Design, Synthesis, and Testing of a Molecular Truck for Colonic Delivery of 5-Aminosalicylic Acid

A molecular scaffold bearing eight terminal alkyne groups was synthesized from sucrose. Eight copies of an azide-terminated, azo-linked precursor to 5-aminosalicylic acid were attached to the scaffold via copper(I)-catalyzed azide–alkyne cycloaddition. The resulting compound was evaluated in a DSS model of colitis in BALB/c mice against sulfasalazine as a control. Two independent studies verified that the novel pro-drug, administered in a dose calculated to result in an equimolar 5-ASA yield, outperformed sulfasalazine in terms of protection from mucosal inflammation and T cell activation. A separate study established that 5-ASA appeared in feces produced 24–48 h following administration of the pro-drug. Thus, a new, orally administered pro-drug form of 5-aminosalicylic acid has been developed and successfully demonstrated

Synthesis and characterization of fourth generation polyester-based dendrimers with cationic amino acids-modified crown as promising water soluble biomedical devices

Dendrimers are nanostructured \u201carchitectural motifs\u201d which fascinate researchers fortheir several potentiality due to well\u2010tailored structure, symmetric tree\u2010like shape,and abilities in entrapping or binding hydrophilic or hydrophobic entities such asgenetic materials, drugs, and target molecules. Nowadays dendrimers inhabit thetop places among the materials suitable for biomedical applications as drug delivery,gene transfection, and imaging. In this work, we report the design and realization oftwo versatile successful procedures to decorate a fourth generation polyester\u2010baseddendrimer matrix with a mixture of four different amino acids. The hydrochloridedendrimers achieved after removal of protecting groups were characterized by acore\u2010shell structure. They harmonized a not charged hydrolysable inner matrixpotentially able to accommodate hydrophobic molecules and a cationic highlyhydrophilic crown conferred by biocompatible amino acids that provided very satis-factory buffer capacity and will allow easy host/guest electrostatic interactions.Their structures and peripheral composition were confirmed by NMR analysis andexperimental molecular weight computed by volumetric titration, while their buffercapacity was obtained by potentiometric titrations. Because in the inner matrix, theachieved hetero dendrimers do not present the high density of positive chargestypical of PAMAM, they ensure a lower level of toxicity. But thanks to the cationicperiphery, as preliminary investigations still in progress have already put in evidence, they were able to entrap not water soluble molecules by electrostatic inter-actions, with the result to increase their water solubility in a very satisfactory oramazing way. They therefore represent two new very promising devices for bio-medical applications

Synthesis and Characterization of Thermally and Chemically Gelling Injectable Hydrogels for Tissue Engineering

Novel, injectable hydrogels were developed that solidify through a dual-gelation, physical and chemical, mechanism upon preparation and elevation of temperature to 37°C. A thermogelling, poly(N-isopropylacrylamide)-based macromer with pendant epoxy rings and a hydrolyticallydegradable polyamidoamine-based diamine crosslinker were synthesized, characterized, and combined to produce in situ forming hydrogel constructs. Network formation through the epoxyamine reaction was shown to be rapid and facile, and the progressive incorporation of the hydrophilic polyamidoamine crosslinker into the hydrogel was shown to mitigate the often problematic tendency of thermogelling materials to undergo significant post-formation gel syneresis. The results suggest that this novel class of injectable hydrogels may be attractive substrates for tissue engineering applications due to the synthetic versatility of the component materials and beneficial hydrogel gelation kinetics and stability

Cervical Mucus Properties Stratify Risk for Preterm Birth

Background: Ascending infection from the colonized vagina to the normally sterile intrauterine cavity is a well-documented cause of preterm birth. The primary physical barrier to microbial ascension is the cervical canal, which is filled with a dense and protective mucus plug. Despite its central role in separating the vaginal from the intrauterine tract, the barrier properties of cervical mucus have not been studied in preterm birth. Methods and Findings: To study the protective function of the cervical mucus in preterm birth we performed a pilot case-control study to measure the viscoelasticity and permeability properties of mucus obtained from pregnant women at high-risk and low-risk for preterm birth. Using extensional and shear rheology we found that cervical mucus from women at high-risk for preterm birth was more extensible and forms significantly weaker gels compared to cervical mucus from women at low-risk of preterm birth. Moreover, permeability measurements using fluorescent microbeads show that high-risk mucus was more permeable compared with low-risk mucus. Conclusions: Our findings suggest that critical biophysical barrier properties of cervical mucus in women at high-risk for preterm birth are compromised compared to women with healthy pregnancy. We hypothesize that impaired barrier properties of cervical mucus could contribute to increased rates of intrauterine infection seen in women with preterm birth. We furthermore suggest that a robust association of spinnbarkeit and preterm birth could be an effectively exploited biomarker for preterm birth prediction.Massachusetts Institute of Technology. Charles E. Reed Faculty Initiative FundBurroughs Wellcome Fund (Preterm Birth Research Grant)National Science Foundation (U.S.). Graduate Research Fellowship Progra

Feasibility of polymer-drug conjugates for non-cancer applications

Polymer-drug conjugates have been intensely studied in the context of improving cancer chemotherapy and yet the only polymer-drug conjugate on the market (MovantikÒ) has a different therapeutic application (relieving opioid-induced constipation). In parallel, a number of studies have recently been published proposing the use of this approach for treating diseases other than cancer. In this commentary, we analyse the many and very diverse applications that have been proposed for polymer-drug conjugates (ranging from inflammation, to cardiovascular diseases) and the rationales underpinning them. We also highlight key design features to be considered when applying polymer-drug conjugates to these new therapeutic areas