Polymersomes

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

Polymersomes: From controlled release to anti-cancer

Self-assemblies of amphiphilic block copolymers are helping to define an emerging, and rapidly metamorphosing, class of novel environmentally sensitive drug delivery systems. This thesis explores the controlled release and drug delivery potential of degradable, diblock copolymer vesicles, polymersomes. This is a systematic presentation of initial physical-chemical characterization of spontaneously self-assembled bilayer vesicles; followed by details on passive uptake of these neutral carriers by cancer cells, ‘macro’-surfactant generation and escape from endolysosomal barriers, and intracellular delivery of cytotoxic drugs to their intracellular targets. Since the final assessment of all drug delivery vehicles is its vivo efficacy, we also show promising initial combination therapy of drug-loaded polymersomes in xenograft model of breast cancer. This in vivo efficacy was contingent upon prolonged circulation and passive residence in the leaky tumor environment. In the end, with an effort towards active tumor targeting, we isolated anti-CD47 ligands to selectively target and trigger apoptosis in selective CD47 expressing epithelial cancers

Polymersomes: From controlled release to anti-cancer

Self-assemblies of amphiphilic block copolymers are helping to define an emerging, and rapidly metamorphosing, class of novel environmentally sensitive drug delivery systems. This thesis explores the controlled release and drug delivery potential of degradable, diblock copolymer vesicles, polymersomes. This is a systematic presentation of initial physical-chemical characterization of spontaneously self-assembled bilayer vesicles; followed by details on passive uptake of these neutral carriers by cancer cells, ‘macro’-surfactant generation and escape from endolysosomal barriers, and intracellular delivery of cytotoxic drugs to their intracellular targets. Since the final assessment of all drug delivery vehicles is its vivo efficacy, we also show promising initial combination therapy of drug-loaded polymersomes in xenograft model of breast cancer. This in vivo efficacy was contingent upon prolonged circulation and passive residence in the leaky tumor environment. In the end, with an effort towards active tumor targeting, we isolated anti-CD47 ligands to selectively target and trigger apoptosis in selective CD47 expressing epithelial cancers

A PP4-phosphatase complex dephosphorylates γ-H2AX generated during DNA replication

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

p16(INK4a) translation suppressed by miR-24

Background: Expression of the tumor suppressor p16 INK4a increases during aging and replicative senescence. Methodology/Principal Findings: Here, 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 39-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/Significance: Together, our results suggest that miR-24 represses the initiation and elongation phases of p16 translation