Farnaz Esmaeili

Folate-receptor-targeted delivery of docetaxel nanoparticles prepared by PLGA–PEG–folate conjugate

For folate-receptor-targeted anticancer therapy, docetaxel (DTX) nanoparticles (NPs) were produced employing polylactide-co-glycolide–polyethylene glycol–folate (PLGA–PEG–FOL) conjugate. The FOL-conjugated di-block copolymer was synthesized by coupling the PLGA–PEG–NH2 di-block copolymer with an activated folic acid. It was expected that FOL moieties were exposed on the micellar surface. The conjugates assisted in the formation of DTX NPs with an average size of 200 nm in diameter through an emulsification/solvent diffusion method. The FOL-targeted NPs showed a greater extent of intracellular uptake in FOL-receptor-positive cancer cells (SKOV3) in comparison with the non-targeted NPs, indicating that the FOL-receptor-mediated endocytosis mechanism could have a role in the cellular uptake of NPs. These results suggested that FOL-targeted DTX NPs could be a potentially useful delivery system for FOL-receptor-positive cancer cells.

Docetaxel-albumin conjugates: preparation, in vitro evaluation and biodistribution studies.

Docetaxel (DTX) is one of the most active chemotherapeutic agents for treating metastatic breast cancer. Its aqueous solubility is very low, hence the available formulation of DTX for clinical use consists of high concentrations of tween80, which has been associated with several hypersensitivity reactions. To reduce the systemic toxicity of DTX as well as to avoid the use of tween80, in this study DTX was chemically conjugated with human serum albumin via a succinic spacer. A high-performance liquid chromatography method was developed for the determination of DTX-albumin conjugate. T47D and SKOV3 cells were used for the evaluation of the in vitro cytotoxicity of the conjugate by MTT assay. Studies were then done on balb/c mice to elucidate the tissue distribution of conjugates after intravenous administration. The albumin-conjugated formulation of DTX with the particle size of 90-110 nm showed enhanced solubility and in vivo characteristics and significantly higher cytotoxicity against tumor cells, for example, IC50 of 6.30 +/- 0.73 nM for T47D cell line compared to free DTX with IC50 of 39.4 +/- 1.75 nM. Conjugation also maintained DTX plasma level at 16.19% up to 2 h after injection compared with 2.51% for Taxotere, hence increasing the chance of nanoparticles uptake by tumor cells.

Preparation of pegylated nano-liposomal formulation containing SN-38: In vitro characterization and in vivo biodistribution in mice

Preparation of pegylated nano-liposomal formulation containing SN-38: In vitro characterization and in vivo biodistribution in mice 7-Ethyl-10-hydroxy-camptothecin (SN-38), a metabolite of irinotecan x HCl, is poorly soluble in aqueous solutions and practically insoluble in most physiologically compatible and pharmaceutically acceptable solvents. Formulation of SN-38 in concentrated pharmaceutical delivery systems for parenteral administration is thus very difficult. Due to their biocompatibility and low toxicity, liposomes were considered for the delivery of SN-38. In this study, pegylated liposomes with distearoylphosphatidylcholine, distearoylphosphatidylethanolamine containing SN-38 were prepared and their characteristics, such as particle size, encapsulation efficiency, in vitro drug release and biodistribution, were investigated. The particle size of liposomes was in the range of 150--200 nm. The encapsulation efficiency and in vitro release rate of pegylated liposomes was higher than those of non-pegylated liposomes. As expected, the distribution of pegylated liposomes in body organs such as liver, kidney, spleen and lung was considerably lower than that of non-pegylated liposomes. Also, their blood concentration was at least 50 % higher than that of non-pegylated liposomes. Priprava pegiliranih nano-liposomskih formulacija sa SN-38: In vitro karakterizacija i in vivo biodistribucija u miševa 7-Etil-10-hidroksi-kamptotecin (SN-38), metabolit irinotekan hidroklorida, vrlo je slabo topljiv u vodenim otopinama i praktički netopljiv u većini fiziološki kompatibilnih i farmaceutski prihvatljivih otapala. Poradi toga je veoma teško formuliranje supstancije SN-38 u koncentrirane sustave za parenteralnu primjenu. Liposomi se zbog svoje biokompatibilnosti i niske toksičnosti čine pogodnim za isporuku SN-38. U ovom radu opisana je priprava pegiliranih liposoma sa SN-38 pomoću distearoilfosfatidilkolina i distearoilfosfatidiletanolamina. Pripravljenim liposomima određena je veličina čestica, sposobnost inkapsuliranja, in vitro oslobađanje i biodistribucija. Veličina čestica liposoma bila je u rasponu 150--200 nm. Sposobnost kapsuliranja i in vitro oslobađanje pegiliranih liposoma bila je veća nego nepegiliranih liposoma. Kao što se očekivalo, distribucija pegiliranih liposoma u jetri, bubregu, slezeni i plućima bila je značajno niža nego nepegiliranih liposoma. Njihova koncentracija u krvi bila je najmanje 50 % viša od nepegiliranih liposoma.

