A Peptidic Thymidylate-Synthase Inhibitor Loaded on Pegylated Liposomes Enhances the Antitumour Effect of Chemotherapy Drugs in Human Ovarian Cancer Cells

There is currently no effective long-term treatment for ovarian cancer (OC) resistant to poly-chemotherapy regimens based on platinum drugs. Preclinical and clinical studies have demonstrated a strong association between development of Pt-drug resistance and increased thymidylate synthase (hTS) expression, and the consequent cross-resistance to the hTS inhibitors 5-fluorouracil (5-FU) and raltitrexed (RTX). In the present work, we propose a new tool to combat drug resistance. We propose to treat OC cell lines, both Pt-sensitive and -resistant, with dual combinations of one of the four chemotherapeutic agents that are widely used in the clinic, and the new peptide, hTS inhibitor, [D-Gln4]LR. This binds hTS allosterically and, unlike classical inhibitors that bind at the catalytic pocket, causes cell growth inhibition without inducing hTS overexpression. The dual drug combinations showed schedule-dependent synergistic antiproliferative and apoptotic effects. We observed that the simultaneous treatment or 24h pre-treatment of OC cells with the peptide followed by either agent produced synergistic effects even in resistant cells. Similar synergistic or antagonistic effects were obtained by delivering the peptide into OC cells either by means of a commercial delivery system (SAINT-PhD) or by pH sensitive PEGylated liposomes. Relative to non-PEGylated liposomes, the latter had been previously characterized and found to allow macrophage escape, thus increasing their chance to reach the tumour tissue. The transition from the SAINT-PhD delivery system to the engineered liposomes represents an advancement towards a more drug-like delivery system and a further step towards the use of peptides for in vivo studies. Overall, the results suggest that the association of standard drugs, such as cDDP and/or 5-FU and/or RTX, with the novel peptidic TS inhibitor encapsulated into PEGylated pH-sensitive liposomes can represent a promising strategy for fighting resistance to cDDP and anti-hTS drugs

Sistemi nanoparticellari per la veicolazione e il direzionamento del farmaco

Dottorato di ricerca in chimica del farmaco. 7. ciclo. Coordinatore G. Cignarella. Tutore E. GalliConsiglio Nazionale delle Ricerche - Biblioteca Centrale - P.le Aldo Moro, 7, Rome; Biblioteca Nazionale Centrale - P.za Cavalleggeri, 1, Florence / CNR - Consiglio Nazionale delle RichercheSIGLEITItal

A hydroxypropylcellulose (HPC) system for the immediate and controlled release of diclofenac sodium

Immediate and controlled release systems were prepared fitting a fast dissolution tablet in the hole of perforated matrices coated on all the surface excepting the hole. The release from the systems of a non steroidalanti-inflammatory drug, diclofenac sodium, was investigated both in water and in gastro-intestinal simulated flluids. A constant drug release was achieved after the complete dissolution of the tablet fitted in the hole. The dissolution of the initial dose was affected by the pH of the simulated gastric fluid. However, as the comparison with a sustained commercial product showed, a higher amount of drug was available from the system in thefirst 150 min

Drug release from perforated matrices containing hydroxypropylcellulose

Perforated matrices were obtained using as excipient hydroxypropylcelluloses having different viscosity degrees. Furosemide release was affected by the polymer viscosity, while it was not related to the releasing surface area. In fact, the matrix having the highest hole diameter, and consequently the lowest releasing surface area, showed the highest release rate. The application of an impermeable coating on all the surfaces, except the hole surface, restricted the releasing surface area reducing the release rate. Furosemide release from the perforated coated matrices was the same regardless of the hole diameter (surface) as the data were related to the unitary releasing surface. The comparative analysis of the drug release mechanism showed the decrease of the erosion (polymer dissolution) component and the increase of the drug diffusion component of the process as the perforated matrices were coated. These results can be justified by the restriction of the matrix swelling produced by the impermeable coating. (C) 1998 Elsevier Science B.V. All rights reserved

The application of a thermosensible gel in the formulation of BSA-loaded PLA microspheres

The application of a thermosensible gel in the formulation of BSA-loaded PLA microsphere

Studio della fotodegradazione di un complesso PABA/alginato per la formulazione di filtri solari

