1,721,006 research outputs found
Encapsulation of all-trans-retinoic acid in polymeric micelles
No full textAll-trans-retinoic acid (ATRA) is being increasingly included in antitumor therapeutical schemes for the treatment of various type of tumors; however the difficulty of increasing plasma concentrations of ATRA in vivo hindered, until now, a correct evaluation of its possible pro-apoptotic effect towards both the proliferating and non proliferating neuroblastic cells.
Recent approaches to enhance the solubility of hydrophobic drugs considered polymeric micelles particularly interesting for their efficiency in trapping lipophilic drugs within their internal core, the possibility to provide small and flexible structures able to easily extravasate in the solid tumor and a propensity to evade scavenging by the mononuclear phagocyte system. Our studies focus on micelles prepared from a water soluble polymer, PVA, conjugated with lipid alkyl chains, thus achieving amphiphilicity, such as that of A-B type block co-polymers. The core of the polymer serves as a non-aqueous reservoir, where the drug is entrapped, but also stabilized against chemical modifications by the physiological environment [1].
All-trans-retinoic acid (ATRA) is now included in many anti-tumour therapeutic schemes. Unfortunately its poor aqueous solubility hampers its parenteral formulation. To date, there is no parenteral formulation of ATRA commercially available, while oral administration of ATRA is associated with progressively diminishing ATRA levels in plasma. An ATRA formulation, obtained by complexation of the drug into polymeric micelles, might be suitable for parenteral administration overcoming these unwanted effects [2]. To this purpose we prepared an amphiphilic polymer by poly-vinylalcohol (PVA) substitution with oleyl amine at 1.5% substitution degree and evaluated its functional properties with regard to ATRA complexation.
EXPERIMENTAL PART
The new amphiphile polymer, PVA-co-oleyl-vinyl carbamate, obtained by PVA partial substitution with oleylamine, contains a carbamate bond, rather than an ester bond, as a spacer between the hydrophilic PVA and the hydrophobic oleyl chains. The polymer thus obtained holds enhanced aqueous solubility in the presence of enhanced substitution degree. The solubilizing ability of the substituted polymer was evaluated towards ATRA in aqueous solutions of the polymer and of drug–polymer mixtures obtained by spray-drying hydro-alcoholic solutions of ATRA and polymer at 1:3, 1:5 and 1:10 drug–polymer weight ratios.
RESULTS AND DISCUSSION
The spray-dried complexes rapidly dissolve in water, providing high levels of ATRA solubilization as a function of the drug–polymer weight ratio. The complexes characterized by 1:5 drug–polymer weight ratio (▲) provided higher levels of ATRA solubilization than 1:3 (▄) and 1:10 (▬) drug–polymer weight ratios respectively. Pre-formed polymeric micelles in water, equilibrated in the presence of excess solid ATRA, provided lower levels of solubilization (●). The drug release from the complexes was very slow in PBS, indicating their suitability in anti-tumour drug targeting, where a fundamental requirement is stability towards drug release for at least 24 h, corresponding to the average circulation time period of macromolecular carriers.
A comparison between the present polymer, containing a polyvinyl backbone linked to oleyl chains by carbamate bonds and a previously studied polymer, based on the same polyvinyl backbone linked to oleyl chains by ester bonds, indicates that the nature of the bond between the main backbone and the oleyl chains strongly influence the physico-chemical characteristics of the final polymer. In the presence of the ester bond the highest polymer aqueous solubility obtained was 30 mg/ml at 37°C at a substitution degree not exceeding 1%. The increase in the substitution degree decreased the polymer solubility.
In the presence of the carbamate bond it was possible to increase both the substitution degree and the aqueous pol..
Modified polyvinylalcohol for encapsulation of all-trans-retinoic acid in polymeric micelles.
No full textAll-trans-retinoic acid (ATRA) is now included in many antitumor therapeutic schemes for the treatment of acute promyelocytic leukaemia, Kaposi's sarcoma, head and neck squamous cell carcinoma, ovarian carcinoma, bladder cancer and neuroblastoma. Unfortunately its poor aqueous solubility hampers its parenteral formulation. To date, there is no parenteral formulation of ATRA commercially available and oral administration of ATRA is associated with progressively diminishing ATRA levels in plasma, which is related to induction of retinoic acid-binding protein and increased drug catabolism by cytochrome P-450-mediated reaction. An ATRA formulation, obtained by complexation of the drug into polymeric micelles, might be suitable for parenteral administration overcoming these unwanted effects. To this purpose we prepared an amphiphilic polymer by polyvinylalcohol (PVA) substitution with oleyl amine at 1.5% substitution degree (mol substituent per 100 mol hydroxyvinylmonomer) and evaluated its functional properties with regard to ATRA complexation. The substituted polymer displayed ability to interact with ATRA both in aqueous solution and in the solid state following spray-drying of drug-polymer hydro-alcoholic solutions. The spray-dried complexes rapidly dissolved in water providing high levels of ATRA solubilization as a function of the drug-polymer weight ratio. The complexes characterized by 1:5 drug-polymer weight ratio provided higher levels of ATRA solubilization than 1:3 and 1:10 drug-polymer weight ratios respectively. Pre-formed polymeric micelles in water equilibrated in the presence of excess solid ATRA provided the lowest levels of solubilization. The drug release from the complexes was very slow in PBS, indicating their suitability in antitumor drug targeting where a fundamental requirement is stability towards drug release for at least 24 h, corresponding to the average circulation time period of macromolecular carriers. The cytotoxicity studies against neuroblastoma cell lines outlined increased cytotoxicity of complexed ATRA with respect to free ATRA, likely due to the increased bioavailability of the hydrophobic drug from the complex. We conclude that ATRA entrapped into self-assembling polymer micelles may be a useful parenteral ATRA formulation overcoming the unwanted pharmacological mechanism that lead to acquired retinoid resistance
Improvement of aqueous solubility of fenretinide and other hydrophobic anti-tumor drugs by complexation with amphiphilic dextrins.
