A novel dual-drug ternary salt cocrystal of piperazine ferulate (PRZ–FLA) with pyrazinamide (PRA), namely, PRZ–FLA–PRA, has been synthesized and characterized. Single-crystal X-ray diffraction reveals that the cocrystal has a formula of (PRZ2+)·(FLA–)2­·(PRA)2, in which the PRZ2+ and FLA– ions form a one-dimensional chain by the strong charge-assisted hydrogen bonds and then interacts with neutral PRA molecules through hydrogen bonds, constructing a three-dimensional supramolecular network. As far as we know, this is the first example of a dual-drug ternary salt cocrystal simultaneously containing both a nephrosis-treating drug and antituberculous agent. The solubility and dissolution rate studies of the cocrystal are conducted under various physiological pH environments to assess the effects of cocrystallization on in vitro release behaviors of PRZ–FLA, and the outcomes suggest that the intrinsic dissolution rate and solubility of PRZ–FLA in the cocrystal are slowed and lowered, respectively, in comparison with the parent drug. The present work not only provides an alternative approach to reduce the release rate, which is in favor of solving issues with the short half-life of PRZ–FLA, but also offers a potential synergistic therapeutic application as a promising combination drug to treat the symptoms of complications from tuberculosis and renal injury.

The occurrence of osteoarthritis (OA) is highly correlated with the reduction of joint lubrication performance, in which persistent excessive inflammation and irreversible destruction of cartilage dominate the mechanism. The inadequate response to monotherapy methods, suboptimal efficacy caused by undesirable bioavailability, short retention, and lack of stimulus-responsiveness, are few unresolved issues. Herein, we report a pH-responsive metal-organic framework (MOF), namely, MIL-101-NH2, for the co-delivery of anti-inflammatory drug curcumin (CCM) and small interfering RNA (siRNA) for hypoxia inducible factor (HIF-2α). CCM and siRNA were loaded via encapsulation and surface coordination ability of MIL-101-NH2. Our vitro tests showed that MIL-101-NH2 protected siRNA from nuclease degradation by lysosomal escape. The pH-responsive MIL-101-NH2 gradually collapsed in an acidic OA microenvironment to release the CCM payloads to down-regulate the level of pro-inflammatory cytokines, and to release the siRNA payloads to cleave the target HIF-2α mRNA for gene-silencing therapy, ultimately exhibiting the synergetic therapeutic efficacy by silencing HIF-2α genes accompanied by inhibiting the inflammation response and cartilage degeneration of OA. The hybrid material reported herein exhibited promising potential performance for OA therapy as supported by both in vitro and in vivo studies and may offer an efficacious therapeutic strategy for OA utilizing MOFs as host materials.

No abstract

The occurrence of osteoarthritis (OA) is highly correlated with the reduction of joint lubrication performance, in which persistent excessive inflammation and irreversible destruction of cartilage dominate the mechanism. The inadequate response to monotherapy methods, suboptimal efficacy caused by undesirable bioavailability, short retention, and lack of stimulus-responsiveness, are few unresolved issues. Herein, we report a pH-responsive metal-organic framework (MOF), namely, MIL-101-NH2, for the co-delivery of anti-inflammatory drug curcumin (CCM) and small interfering RNA (siRNA) for hypoxia inducible factor (HIF-2α). CCM and siRNA were loaded via encapsulation and surface coordination ability of MIL-101-NH2. Our vitro tests showed that MIL-101-NH2 protected siRNA from nuclease degradation by lysosomal escape. The pH-responsive MIL-101-NH2 gradually collapsed in an acidic OA microenvironment to release the CCM payloads to down-regulate the level of pro-inflammatory cytokines, and to release the siRNA payloads to cleave the target HIF-2α mRNA for gene-silencing therapy, ultimately exhibiting the synergetic therapeutic efficacy by silencing HIF-2α genes accompanied by inhibiting the inflammation response and cartilage degeneration of OA. The hybrid material reported herein exhibited promising potential performance for OA therapy as supported by both in vitro and in vivo studies and may offer an efficacious therapeutic strategy for OA utilizing MOFs as host materials.