Preparation and Characterization of PEG-albumin-curcumin Nanoparticles Intended to Treat Breast Cancer.

The aim of present research was to prepare novel serum stable long circulating polymeric nanoparticles for curcumin with a modification to the well known and novel nanoparticle albumin bound technology. polyethylene glycol-albumin-curcumin nanoparticles were prepared using serum albumin and poly ethylene glycol using desolvation technique. Nanoparticles were characterized for encapsulation efficiency, particle size and surface morphology. Drug excipient compatibility was determined using fourier transform infrared spectroscopy. Physical state of the drug in the formulations was known by differential scanning colorimetry. In vitro release and solubility of the drug from nanoparticles were determined. In vivo Drug release, tissue uptake and kupffer cell uptake was determined with optimized nanoformulation in rats after intravenous administration. Cell viability assay was determined using breast cancer cell line MD-MB-231. Entrapment efficiency for prepared nanoparticle was above 95%. The polyethylene glycol-albumin-curcumin nanoparticles exhibited an interesting release profile with small initial burst followed by slower and controlled release. Solubility of the drug from the formulation was increased. A sustained release of drug from nanoparticles was observed for 35 days in both in vitro and in vivo studies with the optimized formulation. Polyethylene glycol-albumin-curcumin nanoparticles showed lesser liver and kupffer cell uptake as compared to that of curcumin-albumin nanoparticles suggesting the bestowment of stealthness to nanoparticles with pegylation. Also, the antiproliferative activity of polyethylene glycol-albumin-curcumin nanoparticle formulation was more as compared to native curcumin. Polyethylene glycol-albumin-curcumin nanoparticles thus developed can be conveniently used in breast cancer with improved efficacy compared to conventional therapies and as an alternate to nanoparticle albumin bound technology which is used in producing Abraxane, albumin based breast cancer targeting nanoparticles of paclitaxel.

Anti-stress activity of N-phthaloyl gamma-aminobutyric acid in rats.

The effect of immobilization restraint stress (RS) on some biochemical and biophysical parameters in rats and their modulation by N-phthaloyl gamma-aminobutyric acid (P.GABA) was studied. RS did not affect the levels of serum Ca2+, inorganic phosphate, bilirubin, total protein, but caused insignificant increase of albumin level and significantly decreased the cholesterol level. This RS induced decrease of serum cholesterol level was reversed by prior treatment with P.GABA, while the albumin content showed a decrease. RS-induced a generalised increase in serum enzyme activity of lactate dehydrogenase (LDH), alkaline phsophatase (AIP), serum glutamate pyruvate transaminase (SGPT) and serum glutamate-oxaloacetate transaminase (SGOT). P.GABA normalised RS-induced increase of LDH and AlP activity, but it further enhanced SGOT and SGPT activities. In synaptosomal membranes, RS caused a decrease in clusterization and fluidity, but the thickness of the membrane increased as studied by fluorescence probes. Prior administration of P.GABA normalised the changes observed in the synaptic membrane.

Antiulcer and gastric secretory activity of N-octanoyl gamma-aminobutyric acid.

A new gamma-aminobutyric acid derivative synthesised in this laboratory, N-octanoyl gamma-aminobutyric acid was found to possess antinociceptive activity but no anticonvulsant activity. The effect of the compound on gastric lesions produced by aspirin, ethanol and stress in rats, was studied and the compound was found to possess effective antiulcer action. Even though, N-octanoyl gamma-aminobutyric acid did not produce a significant change in the volume of gastric acid secretion, however, it decreased the acidity and peptic activity and significantly enhanced the gastric mucus secretion.

Antinociceptive action of N-octanoyl GABA--a new GABA mimetic agent.

A new derivative of gamma-aminobutyric acid (GABA) was synthesized. The compound, N-octanoyl GABA (O-GABA), exhibited positive analgesic response in four different models in mice--tail immersion, hot plate, tail clip and acetic acid induced writhing. The antinociceptive activity was significantly blocked by picrotoxin but not by bicuculline or 3-mercaptopropionic acid. Naloxone failed to reverse the antinociceptive response of O-GABA but a synergistic action was observed with pethidine. Pretreatment with atropine significantly reduced the antinociceptive action of O-GABA. Biochemical tests revealed that O-GABA significantly increased brain GABA levels.

Effect of GABA analogues on various components of maximum electroshock-induced seizures in mice.

Out of fourteen compounds reported here only four [N-valproyl GABA (V.GABA), N-phthaloyl GABA (P.GABA), gamma-phthalimido N-amyl butyramide (PGA) and gamma-phthalimido N-phenyl butyramide (PGP)] gave significant protection to all the four components of maximal electroshock-induced seizures (MES) in mice. It appeared that substitution of either amino or carboxylic or both groups of gamma-aminobutyric acid (GABA) with bulkier groups like aliphatic or aromatic carbons usually produced effective anticonvulsant GABA derivatives. V.GABA and P.GABA were the most effective anticonvulsant GABA derivatives in protecting all the components of MES-induced seizures. They were 2.3 and 1.5 times potent than sodium valproate in molar ratio, but P.GABA has low therapeutic index when compared to V.GABA. The observed anticonvulsant activity may be due to enhanced GABA concentration in the CNS. Probably, the active compound (V.GABA) crossed the blood brain barrier and hydrolysed to GABA and valproic acid to bring about its anticonvulsant action.

Antiulcer and gastric secretory activity of N-phthaloyl gamma-aminobutyric acid.

N-Phthaloyl gamma-aminobutyric acid, a new gamma-aminobutyric acid derivative synthesized in this laboratory, has been found to possess anticonvulsant, antinociceptive and antistress activities. Effects of this derivative on gastric lesions induced by aspirin and ethanol were studied in rats. N-Phthaloyl gamma-aminobutyric acid significantly inhibited both aspirin and alcohol ulceration. The ED50 in each case being 76.34 and 43.65 mg/kg i.p. respectively. The volume of gastric acid secretion was diminished but gastric mucus secretion was significantly enhanced. The antiulcer effect was blocked by bicuculline and 3-mercaptopropionic acid. We conclude that (a) N-phthaloyl gamma-aminobutyric acid possesses antiulcer activity (b) the new derivative is probably a non-specific gamma-aminobutyric acid receptor agonist (c) the observed activity may be due to a mucoprotective action.

Neuropharmacology of amide derivatives of P-GABA.

Three lipophilic amide derivatives of phthaloyl-GABA (P-GABA), namely gamma-phthalimido N-amyl butyramide (PGA), gamma-phthalimido-N-hexylbutyramide (PGH) and gamma-phthalimido N-phenylbutyramide (PGP), were synthesized and evaluated for their hypnotic and anticonvulsant activities in mice. Both PGA and PGH showed moderate hypnotic activity but PGP had no such action. Picrotoxin (0.08 mg/kg) a non-specific GABA antagonist completely abolished the hypnotic action of PGA in subconvulsive doses. Bicuculline (0.04 mg/kg) a GABAA antagonist, 3-mercaptopropionic acid (6 mg/kg) a GAD inhibitor at subconvulsive doses failed to neutralise the hypnotic action of PGA. On the other hand, PGA showed significant protection only against picrotoxin-induced convulsions, but was inactive against other convulsants tested. PGP which has no hypnotic activity, and has a mild anticonvulsant action in all the models except picrotoxin. A definite correlation was observed between the brain GABA and the hypnotic activity of PGA. However the present data indicate that the hypnotic and anticonvulsant activities are mediated probably through different brain GABA-ergic mechanisms.