2 research outputs found
Overcoming the Blood–Brain Barrier for Delivering Drugs into the Brain by Using Adenosine Receptor Nanoagonist
The extremely low permeability of the blood–brain barrier (BBB) poses the greatest impediment in the treatment of central nervous system (CNS) diseases. Recent work indicated that BBB permeability can be up-regulated by activating A<sub>2A</sub> adenosine receptor (AR), which temporarily increases intercellular spaces between the brain capillary endothelial cells. However, due to transient circulation lifetime of adenosine-based agonists, their capability to enhance brain delivery of drugs, especially macromolecular drugs, is limited. In this work, a series of nanoagonists (NAs) were developed by labeling different copies of A<sub>2A</sub> AR activating ligands on dendrimers. <i>In vitro</i> transendothelial electrical resistance measurements demonstrated that the NAs increased permeability of the endothelial cell monolayer by compromising the tightness of tight junctions, the key structure that restricts the entry of blood-borne molecules into the brain. <i>In vivo</i> imaging studies indicated the remarkably up-regulated brain uptake of a macromolecular model drug (45 kDa) after intravenous injection of NAs. Autoradiographic imaging showed that the BBB opening time-window can be tuned in a range of 0.5–2.0 h by the NAs labeled with different numbers of AR-activating ligands. By choosing a suitable NA, it is possible to maximize brain drug delivery and minimize the uncontrollable BBB leakage by matching the BBB opening time-window with the pharmacokinetics of a therapeutic agent. The NA-mediated brain drug delivery strategy holds promise for the treatment of CNS diseases with improved therapeutic efficiency and reduced side-effects
Imaging Tiny Hepatic Tumor Xenografts via Endoglin-Targeted Paramagnetic/Optical Nanoprobe
Surgery is the mainstay
for treating hepatocellular carcinoma (HCC). However, it is a great
challenge for surgeons to identify HCC in its early developmental
stage. The diagnostic sensitivity for a tiny HCC with a diameter less
than 1.0 cm is usually as low as 10–33% for computed tomography
(CT) and 29–43% for magnetic resonance imaging (MRI). Although
MRI is the preferred imaging modality for detecting HCC, with its
unparalleled spatial resolution for soft tissue, the commercially
available contrast agent, such as Gd<sup>3+</sup>-DTPA, cannot accurately
define HCC because of its short circulation lifetime and lack of tumor-targeting
specificity. Endoglin (CD105), a type I membrane glycoprotein, is
highly expressed both in HCC cells and in the endothelial cells of
neovasculature, which are abundant at the tumor periphery. In this
work, a novel single-stranded DNA oligonucleotide-based aptamer was
screened by systematic evolution of ligands in an exponential enrichment
assay and showed a high binding affinity (<i>K</i><sub>D</sub> = 98 pmol/L) to endoglin. Conjugating the aptamers and imaging reporters
on a G5 dendrimer created an HCC-targeting nanoprobe that allowed
the successful visualization of orthotopic HCC xenografts with diameters
as small as 1–4 mm. Significantly, the invasive tumor margin
was clearly delineated, with a tumor to normal ratio of 2.7 by near-infrared
(NIR) fluorescence imaging and 2.1 by <i>T</i><sub>1</sub>-weighted MRI. This multimodal nanoprobe holds promise not only for
noninvasively defining tiny HCC by preoperative MRI but also for guiding
tumor excision via intraoperative NIR fluorescence imaging, which
will probably gain benefit for the patient’s therapeutic response
and improve the survival rate