Drug delivery system for the extended-release of larotrectinib based on a biocompatible Fe-based metal-organic framework: synthesis, characterization, in vitro release properties and antitumor evaluation.

Larotrectinib (Lar) is an orally administered tropomyosin receptor kinase (Trk) inhibitor with broad-spectrum antitumor activity that is available in clinical dosage forms as capsules and oral solutions. Currently, corresponding research is focused on developing new extended-release formulation systems for Lar. In this study, a biocompatible Fe-based metal-organic framework (Fe-MOF) carrier was synthesized by a solvent-based method, and a sustained-release drug delivery system (Lar@Fe-MOF) was constructed by nanoprecipitation and Lar loading. Lar@Fe-MOF was characterized by transmission electron microscopy (TEM), differential scanning calorimetry (DSC), fourier transform infrared (FTIR) spectroscopy, and thermogravimetric analysis (TGA), and its drug loading capacity and drug release properties were measured by ultraviolet-visible (UV-vis) spectroscopy. Then, the toxicity and biocompatibility of the Fe-MOF carriers were evaluated using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and hemocompatibility assays. Finally, the anticancer potential of Lar@Fe-MOF was investigated. The TEM results showed that Lar@Fe-MOF had a homogeneous fusiform nanostructural morphology. The DSC and FTIR results showed that Fe-MOF carriers were successfully synthesized and loaded with Lar, which was mainly in an amorphous form. Lar@Fe-MOF showed a large drug loading capacity (-10%) and significant slow-release properties in vitro. The MTT assay results showed that Lar@Fe-MOF had good dose-dependent anticancer activity. The in vivo pharmacodynamic assay results showed that Fe-MOF significantly increased the anticancer activity of Lar and was biocompatible. In conclusion, the Lar@Fe-MOF system developed in this study is a promising drug delivery platform because it is easy to manufacture, has high biocompatibility and ideal drug release and accumulation, can effectively eliminate tumors with improved safety and is expected to further expand therapeutic applications.

[17α-Hydroxylase deficiency with severe hypertension as the initial symptom in a child].

A 14-year-old female (social gender) patient was admitted to the hospital due to severe hypertension for 11 days. The patient had primary amenorrhea. The blood pressure was 146/90 mm Hg. The skin color was slightly black. The development of secondary sexual characteristics was poor. The labia majora could be observed in the vulva. However, the labia minora, clitoris, vagina, and hymen were absent. The levels of renin, cortisol, and sex hormone were low, while the levels of adrenocorticotropic hormone and gonadotropin were high. The levels of blood potassium and aldosterone were both normal. Radiography indicated retardation of bone age. Ultrasound examination revealed that the ovary and uterus were both absent. The patient had bilateral adrenal hyperplasia and cryptorchid testes located in both inguinal canals. The patient had a 46,XY karyotype. Whole genome sequencing revealed two homozygous mutations, c.985T>C and c.987delC, in exon 6 of the CYP17A1 gene of the patient and heterozygous mutations in the same sites of the parents. The patient was diagnosed with congenital adrenal hyperplasia-17α-hydroxylase deficiency. After treatment with hydrocortisone for 2 months, blood pressure returned to normal and the level of adrenocorticotropic hormone was reduced. According to the request of the patient and the parents, hydrocortisone was replaced with estrogen to allow the patient to live as a female. The patient also received surgical excision of cryptorchid testes to prevent gonadal malignancy. It is concluded that in the differential diagnosis of pediatric hypertension, sexual development should be considered and the levels of adrenocorticotropic hormone and cortisol should be evaluated. The rare disease 17α-hydroxylase deficiency should be considered for patients with low-renin hypertension and gonadal dysgenesis.

Pharmacokinetics and anti-asthmatic potential of non-parenterally administered recombinant human interleukin-1 receptor antagonist in animal models.

The objectives of this study were to define the pharmacokinetics of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) and its effects on allergic asthma, cell adhesion molecules, and upper respiratory tract following non-parenteral administration in animals. Pharmacokinetics and immunomodulating effects of rhIL-1ra were investigated in Sprague-Dawley rats and asthmatic guinea pigs, respectively. Effects on the upper respiratory tract following the applications of rhIL-1ra were investigated on the ex vivo nasal mucosa of Sprague-Dawley rats and in situ in the upper palate of Chinese toads. Absolute bioavailabilities after intratracheal and intranasal administrations of rhIL-1ra were 94.3% and 24.8%, respectively. After administration of rhIL-1ra solution as ultrasonic spraying, the asthmatic symptom in guinea pigs was obviously attenuated. The plasma soluble intercellular cell adhesion molecule (sICAM-1) and P-selectin levels in asthmatic guinea pigs were each dose-dependently reduced with the increase of rhIL-1ra dose. The rhIL-1ra solution after administration via the airway seemed to have no impact on the integrity of nasal mucosa and mucocilia clearance in the upper respiratory tract. The present study provides evidence that rhIL-1ra effectively suppresses allergen-induced asthmatic symptoms through spraying, which corresponds to nasal and pulmonary absorption or both, and the efficacy is associated with downregulation of sICAM-1 and P-selectin expressions.