Cancer-Specific Transgene Expression Mediated by Systemic Injection of Nanoparticles

Abstract

The lack of safe and efficient systemic gene delivery vectors has largely reduced the potential of gene therapy in the clinic. Previously, we have reported that polypropylenimine dendrimer PPIG3/DNA nanoparticles are capable of tumor transfection upon systemic administration in tumor-bearing mice. To be safely applicable in the clinic, it is crucial to investigate the colloidal stability of nanoparticles and to monitor the exact biodistribution of gene transfer in the whole body of the live subject. Our biophysical characterization shows that dendrimers, when complexed with DNA, are capable of forming spontaneously in solution a supramolecular assembly that possesses all the features required to diffuse in experimental tumors through the enhanced permeability and retention effect. We show that these nanoparticles are of sizes ranging from 33 to 286 nm depending on the DNA concentration, with a colloidal stable and well-organized fingerprint-like structure in which DNA molecules are condensed with an even periodicity of 2.8 nm. Whole-body nuclear imaging using small-animal nano-single-photon emission computed tomography/computer tomography scanner and the human Na

Detecting cancers through tumor-activatable minicircles that lead to a detectable blood biomarker

“…To reach this goal, several strategies have been explored including transcriptional targeting of tumors using tumorspecific promoters (24,27,28) and enhanced tumor tropism of both viral and nonviral vectors (29,30). Our efforts are quite similar to these exciting advancements, but instead of a therapeutic transgene for tumor treatment we propose the expression of a secretable reporter gene for the purposes of cancer detection.…”

“…Therefore, although extensive safety testing must be done before eventual clinical translation, our tumoractivatable MC system should be considered relatively safe. Because safety issues are primarily a concern when normal tissues are transfected, it should be noted that our system can be modified to use emerging delivery vehicles, such as more tumor-specific polymeric transfection agents that limit normal tissue transfection (29,43), and/or delivery vehicles targeted to a protein expressed at high levels by cancer cells (44). These newer delivery agents also may yield benefits in the sensitivity and specificity of tumor detection.…”

High resolution SPECT imaging for visualization of intratumoral heterogeneity using a SPECT/CT scanner dedicated for small animal imaging

“…To achieve the necessary level, administration of a substantial amount of radiopharmaceuticals, such as 10-74 MBq/mouse, would be needed. Actually, this and higher amounts of radiopharmaceuticals have been administered in studies on small animal SPECT imaging [2,11,13,21,22]. The level is almost the same as the dose per human in conventional clinical SPECT tests.…”

“…This dosage is very high for actual small animal imaging, and hence, is likely to induce very high radiation in the animals [10]. On the other hand, very recently, increasing numbers of studies have reported the use of these scanners for tumor imaging of small animals [4,[11][12][13][14]. The administered radioactivity used in these studies seems to be reasonable for small animals, but instead, they visualized just tumor masses, not tumor interior, because of insufficient spatial resolution.…”

Delivery of Na/I Symporter Gene into Skeletal Muscle Using Nanobubbles and Ultrasound: Visualization of Gene Expression by PET

“…Two types of plasmids were used: the luciferase reporter vector pGL3 (pGL3-control; Promega), in which the luciferase expression is driven by the Simian virus 40 (SV40) promoter, and the hNIS vector, in which the expression of the hNIS gene is driven by the cytomegalovirus promoter (18). In both cases, the promoters are strong and allow ubiquitous expression of the transgene.…”