Dingcheng Zhu

Fusogenic Reactive Oxygen Species Triggered Charge‐Reversal Vector for Effective Gene Delivery

A novel fusogenic lipidic polyplex (FLPP) vector is designed to fuse with cell membranes, mimicking viropexis, and eject the polyplex into the cytosol, where the cationic polymer is subsequently oxidized by intracellular reactive oxygen species and converts to being negatively charged, efficiently releasing the DNA. The vector delivering suicide gene achieves significantly better inhibition of tumor growth than doxorubicin.

Nonviral cancer gene therapy: Delivery cascade and vector nanoproperty integration☆

&NA; Gene therapy represents a promising cancer treatment featuring high efficacy and limited side effects, but it is stymied by a lack of safe and efficient gene‐delivery vectors. Cationic polymers and lipid‐based nonviral gene vectors have many advantages and have been extensively explored for cancer gene delivery, but their low gene‐expression efficiencies relative to viral vectors limit their clinical translations. Great efforts have thus been devoted to developing new carrier materials and fabricating functional vectors aimed at improving gene expression, but the overall efficiencies are still more or less at the same level. This review analyzes the cancer gene‐delivery cascade and the barriers, the needed nanoproperties and the current strategies for overcoming these barriers, and outlines PEGylation, surface‐charge, size, and stability dilemmas in vector nanoproperties to efficiently accomplish the cancer gene‐delivery cascade. Stability, surface, and size transitions (3S Transitions) are proposed to resolve those dilemmas and strategies to realize these transitions are comprehensively summarized. The review concludes with a discussion of the future research directions to design high‐performance nonviral gene vectors. Graphical abstract Figure. No caption available.

Jumping the nuclear envelope barrier: Improving polyplex-mediated gene transfection efficiency by a selective CDK1 inhibitor RO-3306

Successful transfection of plasmid DNA (pDNA) requires intranuclear internalization of pDNA effectively and the nuclear envelope appears to be one of the critical intracellular barriers for polymer mediated pDNA delivery. Polyethylenimine (PEI), as the classic cationic polymer, compact the negatively charged pDNA tightly and make up stable polyplexes. The polyplexes are too large to enter the nuclear through nuclear pores and it is believed that the nuclear envelope breakdown in mitosis could facilitate the nuclear entry of polyplexes. To jump the nuclear envelope barrier, we used a selective and reversible CDK1 inhibitor RO-3306 to control the G2/M transition of the cell cycle and increased the proportion of mitotic cells which have disappeared nuclear envelope during transfection. Herein, we show that RO-3306 remarkably increases the transfection efficiency of PEI polyplexes through enhanced nuclear localization of PEI and pDNA. However, RO-3306 is less effective to the charge-reversal polymer poly[(2-acryloyl)ethyl(p-boronic acid benzyl)diethylammonium bromide] (B-PDEAEA) which responses to cellular stimuli and releases free pDNA in cytoplasm. Our findings not only offer new opportunities for improving non-viral based gene delivery but also provide theoretical support for the rational design of novel functional polymers for gene delivery. We also report current data showing that RO-3306 synergizes TRAIL gene induced apoptosis in cancer cells.

Gene Delivery: Fusogenic Reactive Oxygen Species Triggered Charge‐Reversal Vector for Effective Gene Delivery (Adv. Mater. 9/2016)

On page 1743, Y. Shen and co-workers describe the design of a novel fusogenic lipidic polyplex (FLPP) vector, which fuses with cell membranes, mimicking viropexis and ejecting the polyplex into the cytosol. There, the cationic polymer is oxidized by intracellular reaction oxygen species, becomes negatively charged, and releases DNA efficiently. This vector delivering suicide genes achieves significantly better inhibition of tumor growth than doxorubicin, making it a candidate for further study in gene therapy and cancer treatment.

Facile synthesis of semi-library of low charge density cationic polyesters from poly(alkylene maleate)s for efficient local gene delivery

Cationic polymers are one of the main non-viral vectors for gene therapy, but their applications are hindered by the toxicity and inefficient transfection, particularly in the presence of serum or other biological fluids. While rational design based on the current understanding of gene delivery process has produced various cationic polymers with improved overall transfection, high-throughput parallel synthesis of libraries of cationic polymers seems a more effective strategy to screen out efficacious polymers. Herein, we demonstrate a novel platform for parallel synthesis of low cationic charge-density polyesters for efficient gene delivery. Unsaturated polyester poly(alkylene maleate) (PAM) readily underwent Michael-addition reactions with various mercaptamines to produce polyester backbones with pendant amine groups, poly(alkylene maleate mercaptamine)s (PAMAs). Variations of the alkylenes in the backbone and the mercaptamines on the side chain produced PAMAs with tunable hydrophobicity and DNA-condensation ability, the key parameters dominating transfection efficiency of the resulting polymer/DNA complexes (polyplexes). A semi-library of such PAMAs was exampled from 7 alkylenes and 18 mercaptamines, from which a lead PAMA, G-1, synthesized from poly(1,4-phenylene bis(methylene) maleate) and N,N-dimethylcysteamine, showed remarkable transfection efficiency even in the presence of serum, owing to its efficient lysosome-circumventing cellular uptake. Furthermore, G-1 polyplexes efficiently delivered the suicide gene pTRAIL to intraperitoneal tumors and elicited effective anticancer activity.

Remotely controlled opening of delivery vehicles and release of cargo by external triggers

Tremendous efforts have been devoted to the development of future nanomedicines that can be specifically designed to incorporate responsive elements that undergo modification in structural properties upon external triggers. One potential use of such stimuli-responsive materials is to release encapsulated cargo upon excitation by an external trigger. Today, such stimuli-response materials allow for spatial and temporal tunability, which enables the controlled delivery of compounds in a specific and dose-dependent manner. This potentially is of great interest for medicine (e.g. allowing for remotely controlled drug delivery to cells, etc.). Among the different external exogenous and endogenous stimuli used to control the desired release, light and magnetic fields offer interesting possibilities, allowing defined, real time control of intracellular releases. In this review we highlight the use of stimuli-responsive controlled release systems that are able to respond to light and magnetic field triggers for controlling the release of encapsulated cargo inside cells. We discuss established approaches and technologies and describe prominent examples. Special attention is devoted towards polymer capsules and polymer vesicles as containers for encapsulated cargo molecules. The advantages and disadvantages of this methodology in both, in vitro and in vivo models are discussed. An overview of challenges associate with the successful translation of those stimuli-responsive materials towards future applications in the direction of potential clinical use is given.