pH-responsive niosome-based nanocarriers of antineoplastic agents.

Differences in pH between the tumour interstitium and healthy tissues can be used to induce conformational changes in the nanocarrier structure, thereby triggering drug release at the desired site. In the present study, novel pH-responsive nanocarriers were developed by modifying conventional niosomes with hexadecyl-poly(acrylic acid)n copolymers (HD-PAAn). Niosomal vesicles were prepared by the thin film hydration method using Span 60, Span 60/Tween 60 and cholesterol as main constituents, and HD-PAA modifiers of different concentrations (0.5, 1, 2.5, 5 mol%). Next, two model substances, a water-soluble fluorescent dye (calcein) and a hydrophobic agent with pronounced antineoplastic activity (curcumin), were loaded in the aqueous core and hydrophobic membrane of the elaborated niosomes, respectively. Physicochemical properties of blank and loaded nanocarriers such as hydrodynamic diameter (Dh), size distribution, zeta potential, morphology and pH-responsiveness were investigated in detail. The cytotoxicity of niosomal curcumin was evaluated against human malignant cell lines of different origins (MJ, T-24, HUT-78), and the mechanistic aspects of proapoptotic effects were elucidated. The formulation composed of Span 60/Tween 60/cholesterol/2.5% HD-PAA17 exhibited optimal physicochemical characteristics (Dh 302 nm; ζ potential -22.1 mV; high curcumin entrapment 83%), pH-dependent drug release and improved cytotoxic and apoptogenic activity compared to free curcumin.

In Situ Gelling Hydroxypropyl Cellulose Formulation Comprising Cannabidiol-Loaded Block Copolymer Micelles for Sustained Drug Delivery.

Cannabidiol (CBD) is a natural terpenophenolic compound with known pharmacological activities, but the poor solubility of CBD in water limits its widespread use in medicine and pharmacy. Polymeric (nano)carriers demonstrated high potential for enhancing the solubility and therapeutic activity of lipophilic drugs such as CBD. Here, we report the elaboration of a novel hydroxypropyl cellulose (HPC)-based in situ gelling formulation for controlled delivery of CBD. In the first stage, nanosized polymeric micelles from poly(ethylene oxide)-block-poly(α-cinnamyl-ε-caprolactone-co-ε-caprolactone) (PEO-b-P(CyCL-co-CL) diblock copolymers) were used to increase the solubility of CBD in water. Different copolymers were assessed, and the carrier with the highest encapsulation efficiency (EE) and drug loading capacity (DLC) was selected for further elaboration of nanocomposite in situ gel formulations. Next, the sol-to-gel transition behavior of HPC as a function of K2SO4 concentration in the aqueous solution was investigated by microcalorimetry and dynamic oscillatory rheology, and the optimal formulation capable of forming a physical gel under physiological conditions was determined. Finally, injectable nanocomposite hydrogels comprising cannabidiol were fabricated, and their drug release profile and cytotoxicity against human tumor cell lines were evaluated. The in situ gels exhibited prolonged drug release over 12 h, controlled by gel erosion, and the cytotoxicity of formulated cannabidiol was comparable with that of a free drug.

Development, Characterization and Pharmacological Evaluation of Cannabidiol-Loaded Long Circulating Niosomes.