Grande attenzione è stata rivolta di recente agli effetti biologici a carico della cute da parte delle radiazioni solari. La tendenza da parte della popolazione ad un’eccessiva esposizione alla luce solare unitamente ad una maggiore conoscenza degli effetti nocivi derivanti ha portato ad un aumento dell’uso di prodotti contenenti differenti filtri solari, ad un crescente interesse nello studio della loro attività fotoprotettiva e alla necessità di ridurne gli effetti collaterali. E’ noto infatti che l’instabilità fotochimica di alcuni filtri solari può comportare una diminuita efficacia d’azione e la formazione di prodotti di degradazione fototossici. L’acido p-amino benzoico (PABA) rappresenta uno dei filtri solari maggiormente impiegati. Nonostante la mancanza di un parere univoco, è stato riportato che il PABA, per esposizione prolungata alla luce solare, si decompone con la formazione di fotoprodotti potenzialmente dannosi (1-3).Poiché le variazioni fotochimiche del PABA coinvolgerebbero il gruppo aminico, il presente studio è stato rivolto al tentativo di diminuire la fotoinstabilità del PABA mediante la formazione di un complesso con un polisaccaride di natura polianionica quale il sodio alginato (4). Mediante determinazioni del comportamento reologico basato sulla valutazione dell’effetto elettroviscoso tipico dei polielettroliti, è stata dimostrata la formazione di un complesso di natura elettrostatica tra il PABA e il sodio alginato in soluzione acquosa. La fotostabilità del complesso PABA/alginato è stata studiata esponendo i campioni a luce solare simulata e analizzandoli a tempi prefissati mediante spettrofotometria UV e TLC. La valutazione dello “shift” del massimo di assorbimento e dei coefficienti di estinzione molare del PABA in complesso con l’alginato rispetto a quelli del PABA come tale potrebbe indicare un effetto positivo della reazione di complessazione sulla fotostabilità e sulla capacità filtrante. Conformemente, lo studio cromatografico sembra dimostrare che il complesso ottenuto presenti una maggior stabilità all’azione della luce solare rispetto al PABA

Sviluppo della formulazione di nanosfere polimeriche aventi dimensioni inferiori a 200 nm per la veicolazione di un farmaco anti-ischemico

Sviluppo della formulazione di nanosfere polimeriche aventi dimensioni inferiori a 200 nm per la veicolazione di un farmaco anti-ischemic

In vitro evaluation of PLA nanoparticles containing a lipophilic drug in water-soluble or insoluble form

Cloricromene (AD6), an anti-ischemic drug, is rapidly metabolised into a stable and active metabolite (cloricromene acid, AD6-acid) poorly soluble in water and less lipophilic than cloricromene. The aim of this study was to evaluate which of the two forms has more possibility to be efficiently encapsulated in nanoparticles based on poly(D,L-lactide) and prepared using the nanoprecipitation method. Increasing the theoretical loading of AD6, an increase in drug actual loading and in the mean particle size occurred, while no formation of nanoparticles was observed when the highest theoretical loading (50 mg) was employed. Changing the pH of the aqueous phase the drug content dramatically increased. However, at a pH value of I I a more rapid hydrolysis of AD6 occurred. When AD6-acid was embedded in the nanoparticles, suitable results concerning both drug content and encapsulation efficiency were achieved. A good control in the release of AD6 from the AD6-loaded nanoparticles was observed while the liberation of AD6-acid from the AD6-acid-loaded nanoparticles was faster than the dissolution of the AD6-acid free. These results confirm that the most easy encapsulable form in nanoparticles is AD6-acid probably owing to its poor water solubility. Further studies will be carried out in order to evaluate if the increase in the liberation of AD6-acid by nanoencapsulation may have outcomes in its bioavaibility in vivo

In vitro evaluation of a potential colonic delivery system that releases drug after a controllable lag-time

In vitro evaluation of a potential colonic delivery system that releases drug after a controllable lag-tim

Application of atomic force microscopy to characterize liposomes as drug and gene carriers

At present, liposomes play a significant role as drug delivery vehicles being considered very promising for gene therapeutics. The in vivo application of these systems widely dependent on their physico-chemical and technological characteristics such as the structure, shape, size distribution, surface modification and drug interaction. To describe the liposomes, different analytical techniques were used. In this paper, we reviewed the application of the atomic force microscopy (AFM), one of the most commonly applied scanning probe microscopy (SPM) techniques, in the description of liposome. The advantages and limitations of these techniques are discussed comparing the reported data with those referred to other well-know microscopical and spectroscopical techniques such as trasmission electron microscopy (TEM) and photon correlation spectroscopy (PCS). A detailed description of the application of AFM to evaluate the formation and the geometry of liposomes/DNA complexes is presented