Polymersomes are self-assembled polymer shells composed of block copolymer amphiphiles. These synthetic amphiphiles have amphiphilicity similar to lipids, but they have much larger molecular weights, so for this reason--along with others reviewed here--comparisons of polymersomes with viral capsids composed of large polypeptide chains are highly appropriate. We summarize the wide range of polymers used to make polymersomes along with descriptions of physical properties such as stability and permeability. We also elaborate on emerging studies of in vivo stealthiness, programmed disassembly for controlled release, targeting in vitro, and tumor-shrinkage in vivo. Comparisons of polymersomes with viral capsids are shown to encompass and inspire many aspects of current designs.

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Polymersomes are self-assembled shells of amphiphilic block copolymers that are currently being developed by many groups for fundamental insights into the nature of self-assembled states as well as for a variety of potential applications. While recent reviews have highlighted distinctive properties - particularly stability - that are strongly influenced by both copolymer type and polymer molecular weight, here we first review some of the more recent developments in computational molecular dynamics (MD) schemes that lend insight into assembly. We then review polymersome loading, in vivo stealthiness, degradation-based disassembly for controlled release, and even tumor-shrinkage in vivo. Comparisons of polymersomes with viral capsids are shown to encompass and inspire many aspects of current designs.

Soft-tissue cells are surprisingly sensitive to the elasticity of their microenvironment, suggesting that traditional culture plastic and glass are less relevant to tissue regeneration and chemotherapeutics than might be achieved. Cells grown on gels that mimic the elasticity of tissue reveal a significant influence of matrix elasticity on adhesion, cytoskeletal organization, and even the differentiation of human adult derived stem cells. Cellular forces and feedback are keys to how cells feel their mechanical microenvironment, but detailed molecular mechanisms are still being elucidated. This review summarizes our initial findings for multipotent stem cells and also the elasticity-coupled effects of drugs on cancer cells and smooth muscle cells. The drugs include the contractility inhibitor blebbistatin, the proliferation inhibitor mitomycin C, an apoptotis-inducing antibody against CD47, and the translation inhibitor cycloheximide. The differential effects not only lend insight into mechano-sensing of the substrate by cells, but also have important implications for regeneration and molecular therapies.

Carrier-mediated delivery of drugs into the cytosol is often limited by either release from the carrier or release from an internalizing endolysosome. Here, loading, delivery, and cytosolic uptake of drug mixtures from degradable polymersomes are shown to exploit both the thick membrane of these block copolymer vesicles and their aqueous lumen as well as pH-triggered release within endolysosomes. Our initial in vivo studies demonstrate growth arrest and shrinkage of rapidly growing tumors after a single intravenous injection of polymersomes composed of poly(ethylene glycol)-polyester. Vesicles are shown to break down into membrane-lytic micelles within hours at 37 degrees C and low pH, although storage at 4 degrees C allows retention of drug for over a month. It is then shown that cell entry of the polymersomes into endolysosomes is followed by copolymer-induced endolysosomal rupture with release of cytotoxic drugs. Above a critical poration concentration (CCPC) that is easily achieved within endolysosomes and that scales with copolymer proportions and molecular weight, the copolymer micelles are seen to disrupt lipid membranes and thereby enhance drug activity. Neutral polymersomes and related macrosurfactant assemblies can thus create novel pathways within cells for controlled release and delivery.

Summary The histone H2A variant H2AX is rapidly phosphorylated in response to DNA double-stranded breaks to produce γ-H2AX. γ-H2AX stabilizes cell cycle checkpoint proteins and DNA repair factors at the break site. We previously found that the protein phosphatase PP2A is required to resolve γ-H2AX foci and complete DNA repair after exogenous DNA damage. Here we describe a three-protein PP4 phosphatase complex in mammalian cells, containing PP4C, PP4R2 and PP4R3β, that specifically dephosphorylates ATR-mediated γ-H2AX generated during DNA replication. PP4 efficiently dephosphorylates γ-H2AX within mononucleosomes in vitro. The effect of PP4 on γ-H2AX is independent of ATR and checkpoint kinase activity. When the PP4 complex is silenced, repair of DNA replication mediated breaks is inefficient, and cells are hypersensitive to DNA replication inhibitors, but not radiomimetic drugs. Therefore γ-H2AX elimination at DNA damage foci is required for DNA damage repair, but accomplishing this task involves distinct phosphatases with potentially overlapping roles.

BackgroundExpression of the tumor suppressor p16INK4a increases during aging and replicative senescence.Methodology/Principal FindingsHere, we report that the microRNA miR-24 suppresses p16 expression in human diploid fibroblasts and cervical carcinoma cells. Increased p16 expression with replicative senescence was associated with decreased levels of miR-24, a microRNA that was predicted to associate with the p16 mRNA coding and 3′-untranslated regions. Ectopic miR-24 overexpression reduced p16 protein but not p16 mRNA levels. Conversely, introduction of antisense (AS)-miR-24 blocked miR-24 expression and markedly enhanced p16 protein levels, p16 translation, and the production of EGFP-p16 reporter bearing the miR-24 target recognition sites.Conclusions/SignificanceTogether, our results suggest that miR-24 represses the initiation and elongation phases of p16 translation.