Lectin-HPMA copolymer conjugates: potential oral drug carriers for targeting diseased tissues

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer-lectin conjugates were investigated for potential use as targeted oral drug carriers for treatment of inflammatory conditions such as colitis. Wheat germ agglutinin (WGA)-HPMA copolymer and peanut agglutinin (PNA)-HPMA copolymer and fluorescein isothiocyanate (FITC)-labeled WGA- and PNA-HPMA copolymer conjugates were synthesized. Conjugate dissociation constants (K_d) for lectin-carbohydrate binding determined by frontal affinity chromatography indicated that no activity reduction of the lectins occurred during the synthesis of these conjugates. K_d values measured were in good agreement with literature findings for similar lectin-carbohydrate interactions, on the order of 10⁻⁵ M⁻¹. Biorecognition of these conjugates by healthy rat intestinal tissue resulted in differential HPMA copolymer-lectin conjugate binding patterns in the same tissue. HPMA copolymer-WGA conjugate showed strong binding in the healthy rat intestinal tissues, while the HPMA copolymer-PNA conjugate showed minimal, but specific binding. This differential binding suggests that site-specific drug delivery via specific lectin recognition may be feasible for treatment of colon inflammation or cancer.     

Synthesis of semitelechelic poly[N-(2-hydroxypropyl)methacryl-amide] by radical polymerization in the presence of alkyl mercaptans

The free radical polymerization of N-(2-hydroxylpropyl)methacrylamide (HPMA) in the presence of chain transfer agents was studied. Methyl 3-mercaptopropionate (MMP) and 2-mercaptoethylamine (MEA) were used as chain transfer agents and 2,2′-azobisisobutyronitrile (AIBN) was used as the initiator. Semitelechelic (ST) polymers produced under various reaction conditions were analyzed by Matrix Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) and size exclusion chromatography (SEC). The molecular weight of the ST polymers was regulated by the initial molar ratio of chain transfer agent to HPMA. The free radicals formed by the decomposition of AIBN initiated a fraction of polymer chains; such chains were not terminated in a functional group. The amount of these polymer chains depended on the concentration and efficiency of the chain transfer agent, concentration of AIBN, and conversion. Decreasing the concentration of AIBN and increasing the concentration of the chain transfer agent reduced the formation of nonfunctionalized polymer chains.     

Synthesis and significant cytostatic activity of 7-hetaryl-7-deazaadenosines

A series of 7-aryl- and 7-hetaryl-7-deazaadenosines was prepared by the cross-coupling reactions of unprotected or protected 7-iodo-7-deazaadenosines with (het)arylboronic acids, stannanes, or zinc halides. Nucleosides bearing 5-membered heterocycles at the position 7 exerted potent in vitro antiproliferative effects against a broad panel of hematological and solid tumor cell lines. Cell cycle analysis indicated profound inhibition of RNA synthesis and induction of apoptosis in treated cells. Intracellular conversion to triphosphates has been detected with active compounds. The triphosphate metabolites showed only a weak inhibitory effect on human RNA polymerase II, suggesting potentially other mechanisms for the inhibition of RNA synthesis and quick onset of apoptosis. Initial in vivo evaluation demonstrated an effect of 7-(2-thienyl)-7-deazaadenine ribonucleoside on the survival rate in syngeneic P388D1 mouse leukemia model.     

Influence of Oral Antidiabetic Drugs on Hyperglycemic Response to Foods in Persons with Type 2 Diabetes Mellitus as Assessed by Continuous Glucose Monitoring System: A Pilot Study

Background

The purpose of this prospective open-label trial was (1) to assess the influence of oral antidiabetic drugs (OAD) on the glycemic index (GI), glucose response curves (GRCs), daily mean plasma glucose (MPG) and (2) to compare the GI of foods in persons with OAD-treated type 2 diabetes mellitus (T2DM) with the respective GI in healthy persons (HP).

