Folic Acid Modified Cationic γ‑Cyclodextrin-oligoethylenimine Star Polymer with Bioreducible Disulfide Linker for Efficient Targeted Gene Delivery

For an efficient folate-targeted delivery, while the interaction between the folate on the carriers and the folate receptor (FR) on the cells is necessary, the recovering and recycling of FR to maintain a high density level of FR on the cellular membrane is also important. Herein, we demonstrate a design and synthesis of a new star-shaped cationic polymer containing a γ-cyclodextrin (γ-CD) core and multiple oligoethylenimine (OEI) arms with folic acid (FA) linked by a bioreducible disulfide bond for efficient targeted gene delivery. The newly synthesized cationic polymer, named γ-CD-OEI-SS-FA, could be cleaved efficiently, and FA was readily released under reductive condition similar to intracellular environment. The γ-CD-OEI-SS-FA polymer was well-characterized and studied in terms of its gene delivery properties in FR-positive KB cells and FR-negative A549 cells under various conditions, in comparison with cationic polymers such as high molecular weight branched polyethylenimine (PEI), γ-CD-OEI star-shaped cationic polymer, γ-CD-OEI-FA polymer where FA was directed linked to the star polymer without disulfide linker. Our data have demonstrated that the new γ-CD-OEI-SS-FA gene carrier had low cytotoxicity and possessed capacity to target and deliver DNA to specific tumor cells that overexpress FRs, as well as functions to recover and recycle FRs onto cellular membranes to facilitate continuous FR-mediated endocytosis to achieve very high levels of gene expression. This study has expanded the strategy of FA-targeted delivery by combining the smart FR-recycling function to achieve the significant enhancement of gene expression. The new FA-targeted and bioreducible carrier may be a promising efficient gene delivery system for potential cancer gene therapy

Supramolecular Anchoring of DNA Polyplexes in Cyclodextrin-Based Polypseudorotaxane Hydrogels for Sustained Gene Delivery

A cyclodextrin-based supramolecular hydrogel system with supramolecularly anchored active cationic copolymer/plasmid DNA (pDNA) polyplexes was studied as a sustained gene delivery carrier. A few biodegradable triblock copolymers of methoxy-poly­(ethylene glycol)-<i>b</i>-poly­(ε-caprolactone)-<i>b</i>-poly­[2-(dimethylamino)­ethyl methacrylate] (MPEG-PCL-PDMAEMA) with well-defined cationic block lengths were prepared to condense pDNA. The MPEG-PCL-PDMAEMA copolymers exhibit good ability to condense pDNA into 275–405 nm polyplexes with hydrophilic MPEG in the outer corona. The MPEG corona imparted greater stability to the pDNA polyplexes and also served as an anchoring segment when the pDNA polyplexes were encapsulated in α-CD-based supramolecular polypseudorotaxane hydrogels. More interestingly, the resultant hydrogels were able to sustain release of pDNA up to 6 days. The pDNA was released in the form of polyplex nanoparticles as it was bound electrostatically to the cationic segment of the MPEG-PCL-PDMAEMA copolymers. The bioactivity of the released pDNA polyplexes at various durations was further investigated. Protein expression level of pDNA polyplexes released over the durations was comparable to that of freshly prepared PEI polyplexes. Being thixotropic and easily prepared without using organic solvent, this supramolecular <i>in situ</i> gelling system has immense potential as an injectable carrier for sustained gene delivery

Long-Term Use of Angiotensin Receptor Blockers and the Risk of Cancer

<div><p>The association between angiotensin receptor blockers (ARBs) and cancer is controversial with meta-analyses of randomized controlled trials and observational studies reporting conflicting results. Thus, the objective of this study was to determine whether ARBs are associated with an overall increased risk of the four most common cancers, namely, lung, colorectal, breast and prostate cancers, and to explore these effects separately for each cancer type. We conducted a retrospective cohort study using a nested case-control analysis within the United Kingdom (UK) General Practice Research Database. We assembled a cohort of patients prescribed antihypertensive agents between 1995, the year the first ARB (losartan) entered the UK market, and 2008, with follow-up until December 31, 2010. Cases were patients newly-diagnosed with lung, colorectal, breast and prostate cancer during follow-up. We used conditional logistic regression to estimate adjusted rate ratios (RRs) and 95% confidence intervals (CIs) of cancer incidence, comparing ever use of ARBs with ever use of diuretics and/or beta-blockers. The cohort included 1,165,781 patients, during which 41,059 patients were diagnosed with one of the cancers under study (rate 554/100,000 person-years). When compared to diuretics and/or beta-blockers, ever use of ARBs was not associated with an increased rate of cancer overall (RR: 1.00; 95% CI: 0.96–1.03) or with each cancer site separately. The use of angiotensin-converting enzyme inhibitors and calcium channel blockers was associated with an increased rate of lung cancer (RR: 1.13; 95% CI: 1.06–1.20 and RR: 1.19; 95% CI: 1.12–1.27, respectively). This study provides additional evidence that the use of ARBs does not increase the risk of cancer overall or any of the four major cancer sites. Additional research is needed to further investigate a potentially increased risk of lung cancer with angiotensin-converting enzyme inhibitors and calcium channel blockers.</p> </div

Adjusted rate ratios of specific cancers associated with use of angiotensin receptor blockers in combination with angiotensin-converting enzyme inhibitors relative to the use of diuretics or beta-blockers.

