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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Kinzler, Kenneth W. Yang, Jian Liu, Guosheng Zhou, Shibin Mccaffery, J. Michael Vogelstein, Bert Hendricks, William Huso, David L. |
| Description | Author Affiliation: Yang J ( Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins, Baltimore, MD 21231, USA.); |
| Abstract | Nanoparticle gene therapy holds great promise for the treatment of malignant disease in light of the large number of potent, tumor-specific therapeutic payloads potentially available for delivery. To be effective, gene therapy vehicles must be able to deliver their therapeutic payloads to metastatic lesions after systemic administration. Here we describe nanoparticles comprised of a core of high molecular weight linear polyethylenimine (LPEI) complexed with DNA and surrounded by a shell of polyethyleneglycol-modified (PEGylated) low molecular weight LPEI. Compared with a state-of-the-art commercially available in vivo gene delivery formulation, i.v. delivery of the core/PEGylated shell (CPS) nanoparticles provided more than a 16,000-fold increase in the ratio of tumor to nontumor transfection. The vast majority of examined liver and lung metastases derived from a colorectal cancer cell line showed transgene expression after i.v. CPS injection in an animal model of metastasis. Histological examination of tissues from transfected mice revealed that the CPS nanoparticles selectively transfected neoplastic cells rather than stromal cells within primary and metastatic tumors. However, only a small fraction of neoplastic cells (<1%) expressed the transgene, and the extent of delivery varied with the tumor cell line, tumor site, and host mouse strain used. Our results demonstrate that these CPS nanoparticles offer substantial advantages over previously described formulations for in vivo nanoparticle gene therapeutics. At the same time, they illustrate that major increases in the effectiveness of such approaches are needed for utility in patients with metastatic cancer. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 36 |
| Volume Number | 110 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2013-09-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Genetic Therapy Luminescent Proteins Genetics Nanoparticles Administration & Dosage Neoplasms Therapy Transfection Animals Cell Line Cell Line, Tumor HCT116 Cells HT29 Cells Hep G2 Cells Chemistry Metabolism Mice Mice, Inbred BALB C Mice, Inbred NOD Mice, Knockout Mice, Nude Mice, SCID Microscopy, Confocal Microscopy, Electron, Transmission Ultrastructure Neoplasm Metastasis Pathology Polyethylene Glycols Polyethyleneimine Xenograft Model Antitumor Assays Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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