Journal of Controlled Release: Official Journal of the Controlled Release Society, 14 Sep 2015

Abstract: Oral delivery is the most convenient and favorable route for chronic administration of peptides and proteins to patients. However, many obstacles are faced when developing such a delivery route. Nanoparticles (NPs) are among the leading innovative solutions for delivery of these drugs. Exenatide is a peptidic drug administered subcutaneously (SC) twice a day chronically as an add-on therapy for the worldwide pandemic disease, diabetes. Many attempts to develop oral nanocarriers for this drug have been unsuccessful due to the inability to retain this hydrophilic macromolecule under sink conditions or to find a suitable cross-linker which does not harm the chemical integrity of the peptide. In this study, we report about an original oral delivery solution based on a mixture of albumin and dextran NPs cross-linked using sodium trimetaphosphate (STMP). Moreover, we suggest a second defense line of gastro-resistant microparticles (MPs) composed of an appropriate ratio of Eudragit® L100-55 (Eudragit L) and hydroxypropylmethylcellulose (HPMC), for additional protection to these NPs presumably allowing them to be absorbed in the intestine intact. Our results demonstrate that such a system indeed improves the relative oral bioavailability of exenatide to a level of about 77% compared to subcutaneous injection due to the presence of dextran in the coating wall of the NPs which apparently promotes the lymphatic uptake in the enterocytes. This technology may be a milestone on the way to deliver other peptides and proteins orally.

European Journal of Pharmaceutics and Biopharmaceutics, 18 Oct 2018

Abstract: One of the major disadvantages associated with macromolecules therapy is that most of them can only be administered parenterally. Exenatide, an efficient anti-diabetic drug, incretin mimetic, is currently administered subcutaneously (SC) causing compliance issues. Nanoparticles (NPs) are considered a promising solution for oral delivery of this drug. In order to overcome exenatide’s inability to cross the enterocytes and to increase its stability in the gastrointestinal (GI) tract, we encapsulated exenatide into a nano-in-micro delivery system. This drug delivery system (DDS) improved the relative oral bioavailability of exenatide, in comparison to Byetta® injection SC. In this study, we report about the efficacy of this DDS to improve glycemic parameters in diabetic ob/ob mice. Our results suggested that our DDS successfully lowered blood glucose levels (BGL) raised insulin levels, decreased glycated hemoglobin and maintained the body weight of the mice. These findings validate the efficacy of this DDS in promoting oral delivery of exenatide and will hopefully improve patient compliance and adherence. The potential of this DDS to encapsulate other leading peptides and proteins, such as insulin, was also evaluated in this study. It was found that peptides up to 6 kDa can be efficiently encapsulated, but the in-vivo performance is also dependent on other physicochemical properties.

Nanomedicine: Nanotechnology, Biology and Medicine, February 2020

Abstract: Systemic cyclosporine A (CsA) therapy shows efficacy in the treatment of recalcitrant severe atopic dermatitis (AD) but elicits severe side-effects. Thus, a topical formulation of CsA nanocapsules (NCs), able to potentially bypass these drawbacks, was developed. CsA-NCs were shown to enhance drug penetration into the various layers of porcine ear skin. Furthermore, the encapsulated CsA was biologically active, as shown in vitro on mouse splenocytes, reflected by inhibition of both cell proliferation and of interleukin (IL)-2 secretion. Ex-vivo efficacy was demonstrated on human skin organ culture by markedly reducing pro-inflammatory cytokines secretion. Finally, CsA-NCs topical formulation elicited improved efficacy in terms of better preservation of the skin barrier integrity, a decrease of the systemic pro-inflammation markers and reduced skin inflammation. The overall results suggest that this original topical platform may provide a novel therapeutic tool of clinical significance compared to the existing topical therapeutic drugs in AD.

Journal of Controlled Release, 10 September 2014, Pages 65-71

Abstract: Polymeric nanocarriers, especially nanospheres (NSs) and nanocapsules (NCs), can promote the penetration of their cargo through the skin barrier, towards improved cutaneous bioavailability. Dehydroepiandrosterone (DHEA), an endogenous hormone exhibiting poor aqueous solubility, was shown to be effective in modulating skin-aging processes following topical application. In this study, we designed adequate DHEA preparations, in an attempt to enable local delivery of the active ingredient to the viable skin layers. In addition, the potential efficiency of DHEA NCs on dermal collagen synthesis was evaluated. Cryo-TEM observations and thermal analysis indicated that DHEA was successfully incorporated within a stable NC-based delivery system. Moreover, higher [³H]-DHEA levels were recorded in the viable skin layers following different incubation periods of NCs on excised pig skin specimens as compared to DHEA oil solution (free molecule). Furthermore, significantly higher (4-fold) skin flux values were observed for the DHEA NCs as compared to the values elicited by the oil control solution. Finally, collagen synthesis in human skin organ culture, assessed by the incorporation of [³H]-proline, was up to 42% higher for DHEA NCs 48 h post-topical application than for the untreated specimens. Overall, these results suggest that poly lactic-co-glycolic acid (PLGA)-based NCs have promising potential to be used topically for various skin disorders.

The European Journal of Internal Medicine, , P23-29, MARCH 01, 2018

Abstract: Endocannabinoids (eCBs) are internal lipid mediators recognized by the cannabinoid-1 and -2 receptors (CB1R and CB2R, respectively), which also mediate the different physiological effects of marijuana. The en-docannabinoid system, consisting of eCBs, their receptors, and the enzymes involved in their biosynthesis and degradation, is present in a vast number of peripheral organs. In this review we describe the role of the eCB/CB1R system in modulating the metabolism in several peripheral organs. We assess how eCBs, via activating the CB1R, contribute to obesity and regulate food intake. In addition, we describe their roles in modulating liver and kidney functions, as well as bone remodeling and mass. Special importance is given to emphasizing the efficacy of the recently developed peripherally restricted CB1R antagonists, which were pre-clinically tested in the management of energy homeostasis, and in ameliorating both obesity- and diabetes-induced metabolic com-
plications.