Bone tumor-homing nanotherapeutics for prolonged retention in tumor microenvironment and facilitated apoptotic process via mevalonate pathway inhibition.

Bone malignancy features a mineralized extracellular matrix primarily composed of hydroxyapatite, which interferes with the distribution and activity of antineoplastic agents. Herein, we report bone tumor-homing polymeric nanotherapeutics consisting of alendronate-decorated chondroitin sulfate A-graft-poly(lactide-co-glycolide) and doxorubicin (DOX), named PLCSA-AD, which displayed a prolonged retention profile in the tumor microenvironment and augmented therapeutic efficacy via inhibition of the mevalonate pathway. PLCSA-AD exhibited a 1.72-fold lower IC50 value than free DOX and a higher affinity for hydroxyapatite than PLCSA in HOS/MNNG cell-based 2D bone tumor-mimicking models. The inhibition of the mevalonate pathway by PLCSA-AD in tumor cells was verified by investigating the cytosolic fraction of unprenylated proteins, where blank PLCSA-AD significantly increased the expression of cytosolic Ras and RhoA without changing their total cellular amounts. In a bone tumor-mimicking xenografted mouse model, AD-decorated nanotherapeutics significantly increased tumor accumulation (1.73-fold) compared with PLCSA, and higher adsorption to hydroxyapatites was observed in the histological analysis of the tumor. As a result, inhibition of the mevalonate pathway and improvement in tumor accumulation led to markedly enhanced therapeutic efficacy in vivo, suggesting that PLCSA-AD could be promising nanotherapeutics for bone tumor treatment.

Formulation of self-microemulsifying drug delivery system (SMEDDS) by D-optimal mixture design to enhance the oral bioavailability of a new cathepsin K inhibitor (HL235).

HL235 is a new cathepsin K inhibitor designed and synthesized to treat osteoporosis. Since HL235 has poor aqueous solubility, a self-microemulsifying drug delivery system (SMEDDS) was formulated to enhance its oral bioavailability. A solubility study of HL235 was performed to select a suitable oil, surfactant and cosurfactant. Pseudoternary phase diagrams were plotted to identify the microemulsion region and to determine the range of components in the isotropic mixture. D-optimal mixture design and a desirability function were introduced to optimize the SMEDDS formulation for the desired physicochemical characteristics, i.e., high drug concentration at 15 min after dilution with simulated gastric fluid (SGF) and high solubilization capacity. The optimized HL235-loaded SMEDDS formulation consisted of 5.0% Capmul MCM EP (oil), 75.0% Tween 20 (surfactant) and 20.0% Carbitol (cosurfactant). The droplet size of the microemulsion formed by the optimized formulation was 10.7 ±â€¯1.6 nm, and the droplets were spherical in shape. Pharmacokinetic studies in rats showed that the relative oral bioavailability of the SMEDDS formulation increased up to 3.22-fold compared to its solution in DMSO:PEG400 (8:92, v/v). Thus, the formulation of SMEDDS optimized by D-optimal mixture design could be a promising approach to improve the oral bioavailability of HL235.