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A nanoparticle formulation that selectively transfects metastatic tumors in mice.
|Title||A nanoparticle formulation that selectively transfects metastatic tumors in mice.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Yang J, Hendricks W, Liu G, McCaffery MJ, Kinzler KW, Huso DL, Vogelstein B, Zhou S|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Date Published||2013 Sep 3|
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.
|Alternate Journal||Proc. Natl. Acad. Sci. U.S.A.|