Cannabidiol (CBD) is a promising drug candidate with pleiotropic pharmacological activity, whose low aqueous solubility and unfavorable pharmacokinetics have presented obstacles to its full clinical implementation. The rational design of nanocarriers, including niosomes for CBD encapsulation, can provide a plausible approach to overcoming these limitations. The present study is focused on exploring the feasibility of copolymer-modified niosomes as platforms for systemic delivery of CBD. To confer steric stabilization, the niosomal membranes were grafted with newly synthesized amphiphilic linear or star-shaped 3- and 4-arm star-shaped copolymers based on polyglycidol (PG) and poly(ε-caprolactone) (PCL) blocks. The niosomes were prepared by film hydration method and were characterized by DLS, cryo-TEM, encapsulation efficacy, and in vitro release. Free and formulated cannabidiol were further investigated for cytotoxicity and pro-apoptotic and anti-inflammatory activities in vitro in three human tumor cell lines. The optimal formulation, based on Tween 60:Span60:Chol (3.5:3.5:3 molar ration) modified with 2.5 mol% star-shaped 3-arm copolymer, is characterized by a size of 235 nm, high encapsulation of CBD (94%), and controlled release properties. Niosomal cannabidiol retained the antineoplastic activity of the free agent, but noteworthy superior apoptogenic and inflammatory biomarker-modulating effects were established at equieffective exposure vs. the free drug. Specific alterations in key signaling molecules, implicated in programmed cell death, cancer cell biology, and inflammation, were recorded with the niosomal formulations.

Pyrenebutyrate Pt(IV) Complexes with Nanomolar Anticancer Activity.

Research on platinum-based anticancer drugs continuously strives to develop new non-classical platinum complexes. Pt(IV) prodrugs are the most promising, and their activation-by-reduction mechanism of action is being explored as a prospect for higher selectivity and efficiency. Herein, we present the anticancer potency and chemical reactivity of Pt(IV) complexes formed by linking pyrene butyric acid with cisplatin. The results from cytotoxicity screening on 10 types of cancer cell lines and non-malignant cells (HEK-293) indicated IC50 values as low as 50-70 nM for the monosubstituted Pt(IV) complex against leukemia cell lines (HL-60 and SKW3) and a cisplatin-resistant derivative (HL-60/CDDP). Interestingly, the bis-substituted complex is virtually non-toxic to both healthy and cancerous cells of adherent types. Nevertheless, it shows high cytotoxicity against multidrug-resistant derivatives HL-60/CDDP and HL-60/Dox. The reactivity of the complexes with biological reductants was monitored by the NMR method. Furthermore, the platinum uptake by the treated cells was examined on two types of cellular cultures: adherent and suspension growing, and proteome profiling was conducted to track expression changes of key apoptosis-related proteins in HL-60 cells. The general conclusion points to a possible cytoskeletal entrapment of the bulkier bis-pyrene complex that could be limiting its cytotoxicity to adherent cells, both cancerous and healthy ones.

Cinnamyl-Modified Polyglycidol/Poly(ε-Caprolactone) Block Copolymer Nanocarriers for Enhanced Encapsulation and Prolonged Release of Cannabidiol.

The present study describes the development of novel block copolymer nanocarriers of the phytocannabinoid cannabidiol (CBD), designed to enhance the solubility of the drug in water while achieving high encapsulation efficiency and prolonged drug release. Firstly, a well-defined amphiphilic block copolymer consisting of two outer hydrophilic polyglycidol (PG) blocks and a middle hydrophobic block of poly(ε-caprolactone) bearing pendant cinnamyl moieties (P(CyCL-co-CL)) were synthesized by the click coupling reaction of PG-monoalkyne and P(CyCL-co-CL)-diazide functional macroreagents. A non-modified polyglycidol/poly(ε-caprolactone) amphiphilic block copolymer was obtained as a referent system. Micellar carriers based on the two block copolymers were formed via the solvent evaporation method and loaded with CBD following two different protocols-loading during micelle formation and loading into preformed micelles. The key parameters/characteristics of blank and CBD-loaded micelles such as size, size distribution, zeta potential, molar mass, critical micelle concentration, morphology, and encapsulation efficiency were determined by using dynamic and static multiangle and electrophoretic light scattering, transmission electron microscopy, and atomic force microscopy. Embedding CBD into the micellar carriers affected their hydrodynamic radii to some extent, while the spherical morphology of particles was not changed. The nanoformulation based on the copolymer bearing cinnamyl moieties possessed significantly higher encapsulation efficiency and a slower rate of drug release than the non-modified copolymer. The comparative assessment of the antiproliferative effect of micellar CBD vs. the free drug against the acute myeloid leukemia-derived HL-60 cell line and Sezary Syndrome HUT-78 demonstrated that the newly developed systems have pronounced antitumor activity.

