No abstract

Chemodynamic therapy (CDT) can efficiently destroy tumor cells via Fenton reaction in the presence of H 2 O 2 and a robust catalyst. However, it has faced severe challenges including the limited amounts of H 2 O 2 and inefficiency of catalysts.Here, an adenosine triphosphate (ATP)-responsive autocatalytic Fenton nanosystem (GOx@ZIF@MPN), incorporated with glucose oxidase (GOx) in zeolitic imidazolate framework (ZIF) and then coated with metal polyphenol network (MPN), was designed and synthesized for tumor ablation with self-supplied H 2 O 2 and TA-mediated acceleration of Fe(III)/Fe(II) conversion. In the ATP-overexpressed tumor cells, the outer shell MPN of GOx@ZIF@MPN was degraded into Fe(III) and tannic acid (TA) and the internal GOx was exposed. Then, GOx reacted with the endogenous glucose to produce plenty of H 2 O 2 , and TA reduced Fe(III) to Fe(II), which is a much more vigorous catalyst for the Fenton reaction. Subsequently, self-produced H 2 O 2 was catalyzed by Fe(II) to generate highly toxic hydroxyl radical (•OH) and Fe(III). The produced Fe(III) with low catalytic activity was quickly reduced to reactive Fe(II) mediated by TA, forming an accelerated Fe(III)/Fe(II) conversion to guarantee efficient Fenton reaction-mediated CDT. This autocatalytic Fenton nanosystem might provide a good paradigm for effective tumor treatment.

The kidney plays a vital role in the body's defense against potentially toxic xenobiotics and metabolic waste products through elimination pathways. In particular, secretory transporters in the proximal tubule are major determinants of the disposition of xenobiotics, including many prescription drugs. In the past decade, considerable progress has been made in understanding the impact of renal transporters on the disposition of many clinically used drugs. In addition, renal transporters have been implicated as sites for numerous clinically important drug-drug interactions. This review begins with a description of renal drug handling and presents relevant equations for the calculation of renal clearance, including filtration and secretory clearance. In addition, data on the localization, expression, substrates, and inhibitors of renal drug transporters are tabulated. The recent US Food and Drug Administration drug-drug interaction draft guidance as it pertains to the study of renal drug transporters is presented. Renal drug elimination in special populations and transporter splicing variants are also described.

Significance This manuscript describes a previously unidentified mechanism for organic cation transporter 1 (OCT1), the major hepatic metformin transporter, in hepatic steatosis. Here we show that OCT1, long thought to function primarily as a transporter for drugs, functions as a major thiamine transporter in the liver, which has profound implications in cellular metabolism. Collectively, our results point to an important role of thiamine (through OCT1) in hepatic steatosis and suggest that the modulation of thiamine disposition by metformin may contribute to its pharmacologic effects.

Interindividual variation in response to metformin, first-line therapy for type 2 diabetes, is substantial. Given that transporters are determinants of metformin pharmacokinetics, we examined the effects of promoter variants in both multidrug and toxin extrusion protein 1 (MATE1) (g.−66T→C, rs2252281) and MATE2 (g.−130G→A, rs12943590) on variation in metformin disposition and response. The pharmacokinetics and glucose-lowering effects of metformin were assessed in healthy volunteers (n = 57) receiving metformin. The renal and secretory clearances of metformin were higher (22% and 26%, respectively) in carriers of variant MATE2 who were also MATE1 reference (P < 0.05). Both MATE genotypes were associated with altered post-metformin glucose tolerance, with variant carriers of MATE1 and MATE2 having an enhanced (P < 0.01) and reduced (P < 0.05) response, respectively. Consistent with these results, patients with diabetes (n = 145) carrying the MATE1 variant showed enhanced metformin response. These findings suggest that promoter variants of MATE1 and MATE2 are important determinants of metformin disposition and response in healthy volunteers and diabetic patients.

Bacteria preferentially accumulating in tumor microenvironments can be utilized as natural vehicles for tumor targeting. However, neither current chemical nor genetic approaches alone can fully satisfy the requirements on both stability and high efficiency. Here, we propose a strategy of “charging” bacteria with a nano-photocatalyst to strengthen their metabolic activities. Carbon nitride (C3N4) is combined with Escherichia coli (E. coli) carrying nitric oxide (NO) generation enzymes for photo-controlled bacterial metabolite therapy (PMT). Under light irradiation, photoelectrons produced by C3N4 can be transferred to E. coli to promote the enzymatic reduction of endogenous NO3– to cytotoxic NO with a 37-fold increase. In a mouse model, C3N4 loaded bacteria are perfectly accumulated throughout the tumor and the PMT treatment results in around 80% inhibition of tumor growth. Thus, synthetic materials-remodeled microorganism may be used to regulate focal microenvironments and increase therapeutic efficiency.

Double-network (DN) hydrogels with high strength and toughness have been developed as promising materials. Herein, we explored a dual physically cross-linked polyacrylamide/xanthan gum (PAM/XG) DN hydrogel. The nonchemically cross-linked PAM/XG DN hydrogels exhibited fracture stresses as high as 3.64 MPa (13 times higher than the pure PAM single network hydrogel) and compressive stresses at 99% strain of more than 50 MPa. The hydrogels could restore their original shapes after continuously loading-unloading tensile and compressive cyclic tests. In addition, the PAM/XG DN hydrogels demonstrated excellent fatigue resistance, notch-insensitivity, high stability in different harsh environments, and remarkable self-healing properties, which might result from their distinctive physical-cross-linking structures. The attenuated total reflectance infrared spectroscopy (ATR-IR) and dynamic thermogravimetric analysis (TGA) results indicated that there were no chemical bonds (only hydrogen bonds) between the XG and PAM networks. The PAM/XG DN hydrogel synthesis offers a new avenue for the design and construction of DN systems, broadening current research and applications of hydrogels with excellent mechanical properties.

Tumor hypoxia severely limits the efficacy of traditional photodynamic therapy (PDT). Here, a liposome-based nanoparticle (designated as LipoMB/CaO ) with O self-sufficient property for dual-stage light-driven PDT is demonstrated to address this problem. Through a short time irradiation, O activated by the photosensitizer methylene blue (MB) can induce lipid peroxidation to break the liposome, and enlarge the contact area of CaO with H O, resulting in accelerated O production. Accelerated O level further regulates hypoxic tumor microenvironment and in turn improves O generation by MB under another long time irradiation. In vitro and in vivo experiments also demonstrate the superior competence of LipoMB/CaO to alleviate tumor hypoxia, suppress tumor growth and antitumor metastasis with low side-effect. The O self-sufficient LipoMB/CaO nanoplatform with dual-stage light manipulation is a successful attempt for PDT against hypoxic tumor.