An updated meta-analysis on the efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitor treatment of anemia in nondialysis-dependent chronic kidney disease.

BACKGROUND: Renal anemia, a common complication and threat factor of chronic kidney disease (CKD), has long been treated with injectable erythropoietin-stimulating agents (ESAs). As concerns regarding cardiovascular safety and erythropoietin resistance to ESAs have emerged, alternative therapies are urgently needed. Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), an oral agent, has been proven to be effective in improving renal anemia. However, the effects of HIF-PHIs on nondialysis-dependent CKD (NDD-CKD) have yet to be supported by updated meta-analyses. METHODS: A meta-analysis of clinical randomized controlled trials (RCTs) on HIF-PHI treatment of NDD-CKD patients based on PubMed, EMBASE, and Cochrane databases as of July 16th, 2023, was conducted. The primary outcomes were the level of hemoglobin (Hb) postintervention and the ratio of Hb responses. Most of the analysis was conducted via RevMan 5.3 software using a random-effects model. Stata (version 15.0) was used to analyze the publication bias. RESULTS: Twenty-two studies with a total of 7178 subjects in the HIF-PHI group, 3501 subjects in the ESA group and 2533 subjects in the placebo group were enrolled. HIF-PHIs increased the level of Hb and improved iron metabolism but were not inferior to ESAs in terms of safety. CONCLUSIONS: HIF-PHIs may be a convenient and safe alternative to ESAs in patients with NDD-CKD and anemia.

Bubble-generating polymersomes loaded with both indocyanine green and doxorubicin for effective chemotherapy combined with photothermal therapy.

The combination of chemotherapy and photothermaltherapy (PTT) via stimuli-responsive nanovesicles has great potential in tumor treatment. In the present study, bubble-generating polymersomes, which can generate bubbles in response to low pH or hyperthermia, were fabricated to simultaneously encapsulate chemotherapeutic drug and photosensitizing agent for the synergistic chemo-photothermal tumor therapy. Photosensitizer indocyanine green (ICG) was encapsulated into the bilayer of polymersomes formed by amphiphilic triblock copolymer PCL8000-PEG8000-PCL8000 through thin film re-hydration method, while chemotherapeutic doxorubicin (DOX) was loaded into the hydrophilic lumen using a transmembrane ammonium bicarbonate gradient loading procedure. Under acidic condition or laser irradiation, the ammonium bicarbonate (NH4HCO3) encapsulated in the bubble-generating DOX-ICG-co-delivery polymersomes (BG-DIPS) would decompose to produce CO2 bubbles, resulting in destruction of vesicle structure and rapid drug release. In vitro drug release study confirmed that acidic environment and NIR laser irradiation could accelerate DOX release from the BG-DIPS. Cellular uptake study indicated that laser-induced hyperthermia highly enhanced endocytosis of BG-DIPS into 4T1-Luc cancer cells. In vitro cytotoxicity study demonstrated that BG-DIPS exhibited much higher cytotoxicity than free drugs under laser irradiation. In vivo biodistribution study indicated that BG-DIPS could accumulate in the tumor region, prolong drug retention, and increase photothermal conversion efficiency. Furthermore, in vivo antitumor study showed that BG-DIPS with laser irradiation efficiently inhibited 4T1-Luc tumor growth with reduced systemic toxicity. Hence, the formulated bubble-generating polymersomes system was a superior multifunctional nanocarrier for stimuli-response controlled drug delivery and combination chemo-photothermal tumor therapy. STATEMENT OF SIGNIFICANCE: The combination of chemotherapy and photothermaltherapy via stimuli-responsive nanovesicles has great potential in tumor treatment. Herein, bubble-generating polymersomes, which can generate bubbles in response to low pH or hyperthermia, were fabricated to simultaneously encapsulate chemotherapeutic drug (DOX) and photosensitizing agent (ICG) for the synergistic chemo-photothermal tumor therapy. The results in vitro and in vivo demonstrated that bubble-generating DOX-ICG-co-delivery polymersomes (BG-DIPS) would accelerate DOX release from the BG-DIPS and accumulate in the tumor region, prolong drug retention, and increase photothermal conversion efficiency. BG-DIPS with laser irradiation could efficiently inhibited 4T1-Luc tumor growth with reduced systemic toxicity. Hence, the formulated bubble-generating polymersomes system was a superior multifunctional nanocarrier for stimuli-response controlled drug delivery and combination chemo-photothermal tumor therapy.

Dual pH/reduction-responsive hybrid polymeric micelles for targeted chemo-photothermal combination therapy.

The combination of chemotherapy and photothermal therapy in multifunctional nanovesicles has emerged as a promising strategy to improve cancer therapeutic efficacy. Herein, we designed new pH/reduction dual-responsive and folate decorated polymeric micelles (FA Co-PMs) as theranostic nanocarrier to co-encapsulate doxorubicin (DOX) and indocyanine green (ICG) for targeted NIR imaging and chemo-photothermal combination therapy. The Co-PMs exhibited nano-sized structure (∼100 nm) with good monodispersity, high encapsulation efficiency of both ICG and DOX, triggered DOX release in response to acid pH and reduction environment, and excellent temperature conversion with laser irradiation. In vitro cellular uptake study indicated FA Co-PMs achieved significant targeting to BEL-7404 cells via folate receptor-mediated endocytosis, and laser-induced hyperthermia further enhanced drug accumulation into cancer cells. In vivo biodistribution study indicated that FA Co-PMs prolonged drug circulation and enhanced drug accumulation into the tumor via EPR effect and FA targeting. Furthermore, the ICG-based photo-triggered hyperthermia combined with DOX-based chemotherapy synergistically induced the BEL-7404 cell death and apoptosis, and efficiently suppressed the BEL-7404 xenografted tumor growth while significantly reduced systemic toxicity in vivo. Therefore, the designed dual-responsive Co-PMs were promising theranostic nanocarriers for versatile antitumor drug delivery and imaging-guided cancer chemo-photothermal combination therapy. STATEMENT OF SIGNIFICANCE: The combination of chemotherapy and photothermal therapy in multifunctional nanovesicles has emerged as a promising strategy to improve cancer therapeutic efficacy. Herein, we designed novel pH/reduction dual-responsive and folate decorated polymeric micelles (FA Co-PMs) as theranostic nanocarrier to co-encapsulate doxorubicin (DOX) and indocyanine green (ICG) for targeted NIR imaging and chemo-photothermal combination therapy. The Co-PMs triggered DOX release in response to acid pH and reduction environment and exhibited excellent temperature conversion with laser irradiation. The results indicated FA Co-PMs achieved significant targeting to BEL-7404 cells in vitro and efficiently suppressed the BEL-7404 xenografted tumor growth while significantly reduced systemic toxicity in vivo. Therefore, the designed dual-responsive Co-PMs displayed great potential in imaging-guided cancer chemo-photothermal combination therapy as theranostic nanocarriers.