Exploring Phytochemical Composition and In Vivo Anti-Inflammatory Potential of Grape Seed Oil from an Alternative Source after Traditional Fermentation Processes: Implications for Phytotherapy.

This study aimed to analyze the composition of grape seed oil (GSO) derived from an alternative source after traditional fermentation processes and its potential anti-inflammatory effects using an in vivo model of carrageenan-induced inflammation in mice. Gas chromatography high-resolution electron ionization mass spectrometry (GC-HR-EIMS) analysis identified eight main components in the GSO extract, including myristic acid methyl ester, palmitoleic acid methyl ester, methyl isoheptadecanoate, cis-linoleic acid, oleic acid methyl ester, linoleic acid stereoisomer, linoleic acid ethyl ester, and methyl (6E, 9E, 12E, 15E)-docose-6,9,12,15-tetraenoate. No significant differences were observed in the main fatty acids between commercially available grape seed oil and GSO extract obtained from fermented grape seeds. In the carrageenan-induced inflammation model, treatment with GSO resulted in a significant reduction in paw edema at 180 min, as in the reduction observed with diclofenac treatment. Combined treatment with GSO and diclofenac showed enhanced anti-inflammatory effects. Additionally, GSO exhibited antioxidative effects by decreasing the levels of glutathione (GSH) and malondialdehyde (MDA) in the serum. Chronic treatment with GSO for ten days did not provide a protective effect on inflammation. These findings suggest that GSO could be used as an alternative raw material and could possess anti-inflammatory and antioxidative properties. Further studies are needed to explore its potential therapeutic applications.

Pharmacological Activities of Schiff Bases and Their Derivatives with Low and High Molecular Phosphonates.

This review paper is focused on the design of anthracene and furan-containing Schiff bases and their advanced properties as ligands in complex transition metal ions The paper also provides a brief overview on a variety of biological applications, namely, potent candidates with antibacterial and antifungal activity, antioxidant and chemosensing properties. These advantageous properties are enhanced upon metal complexing. The subject of the review has been extended with a brief discussion on reactivity of Schiff bases with hydrogen phosphonates and the preparation of low and high molecular phosphonates, as well as their application as pharmacological agents. This work will be of interest for scientists seeking new challenges in discovering advanced pharmacological active molecules gaining inspiration from the versatile families of imines and aminophosphonates.

Micellar Form of a Ferrocene-Containing Camphor Sulfonamide with Improved Aqueous Solubility and Tumor Curing Potential.

The discovery of new anticancer drugs with а higher, more specific activity and diminished side effects than the conventional chemotherapeutic agents is a tremendous challenge to contemporary medical research and development. To achieve a pronounced efficacy, the design of antitumor agents can combine various biologically active subunits in one molecule, which can affect different regulatory pathways in cancer cells. We recently demonstrated that a newly synthesized organometallic compound, a ferrocene-containing camphor sulfonamide (DK164), possesses promising antiproliferative activity against breast and lung cancer cells. However, it still encounters the problem of solubility in biological fluids. In this work, we describe a novel micellar form of DK164 with significantly improved solubility in aqueous medium. DK164 was embedded in biodegradable micelles based on a poly(ethylene oxide)-b-poly(α-cinnamyl-ε-caprolactone-co-ε-caprolactone)-b-poly(ethylene oxide) triblock copolymer (PEO113-b-P(CyCL3-co-CL46)-b-PEO113), and the physicochemical parameters (size, size distribution, zeta potential, encapsulation efficiency) and biological activity of the obtained system were studied. We used cytotoxicity assays and flow cytometry to determine the type of cell death, as well as immunocytochemistry to assess the influence of the encapsulated drug on the dynamics of cellular key proteins (p53 and NFkB) and the process of autophagy. According to our results, the micellar form of the organometallic ferrocene derivate (DK164-NP) exhibited several advantages compared to the free substance, such as higher metabolic stability, better cellular uptake, improved bioavailability, and long-term activity, maintaining nearly the same biological activity and anticancer properties of the drug.