<p>Adjusted rate ratios of specific cancers associated with use of angiotensin receptor blockers in combination with angiotensin-converting enzyme inhibitors relative to the use of diuretics or beta-blockers.</p

Additional file 1: of Influencing factors associated with the mode of birth among childbearing women in Hunan Province: a cross-sectional study in China

A full List of Questionnaire. (DOC 67 kb

Additional file 2: of Influencing factors associated with the mode of birth among childbearing women in Hunan Province: a cross-sectional study in China

Dataset of Survey. (XLS 1417 kb

Crude and adjusted rate ratios of cancer associated with antihypertensive agents relative to diuretic and/or beta-blocker use.

<p>Abbreviations: RR, rate ratio; CI, confidence interval; ARB, angiotensin receptor blocker; ACEI, angiotensin-converting enzyme inhibitor; CCB, calcium channel blocker; DDD, defined daily doses.</p>*<p>Cases and controls were matched on year of birth, year of cohort entry, sex, prevalent user status, and duration of follow-up.</p>†<p>Adjusted for excessive alcohol use, body mass index, smoking, diabetes, previous cancer, and ever of aspirin, statins, and NSAIDs.</p>‡<p>Defined as receiving prescriptions for both agents on the same day on at least one occasion.</p>§<p>Dose-response analyses conducted among the 5583 cases and 56,817 controls exposed to ARBs. Categories based on tertiles.</p

Crude and adjusted rate ratios of lung, colorectal, prostate and breast cancer associated with antihypertensive agents relative to diuretic and/or beta-blocker use.

<p>Abbreviations: RR, rate ratio; CI, confidence interval; ARB, angiotensin receptor blocker; ACEI, angiotensin-converting enzyme inhibitor; CCB, calcium channel blocker.</p>*<p>Cases and controls were matched on year of birth, year of cohort entry, sex, prevalent user status, and duration of follow-up.</p>†<p>All models were adjusted for excessive alcohol use, body mass index, smoking, diabetes, previous cancer, and ever of aspirin, statins, and NSAIDs. In addition, cholecystectomy, inflammatory bowel disease and history of polyps for colorectal cancer; benign prostatic hyperplasia, 5-alpha reductase inhibitors, and number of PSA tests for prostate cancer; oophorectomy, use of hormone replacement therapy, and prior use of oral contraceptives for breast cancer.</p>‡<p>Defined prescriptions of both agents overlapping each other for at least one day.</p

Adjusted rate ratios of specific cancers associated with use of angiotensin receptor blockers relative to the use of diuretics or beta-blockers.

<p>Adjusted rate ratios of specific cancers associated with use of angiotensin receptor blockers relative to the use of diuretics or beta-blockers.</p

Zinc Stable Isotope Fractionation Mechanisms during Adsorption on and Substitution in Iron (Hydr)oxides

The Zn isotope fingerprint is widely used as a proxy of various environmental geochemical processes, so it is crucial to determine which are the mechanisms responsible for isotopic fractionation. Iron (Fe) (hydr)oxides greatly control the cycling and fate and thus isotope fractionation factors of Zn in terrestrial environments. Here, Zn isotope fractionation and related mechanisms during adsorption on and substitution in three FeOOH polymorphs are explored. Results demonstrate that heavy Zn isotopes are preferentially enriched onto solids, with almost similar isotopic offsets (Δ66/64Znsolid‑solution = 0.25–0.36‰) for goethite, lepidocrocite, and feroxyhyte. This is consistent with the same average Zn–O bond lengths for adsorbed Zn on these solids as revealed by Zn K-edge X-ray absorption fine structure spectroscopy. In contrast, at an initial Zn/Fe molar ratio of 0.02, incorporation of Zn into goethite and lepidocrocite by substituting for lattice Fe preferentially sequesters light Zn isotopes with Δ66/64Znsubstituted‑stock solution of −1.52 ± 0.09‰ and −1.18 ± 0.15‰, while Zn-substituted feroxyhyte (0.06 ± 0.11‰) indicates almost no isotope fractionation. This is closely related to the different crystal nucleation and growth rates during the Zn-doped FeOOH formation processes. These results provide direct experimental evidence of incorporation of isotopically light Zn into Fe (hydr)oxides and improve our understanding of Zn isotope fractionation mechanisms during mineral–solution interface processes