PEG–Polypeptide Block Copolymers as pH-Responsive Endosome-Solubilizing Drug Nanocarriers

Herein we report the potential of click chemistry-modified polypeptide-based block copolymers for the facile fabrication of pH-sensitive nanoscale drug delivery systems. PEG–polypeptide copolymers with pendant amine chains were synthesized by combining N-carboxyanhydride-based ring-opening polymerization with post-functionalization using azide–alkyne cycloaddition. The synthesized block copolymers contain a polypeptide block with amine-functional side groups and were found to self-assemble into stable polymersomes and disassemble in a pH-responsive manner under a range of biologically relevant conditions. The self-assembly of these block copolymers yields nanometer-scale vesicular structures that are able to encapsulate hydrophilic cytotoxic agents like doxorubicin at physiological pH but that fall apart spontaneously at endosomal pH levels after cellular uptake. When drug-encapsulated copolymer assemblies were delivered systemically, significant levels of tumor accumulation were achieved, with efficacy against the triple-negative breast cancer cell line, MDA-MB-468, and suppression of tumor growth in an in vivo mouse model.Novartis Institutes of Biomedical ResearchNational Institutes of Health (U.S.) (Centers for Cancer Nanotechnology Excellence Grant P30 CA14051)National Institutes of Health (U.S.) (Centers for Cancer Nanotechnology Excellence Grant 5 U54 CA151884-02)National Science Foundation (U.S.). Graduate Research FellowshipNatural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship

Impact of Optimized Breastfeeding on the Costs of Necrotizing Enterocolitis in Extremely Low Birthweight Infants

To estimate risk of NEC for ELBW infants as a function of preterm formula and maternal milk (MM) intake and calculate the impact of suboptimal feeding on NEC incidence and costs

Spinal Angiolipomas: A Puzzling Case and Review of a Rare Entity

Patients with spinal epidural abscesses (SEAs) may have a variable presentation. Such an infection has a typical appearance on magnetic resonance imaging (MRI) and enhances with gadolinium. We present a case that was a diagnostic challenge where pre- and intra-operative findings resulted in conflicting impressions. The mimicker was a spinal angiolipoma (SAL). The authors then provide a thorough review of this rare spinal neoplasm. A 55-year-old man presented with back pain, paresis, paresthesia, and urinary retention. MRI was indicative of a longitudinal epidural thoracic mass with a signal homogeneous to nearby fat, curvilinear vessels, and lack of enhancement. Although at emergent surgery, the lesion was found to contain abundant purulent material. Microbiology was positive for methicillin-resistant Staphylococcus aureus and consistent with SEA without evidence of neoplasia. While the imaging features were suggestive of an angiolipoma, the findings at surgery made SEA more likely, which were validated histopathologically. The diagnosis of SEA is often clear-cut, and the literature has reported only a few instances in which it masqueraded as another process such as lymphoma or myelitis. The case highlights SEA masquerading as an angiolipoma, and further demonstrates to clinicians that obtaining tissue diagnosis plays a crucial role diagnostically and therapeutically. SALs, on the other hand, are slow-growing tumors that can be infiltrating or noninfiltrating. They typically present with chronic symptoms and T1-MRI shows an inhomogeneous picture. Complete surgical excision is standard of care and patients tend to do well afterward

Development and Application of the Metalloprotease Activity Multiplexed Bead-Based Immunoassay (MAMBI)

Metalloproteinases (MMPs) are zinc-dependent endopeptidases that cleave various proteins to regulate normal and diseased cellular functions, and as such, they play significant roles in human tissue development, homeostasis, and the pathogenesis of many diseases, including cancers, endometriosis, arthritis, etc. Most MMPs are produced as zymogenic latent enzymes that must be cleaved to activate their catalytic regions, and localized endogenous protein inhibitors further regulate activity. Accordingly, they operate within recursive networks to degrade extracellular matrix proteins and regulate cell signaling by cleaving growth factors and receptors at the cell surface and in the local pericellular environment. Thus, high-resolution information about the concentrations of specific active MMPs, revealing their intricate regulatory networks, may improve disease diagnosis and treatment. Here, we introduce a new and readily mastered method for measuring MMP activities in a multiplex fashion. We integrate aspects of activity-based enzyme labeling with commercial high-throughput, multiplexed protein quantification to yield the metalloproteinase activity multiplexed bead-based immunoassay (MAMBI). Assays of recombinant active MMP-1, -2, -3, -7, -8, -9, -12, and -13 establish the sensitivity and selectivity of MAMBI detection. Levels of active native MMPs are similarly characterized in conditioned cell culture medium, menstrual effluent, and uterine tissue. In a single MAMBI (5 μL), we achieve sensitivities equal to those from leading single-plex MMP activity detection strategies (e.g., 10-15 M for MMP-1). We also demonstrate high-throughput inhibitor screening via the MAMBI approach in complex, patient-derived samples.National Institutes of Health (Grant R01 EB010246