Curcumin and Capsaicin-Loaded Ag-Modified Mesoporous Silica Carriers: A New Alternative in Skin Treatment.

Biologically active substances of natural origin offer a promising alternative in skin disease treatment in comparison to synthetic medications. The limiting factors for the efficient application of natural compounds, such as low water solubility and low bioavailability, can be easily overcome by the development of suitable delivery systems. In this study, the exchange with the template procedure was used for the preparation ofa spherical silver-modified mesoporous silica nanocarrier. The initial and drug-loaded formulations are fully characterized by different physico-chemical methods. The incipient wetness impregnation method used to load health-promoting agents, curcumin, and capsaicin in Ag-modified carriers separately or in combinationresulted in high loading efficiency (up to 33 wt.%). The interaction between drugs and carriers was studied by ATR-FTIR spectroscopy. The release experiments of both active substances from the developed formulations were studied in buffers with pH 5.5, and showed improved solubility. Radical scavenging activity and ferric-reducing antioxidant power assays were successfully used for the evaluation of the antiradical and antioxidant capacity of the curcumin or/and capsaicin loaded on mesoporous carriers. Formulations containing a mixture of curcumin and capsaicin were characterized bypotentiation of their antiproliferative effect against maligning cells, and it was confirmed that the system for simultaneous delivery of both drugs has lower IC50 values than the free substances.The antibacterial tests showed better activity of the obtained delivery systems in comparison with the pure curcumin and capsaicin. Considering the obtained results, it can be concluded that the obtained delivery systems are promising for potential dermal treatment.

Formulation and Evaluation of Hybrid Niosomal In Situ Gel for Intravesical Co-Delivery of Curcumin and Gentamicin Sulfate.

The current study describes the elaboration of a hybrid drug delivery platform for an intravesical application based on curcumin/gentamicin sulfate simultaneously loaded niosomes incorporated into thermosensitive in situ gels. Series of niosomes were elaborated via the thin film hydration method, evaluating the impact of non-ionic surfactants', cholesterol's, and curcumin's concentration. The formulation composed of equimolar ratio of Span 60, Tween 60, and 30 mol% cholesterol was selected as the optimal composition, due to the high entrapment efficiency values obtained for both drugs, and appropriate physicochemical parameters (morphology, size, PDI, and zeta potential), therefore, was further incorporated into Poloxamers (407/188) and Poloxamers and chitosan based in situ gels. The developed hybrid systems were characterized with sol to gel transition in the physiological range, suitable rheological and gelling characteristics. In addition, the formed gel structure at physiological temperatures determines the retarded dissolution of both drugs (vs. niosomal suspension) and sustained release profile. The conducted microbial studies of selected niosomal in situ gels revealed the occurrence of a synergetic effect of the two compounds when simultaneously loaded. The findings indicate that the elaborated thermosensitive niosomal in situ gels can be considered as a feasible platform for intravesical drug delivery.

PEG-Modified tert-Octylcalix[8]arenes as Drug Delivery Nanocarriers of Silibinin.

The hepatoprotective properties of silibinin, as well its therapeutic potential as an anticancer and chemo-preventive agent, have failed to progress towards clinical development and commercialization due to this material's unfavorable pharmacokinetics and physicochemical properties, low aqueous solubility, and chemical instability. The present contribution is focused on the feasibility of using PEGylated calixarene, in particular polyoxyethylene-derivatized tert-octylcalix[8]arene, to prepare various platforms for the delivery of silibinin, such as inclusion complexes and supramolecular aggregates thereof. The inclusion complex is characterized by various instrumental methods. At concentrations exceeding the critical micellization concentration of PEGylated calixarene, the tremendous solubility increment of silibinin is attributed to the additional solubilization and hydrophobic non-covalent interactions of the drug with supramolecular aggregates. PEG-modified tert-octylcalix[8]arenes, used as drug delivery carriers for silibinin, were additionally investigated for cytotoxicity against human tumor cell lines.

