Brain Delivery of Drug and MRI Contrast Agent: Detection and Quantitative Determination of Brain Deposition of CPT-Glu Using LC–MS/MS and Gd-DTPA Using Magnetic Resonance Imaging

Abstract

Successful treatment and diagnosis of neurological diseases depend on reliable delivery of molecules across the blood-brain barrier (BBB), which restricts penetration of pharmaceutical drugs and diagnostic agents into the brain. Thus, developing new non-invasive strategies to improve drug delivery across the BBB is critically needed. This study was aimed at evaluating the activity of HAV6 peptide (Ac-SHAVSS-NH2) in improving brain delivery of camptothecin-glutamate (CPT-Glu) conjugate and gadolinium-diethylenetriaminepentaacetate (Gd-DTPA) contrast agent in Sprague-Dawley rats. Brain delivery of both CPT-Glu and Gd-DTPA was evaluated in an in situ rat brain perfusion model in the presence and absence of HAV6 peptide (1.0 mM). Gd-DTPA (0.6 mmol/kg) was intravenously (i.v.) administered with and without HAV6 peptide (0.019 mmol/kg) in rats. The detection and quantification of CPT-Glu and Gd-DTPA in the brain were carried out by LC-MS/MS and quantitative magnetic resonance imaging (MRI), respectively. Rats perfused with CPT-Glu in combination with HAV6 had significantly higher deposition of drug in the brain compared to CPT-Glu alone. MRI results also showed that administration of Gd-DTPA in the presence of HAV6 peptide led to significant accumulation of Gd-DTPA in various regions of the brain in both the in situ rat brain perfusion and in vivo studies. All observations taken together indicate that HAV6 peptide can disrupt the BBB and enhance delivery of small molecules into the brain.

Improving Brain Delivery of Biomolecules via BBB Modulation in Mouse and Rat: Detection using MRI, NIRF, and Mass Spectrometry

“…, mice and rats) would provide advantages in treating various brain pathologies and studying brain functions at the cellular level. Previously, cadherin peptides have been shown to improve in vivo delivery of small-to-large marker molecules, including 25 kDa IRdye-800cw PEG, into the brains of mice and/or rats 16 - 18 , 20 . In in vivo Balb/c mice, HAV6 peptide also enhances the delivery of IRdye-800cw PEG in the lung, kidney, and small intestine 17 .…”

“…Previously, ADTC5 peptide was shown to enhance brain delivery of 14 C-mannitol in an in situ rat brain perfusion model 18 . In addition, HAV6 peptide has been shown to enhance brain delivery of an MRI contrast agent, Gd-DTPA, in in situ brain perfusion and in vivo in Sprague-Dawley rats 16 . These results suggest that ADTC5 could also enhance the brain delivery of cIBR in rats.…”

“…Previously, HAV and ADT peptides have been shown to enhance the in vivo brain delivery of small-to-large marker molecules ( e.g. , 14 C-mannitol, gadopentetic acid, and 25 kDa polyethylene glycols (PEG)) in mice and rats 16 - 20 . However, the utility of HAV and ADT peptides in enhancing in vivo brain delivery of proteins and peptides has not yet been evaluated.…”

Quantitative imaging of pO2 in orthotopic murine gliomas: hypoxia correlates with resistance to radiation

“…Pimonidazole is a widely-used hypoxic marker that binds to thiol-containing proteins specifically in hypoxic (pO 2 < 10 mmHg) cells and retains over hours in the tissue [34,35,36]. In general, BBB restricts the transport of hydrophilic or high molecular drugs into the brain to maintain the brain internal milieu and influences their distribution when we consider in vivo imaging of intracranial lesions using contrast materials [37,38]. In previous reports, acceptable distribution of pimonidazole in the brain tumor as well as normal brain tissue has been described both in orthotopic xenograft models and human patients, indicating pimonidazole enters brain tissue through BBB [39,40].…”

Mass Spectrometry Imaging in Nanomedicine: Unraveling the Potential of MSI for the Detection of Nanoparticles in Neuroscience

“…21,23 MSI can be complemented with in vivo molecular techniques such as MRI. Combined, MSI and MRI have been used to study drug delivery in a rat brain perfusion model 74 as well as the spatial distribution of alkaloids in plants and fruits. 75 MSI and MRI can be used to study the whole body 76 as well as individual organs.…”