Tuning the Physicochemical Characteristics of Particle-Based Carriers for Intraperitoneal Local Chemotherapy.

Over the last few decades, intraperitoneal (IP) local drug delivery, providing high drug concentrations with prolonged retention in the peritoneal cavity, has opened a new horizon for the management of life-threatening peritoneal disorders, such as peritoneal carcinomatosis (PC). However, clinical translation of this strategy is hampered by several hurdles, namely premature clearance of small-sized molecules from the peritoneum, limited distribution within the peritoneal space and inadequate penetration into the target tissues. To address these challenges, incorporation of therapeutic agents into the particulate-based drug delivery systems has brought new hope in this direction. Nonetheless, as yet, there has been no formulation specifically approved for IP delivery. To gain this goal, it is crucial to have a detailed understanding of the correlation between the physicochemical characteristics of particle-based carriers and their biological fate and anticancer efficacy after IP administration. The main focus of this review, therefore, concerns the significance of these characteristics, namely composition, particle size, charge, coating and presence of targeting moieties in the design of carriers for successful IP delivery. Graphical Abstract Physicochemical characteristics of particle-based carriers influence their peritoneal residence time, biological fate and anticancer efficacy after intraperitoneal administration.

Discovery of phthalimide derivatives as novel inhibitors of a soluble epoxide hydrolase.

Soluble epoxide hydrolase (sEH) inhibitors are effective in reducing blood pressure, inflammation, and pain in a number of mammalian disease models. As most classical urea-based sEH inhibitors suffer from poor solubility and pharmacokinetic properties, the development of novel sEH inhibitors with an improved pharmacokinetic specification has received a great deal of attention. In this study, a series of amide-based sEH inhibitors bearing a phthalimide ring as the novel secondary pharmacophore (P2 ) was designed, synthesized, and evaluated. Docking results illustrated that the amide group as the primary pharmacophore (P1 ) was placed at a suitable distance from the three key amino acids (Tyr383, Tyr466, and Asp335) for an effective hydrogen bonding. In agreement with these findings, most of the newly synthesized compounds demonstrated moderate to high sEH inhibitory activities, relative to 12-(3-adamantan-1-yl-ureido)dodecanoic acid as the reference standard. Compound 12e with a 4-methoxybenzoyl substituent exhibited the highest sEH inhibitory activity, with an IC50 value of 1.06 nM. Moreover, the ADME properties of the compounds were evaluated in silico, and the results revealed appropriate predictions.

Cerasome Versus Liposome: A Comparative Pharmacokinetic Analysis Following Intravenous Administration into Rats.

Background: Cerasomes, due to their external siloxane network, demonstrate markedly higher physicochemical stability and, therefore, easier handling and storage than liposomes. Objectives: The main objective of this study was to compare the pharmacokinetics (PK) of cerasome and liposome following intravenous administration. The PK of PEGylated and non-PEGylated cerasomes was also compared to see whether the presence of a hydrophilic siloxane network on the surface of cerasomes can play the role of polyethylene glycol (PEG) in increasing the blood circulation of these vesicles. Methods: Silver sulfide (Ag2S) quantum dots (Qds)-loaded PEGylated and non-PEGylated cerasomes and PEGylated liposomes were fabricated and thoroughly characterized in terms of particle size, polydispersity index, zeta potential, entrapment efficiency, and in vitro stability. For pharmacokinetic evaluation, the free Qds and the selected formulations were intravenously injected into rats, and blood samples were collected for up to 72 hours. Pharmacokinetic parameters were calculated by the non-compartmental method. Results: Both cerasomal and liposomal carriers significantly improved the PK of Qds. For example, the elimination half-life (t1/2) and the area under the plasma concentration-time curve from time 0 to time infinity (AUC0-∞) for the free Qds were 4.39 h and 8.01 µg/mL*h and for cerasomal and liposomal formulations were 28.82 versus 26.95 h and 73.25 versus 62.02 µg/mL*h, respectively. However, compared to each other, the plasma concentration-time profiles of PEGylated cerasomes and liposomes displayed similar patterns, and the statistical comparison of their pharmacokinetic parameters did not show any significant difference between the two types of carriers. For PEGylated cerasomes, t1/2 and AUC0-∞ values were respectively 1.6 and 3.3 times greater than the classic cerasome, indicating that despite the presence of a hydrophilic siloxane network, the incorporation of PEG is necessary to reduce the clearance of cerasomes. Conclusions: The comparable PK of PEGylated cerasomes and liposomes, along with the higher physicochemical stability of cerasomes, can be considered an important advantage for the clinical application of cerasomes. Additionally, the easy surface functionalizing ability of cerasomes confers a dual advantage over liposomes. The study findings also showed that the presence of a hydrophilic siloxane network on the surface of cerasomes alone is not enough to make them circulate long.

Pharmacokinetics, tissue distribution and peritoneal retention of Ag2S quantum dots following intraperitoneal administration to mice.

OBJECTIVES: To investigate the pharmacokinetics, biodistribution and peritoneal retention of Ag2S quantum dots (Qds) after intraperitoneal (IP) injection into mice and to compare the results with those reported for the intravenous (IV) injection of these particles. METHODS: Ag2S Qds was prepared by a simple one-step co-precipitation method and was injected intraperitoneally into mice. Six animals were sacrificed at predetermined time points, and blood, peritoneal content and tissue samples were collected. Ag concentration that represents the concentration of Qds was analysed by atomic absorption spectrophotometry. KEY FINDINGS: Detectability of Qds in the peritoneal sample up to 2 h indicated that, compared with small drug molecules, the absorption of Ag2S Qds from the peritoneal cavity occurred at a slower rate. The AUC tissue/AUC blood ratio in the liver and intestine after IP injection (0.55 and 0.98, respectively) was considerably lower than those for the bolus injection (217 and 94, respectively), while this ratio in the spleen and lungs was markedly higher than the IV route. CONCLUSIONS: Overall, the obtained results suggest that IP injection of Ag2S Qds could be more effective for drug delivery to/imaging of the spleen and lungs, whereas the IV injection for the drug delivery to/imaging of the liver and intestine.