Nanoarchitectonics of Multifunctional Niosomes for Advanced Drug Delivery.

Niosomes are a type of vesicular nanocarrier exploited for enhancing the therapeutic efficacy of various drugs in clinical practice. Niosomes comprise a bilayer hydrophobic membrane enclosing a central cavity filled with an aqueous phase, and therefore, they can encapsulate and deliver both hydrophobic and hydrophilic substances. Niosomal nanocarriers are preferred over other bilayer structures such as liposomes due to their chemical stability, biodegradability, biocompatibility, low production cost, low toxicity, and easy storage and handling. In addition, the niosomal membrane can be easy modified by the inclusion of ligands or stimulus-sensitive segments for achieving targeted delivery and triggered release of the encapsulated cargo. This mini-review outlines the current advances in designing functional niosomes and their use as platforms for developing advanced drug and gene delivery systems.

Polysaccharide Cryogels Containing ß-Cyclodextrin for the Delivery of Cannabidiol.

Cannabidiol (CBD) has attracted increasing interest due to its therapeutic potential for treating numerous diseases. However, CBD is very lipophilic and has very unfavorable pharmacokinetics and low bioavailability. Efforts are focused on developing drug delivery systems for enhanced solubilization and therapeutic activity of CBD. Here, we report the preparation of original super-macroporous cryogels from 2-hydroxyethyl cellulose (HEC) and ß-cyclodextrin (ß-CD) designed for the topical delivery of CBD. The cryogels were synthesized by photochemical crosslinking in a frozen aqueous system, purified, and then loaded with CBD. The effect of HEC/ß-CD mass ratio (100:0; 50:50; 40:60 and 20:80) in the reaction mixture on the reaction efficiency, physico-mechanical properties of cryogels, drug release profile, and antineoplastic potential were evaluated in detail. The cryogels showed a bi-phasic release behavior: initial burst release in the first 3 hours followed by slower drug release which can be beneficial in the treatment of cutaneous neoplastic diseases.

Tamoxifen Delivery System Based on PEGylated Magnetic MCM-41 Silica.

Magnetic iron oxide containing MCM-41 silica (MM) with ~300 nm particle size was developed. The MM material before or after template removal was modified with NH2- or COOH-groups and then grafted with PEG chains. The anticancer drug tamoxifen was loaded into the organic groups' modified and PEGylated nanoparticles by an incipient wetness impregnation procedure. The amount of loaded drug and the release properties depend on whether modification of the nanoparticles was performed before or after the template removal step. The parent and drug-loaded samples were characterized by XRD, N2 physisorption, thermal gravimetric analysis, and ATR FT-IR spectroscopy. ATR FT-IR spectroscopic data and density functional theory (DFT) calculations supported the interaction between the mesoporous silica surface and tamoxifen molecules and pointed out that the drug molecule interacts more strongly with the silicate surface terminated by silanol groups than with the surface modified with carboxyl groups. A sustained tamoxifen release profile was obtained by an in vitro experiment at pH = 7.0 for the PEGylated formulation modified by COOH groups after the template removal. Free drug and formulated tamoxifen samples were further investigated for antiproliferative activity against MCF-7 cells.

Development and evaluation of doxycycline niosomal thermoresponsive in situ gel for ophthalmic delivery.