Methods

Tested foods containing 50 g of carbohydrates were eaten for breakfast and dinner after 10 and 4 h of fasting, respectively. Glycemic index, GRC, and MPG were obtained using the CGMS^®System Gold™ (CGMS). In T2DM patients [n = 16; age (mean ± standard error) 56.0 ± 2.25 years], foods were tested four times: tests 1, 2, and 3 were performed within one week in which placebo was introduced on day 2, and test 4 was carried out five weeks after reintroduction of OAD. Glycemic indexes, GRC, and MPG from tests 1, 2, 3, and 4 were compared. In a control group of 20 HP (age 24.4 ± 0.71 years), the mean GIs were calculated as the mean from 20 subject-related GIs.

Results

In T2DM patients, subject-related assessment of GIs, GRC, and MPG distinguished persons with and without OAD effect. Nevertheless, the group-related GIs and the MPG on days 2, 8, and 39 showed no significant difference. There was no significant difference between the GIs in OAD-treated T2DM patients (test 4) versus HP (except in apple baby food). Glucose response curves were significantly larger in T2DM patients (test 4) versus HP.

Conclusions

Determination of GRC and subject-related GI using the CGMS appears to be a potential means for the evaluation of efficacy of OAD treatment. Further studies are underway.     

Saccharide-mediated interactions of boar sperm surface proteins with components of the porcine oviduct

The role of boar seminal plasma proteins attached to the sperm plasma membrane during ejaculation has been studied in saccharide-mediated events in the female reproductive tract. Heparin-binding (Hep(+)) proteins (DQH sperm surface protein, and AQN and AWN spermadhesins) and their aggregated forms (fractions II and III) interacted more strongly with both oviductal epithelium cells and fluid than non-heparin-binding (Hep(-)) proteins (PSP I and PSP II spermadhesins) and their heterodimer (fraction IV), and interactions correlate with affinity of these proteins to yeast mannan. Indirect immunofluorescence (IMF) showed that the AQN 1 spermadhesin and fraction II bind to the apical glycocalyx of the ampulla, as well as the isthmic and uterine tubal junction regions of the oviductal sections. IMF demonstrated the recognition of AQN 1 and fraction II and mannosyl components of oviductal epithelium. We suggest that Hep(+) proteins (especially AQN 1, fraction II) on sperm could enable sperm binding to oviductal epithelium and thus participate in formation of the sperm oviductal reservoir. Interactions of Hep(+) proteins to oviductal epithelium were inhibited by mannan, hyaluronic acid and sialylated O-glycoproteins. No or slight inhibition was observed with sulphated polysaccharides (heparin, chondroitin sulphate) and simple monosaccharides. Besides that, attachment of boar seminal plasma proteins to oviductal epithelium cells was affected by oviductal fluid, the natural environment in the oviduct. Moreover, the ability of hyaluronic acid to inhibit the interaction of sperm surface proteins to the oviduct might play a role in sperm release from the oviductal reservoir and in the capacitation process.     

Inverse correlation between plasma Beta-carotene and interleukin-6 in patients with advanced coronary artery disease

The interrelationships between plasma beta-carotene, alpha-tocopherol, and the level of systemic inflammation and oxidative stress were investigated in patients with advanced coronary artery disease (CAD). Plasma beta-carotene, alpha-tocopherol, malondialdehyde, free radicals, interleukin-6, high sensitive C-reactive protein levels, and other risk factors of CAD were determined in a group of patients with advanced CAD [significant stenosis according to coronarographic examination (n=91) and a control group of examined patients with coronary arteries with no stenosis (n=49)]. Between-group differences in continuous variables were analyzed with the Hotelling T2-test (software NCSS2000), analyses of correlation matrix with the software STATISTICA. Advanced CAD coincided with significantly lower plasma concentrations of high-density lipoprotein (HDL)-cholesterol and beta-carotene as well as with elevated levels of all inflammatory markers, but only with mild increase of oxidative stress. Beta-carotene significantly inversely correlated with interleukin-6. This inverse correlation could suggest potential protective effect of beta-carotene on atherosclerosis due to the inhibition of inflammatory processes.     

Analysis of Real-world Data on Postremission Therapy for Acute Myeloid Leukemia With Intermediate Risk Cytogenetics in First Complete Remission

Background

We retrospectively analyzed data from 310 patients with acute myeloid leukemia with intermediate-risk cytogenetics in first complete remission (CR1) to evaluate the usage and efficacy of various types of postremission therapy.