The overarching goal is to merge lanthanide detection-based nanotechnology for multiplex detection with tumor-targeting peptides to innovate in the field of cancer detection and to facilitate targeted delivery to solid tumors. The development of this technology requires the merging of an understanding of tumor biology with nanotechnology chemistry, and is aligned with the focused nanotechnology initiative of the NCI. Such emphasis by the NCI acknowledges the positive impact on cancer diagnosis and treatment that can be gained through collaborative approaches and the merging of technologies. This proposal will result in 1) the development of novel luminescent dendrimer-lanthanide nanotechnology on the principle that the nanoscale size of a dendrimer scaffold can address and improve upon the limitations of current luminescent lanthanide reporters and 2) a proof of concept demonstration of the utility of such nanoscale molecules for multiplex detection in a mouse model of cancer. The multiplex detection will be realized through synthesizing lanthanide-coordinating PAMAM (polyamidoamine) dendrimer scaffolds with an outer ring of tumor vasculature-targeting peptides;resulting in peptide-dendrimer molecules carrying lanthanide cations (Ln-PD). This proposal will exploit the unique luminescent properties of Ln-PD (long life, unique signatures, and sharp emission bands) to allow sensitive and discriminating detection against the background of natural biologic autofluorescence. The strong emission signal of lanthanide-nanomolecules is possible through the innovative use of sensitizers attached to the branch termini of the PAMAM;an approach which overcomes low quantum yield by increasing the absorption of excitation light energy and transferring it to several internally located lanthanides. In turn, the lanthanides emit a strong and spectroscopically unique signal. After characterizing in vitro and verifying with ex vivo studies, the Ln-PD (targeted to the tumor vasculature by peptides RGD and RRL) will be quantified in a multiplex application in the SCC SF/VII mouse model of squamous cell cancer. Successful completion of the proposal will demonstrate the functional nature of lanthanide-based detection systems which may by realized through improved applications in luminescence microscopy and bioassays. Subsequently, any improvement in the sensitivity of detection of tumors and their microenvironments will positively impact the ability of scientific discovery and improvements in clinical medicine.
This project aims to use nanotechnology of dendrimers to improve the detection of and delivery to cancers through the innovative use of chemistry to modify the dendrimers. Additionally, small proteins will be attached to the dendrimers to allow assay of ability of the dendrimers to home to tumor model systems.
| Alcala, Marco A; Kwan, Shu Ying; Shade, Chad M et al. (2011) Luminescence targeting and imaging using a nanoscale generation 3 dendrimer in an in vivo colorectal metastatic rat model. Nanomedicine 7:249-58 |
| Alcala, Marco A; Shade, Chad M; Uh, Hyounsoo et al. (2011) Preferential accumulation within tumors and inýývivo imaging by functionalized luminescent dendrimer lanthanide complexes. Biomaterials 32:9343-52 |
