Liposomal PHD2 Inhibitors and the Enhanced Efficacy in Stabilizing HIF-1α

Prolyl hydroxylase domain-containing protein 2 (PHD2) inhibition, which stabilizes hypoxia-inducible factor (HIF)-1α and thus triggers adaptation responses to hypoxia in cells, has become an important therapeutic target. Despite the proven high potency, small-molecule PHD2 inhibitors such as IOX2 may require a nanoformulation for favorable biodistribution to reduce off-target toxicity. A liposome formulation for improving the pharmacokinetics of an encapsulated drug while allowing a targeted delivery is a viable option. This study aimed to develop an efficient loading method that can encapsulate IOX2 and other PHD2 inhibitors with similar pharmacophore features in nanosized liposomes. Driven by a transmembrane calcium acetate gradient, a nearly 100% remote loading efficiency of IOX2 into liposomes was achieved with an optimized extraliposomal solution. The electron microscopy imaging revealed that IOX2 formed nanoprecipitates inside the liposome’s interior compartments after loading. For drug efficacy, liposomal IOX2 outperformed the free drug in inducing the HIF-1α levels in cell experiments, especially when using a targeting ligand. This method also enabled two clinically used inhibitors—vadadustat and roxadustat—to be loaded into liposomes with a high encapsulation efficiency, indicating its generality to load other heterocyclic glycinamide PHD2 inhibitors. We believe that the liposome formulation of PHD2 inhibitors, particularly in conjunction with active targeting, would have therapeutic potential for treating more specifically localized disease lesions.

Solution for elliptic inclusion in an infinite plate with remote loading and Eshelby’s eigenstrain of polynomial type

In this paper, a particular inhomogeneous inclusion problem is studied. In the problem, Eshelby’s eigenstrain takes the type [Formula: see text], where m+ n = 2, and the remote loadings [Formula: see text], [Formula: see text] are applied. In the solution, the complex variable method is used. The continuity conditions along the interface of the matrix and the inclusion are formulated exactly. Because the stress field is no longer uniform in inclusion in this case, the studied problem has an inherent difficulty. After some manipulation, the final result for stress components [Formula: see text], [Formula: see text] and [Formula: see text] in inclusion are obtainable. In the present study, [Formula: see text], [Formula: see text] and [Formula: see text] are no longer uniform.

Efficient aqueous remote loading of peptides in poly(lactic-co-glycolic acid)

Poly(lactic-co-glycolic acid) (PLGA) long-acting release (LAR) depots are effective for extending the duration of action of peptide drugs. New market approvals have been slow with dated organic-solvent-based microencapsulation approaches. We describe efficient organic-solvent-free remote encapsulation based on the capacity of common acid-capped PLGA to bind, and absorb into the polymer phase, net positively charged peptides in aqueous solution after short exposure at modest temperature. Leuprolide encapsulated by this approach in low-molecular-weight PLGA 75/25 microspheres slowly and continuously released peptide for over 56 days in vitro and suppressed testosterone production in rats in an equivalent manner as the 1-month Lupron Depot®. The technique is generalizable to encapsulate a number of net cationic peptides of various size, including octreotide, with competitive loading and encapsulation efficiencies to traditional techniques. In certain cases, in vitro and in vivo performance of remote-loaded PLGA microspheres exceeded that relative to marketed products and displayed important features not currently possible with existing encapsulation strategies.

Design and Characterization of Glyceryl Monooleate-Nanostructures Containing Doxorubicin Hydrochloride

Glyceryl monooleate (GMO) is one of the most popular amphiphilic lipids, which, in the presence of different amounts of water and a proper amount of stabilizer, can promote the development of well defined, thermodynamically stable nanostructures, called lyotropic liquid crystal dispersions. The aim of this study is based on the design, characterization, and evaluation of the cytotoxicity of lyotropic liquid crystal nanostructures containing a model anticancer drug such as doxorubicin hydrochloride. The drug is efficiently retained by the GMO nanosystems by a remote loading approach. The nanostructures prepared with different non-ionic surfactants (poloxamers and polysorbates) are characterized by different physico-chemical features as a function of several parameters, i.e., serum stability, temperature, and different pH values, as well as the amount of cryoprotectants used to obtain suitable freeze-dried systems. The nanostructures prepared with poloxamer 407 used as a stabilizer show an increased toxicity of the entrapped drug on breast cancer cell lines (MCF-7 and MDA-MB-231) due to their ability to sensitize multidrug-resistant (MDR) tumor cells through the inhibition of specific drug efflux transporters. Moreover, the interaction between the nanostructures and the cells occurs after just a few hours, evidencing a huge cellular uptake of the nanosystems.

The symmetry and loading-independency of multiple inclusions enclosing uniform stresses in an infinite elastic plane

The identification of multiple interacting inclusions with uniform internal stresses in an infinite elastic matrix subjected to a uniform remote loading is of fundamental importance in the mechanics and design of particulate composite materials. In anti-plane shear and plane deformations, certain sufficient conditions have been established in the literature which guarantee uniform internal stresses inside multiple interacting inclusions displaying various symmetries when the matrix is subjected to specific uniform remote loading. Correspondingly, sufficient conditions which allow for the design of multiple interacting inclusions independent of any specific form of (uniform) remote loading have also been established. In this paper, we demonstrate rigorously that, in all cases, these sufficient conditions are also necessary conditions and indeed allow for the identification of all possible collections of such inclusions.