Systemic fungal infections are an increasingly prevalent health problem, especially among immunocompromised patients. Antifungal drug development lags far behind in comparison to other types of antimicrobial drugs. Current commercially available antifungals are limited by their insufficient potency, side effects, drug-drug interactions, developing drug-resistance, and narrow formulation options. Here, we report the preparation and evaluation of two novel PEG amide conjugates of amphotericin B (AMB (1)): AB1 (4) and AM2 (5). These compounds are nonlabile, they are prepared in only two and three synthetic steps, respectively, and they show antifungal activity against a wide range of clinical fungal isolates. Their toxicity is significantly lower, and their water solubility is up to 5000-fold higher than that of AMB (1). In vivo efficacy studies in a mouse model of systemic candidiasis showed that AM2 (5) successfully cured all the mice at concentrations above 3.5 mg/kg body weight. In conclusion, these properties make AB1 (4) and AM2 (5) promising candidates for clinical use.

Complete tumor removal during surgery has a great impact on patient survival. To that end, the surgeon should detect the tumor, remove it and validate that there are no residual cancer cells left behind. Residual cells at the incision margin of the tissue removed during surgery are associated with tumor recurrence and poor prognosis for the patient. In order to remove the tumor tissue completely with minimal collateral damage to healthy tissue, there is a need for diagnostic tools that will differentiate between the tumor and its normal surroundings.Methods: We designed, synthesized and characterized three novel polymeric Turn-ON probes that will be activated at the tumor site by cysteine cathepsins that are highly expressed in multiple tumor types. Utilizing orthotopic breast cancer and melanoma models, which spontaneously metastasize to the brain, we studied the kinetics of our polymeric Turn-ON nano-probes.Results: To date, numerous low molecular weight cathepsin-sensitive substrates have been reported, however, most of them suffer from rapid clearance and reduced signal shortly after administration. Here, we show an improved tumor-to-background ratio upon activation of our Turn-ON probes by cathepsins. The signal obtained from the tumor was stable and delineated the tumor boundaries during the whole surgical procedure, enabling accurate resection.Conclusions: Our findings show that the control groups of tumor-bearing mice, which underwent either standard surgery under white light only or under the fluorescence guidance of the commercially-available imaging agents ProSense® 680 or 5-aminolevulinic acid (5-ALA), survived for less time and suffered from tumor recurrence earlier than the group that underwent image-guided surgery (IGS) using our Turn-ON probes. Our "smart" polymeric probes can potentially assist surgeons' decision in real-time during surgery regarding the tumor margins needed to be removed, leading to improved patient outcome.

We disclose a hypervalent iodine mediated α-alkylative umpolung reaction of carbonyl compounds with dialkylzinc as the alkyl source. The reaction is applicable to all common classes of ketones including 1,3-dicarbonyl compounds and regular ketones via their lithium enolates. The α-alkylated carbonyl products are formed in up to 93% yield. An ionic mechanism is inferred based on meticulous analysis, NMR studies, trapping and crossover experiments, and computational studies.

TEMPO catalyzes the direct oxidation of aldehydes to mixed anhydrides in the presence of a carboxylic acid. The anhydrides can be converted in situ to esters, secondary, tertiary or Weinreb amides in high yield. Oxidation of the aldehyde directly to 2-propyl esters is also possible using only catalytic amounts of acid. The oxidation reactions are rapid and take place under mild conditions.

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Targeted therapies against cancer can relieve symptoms and induce remission; however, they often present limited duration of disease control, cause side effects, and may induce acquired resistance. Therefore, there is great motivation to develop a unique delivery system, targeted to the tumor, in which several active entities can be combined, the therapeutic index can be increased by reducing systemic exposure, and their synergistic activity can be enhanced. To meet these goals, the biocompatible and biodegradable poly(α,l‐glutamic acid) (PGA) is chosen as a nanocarrier that facilitates extravasation‐dependent tumor targeting delivery. The RAS/RAF/MEK/ERK pathway when aberrantly activated in melanoma, can lead to uncontrolled cell proliferation, induced invasion, and reduced apoptosis. Here, two drugs targeting this pathway are selected: a MEK1/2 inhibitor (selumetinib, SLM) and a modified BRAF inhibitor (modified dabrafenib, mDBF) that exhibit synergism in vitro. The combination of PGA conjugated to SLM and mDBF (PGA–SLM–mDBF) is synthesized and characterized. PGA–SLM–mDBF inhibits the proliferation of melanoma cells and decreases their migratory and sprouting abilities without inducing a hemolytic effect. Moreover, it exhibits superior antitumor activity in a mouse model of primary melanoma and prolonged survival at a lower dose than the free drugs.

RNA interference (RNAi) can contribute immensely to the area of personalized medicine by its ability to target any gene of interest. Nevertheless, its clinical use is limited by lack of efficient delivery systems. Polymer therapeutics can address many of the challenges encountered by the systemic delivery of RNAi, but suffer from inherent drawbacks such as polydispersity and batch to batch heterogeneity. These characteristics may have far-reaching consequences when dealing with therapeutic applications, as both the activity and the toxicity may be dependent on the length of the polymer chain. To investigate the consequences of polymers' heterogeneity, we have synthesized two batches of aminated poly(α)glutamate polymers (PGAamine), differing in their degree of polymerization, but not in the monomer units or their conjugation. Isothermal titration calorimetry study was conducted to define the binding affinity of these polymers with siRNA. Molecular dynamics simulation revealed that Short PGAamine:siRNA polyplexes exposed a higher amount of amine moieties to the surroundings compared to Long PGAamine. This resulted in a higher zeta potential, leading to faster degradation and diminished gene silencing. Altogether, our study highlights the importance of an adequate physico-chemical characterization to elucidate the structure-function-activity relationship, for further development of tailor-designed RNAi delivery vehicles.

2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO) catalyzes the direct oxidation of primary alkyl alcohols to symmetric esters at 1-2 mol% loadings. These rapid reactions take place at room temperature to afford the products in yields of 55-99%.