The present study was focused on the development of doxycycline niosomal thermosensitive in situ gel for ophthalmic application. For this purpose, in situ gel formulations based on Poloxamer 407 alone and in combination with hydroxypropyl methylcellulose were prepared by cold method and evaluated in terms of sol-gel transition temperature, gelling time and capacity. The addition of hydroxypropyl methylcellulose to the composition led to decrease in the phase transition temperature of the systems. Conversely, the inclusion of doxycycline niosomes to the formulations didn''t have a significant influence on their gelling and rheological properties. Doxycycline niosomal in situ gel based on 15%w/w Poloxamer and 1.5% w/w hydroxypropyl methylcellulose was characterized with gelation temperature of 34 °C, appropriate for ophthalmic application, pseudoplastic flow behavior and very good physical stability. In vitro release studies indicated slower and sustained doxycycline release from the developed in situ gel as compared to niosomes. The conducted microbiological studies revealed its enhanced antibacterial activity with respect to doxycycline solution and doxycycline in situ gel. The obtained results indicate that the elaborated niosomal in situ gel may serve as a promising system for ophthalmic delivery of doxycycline, ensuring sufficient therapeutic concentration and sustained drug release.

Enhanced cellular uptake of platinum by a tetracationic Pt(II) nanocapsule and its implications to cancer treatment.

Despite the known limitations of cisplatin chemotherapy, the treatment of cancer by platinum-based drugs remains the method of choice for many oncologists. The advancement in drug delivery formulations and protocols of combined treatments provided effective tools to ameliorate the side effects of platinum-based therapies. Another approach to improve the pharmacological profiles of anticancer platinum drugs is to properly modify their structure and composition, which has produced numerous platinum complexes with improved therapeutic effect. Recently, we have demonstrated the strong anticancer potency of supramolecular nanocapsules that form by self-assembly of four bis-anthracene ligands with two metal ions, either Pt(II) or Pd(II). Herein, we focus our study on the Pt(II) nanocapsule and its uptake by two types of cancer cells, suspension cultures of HL-60 cells and the adherent cancer cells HT-29. Comparison of the platinum uptake by cancer cells treated with the nanocapsule and with cisplatin evidenced superior uptake of platinum caused by the nanocapsule, which in HT-29 and HL-60 cells prevails by 21 and 31 times, respectively. Morphological changes in the HL-60 cells induced by the Pt(II) nanocapsule were studied by transmission electron microscopy (TEM) which provided plausible explanation of the uptake results. These data corroborate also with the known nanocapsule's very high cytotoxicity, better selectivity, and lack of cross-resistance with cisplatin. Additionally, our estimations of the drug-drug interactions in combined treatments established the propensity of the nanocapsule to exert supra-additive cytotoxicity in combination with cisplatin against the bladder cancer T-24 cells. All these findings define the scope for more detailed pharmacological characterization of the presented Pt(II) nanocapsule.

Nanocomposite Cryogel Carriers from 2-Hydroxyethyl Cellulose Network and Cannabidiol-Loaded Polymeric Micelles for Sustained Topical Delivery.

In this contribution, we report the development of original nanocomposite cryogels for sustained topical delivery of hydrophobic natural active substances such as cannabidiol (CBD). The cryogels were fabricated by a method involving cryogenic treatment and photo-crosslinking of aqueous systems containing biodegradable 2-hydroxyethyl cellulose (HEC) and CBD-loaded polymeric micelles. The preparation of the water-soluble form of CBD was a key element for the successful drug loading in the one-pot reaction. The main physical, mechanical and biological characteristics of CBD-loaded and blank cryogels such as gel fraction yield, swelling degree, morphology, storage and loss moduli, and cytotoxicity were studied in detail. The advantage of nanocomposite over pure HEC cryogel carriers in terms of achieving a sustained release profile was also demonstrated.

Verapamil delivery systems on the basis of mesoporous ZSM-5/KIT-6 and ZSM-5/SBA-15 polymer nanocomposites as a potential tool to overcome MDR in cancer cells.

