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Kang H.C.,University of Utah | Kang H.-J.,Kyung Hee University | Bae Y.H.,University of Utah | Bae Y.H.,Utah Inha Drug Delivery Systems and Advanced Therapeutics Research Center
Biomaterials | Year: 2011

To improve transfection efficiency and reduce the cytotoxicity of polymeric gene vectors, reducible polycations (RPC) were synthesized from low molecular weight (MW) branched polyethyleneimine (bPEI) via thiolation and oxidation. RPC (RPC-bPEI0.8 kDa) possessed MW of 5 kDa-80 kDa, and 50%-70% of the original proton buffering capacity of bPEI0.8 kDa was preserved in the final product. The cytotoxicity of RPC-bPEI0.8 kDa was 8-19 times less than that of the gold standard of polymeric transfection reagents, bPEI25 kDa. Although bPEI0.8 kDa exhibited poor gene condensing capacities (∼2 μm at a weight ratio (WR) of 40), RPC-bPEI0.8 kDa effectively condensed plasmid DNA (pDNA) at a WR of 2. Moreover, RPC-bPEI0.8 kDa/pDNA (WR ≥2) formed 100-200 nm-sized particles with positively charged surfaces (20-35 mV). In addition, the results of the present study indicated that thiol/polyanions triggered the release of pDNA from RPC-bPEI0.8 kDa/pDNA via the fragmentation of RPC-bPEI0.8 kDa and ion-exchange. With negligible polyplex-mediated cytotoxicity, the transfection efficiencies of RPC-bPEI0.8 kDa/pDNA were approximately 1200-1500-fold greater than that of bPEI0.8 kDa/pDNA and were equivalent or superior (∼7-fold) to that of bPEI25 kDa/pDNA. Interestingly, the distribution of high MW RPC-bPEI0.8 kDa/pDNA in the nucleus of the cell was higher than that of low MW RPC-bPEI0.8 kDa/pDNA. Thus, the results of the present study suggest that RPC-bPEI0.8 kDa has the potential to effectively deliver genetic materials with lower levels of toxicity. © 2010 Elsevier Ltd. Source


Tian L.,University of Utah | Bae Y.H.,University of Utah | Bae Y.H.,Utah Inha Drug Delivery Systems and Advanced Therapeutics Research Center
Colloids and Surfaces B: Biointerfaces | Year: 2012

Tumors have been a highlight in the research of nanomedicine for decades. Despite all the efforts in the decoration of the nano systems, tumor specific targeting is still an issue due to the heterogeneous nature of tumors. Hypoxia is frequently observed in solid tumors. The consequent acidification of tumor extracellular matrices may bring new insight to tumor targeting. In this review, we present the polymeric nano systems that target tumor extracellular pH (pH e). © 2011 Elsevier B.V. Source


Mishra D.,University of Utah | Kang H.C.,University of Utah | Bae Y.H.,University of Utah | Bae Y.H.,Utah Inha Drug Delivery Systems and Advanced Therapeutics Research Center
Biomaterials | Year: 2011

This study investigated the potential of creating a charged polymeric micelle-based nucleic acid delivery system that could easily be reconstituted by the addition of water. (PLGA36kDa)2-b-bPEI25kDa (PLGA MW 36 kDa, bPEI Mw 25 kDa, PLGA:bPEI block ratio = 2) was synthesized and used to prepare cationic micelles. The copolymer retained proton-buffering capability from the bPEI block within the endosomal pH range. Micelle/pDNA complexes retained their particle size (100-150 nm) and surface charge (30-40 mV) following reconstitution. It was found that adding a small amount of low molecular weight bPEI (1.8 kDa) completely shielded pDNA in the micelle/pDNA complexes and enhanced transfection efficiency 50-100 fold for both fresh and reconstituted complexes without affecting complex size. Transfection efficiency for " reconstituted" micelle/pDNA/bPEI1.8kDa (WR 1) complexes was 16-fold higher than its " fresh" counterpart. Although transfection levels achieved using " reconstituted" micelle/pDNA/bPEI1.8kDa complexes were 3.6-fold lower than control " fresh" bPEI25kDa/pDNA (N/P 5) complexes, transfection levels were 39-fold higher than " reconstituted" bPEI25kDa/pDNA (N/P 5) complexes. The micelle/pDNA/bPEI1.8kDa system showed very low cytotoxicity in MCF7 cells even with pDNA doses up to 20 μg, and transfection levels increased linearly with increasing pDNA dose. These results indicate that this PLGA-b-bPEI polymeric micelle-based system is well suited as a reconstitutable gene delivery system, and has high potential for use as a delivery system for gene therapy applications. © 2011 Elsevier Ltd. Source


Park H.,University of Utah | Nichols J.W.,University of Utah | Kang H.C.,Catholic University of Korea | Bae Y.H.,University of Utah | Bae Y.H.,Utah Inha Drug Delivery Systems and Advanced Therapeutics Research Center
Polymers for Advanced Technologies | Year: 2014

Bioreducible polymers have attracted intense attention as a gene carrier due to their low cell toxicity compared to other polymer-based gene delivery counterparts. We have synthesized low-molecular-weight spermine-originated bioreducible polyspermines (BPSs) to serve as a plasmid DNA (pDNA) carrier complex with low cytotoxicity and high transfection efficiency. Spermine is biogenic and ubiquitous and is of benefit to nucleic acid delivery in many respects. We found that the BPSs formed nano-sized, positively charged complexes with pDNA. In addition, they showed a high buffering capacity from the polyamine-based proton sponge effect which facilitates endosomal escape. With degradable characteristics in thiol-rich (intracellular) environments, BPSs exhibited significantly improved cell viability and suitable transfection efficiency across several cell lines in comparison to linear and branched polyethylenimine, the current gold standards of non-viral gene carriers. BPSs appear to be promising polymers for use as effective pDNA carriers. © 2014 John Wiley & Sons, Ltd. Source


Kang H.C.,Catholic University of Korea | Cho H.,Catholic University of Korea | Bae Y.H.,University of Utah | Bae Y.H.,Utah Inha Drug Delivery Systems and Advanced Therapeutics Research Center
Molecular Pharmaceutics | Year: 2015

Double helix nucleic acids were used as a combination drug carrier for doxorubicin (DOX), which physically intercalates with DNA double helices, and cisplatin (CDDP), which binds to DNA without an alkylation reaction. DNA interacting with DOX, CDDP, or both was complexed with positively charged, endosomolytic polymers. Compared with the free drug, the polyplexes (100-170 nm in size) delivered more drug into the cytosol and the nucleus and demonstrated similar or superior (up to a 7-fold increase) in vitro cell-killing activity. Additionally, the gene expression activities of most of the chemical drug-loaded plasmid DNA (pDNA) polyplexes were not impaired by the physical interactions between the nucleic acid and DOX/CDDP. When a model reporter pDNA (luciferase) was employed, it expressed luciferase protein at 0.7- to 1.4-fold the amount expressed by the polyplex with no bound drugs (a control), which indicated the fast translocation of the intercalated or bound drugs from the "carrier DNA" to the "nuclear DNA" of target cells. The proposed concept may offer the possibility of versatile combination therapies of genetic materials and small molecule drugs that bind to nucleic acids to treat various diseases. © 2015 American Chemical Society. Source

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