No full textThis study relates to the preparation of a series of amphiphilic dextrins and their evaluation as complexing agents for anti-tumor hydrophobic drugs such as fenretinide, paclitaxel, etoposide, and camptothecin. The amphiphilic dextrins were obtained by conjugation of low molecular weight dextrin (average molecular weight 1670, average polymerization degree 9.33 glucose monomer) with hydrocarbon chains at substitution degree of about 0.1 mole hydrocarbon chain per mole of glucose monomer, as confirmed by 1H-NMR spectra. The conjugates were highly soluble in water and dissolved with formation of nano-aggregates endowed with hydrophobic inner cores able to host hydrophobic drugs by complexation. Complexation raised hydrophobic drugs aqueous solubility; the best results were obtained with fenretinide. Solid complexes with fenretinide were prepared by using three different approaches: the kneading method, the co-solubilisation method, and the co-precipitation method. Kneading method provided the complexes endowed with the best functional properties. Thermogravimetric analysis on solid samples suggested a notable thermal stability up to 300 degrees C for both the conjugated dextrins and the solid complexes. In differential scanning calorimetry profiles no significant differences were observed among amphiphilic dextrins and complexed drug, indicating that the guest molecule exists in an amorphous state in the solid matrices. Particle size analysis confirmed the dimensional suitability of the complexes for parenteral administration. Moreover, sustained drug release, in vitro, has been observed from all the complexes analyzed. Regarding the biological effects, the cytotoxicity of complexed fenretinide towards HTLA-230 neuroblastoma cell line was always higher than the free drug, suggesting that complexation increased drug bioavailability. These findings, taken together, indicated that these biodegradable, self-assembling dextrin conjugates may be regarded as new potential complexing agents for hydrophobic drugs and, in particular, for fenretinide, to increase drug solubility, bioavailability, and thus therapeutic efficacy
Calcium/Cobalt Alginate Beads as Functional Scaffolds for Cartilage Tissue Engineering
Full text linkArticular cartilage is a highly organized tissue with complex biomechanical properties. However, injuries to the cartilage usually lead to numerous health concerns and often culminate in disabling symptoms, due to the poor intrinsic capacity of this tissue for self-healing. Although various approaches are proposed for the regeneration of cartilage, its repair still represents an enormous challenge for orthopedic surgeons. The field of tissue engineering currently offers some of the most promising strategies for cartilage restoration, in which assorted biomaterials and cell-based therapies are combined to develop new therapeutic regimens for tissue replacement. The current study describes the in vitro behavior of human adipose-derived mesenchymal stem cells (hADSCs) encapsulated within calcium/cobalt (Ca/Co) alginate beads. These novel chondrogenesis-promoting scaffolds take advantage of the synergy between the alginate matrix and Co+2 ions, without employing costly growth factors (e.g., transforming growth factor betas (TGF-βs) or bone morphogenetic proteins (BMPs)) to direct hADSC differentiation into cartilage-producing chondrocytes
Nanospermidine in Combination with Nanofenretinide Induces Cell Death in Neuroblastoma Cell Lines
Full text linkA new strategy to cause cell death in tumors might be the increase of intracellular polyamines at concentrations above their physiological values to trigger the production of oxidation metabolites at levels exceeding cell tolerance. To test this hypothesis, we prepared nanospermidine as a carrier for spermidine penetration into the cells, able to escape the polyamine transport system that strictly regulates intracellular polyamine levels. Nanospermidine was prepared by spermidine encapsulation in nanomicelles and was characterized by size, zeta potential, loading, dimensional stability to dilution, and stability to spermidine leakage. Antitumor activity, ROS production, and cell penetration ability were evaluated in vitro in two neuroblastoma cell lines (NLF and BR6). Nanospermidine was tested as a single agent and in combination with nanofenretinide. Free spermidine was also tested as a comparison. The results indicated that the nanomicelles successfully transported spermidine into the cells inducing cell death in a concentration range (150–200 uM) tenfold lower than that required to provide similar cytotoxicity with free spermidine (1500–2000 uM). Nanofenretinide provided a cytostatic effect in combination with the lowest nanospermidine concentrations evaluated and slightly improved nanospermidine cytotoxicity at the highest concentrations. These data suggest that nanospermidine has the potential to become a new approach in cancer treatment. At the cellular level, in fact, it exploits polyamine catabolism by means of biocompatible doses of spermidine and, in vivo settings, it can exploit the selective accumulation of nanomedicines at the tumor site. Nanofenretinide combination further improves its efficacy. Furthermore, the proven ability of spermidine to activate macrophages and lymphocytes suggests that nanospermidine could inhibit immunosuppression in the tumor environment
Effect on drug concentration in the monomer/cross-linker mixture on the loading levels and the release kinetics of non-steroidal anti-inflammatory drugs from ethylene glycol dimethacrylate cross-linked polyhydroxyethyl methacrylate microspheres
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Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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