Xiangrui Liu

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.

Esterase‐Activated Charge‐Reversal Polymer for Fibroblast‐Exempt Cancer Gene Therapy

Selective gene expression in tumors via responsive dissociation of polyplexes triggered by intracellular signals is demonstrated. An esterase-responsive charge-reversal polymer mediates selective gene expression in the cancer cells high in esterases over fibroblasts low in esterase activity. Its gene therapy with the TRAIL suicide gene effectively induces apoptosis of HeLa cells but does not activate fibroblasts to secrete WNT16B, enabling potent cancer gene therapy with few side effects.

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.

A Tumor-Specific Cascade Amplification Drug Release Nanoparticle for Overcoming Multidrug Resistance in Cancers

A cascade amplification release nanoparticle (CARN) is constructed by the coencapsulation of β-lapachone and a reactive-oxygen-species (ROS)-responsive doxorubicin (DOX) prodrug, BDOX, in polymeric nanoparticles. Releasing β-lapachone first from the CARNs selectively increases the ROS level in cancer cells via NAD(P)H:quinone oxidoreductase-1 (NQO1) catalysis, which induces the cascade amplification release of DOX and overcomes multidrug resistance (MDR) in cancer cells, producing a remarkably improved therapeutic efficacy against MDR tumors with minimal side effects.

Amphiphilic drugs as surfactants to fabricate excipient-free stable nanodispersions of hydrophobic drugs for cancer chemotherapy.

Nanoformulations have been extensively explored to deliver water-insoluble drugs, but they generally use exotic new materials, for instance, amphiphilic block copolymers, which must first go through extensively clinical trials and be approved as drug excipients before any clinical uses. We hypothesize that using clinical amphiphilic drugs as surfactants to self-assemble with and thus solubilize hydrophobic drugs will lead to readily translational nanoformulations as they contain no new excipients. Herein, we show the first example of such excipient-free nanodispersions using an amphiphilic anti-tumor drug, irinotecan hydrochloride (CPT11). CPT11 self-assembles with its insoluble active parent drug, 7-ethyl-10-hydroxy camptothecin (SN38), into stable and water-dispersible nanoparticles, increasing SN38s water solubility by thousands of times up to 25 mg/mL with a loading efficiency close to 100%. The versatility of this approach is also demonstrated by fabricating nanodispersions of CPT11 with other water-insoluble drugs including paclitaxel (PTX) and camptothecin (CPT). These nanodispersions have much increased bioavailability and thereby improved anti-cancer activities. Thus, this strategy, using clinically proven amphiphilic drugs as excipients to fabricate nanodispersions, avoids new materials and makes readily translational nanoformulations of hydrophobic drugs.

Facile synthesis of size-tunable stable nanoparticles via click reaction for cancer drug delivery

The stability and size of polymeric nanoparticles are two of the most important parameters determining their pharmacokinetics and tumor/drug accumulation efficiency in cancer-drug delivery. Herein, we report a facile one-pot synthesis of crosslinked nanoparticles (CNPs) with tunable sizes and polyethylene glycol (PEG) shells via click reactions. Simply by adjusting the contents of the macromonomer (PEG monoacrylate) in its reaction with ethylene diacrylate and a crosslinker containing hexa-thiols groups, the sizes of the resulting PEGylated crosslinked nanoparticles could be easily tuned from 10 to 90 nm. These nanoparticle cores could encapsulate hydrophobic drugs such as doxorubicin (DOX), and the unreacted thiol and acrylate groups could be used for drug conjugation or labeling. Thus, the nanoparticles provide a multifunctional platform for drug delivery. In vivo studies showed that the larger nanoparticles (about 83.7 nm) had a much longer blood-circulation time and better tumor-targeting efficiency. One of our most important findings was that the drug encapsulated in the crosslinked nanoparticles, even though little was released at pH 7.4 under in vitro conditions, had much faster blood clearance than the nanoparticles’ carrier, suggesting that drug release in the bloodstream was significant.

Structural modifications due to interface chemistry at metal-nitride interfaces

Based on accurate first principles density functional theory (DFT) calculations, an unusual phenomenon of interfacial structural modifications, due to the interface chemistry influence is identified at two metal-nitride interfaces with strong metal-nitrogen affinity, Al/TiN {111} and Al/VN {111} interfaces. It is shown that at such interfaces, a faulted stacking structure is energetically preferred on the Al side of the interface. And both intrinsic and extrinsic stacking fault energies in the vicinity Al layers are negligibly small. However, such phenomenon does not occur in Pt/TiN and Pt/VN interfaces because of the weak Pt-N affinity. Corresponding to structural energies of metal-nitride interfaces, the linear elasticity analysis predicts characteristics of interfacial misfit dislocations at metal-nitride interfaces.

A non-cytotoxic dendrimer with innate and potent anticancer and anti-metastatic activities

The structural perfection and multivalency of dendrimers have made them useful for biodelivery and bioactivity via peripheral functionalization and the modulation of core-forming structures and dendrimer generations. Yet only few dendrimers have shown inherent therapeutic activity arising from their inner repeating units. Here, we report the synthesis and characterization of a polyacylthiourea dendrimer with inherent potent anticancer activity and the absence of cytotoxicity in mice. The poly(ethylene glycol)-functionalized fourth generation of the dendrimer, which can be efficiently synthesized from sequential click reactions of orthogonal monomers, displays low in vivo acute and subacute toxicities yet potently inhibits tumour growth and metastasis. The dendrimer’s in vivo anticancer activity arises from the depletion of bioavailable copper and the subsequent inhibition of angiogenesis and cellular proliferation. When compared with some clinically used cytotoxin drugs, the dendrimer exerts inherent anticancer activity via non-cytotoxic pathways and leads to higher therapeutic efficacy, yet without cytotoxin-induced side effects.A dendrimer that depletes bioavailable copper and leads to the suppression of tumour angiogenesis acts as a potent and non-cytotoxic anticancer therapeutic.

Dendrimers with the protocatechuic acid building block for anticancer drug delivery

Protocatechuic acid (3,4-dihydroxybenzoic acid; PCA) is a well-known antioxidant compound and a potential antitumor drug that is commonly found in fruits and vegetables. This article describes the development of novel biodegradable dendrimers that contain PCA as a building block. The structures of the dendrimers were characterized by nuclear magnetic resonance, gel permeation chromatography, and matrix-assisted laser-desorption ionization time-of-flight mass spectrometry. PCA dendrimers could serve as potential anticancer drugs and also as nanocarriers for anticancer drug delivery. PCA dendrimers can easily be loaded with hydrophobic drugs such as doxorubicin that benefit from the binding interaction between PCA and the drug. Doxorubicin-loaded PCA dendrimers exhibited pH and redox-dual responsive drug release in vitro. The antitumor effect of PCA dendrimers to which polyethylene glycol polymer chains have been attached and doxorubicin-loaded dendrimers was preliminarily evaluated both in vitro and in vivo.

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.