Abstract
The possibility of using gene therapy for the treatment of cancer is limited by the lack of safe, intravenously administered delivery systems able to selectively deliver therapeutic genes to tumors. In this study, we investigated if the conjugation of the polypropylenimine dendrimer to lactoferrin and lactoferricin, whose receptors are overexpressed on cancer cells, could result in a selective gene delivery to tumors and a subsequently enhanced therapeutic efficacy. The conjugation of lactoferrin and lactoferricin to the dendrimer significantly increased the gene expression in the tumor while decreasing the non-specific gene expression in the liver. Consequently, the intravenous administration of the targeted dendriplexes encoding TNFα led to the complete suppression of 60% of A431 tumors and up to 50% of B16-F10 tumors over one month. The treatment was well tolerated by the animals. These results suggest that these novel lactoferrin- and lactoferricin-bearing dendrimers are promising gene delivery systems for cancer therapy. From the Clinical EditorSpecific targeting of cancer cells should enhance the delivery of chemotherapeutic agents. This is especially true for gene delivery. In this article, the authors utilized a dendrimer-based system and conjugated this with lactoferrin and lactoferricin to deliver anti-tumor genes. The positive findings in animal studies should provide the basis for further clinical studies.
Highlights
The possibility of using gene therapy for the treatment of cancer is limited by the lack of safe, intravenously administered delivery systems able to selectively deliver therapeutic genes to tumors
We have recently demonstrated that the intravenous administration of this dendrimer conjugated to transferrin (Tf), whose receptors are overexpressed on cancer cells, resulted in gene expression mainly in the tumors after intravenous administration.[4]
Conjugation of lactoferrin and lactoferricin to DAB Lactoferrin (LF) and lactoferricin (LFC) were conjugated to generation 3- diaminobutyric polypropylenimine dendrimer (DAB) in a similar manner to that we previously reported for the preparation of other conjugates.[4,9,10,11,12]
Summary
The possibility of using gene therapy for the treatment of cancer is limited by the lack of safe, intravenously administered delivery systems able to selectively deliver therapeutic genes to tumors. We investigated if the conjugation of the polypropylenimine dendrimer to lactoferrin and lactoferricin, whose receptors are overexpressed on cancer cells, could result in a selective gene delivery to tumors and a subsequently enhanced therapeutic efficacy. The treatment was well tolerated by the animals These results suggest that these novel lactoferrin- and lactoferricin-bearing dendrimers are promising gene delivery systems for cancer therapy. Despite numerous advances in the field of cancer gene therapy, the use of therapeutic genes in cancer treatment is still limited by the lack of safe, intravenously administered delivery systems able to carry therapeutic DNA selectively to the tumors, without secondary effects to healthy tissues.[1]. In order to remediate to this problem, numerous non-viral gene delivery systems are currently under development, due to advantages such as their low toxicity, stability and high
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