Endosomal escape is a bottleneck in the efficient delivery of therapeutics using nanoparticles; therefore understanding how this property can be optimized is important for achieving better therapeutic outcomes. It has been demonstrated that pH-responsive nanoparticles (pHlexi nanoparticles) have potential to achieve effective escape from the endosomal compartments of the cell. In this paper a library of five pHlexi particles with tunable disassembly pH were synthesized by combining poly(ethylene glycol)-b-poly(2-(diethylamino)ethyl methacrylate) (PEG-b-PDEAEMA) with random copolymers of 2-(diethylamino)ethyl methacrylate and 2-(diisopropylamino)ethyl methacrylate. A series of cellular studies were conducted to investigate the effect of particle composition on in vitro behavior. Endosomal escape was probed using a calcein escape assay in NIH/3T3 fibroblast cells, demonstrating endosomal escape increased with increasing particle concentration. Interestingly, it was shown that endosomal escape was most efficient with particles that disassemble at high (pH 7.2) or low (pH 4.9) pH, with particles that disassemble between pH 5.8 and 6.6 inducing decreased levels of endosomal escape. This change in endosomal escape behavior suggests particles can induce escape by different pathways. The results show that tuning the core component of pHlexi particles can improve the effectiveness of endosomal escape capabilities and thus their ability to act as effective delivery systems.

The effective escape of nanocarriers from endosomal compartments of the cell remains a major hurdle in nanomedicine. The endosomal escape of pH-responsive, self-assembled, dual component particles based on poly[2-(diethylamino)ethyl methacrylate)(PDEAEMA) and poly(ethylene glycol)-b-poly[2-(diethylamino)ethyl methacrylate) (PEG-b-PDEAEMA) has been recently reported. Herein, we report that polymer molecular weight (M ) can be used to tune endosomal escape of nanoparticle delivery systems. PDEAEMA of M 7 kDa, 27 kDa, 56 kDa and 106 kDa was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization and co-assembled with PEG-b-PDEAEMA (16 kDa) via nanoprecipitation. All particles had similar size, displayed pH-responsive behaviour, and low toxicity regardless of molecular weight. Ovalbumin was loaded in the particles to demonstrate loading and release capabilities and as a marker to study internalization and endosomal escape. Association and endosomal escape was found to depend on molecular weight, with enhanced escape observed for high M PDEAEMA: 42% of cells with particle induced endosomal escape for 106 kDa nanoparticles, compared to minimal escape for 7 kDa particles. The results show that a simple variation in molecular weight can enhance the endosomal escape of polymeric carriers, and thus improve their effectiveness for intracellular delivery of therapeutics.

Controlling the rate of hydrolysis of polymer conjugates is of paramount importance for the timely and precise delivery of drugs, corrosion inhibitors, healing agents, and phytosanitary products. Thioether ester groups as cleavable linkages are interesting because they can be easily synthesized via efficient thiol–ene reactions. We demonstrate here that the hydrolysis rate and selectivity of thioether ester groups can be tuned by several orders of magnitude by insertion of substituent groups. Small molecules and polymers are prepared with substituents, allowing for a long sustained and selective release of active molecules such as corrosion inhibitors. This design is applied for preparing coatings for metals which display an excellent anticorrosion performance.

Histogram deconvolution flow cytometry enables improved quantification of nanomaterial-cell interactions. The algorithm identifies the positive cells in highly overlapped populations and calculates the fluorescence intensity of the positive population. This technique performs better than commercially available methods with the additional benefit of visualizing the output.

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