A Lysosome-Targeting Self-Condensation Prodrug-Nanoplatform System for Addressing Drug Resistance of Cancer.

Lysosome-targeting self-assembling prodrugs had emerged as an attractive approach to overcome the acquisition of resistance to chemotherapeutics by inhibiting lysosomal sequestration. Taking advantage of lysosomal acidification induced intracellular hydrolytic condensation, we developed a lysosomal-targeting self-condensation prodrug-nanoplatform (LTSPN) system for overcoming lysosome-mediated drug resistance. Briefly, the designed hydroxycamptothecine (HCPT)-silane conjugates self-assembled into silane-based nanoparticles, which were taken up into lysosomes by tumor cells. Subsequently, the integrity of the lysosomal membrane was destructed because of the acid-triggered release of alcohol, wherein the nanoparticles self-condensed into silicon particles outside the lysosome through intracellular hydrolytic condensation. Significantly, the LTSPN system reduced the half-maximal inhibitory concentration (IC50) of HCPT by approximately 4 times. Furthermore, the LTSPN system realized improved control of large established tumors and reduced regrowth of residual tumors in several drug-resistant tumor models. Our findings suggested that target destructing the integrity of the lysosomal membrane may improve the therapeutic effects of chemotherapeutics, providing a potent treatment strategy for malignancies.

Kinetic modeling of malondialdehyde reactivity in oil to simulate actual malondialdehyde formation upon lipid oxidation.

The reactivity of malondialdehyde in saturated glycerol triheptanoate oil was studied over a wide temperature range (298.15-453.15 K). With respect to the non-ideal character of a lipid medium, a kinetic model was proposed that described the experimental malondialdehyde data by a reversible hydrolytic cleavage and an irreversible aldol self-condensation reaction. Significant parameter estimates were obtained by using a global one-step non-linear regression procedure. The aldol self-condensation of malondialdehyde showed to be the main degradation route of malondialdehyde in oils. Simulation of the malondialdehyde formation during lipid oxidation of sunflower oil demonstrated that, depending on the heating time, the experimentally obtained malondialdehyde concentrations can substantially underestimate the ongoing lipid oxidation.

Methods for Generating Vascularized Islet-Like Organoids Via Self-Condensation.

Despite the promise of emerging organoid-based approaches, building additional complexity, such as the vascular network, remains a major challenge toward regenerative therapy. Recently, we developed a complex organoid engineering method by "self-condensation," wherein mesenchymal cell-dependent contraction enables large-scale condensation from heterotypic multiple progenitors. Here, we describe the adaptation of this protocol for generating three-dimensional (3D) pancreatic condensates from dissociated ß cell lines (MIN6) together with blood vessel-forming progenitors. This protocol achieves 3D pancreatic islet-like organoid self-organization with endothelialized networks through mesenchymal stem cell-dependent contraction. Transplantation of pancreatic islet-like organoids treats diabetes in mice effectively. Given the donor shortage associated with clinical islet transplantation, our approach offers a promising alternative toward therapeutic organoid transplantation. © 2018 by John Wiley & Sons, Inc.