Cellular cytotoxicity and in-vivo biodistribution of docetaxel poly(lactide-co-glycolide) nanoparticles

Docetaxel (DTX) is one of the most effective antineoplastic drugs. However, its current clinical administration, formulated in tween80, causes serious side effects. This study is focused on preparation and evaluation of poly(lactide-co-glycolide) nanoparticles (NPs) containing DTX to remove tween80. Drug encapsulation efficiency, in-vitro drug release, cellular cytotoxicity, and in-vivo biodistribution of NPs in mice after intravenous administration were investigated. The average diameter of the NPs was approximately 172–178 nm with encapsulation efficiency of 68%. A burst release of approximately 30% (w/w) of the loaded drug followed by a sustained release profile was observed. Cellular mortality of the NPs was more than or at least as great as DTX free drug; for example, cell viability measured at 100 nmol/l drug concentration was decreased from 50.9% for DTX free drug to 15.9% for the NP formulation after 48 h incubation with T47D cells. The DTX plasma amount remained at a good level (13% of the initial dose) in the NP formulation compared with the DTX conventional formulation, which is approximately 0.5% of the initial dose, was present in plasma up to 2 h. Poly(lactide-co-glycolide) NPs containing DTX prepared in this study may be regarded as a suitable and superior formulation for the current formulation in the market containing tween80 with improved cancerous cell mortality and biodistribution characteristics.

Preparation of PLGA nanoparticles using TPGS in the spontaneous emulsification solvent diffusion method

D-alpha-tocopheryl poly (ethylene glycol) 1000 succinate (TPGS) is a widely used form of vitamin E that has been used as a solubilizer, an emulsifier and as a vehicle for drug delivery formulations. In this study, poly lactide-co-glycolide (PLGA) nanoparticles were prepared by spontaneous emulsification solvent diffusion (SESD) method. TPGS as an emulsifier and further as a matrix material blended with PLGA was used to enhance the encapsulation efficiency and improve the drug release profile of nanoparticles. Rifampicin and estradiol valerate were used as model drugs with different water solubility. The effect of formulation parameters such as drug/polymer ratio, oil phase combination, volume and surfactant content was evaluated. The surface morphology and size of the nanoparticles were studied by scanning electron microscopy (SEM) and laser light scattering. Drug encapsulation efficiency and in vitro drug release profiles of nanoparticles were determined using high performance liquid chromatography (HPLC). The nanoparticles prepared in this study were spherical with size range of 150–250 nm. It was shown that TPGS was a good emulsifier for producing nanoparticles of hydrophobic drugs and improving the encapsulation efficiency and drug loading and drug release profile of nanoparticles. However, the drug loading efficiency of rifampicin, a slightly water-soluble molecule, was significantly lower than that of estradiol valerate, a water insoluble molecule.