Long acting tariquidar loaded stearic acid-modified hydroxyapatite enhances brain penetration and antitumor effect of temozolomide.

Temozolomide (TMZ) is the first line chemotherapy for glioblastoma (GBM) treatment, but the P-glycoprotein (P-gp) expressed in blood-brain barrier (BBB) will pump out TMZ from the brain leading to decreased TMZ concentration. Tariquidar (TQD), a selective and potent P-gp inhibitor, may be suitable for combination therapy to increase concentration of TMZ in brain. Hydroxyapatite (HAP) is a biodegradable material with sustained release characteristics, and stearic acid surface-modified HAP (SA-HAP) can increase hydrophobicity to facilitate TQD loading. TQD-loaded stearic acid surface-modified HAP (SA-HAP-TQD) was prepared with optimal size and high TQD loading efficiency, and in vitro release and cellular uptake of SA-HAP-TQD showed that SA-HAP-TQD were taken up into lysosome and continuously released TQD from macrophages. In vivo studies have found that over 70% of SA-HAP was degraded and 80% of TQD was released from SA-HAP-TQD 28 days after administration. SA-HAP-TQD could increase brain penetration of TMZ, but it would not enhance adverse effects of TMZ in healthy mice. SA-HAP-TQD and TMZ combination had longer median survival than TMZ single therapy in GL261 orthotopic model. These results suggest that SA-HAP-TQD has sustained release characteristics and are potential for improving antitumor effect with TMZ treatment.

Drug delivery of extracellular vesicles: Preparation, delivery strategies and applications.

Extracellular vesicles (EV) are cell-originated vesicles exhibited with characteristics similar to the parent cells. Several studies have suggested the therapeutic potential of EV since they played as an intercellular communicator and modulate disease microenvironment, and thus EV has been widely studied in cancer management and tissue regeneration. However, merely application of EV revealed limited therapeutic outcome in different disease scenario and co-administration of drugs may be necessary to exert proper therapeutic effect. The method of drug loading into EV and efficient delivery of the formulation is therefore important. In this review, the advantages of using EV as drug delivery system compared to traditional synthetic nanoparticles will be emphasized, followed by the method of preparing EV and drug loading. The pharmacokinetic characteristics of EV was discussed, together with the review of reported delivery strategies and related application of EV in different disease management.

Nanostructured Lipid Carrier Gel Formulation of Recombinant Human Thrombomodulin Improve Diabetic Wound Healing by Topical Administration.

Recombinant human thrombomodulin (rhTM), an angiogenesis factor, has been demonstrated to stimulate cell proliferation, keratinocyte migration and wound healing. The objective of this study was to develop nanostructured lipid carrier (NLC) formulations encapsulating rhTM for promoting chronic wound healing. RhTM-loaded NLCs were prepared and characterized. Encapsulation efficiency was more than 92%. The rate of rhTM release from different NLC formulations was influenced by their lipid compositions and was sustained for more than 72 h. Studies on diabetic mouse wound model suggested that rhTM-NLC 1.2 µg accelerated wound healing and was similar to recombinant human epidermal growth factor-NLC (rhEGF-NLC) 20 µg. By incorporating 0.085% carbopol (a highly crosslinked polyacrylic acid polymer) into rhTM NLC, the NLC-gel presented similar particle characteristics, and demonstrated physical stability, sustained release property and stability within 12 weeks. Both rhTM NLC and rhTM NLC-gel improved wound healing of diabetic mice and cell migration of human epidermal keratinocyte cell line (HaCaT) significantly. In comparison with rhTM solution, plasma concentrations of rhTM post applications of NLC and NLC-gel formulations were lower and more sustained in 24 h. The developed rhTM NLC and rhTM NLC-gel formulations are easy to prepare, stable and convenient to apply to the wound with reduced systemic exposure, which may warrant potential delivery systems for the care of chronic wound patients.

Topical application of sebacoyl dinalbuphine ester-loaded nanostructured lipid carriers alleviate pruritus in scratching mouse model.

Sebacoyl dinalbuphine ester (SDE) is a nalbuphine (NA) prodrug capable of biotransformation in vivo and prolong the duration of NA, maximize its effect in pain and pruritus management. However, the large molecular weight, low skin penetration, and stability concerns of SDE make it difficult to be used in local skin delivery. Nanostructured lipid carrier (NLC) is a lipid-based nanoparticulate system that has the potential for formulating SDE in order to promote drug delivery through the skin. The aim of this study was to develop SDE-loaded NLC formulations (SDE-NLC) with good stability, sustained release characteristics, and sufficient antipruritic effect. SDE was successfully encapsulated into NLC and the formulation increased the stability of SDE, enhanced skin penetration through hair follicles, and sustained SDE release during pruritus management. We also demonstrated that topical application of SDE-NLCs significantly reduced the number of scratches in pruritus-induced mice. Both NA and SDE were found in the skin strata, but only NA was detectable in the plasma, indicating rapid conversion of SDE into NA. All results demonstrated that SDE-NLC formulation protected SDE from degradation in vitro, while the released prodrug was converted into NA in vivo and extended antipruritic effect. The formulation has the potential of improving the life quality of patients with chronic pruritus.