydrophilic/lipophilic balance of porphyrin-polyamine derivatives and the production of singlet oxygen. All these compounds possess physicochemical features required for their use in PDT. Then, we investigated the photocytotoxic efficacy of these porphyrin-polyamine derivatives and the cell death pathway implicated. All compounds appear to be more efficient than Photofrin® to induce HaCat and MCF7 cell death, essentially by apoptosis. Collectively, these data show that porphyrin-polyamine conjugates could be promising phototherapeutic agents.

Triazinyl porphyrin-based photoactive cotton fabrics: preparation, characterization, and antibacterial activity.

In the present work, we report on the synthesis of cellulose cotton fibers bearing different types of photosensitizers with the aim to prepare new efficient polymeric materials for antimicrobial applications. Anionic, neutral, and cationic amino porphyrins have been covalently grafted on cotton fabric, without previous chemical modification of the cellulosic support, using a 1,3,5-triazine derivative as the linker. The obtained porphyrin-grafted cotton fabrics were characterized by infrared (ATR-FTIR), diffuse reflectance UV-vis (DRUV) spectroscopies, and thermogravimetric analysis (TGA) to confirm the triazine linkage. Antimicrobial activity of porphyrin-cellulose materials was tested under visible light irradiation against Staphylococcus aureus and Escherichia coli . The results showed excellent activity on the Gram-positive bacterium, showing structure-activity relationship, although no photodamage of the Gram-negative microorganism was recorded. A mechanism of bacterial inactivation by photosensitive surfaces is proposed.

Synthesis of tetraglucosyl- and tetrapolyamine-tetrabenzoporphyrin conjugates for an application in PDT.

This paper reports the synthesis and characterization of a new class of tetrabenzoporphyrins bearing glucosyl or polyamine units on meso positions to improve the targeting of cancer cells. Photocytotoxic activity of these photosensitizers was tested on cell lines HaCaT and MCF-7 and compared to Photofrin II.

DNA photocleavage by porphyrin-polyamine conjugates.

A series of polyamine-porphyrin conjugates bearing two (cis or trans position) or four units of spermidine or spermine was synthesized. We studied the binding of these cationic porphyrins to calf thymus DNA by the means of UV-vis spectroscopy and we investigated their ability to cleave plasmid DNA in the presence of light. DNA binding and DNA photocleavage abilities were found to depend on structural characteristics as (a) the relative positions of the side chains on the porphyrin ring and (b) the nature of the attached side chains (spermidine or spermine). DNA cleavage was also studied in the presence of a singlet oxygen quencher (NaN(3)) and in the presence of a hydroxyl radical scavenger (mannitol). Singlet oxygen was the major species responsible for the cleavage of DNA previously observed. Collectively, these data show that polyamine-porphyrin conjugates could be promising phototherapeutic agents.

One-pot silver nanoring synthesis.

Silver colloidal nanorings have been synthesized by reducing silver ions with NaBH4 in trisodium citrate buffers. pH increase, by addition of NaOH, was used to speed up reduction reaction. The UV-vis absorption spectra of resulting silver nanorings showed two peaks accounting for transverse and longitudinal surface plasmon resonance, at ≈400 nm, and between 600 and 700 nm, respectively. The shapes of these silver nanoparticles (nanorings) depended on AgNO3/NaBH4 ratio, pH and reaction temperature. Particles were analysed by transmission electron microscopy, scanning electron microscopy and X-ray diffraction. A reaction pathway is proposed to explain silver nanoring formation.

3-Substituted pyrazinone nucleosides--a new family of D4T analogues.

The synthesis of a new family of D4T analogues is described to study the influence of pyrazinone base on antiretroviral power. Substitution of 3H by methyl or n-decyl increases the lipophilic character and may facilitate diffusion across cell membranes. The compounds were characterized by (1)H NMR and infrared spectroscopy. Antiviral (HIV-1) properties of these compounds were examined.