Design and Function of a Dendrimer-Based Therapeutic Nanodevice Targeted to Tumor Cells Through the Folate Receptor

Purpose . We sought to develop nanoscale drug delivery materials that would allow targeted intracellular delivery while having an imaging capability for tracking uptake of the material. A complex nanodevice was designed and synthesized that targets tumor cells through the folate receptor.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41493/1/11095_2004_Article_378868.pd

Intravascular and Endobronchial DNA Delivery to Murine Lung Tissue Using a Novel, Nonviral Vector

Gene transfer to the lung can be achieved via either the airway or the pulmonary vasculature. We evaluated gene transfer and expression by intravascular and endobronchial routes, using DNA complexed with G9 PAMAM dendrimer or naked plasmid DNA. Intravascular tail vein delivery of dendrimer-complexed pCF1CAT plasmid resulted in high levels of transgene expression in the lung at 12 and 24 hr, followed by a second peak of expression 3 to 5 days after administration. After intravenous administration of the complexes, CAT expression was never observed in organs other than the lung. There were only minimal levels of CAT protein expressed in the lung after intravenous administration of naked plasmid DNA. Repeated intravascular doses of the dendrimer-complexed plasmid, administered four times at 4-day intervals, maintained expression at 15-25% of peak concentrations achieved after the initial dose. Endobronchial delivery of naked pCF1CAT plasmid produced significant amounts of CAT protein in the lung. Comparison of intratracheal and intranasal routes resulted in similar expression levels of CAT in the lung and trachea. However, in juxtaposition to vascular delivery, intranasal delivery of dendrimer-complexed plasmid DNA gave lower levels of CAT expression than that observed with naked plasmid DNA. In situ localization of CAT enzymatic activity suggested that vascular administration seemed to achieve expression in the lung parenchyma, mainly within the alveoli, while endobronchial administration primarily targeted bronchial epithelium. Our results show that intravenously administered G9 dendrimer is an effective vector for pulmonary gene transfer and that transgene expression can be prolonged by repeated administration of dendrimer-complexed DNA.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63314/1/10430340050057468.pd

The Synthesis and Testing of Anti-Cancer Therapeutic Nanodevices

Nanotechnology provides the sized materials that can be synthesized and function in the same general size range and Biologic structures. We have attempted to develop forms of anticancer therapeutics based on nanomaterials. Our project seeks to develop dendritic polymer nanodevices that serve as a means for the detection of cancer cells, the identification of cancer signatures, and the targeted delivery of anti-cancer therapeutics (cis-platin, methotrexate, and taxol) and contrast agents to tumor cells. Initial studies documented the synthesis and function of a targeting module, several drug delivery components, and two imaging/contrast agents. Analytical techniques have been developed and used to confirm the structure of the device. Progress has been made on the specifically triggered release of the therapeutic agent within a tumor using high-energy lasers. The work to date has demonstrated the feasibility of the nano-device concept in actual cancer cells in vitro.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44459/1/10544_2004_Article_338256.pd

Effects of intravenous administration of prostacyclin on regional blood circulation in awake rats

1. The effects of intravenous infusion of prostacyclin (PGI(2), 0.1, 0.2, 0.3 and 1.0 μg kg(−1) min(−1) lasting 5 min) on regional blood flow and regional vascular resistance have been studied in awake rats using the radioactive microsphere method. 2. The control values of blood flow to the heart, kidney, small intestine, hind limb muscle, pericranial skin and brain as well as the corresponding vascular resistance were not modified by an i.v. infusion (0.1 ml min(−1)) of Tris-buffer (the vehicle of PGI(2)). 3. The i.v. infusion of PGI(2) produced graded dose-dependent decreases of MAP (r=0.87, P<0.001; ED(20)=0.73 [0.13–2.55] μg kg(−1) min(−1)) as well as decreases of vascular resistance in the heart (r=0.83, P<0.001; ED(30)=0.17 [0.09–0.31] μg kg(−1) min(−1)), pericranial skin (r=0.88, P<0.001; ED(30)=0.28 [0.18–0.43] μg kg(−1) min(−1)) and small intestine (r=0.74, P<0.001; ED(30)=0.21 [0.11–0.39] μg kg(−1) min(−1)), which led to dose-related increases of blood flow to these territories. 4. On the contrary, PGI(2) increased vascular resistance in skeletal muscle (r=0.73, P<0.001; ED(30)=0.20 [0.10–0.39] μg kg(−1) min(−1)) with corresponding reductions in blood flow. The low doses reduced renal blood flow but there were no significant changes during the high ones. Cerebral vessels did not dilate during any infusion of PGI(2) and cerebral blood flow decreased as MAP fell (r=0.56, P<0.01). 5. We conclude that, in awake rats, the coronary vessels are extremely sensitive to the vasodilating effect of PGI(2) and that the mesenteric vessels and those of the pericranial skin are very responsive too. Moreover, autoregulation is inefficient to maintain cerebral blood flow during infusion of PGI(2)