lxt-101 and Prostatic-Neoplasms

LXT-101, a cationic peptide is a novel antagonist of gonadotropin-releasing hormone (GnRH) for prostate cancer treatment. However, effective delivery of peptide drugs into the body by the oral route remains a major challenge due to their origin properties with high molecular weights, strong polarity and low stability in the gastrointestinal (GI) tract. In this study, we have developed a novel oral delivery of oil-based formulation in which therapeutic peptide LXT-101 are solubilized in oils and with this solution as oil phase, an optimum formulation of self-microemulsifying drug delivery system (SMEDDS) was developed. The peptide stability with the SMEDDS formulation in artificial gastric and intestinal fluid was tested in vitro. On the other hand, the testosterone level and plasma concentration of LXT-101 in rats after oral administration of the SMEDDS formulation were investigated in vivo. The data in vitro indicated that LXT-101 in the SMEDDS formulation was stable over 8 h in artificial gastric and intestinal fluid. LXT-101 can be absorbed in vivo and suppression of testosterone maintained in castration level within 12 h can be achieved effectively after SMEDDS formulation administered orally at a dose of 3.5 mg/kg. The approach can provide a potential way for delivery peptides by oral.

Topics: Administration, Oral; Animals; Castor Oil; Castration; Gonadotropin-Releasing Hormone; Hormone Antagonists; Male; Oligopeptides; Pancreatin; Pepsin A; Phosphatidylcholines; Phosphatidylglycerols; Propylene Glycol; Prostatic Neoplasms; Rats; Rats, Wistar; Testosterone

The introduction of luteinizing hormone-releasing hormone (LHRH) analogs and their antagonists is revolutionizing the treatment of prostate cancer. In this study, poly(D,L-lactideco-glycolide) (PLGA) microspheres containing a highly potent LHRH antagonist (LXT-101) of interest in the indication of prostate cancer were evaluated on release mechanisms in vitro and biological performance in vivo. LXT-101 microspheres were prepared by the water/oil/water double emulsion method and the solid/oil/oil method. The results showed that the mechanism of LXT-101 releasing from PLGA 14,000 microspheres was the cooperation of drug diffusion and polymer degradation. This clarified the relationship between the microsphere characterization and hormone level in vivo. The larger microspheres (33 μm) could inhibit the testosterone level to castration for a longer time (35 days) than the smaller microspheres (15 μm, 14 days). The formulation containing the hydrophilic additive (polyethylene glycol 6000) could suppress the testosterone level to castration for a longer time (> 35 days) than the formulation without polyethylene glycol (14 days). The appearance of testis, vesicular seminalis, and prostates changed after treatment. The weights of sexual organs decreased significantly. The in-vivo release of the LXT-101 PLGA 14,000 microspheres curve showed that in-vivo release started immediately after day 1 (22.7%) and was rapid during the first 5 days (40.2% release). The LXT-101 microspheres could be a promising drug delivery system candidate to treat sex hormone-dependent tumors and other related disorders.

Topics: Animals; Antineoplastic Agents; Dioxanes; Drug Delivery Systems; Gonadotropin-Releasing Hormone; Humans; Lactic Acid; Male; Microspheres; Oligopeptides; Orchiectomy; Particle Size; Polyethylene Glycols; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Prostate; Prostatic Neoplasms; Rats; Rats, Sprague-Dawley; Receptors, LHRH; Testis; Testosterone

Multivesicular liposomes (MVLs) are often used as an appropriate carrier for delivering peptides due to high drug loading, relative stability and extended-release behaviour. However, when cationic amphipathic peptides are involved, some challenges may be encountered, including instability of multiple emulsions due to interaction between peptides and lipid membranes (electrostatic and hydrophobic interaction). LXT-101, a cationic amphipathic peptide, is a novel antagonist of gonadotropin-releasing hormone (GnRH) for prostate cancer treatment. The purpose of the current research was to explore simple methods of determining the interaction between peptide and lipid bilayer and to prepare MVLs of LXT-101 (DepoLXT-101) by the modified DepoFoam technique.. The anionic surfactants were added in the process of DepoLXT-101 preparation in order to minimize the effect of instability resulting from cationic peptides.. DepoLXT-101 was obtained with good efficiency and reproduction. The integrity of encapsulated peptide was maintained as shown by RP-HPLC. DepoLXT-101 particles were characterized by morphology and particle size distribution and in-vitro release was also investigated. The release behaviour in vitro in medium of sodium chloride at 37°C showed that 70-90% of LXT-101 was released slowly from MVLparticles over 11 days. According to the fitting results of Ritgar-Pepps model, the in-vitro release of DepoLXT-101 was mainly governed by Fick's diffusion.. The data obtained from in-vivo study indicated that a sustained anticancer effect can be achieved over a 7-day period with subcutaneous administration of DepoLXT-101 in rats.

Topics: Animals; Antineoplastic Agents; Cations; Delayed-Action Preparations; Diffusion; Drug Carriers; Drug Compounding; Drug Stability; Gonadotropin-Releasing Hormone; Hormone Antagonists; Hydrophobic and Hydrophilic Interactions; Male; Oligopeptides; Particle Size; Prostatic Neoplasms; Rats; Rats, Wistar; Solubility; Surface-Active Agents; Unilamellar Liposomes