Lifen Zhang

Correction for ‘Enhanced DNA release from disulfide-containing layered nanocomplexes by heparin-electrostatic competition’ by Zhenzhen Chen et al., J. Mater. Chem. B, 2015, 3, 225–237, https://doi.org/10.1039/c4tb01113a.

Although some modifications of polyethyleneimine (PEI) properties have been explored to balance the transfection efficiency and cytotoxicity, its successful plasmid delivery in vitro and in vivo to realize its true therapeutic potentials remains a major challenge, mainly due to intracellular trafficking barriers. Herein, we present a delivery nanocarrier Pluronic-PEI-SS by conjugating reducible disulfide-linked PEI (PEI-SS) to biocompatible Pluronic for enhanced DNA delivery and transfection efficiency in vitro and in vivo. Pluronic-PEI-SS strongly condensed plasmid DNA to low positively charged nanocomplexes, exhibited good stability against deoxyribonuclease I digestion, and tended to be easily degraded in the presence of reducing agent 1,4-dithiothreitol. The in vitro transfection of the complex Pluronic-PEI-SS/DNA into HeLa and 293T cells resulted in lower cytotoxicity as well as significantly higher cellular uptake, nucleus transfection, and gene expression than Pluronic-PEI (25 kDa), PEI-SS, and PEI 25 kDa given alone. Furthermore, the in vivo transfection study demonstrated that Pluronic-PEI-SS/DNA complexes induced a higher enrichment than the commercial PEI/DNA complex in the tumor, indicating their potential application as biocompatible vector in gene delivery.

Cancer stem cells (CSCs) are responsible for cancer drug resistance with high expression of ABCG2, which pumps the internalized chemotherapeutic out to escape drug-induced cytotoxicity. Here, we established a functionalized mesoporous silica nanoparticle (MSN) system to deliver shABCG2 and doxorubicin (Dox) synergistically. With excellent cell uptake and endosomal escape capacities, the dual-delivery carriers internalized shABCG2 and Dox into CSCs efficiently. ABCG2 depletion increased intracellular and intranuclear Dox enrichment, drove vigorous Dox-induced cell death, and impaired the self-renewal of CSCs. Additionally, the nanoparticles eliminated tumors efficiently and reduced tumor initiation by CSCs in vivo, with negligible side effects. Our findings suggest that well-designed delivery systems for conventional chemotherapeutic agents are promising for CSC therapy.

PH responsive charge-reversible GO–PEI–PEG/DOX/CS-Aco/PEI/shABCG2 nanocomplexes for efficient intracellular DOX and shABCG2 co-delivery.

Polycationic vectors are often used to deliver DNA for cancer therapies, but their inefficiency in releasing DNA from the polyplexes after endosomal escape limits DNA transcription and their efficient application in vivo. In this study, DNA/PEI polyplexes were cross-linked by a reduction-sensitive disulfide bond and then further complexed with electrostatic competitive heparin (HP) and hyaluronidase (HAase)-sensitive hyaluronate (HA) to obtain DNA/PEIS/HA–HP (DPSHA–HP). DPSHA–HP was stable in an extracellular environment (pH = 7.4) and degraded by HAase after targeted HA receptor CD44-mediated cell endocytosis, causing the outer shielding of the nanocomplex to loosen. The resulting partially exposed disulfide-linked DNA/PEI nanocomplexes efficiently ruptured the endosome, facilitating the cleavage of disulfide bonds and the release of DNA/PEI polyplexes into the cytoplasm, where DNA release from the polyplexes was remarkably enhanced due to strong electrostatic competition of HP with PEI. Consequently, DPSHA–HP exhibited excellent DNA transfection of the target cells, better than disulfide cross-linked DNA/PEI (25 kDa) and DNA/PEIS/HA. Moreover, these novel layered nanocomplexes have high efficiency in down-regulating B-cell-specific Moloney murine leukemia virus insertion site 1 (Bmi-1) and exhibit significant inhibition of tumor formation with minimal toxicity in a mouse tumor model.

Polycationic vectors have been used to deliver short hairpin RNAs (shRNAs) to knock-down genes for cancer therapies, but their inefficiency in lysosomal escape and shRNA release causes their low gene transcription efficiency. Herein, a three-layered polyethyleneimine (PEI)-coated gold nanocomplex interlaid with a pH-responsive charge-reversible chitosan-aconitic anhydride (CS-Aco) is constructed: a Au-PEI/CS-Aco/PEI/shRNA nanoparticle. The negatively charged CS-Aco hydrolyzes into positively charged CS in lysosomes, causing the nanocomposite to disassemble. The released Au-PEI nanoparticles efficiently rupture the lysosomes and thus release the PEI/shRNA polyplexes into cytoplasm, where they quickly disassociate because the PEI chains are short (1.2 kDa). As a consequence, the nanocomplexes display higher shRNA delivery efficiency than the 25 kDa PEI, and efficiently deliver shABCG2 to tumors and markedly silence ABCG2 expression, which sensitizes HepG2 cells to the drugs with minimal toxicity.

To improve the circulation time and transfection efficiency of the polyplexes used in gene delivery, a series of Pluronic®/Pluronic®F127–PEI–SS/pDNA complexes (PFPS/pDNA), based on the addition of different kinds of Pluronics® to the reducible disulfide‐bonds‐containing Pluronic®F127–PEI–SS/pDNA (FPS/pDNA) polyplexes, was prepared and evaluated in Bcap and Hela cells in vitro and in vivo. The addition of Pluronics® with molecular weights and hydrophilic–lipophilic balance (HLBs) different from that in the FPS/pDNA complex resulted in five PFPS(1–5)/pDNA complexes, and the correlation between the structure of the free Pluronic® and the properties of the PFPS/pDNA complexes was investigated. The addition of Pluronics® resulted in slightly larger or same‐sized nanoparticles of PFPS/pDNA at a constant N/P ratio. The PFPS copolymer displayed strong stability against DNase I digestion and serum degradation. PFPS‐4 containing added Pluronic® L35, with an intermediate HLB of 19, showed a much higher transfection efficiency and less cytotoxicity than FPS or PEI‐25 kDa in vitro. PFPS‐4 also exhibited a considerably longer blood circulation time than FPS or PEI‐25 kDa in vivo in mice, indicating that the addition of an intermediate Pluronic® can enhance the transfection efficiency of gene delivery systems. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 102B: 1268–1276, 2014.

Peer reviewed article authored by (Zhang L, Chen Z, Li Y). Read article or submit your manuscript for publishing.