ZSM-5/KIT-6 and ZSM-5/SBA-15 nanoparticles were synthesized and further modified by a post-synthesis method with (CH2)3SO3H and (CH2)3NHCO(CH2)2COOH groups to optimize their drug loading and release kinetic profiles. The verapamil cargo drug was loaded by incipient wetness impregnation both on the parent and modified nanoporous supports. Nanocarriers were then coated with a three-layer polymeric shell composed of chitosan-k-carrageenan-chitosan with grafted polysulfobetaine chains. The parent and drug loaded formulations were characterized by powder XRD, N2 physisorption, thermal analysis, AFM, DLS, TEM, ATR-FT-IR and solid state NMR spectroscopies. Loading of verapamil on such nanoporous carriers and their subsequent polymer coating resulted in a prolonged in vitro release of the drug molecules. Quantum-chemical calculations were performed to investigate the strength of the interaction between the specific functional groups of the drug molecule and (CH2)3SO3H and CH2)3NHCO(CH2)2COOH groups of the drug carrier. Furthermore, the ability of the developed nanocomposites to positively modulate the intracellular internalization and thereby augment the antitumor activity of the p-gp substrate drug doxorubicin was investigated in a comparative manner vs. free drug in a panel of MDR positive (HL-60/Dox, HT-29) and MDR negative (HL-60) human cancer cell lines using the Chou-Talalay method.

Design and in vitro evaluation of doxycycline hyclate niosomes as a potential ocular delivery system.

Niosomes have been considered as promising nanoscale carriers for ocular drug delivery, since they have been shown to increase the bioavailability of various drugs and to improve their efficacy. The main objective of this study was to prepare and characterize niosomes for ocular delivery of doxycycline hyclate. Niosomes were prepared using various surfactants (namely Span 20, Span 60, Span 80, Tween 60) and cholesterol in different molar ratios, using the thin film hydration method followed by multiple membrane extrusion or the reverse-phase evaporation method. In our hands highest entrapment efficiency was encountered with the formulation composed of Span 60 and cholesterol, prepared by the reverse phase evaporation method. Transmission electron microscopy and dynamic light scattering were used to assess the morphology, size and size distribution paterns of prepared niosomes. In vitro release studies showed sustained release of doxycycline from niosomes. After 2 months of storage at 4 °C the doxycycline-loaded niosomes remained physically stable in terms of encapsulation efficiency and particle size. The performed Draize test revealed that the prepared niosomes were well tolerated by the eye. Taken together our findings indicate that niosomes could be considered as a plausible drug delivery platform for for ophthalmic application of doxycycline.

Delineation of proapoptotic signaling of anthracene-shelled M2L4 metallacapsules and their synergistic activity with curcumin in cisplatin-sensitive and resistant tumor cell lines.

Since the introduction of cisplatin into clinical practice a few decades ago, the topic of metal-based drugs has expanded significantly. Recent examples emphasize on metallosupramolecules as an emerging class of compounds with diverse properties. They can trigger unique cellular events in malignant cells or serve as molecular hosts for various biologically active compounds, including anticancer agents. The anthracene-shelled M2L4 coordination nanocapsules under research have already proved very high anticancer potency with remarkable selectivity and lack of cross-resistance. In this study, we provide an oncopharmacological evaluation of the Pt(II)- and Pd(II)-clipped M2L4 nanocapsules; we report a thorough analysis of their synergistic effects in combined treatments with the pleiotropic anticancer agent curcumin. We examined changes in cellular expression of several apoptosis-related proteins in a panel of tumor cell lines with different chemosensitivity towards cisplatin, i.e. HT-29, HL-60 and its resistant strains HL-60/CDDP and HL-60/Dox, in order to assess the molecular mechanisms of their antitumor activity The results of the immunoassay concluded activation of the mitochondrial apoptotic pathway in all the screened tumor lines. A prevalent modulation of the extrinsic apoptotic signaling cascade was observed in the chemoresistant variants. Curcumin interactions of the tested compounds were estimated against the cisplatin-refractory cell line HT-29 via the Chou-Talalay method (CTM), whereby the palladium species yielded superior synergistic activity as compared to their platinum analogues.