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

Dual Responsiveness of a Tunable Thermosensitive Polypeptide

The temperature- and pH-dependent solubility of poly(γ-propargyl l-glutamate) (PPLG) functionalized through a copper-catalyzed 1,3-cycloaddition reaction between an alkyne and an azide can be tuned with precision over a broad range of conditions by varying the ratio of substitution of short oligo(ethylene glycol) and diisopropylamine side groups.National Institutes of Health (U.S.) (NIH Biomechanics Training Grant)National Institutes of Health (U.S.) (NIH R01 EB010246-03)National Science Foundation (U.S.) (NSF DMR Grant Number 0705234)National Institutes of Health (U.S.) (grant U54-CA112967)United States. Environmental Protection Agency (EPA STAR fellowship

Dual Responsiveness of a Tunable Thermosensitive Polypeptide

The temperature- and pH-dependent solubility of poly­(γ-propargyl l-glutamate) (PPLG) functionalized through a copper-catalyzed 1,3-cycloaddition reaction between an alkyne and an azide can be tuned with precision over a broad range of conditions by varying the ratio of substitution of short oligo­(ethylene glycol) and diisopropylamine side groups

Multimodal Switching of Conformation and Solubility in Homocysteine Derived Polypeptides

We report the design and synthesis of poly(S-alkyl-L-homocysteine)s, which were found to be a new class of readily prepared, multiresponsive polymers that possess the unprecedented ability to respond in different ways to different stimuli, either through a change in chain conformation or in water solubility. The responsive properties of these materials are also effected under mild conditions and are completely reversible for all pathways. The key components of these polymers are the incorporation of water solubilizing alkyl functional groups that are integrated with precisely positioned, multiresponsive thioether linkages. This promising system allows multimodal switching of polypeptide properties to obtain desirable features, such as coupled responses to multiple external inputs