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Owing to the complexity of tumorgenesis, combination therapy has proven to be a viable strategy for cancer treatment in recent years. However, the delivery and site-specific release of different therapeutic agents remain a major challenge in combination therapy. In this study, a polymeric nanovesicle based on a copolymer of polyethylene glycol and a polypeptide derivative was introduced as a vector to simultaneously deliver hydrophobic gefitinib and hydrophilic doxorubicin hydrochloride for multi-target combination therapy. The vesicle incorporating the two drugs exhibited prominent pH/reduction sensitivities to trigger the release of gefitinib and doxorubicin inside cancer cells. The two drugs codelivered by the polymeric nanovesicle exhibited a joint anticancer effect both in vitro and in vivo. In particular, a remarkable therapeutic effect was demonstrated in animal studies using a mouse N2a neuroblastoma model. This study reveals the potential of reduction and pH dual-responsive nanovesicles bearing gefitinib and doxorubicin as an effective nano-medicine for cancer treatment. Fig. 1 Illustrative preparation of nanovesicle as well as the dual sensitive release of DOX and gefitinib inside tumor cell.This journal is

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Objectives To investigate the association of eight variants of four matrix metalloproteinase (MMP) genes with ischemic stroke (IS) and whether interactions among these single nucleotide polymorphisms (SNPs) increases the risk of IS. Methods Among 547 patients with ischemic stroke and 350 controls, matrix‐assisted laser desorption/ionization time of flight mass spectrometry was used to examine eight variants arising from four different genes, including MMP‐1 (rs1799750), MMP‐2 (rs243865, rs2285053, rs2241145), MMP‐9 (rs17576), and MMP‐12 (rs660599, rs2276109, and rs652438). Gene–gene interactions were employed using generalized multifactor dimensionality reduction (GMDR) methods. Results The frequency of rs17576 was significantly higher in IS patients than in controls (p = .033). Logistic regression analysis revealed the AG and GG genotypes of rs17576 to be associated with a higher risk for IS, with the odds ratio and 95% confidence interval being 2.490 (1.251–4.959) and 2.494 (1.274–4.886), respectively. GMDR analysis showed a significant SNP‐SNP interaction between rs17576 and rs660599 (the testing balanced accuracy was 53.70% and cross‐validation consistency was 8/10, p = .0107). Logistic regression analysis showed the interaction between rs17576 and rs660599 to be an independent risk factor for IS with an odds ratio of 1.568 and a 95% confidence interval of 1.152–2.135. Conclusion An MMP‐9 rs17576 polymorphism is associated with increased IS risk in the Han Hakka population and interaction between MMP‐9 rs17576 and MMP‐12 rs660599 is associated with increased IS risk as well.