1,721,004 research outputs found
Improvement of aqueous solubility of fenretinide and other hydrophobic anti-tumor drugs by complexation with amphiphilic dextrins
No full textImprovement of aqueous solubility of fenretinide and other hydrophobic anti-tumor drugs by complexation with amphiphilic dextrins
No full textImprovement 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
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. (c) 2004 Elsevier B.V. All rights reserved
In vitro and in vivo antitumor activity of the novel derivatized polyvinyl alcohol-based polymer P10(4).
No full textLaboratory of Oncology, G. Gaslini Children's Hospital, Genoa, Italy.
PURPOSE: The major limitation to successful chemotherapy of neuroblastoma is the
toxicity of traditional antitumor drugs. Hence, less toxic and more effective
drugs are to be found, and novel formulations of conventional compounds allowing
a more favorable biodistribution should be sought for. In an attempt to pursue
this task, we recently synthesized an amphiphilic polymer based on a polyvinyl
alcohol backbone [P10(4)]. EXPERIMENTAL DESIGN: The cytotoxic activity of P10(4)
was evaluated both in vitro on neuroblastoma and melanoma cell lines and in vivo
in pseudometastatic neuroblastoma models. Apoptosis was assessed by morphology,
cytofluorimetric analysis of DNA content, and DNA fragmentation assay. Caspases
activation was investigated by kits specific for caspase-1, caspase-2,
caspase-3, caspase-4, caspase-6, caspase-7, caspase-8, caspase-9, caspase-10,
and caspase-13. Colony formation was evaluated by soft agar assay. RESULTS:
P10(4) exerted a potent cytotoxic activity on different neuroblastoma and
melanoma cell lines through induction of both extrinsic and intrinsic caspase
cascades and subsequent apoptosis. Moreover, the clonogenic potential of cells
that survived P10(4) treatment was strongly reduced. Next, we tested the effects
of P10(4) in nude mice injected with both a human and a murine neuroblastoma
cell lines i.v. P10(4) significantly increased the life span and the long-term
survival of treated mice over controls. No side effects were observed, even at
doses higher than those used for therapeutic purposes. CONCLUSIONS: Our data
suggest that P10(4) holds promise as an anticancer compound and, because of its
lack of interaction with DNA, is unlikely to give rise to drug resistance
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
Preparation and evaluation of polyvinyl alcohol-co-oleylvinyl ether derivatives as tumor-specific cytotoxic systems
No full textA series of poly(vinyl alcohol) amphiphilic derivatives have been prepared to obtain polymeric aggregates in aqueous phase holding thermodynamic instability. The aim was to evaluate their ability to interact with tumor cells eliciting selective cytotoxicity. The poly(vinyl alcohol) derivatives were prepared by partial substitution of poly(vinyl alcohol) (MW 10 kDa) with both oleyl chains and poly(ethylene glycol) monoethyl ethers (PEGMEE) of different molecular weights. The substitution degree was 1.5% for the oleyl chains and 1% for the PEGMEE chains (moles of substituent per 100 mol of hydroxyvinyl monomer). The polyvinyl derivatives obtained easily dissolved in water. Dynamic and static light scattering measurements on the polymer aqueous solutions indicated the formation of polymeric aggregates characterized by low polydispersity (0.232-0.299) and mean size (218-382 nm) in the range suitable for intravenous administration. Moreover, they were characterized by different packing densities and thermodynamic instabilities driving the polymers to interact with hydrophobic membranes. Among the analyzed polymers, the poly(vinyl alcohol)-co-oleylvinyl ether substituted with triethylene glycol monoethyl ether (P10(4)) provided in solution the highest affinity for hydrophobic membranes. P10(4), moreover, was the most cytotoxic toward the tumor cell lines analyzed (neuroblastoma: SH-SY5Y, IMR-32, HTLA-230. melanoma: MZ2-MEL, RPMI7932.), while it did not appreciably alter the viability of the normal resting lymphocytes. The peculiar behavior of the P10(4) aggregates has been correlated to their high thermodynamic instability in solution due to the high packing density that triggers the polymeric aggregates to interact with hydrophobic membranes such as the tumor cell membranes, thus eliciting cytotoxicity
Antitumor activity of Sodium ascorbate against neuroblastoma cell lines in vitro
No full textBACKGROUND: Neuroblastoma (NB) is an extra-cranial solid tumour of childhood. In spite of the good clinical response to first-line therapy, complete eradication of NB cells is rarely achieved. Thus, new therapeutic strategies are needed to eradicate surviving NB cells and prevent relapse. Sodium ascorbate has been recently reported to induce apoptosis of B16 melanoma cells through down-regulation of the transferrin receptor, CD71. Since NB and melanoma share the same embryologic neuroectodermal origin, we used different human NB cell lines to assess whether the same findings occurred.
RESULTS: We could observe dose- and time-dependent induction of apoptosis in all NB cell lines. Sodium ascorbate decreased the expression of CD71 and caused cell death within 24 h. An increase in the global and specific caspase activity took place, as well as an early loss of the mitochondrial transmembrane potential. Moreover, intracellular iron was significantly decreased after exposure to sodium ascorbate. Apoptotic markers were reverted when the cells were pretreated with the iron donor ferric ammonium citrate (FAC), further confirming that iron depletion is responsible for the ascorbate-induced cell death in NB cells.
CONCLUSION: Sodium ascorbate is highly toxic to neuroblastoma cell lines and the specific mechanism of vitamin C-induced apoptosis is due to a perturbation of intracellular iron levels ensuing TfR-downregulation
Preparation and evaluation of polyvinyl alcohol-co-oleylvinyl ether derivatives as tumor-specific cytotoxic systems
No full textA series of poly(vinyl alcohol) amphiphilic derivatives have been prepared to obtain polymeric aggregates in aqueous phase holding thermodynamic instability. The aim was to evaluate their ability to interact with tumor cells eliciting selective cytotoxicity. The poly(vinyl alcohol) derivatives were prepared by partial substitution of poly(vinyl alcohol) (MW 10 kDa) with both oleyl chains and poly(ethylene glycol) monoethyl ethers (PEGMEE) of different molecular weights. The substitution degree was 1.5% for the oleyl chains and 1% for the PEGMEE chains (moles of substituent per 100 mol of hydroxyvinyl monomer). The polyvinyl derivatives obtained easily dissolved in water. Dynamic and static light scattering measurements on the polymer aqueous solutions indicated the formation of polymeric aggregates characterized by low polydispersity (0.232-0.299) and mean size (218-382 nm) in the range suitable for intravenous administration. Moreover, they were characterized by different packing densities and thermodynamic instabilities driving the polymers to interact with hydrophobic membranes. Among the analyzed polymers, the poly(vinyl alcohol)-co-oleylvinyl ether substituted with triethylene glycol monoethyl ether (P10(4)) provided in solution the highest affinity for hydrophobic membranes. P10(4), moreover, was the most cytotoxic toward the tumor cell lines analyzed (neuroblastoma: SH-SY5Y, IMR-32, HTLA-230. melanoma: MZ2-MEL, RPMI7932.), while it did not appreciably alter the viability of the normal resting lymphocytes. The peculiar behavior of the P10(4) aggregates has been correlated to their high thermodynamic instability in solution due to the high packing density that triggers the polymeric aggregates to interact with hydrophobic membranes such as the tumor cell membranes, thus eliciting cytotoxicity. © 2005 American Chemical Society
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