6 research outputs found
Vaginal Delivery of Paclitaxel via Nanoparticles with Non-Mucoadhesive Surfaces Suppresses Cervical Tumor Growth
Local delivery of chemotherapeutics in the cervicovaginal tract using nanoparticles may reduce adverse side effects associated with systemic chemotherapy, while improving outcomes for early stage cervical cancer. We hypothesize drug-loaded nanoparticles must rapidly penetrate cervicovaginal mucus (CVM) lining the female reproductive tract to effectively deliver their payload to underlying diseased tissues in a uniform and sustained manner. We develop paclitaxel-loaded nanoparticles, composed entirely of polymers used in FDA-approved products, which rapidly penetrate human CVM and provide sustained drug release with minimal burst effect. We further employ a mouse model with aggressive cervical tumors established in the cervicovaginal tract to compare paclitaxel-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (conventional particles , or CP) and similar particles coated with Pluronic® F127 (mucus-penetrating particles , or MPP). CP are mucoadhesive and, thus, aggregated in mucus, while MPP achieve more uniform distribution and close proximity to cervical tumors. Paclitaxel-MPP suppress tumor growth more effectively and prolong median survival of mice compared to free paclitaxel or paclitaxel-CP. Histopathological studies demonstrate minimal toxicity to the cervicovaginal epithelia, suggesting paclitaxel-MPP may be safe for intravaginal use. These results demonstrate for the first time the in vivo advantages of polymer-based MPP for treatment of tumors localized to a mucosal surface
The effect of the mTOR inhibitor rapamycin on glucoCEST signal in a preclinical model of glioblastoma
Purpose: The mammalian target of rapamycin is an enzyme that regulates cell metabolism and proliferation. It is up-regulated in aggressive tumors, such as glioblastoma, leading to increased glucose uptake and consumption. It has been suggested that glucose CEST signals reflect the delivery and tumor uptake of glucose. The inhibitor rapamycin (sirolimus) has been applied as a glucose deprivation treatment; thus, glucose CEST MRI could potentially be useful for monitoring the tumor responses to inhibitor treatment. Methods: A human U87-EGFRvIII xenograft model in mice was studied. The mice were treated with a mammalian target of Rapamycin inhibitor, rapamycin. The effect of the treatment was evaluated in vivo with dynamic glucose CEST MRI. Results: Rapamycin treatment led to significant increases (P < 0.001) in dynamic glucose-enhanced signal in both the tumor and contralateral brain as compared to the no-treatment group, namely a maximum enhancement of 3.7% ± 2.3% (tumor, treatment) versus 1.9% ± 0.4% (tumor, no-treatment), 1.7% ± 1.1% (contralateral, treatment), and 1.0% ± 0.4% (contralateral, no treatment). Dynamic glucose-enhanced contrast remained consistently higher in treatment versus no-treatment groups for the duration of the experiment (17 min). This was confirmed with area-under-curve analysis. Conclusion: Increased glucose CEST signal was found after mammalian target of Rapamycin inhibition treatment, indicating potential for dynamic glucose-enhanced MRI to study tumor response to glucose deprivation treatment
Biophysical Characterization of Human Protamine‑1 as a Responsive CEST MR Contrast Agent
The protamines are a low-molecular-weight,
arginine-rich family
of nuclear proteins that protect chromosomal DNA in germ cells by
packing it densely using electrostatic interactions. Human protamine-1
(hPRM1) has been developed as a magnetic resonance imaging (MRI) chemical
exchange saturation transfer (CEST) reporter gene, based on a sequence
that is approximately 50% arginine, which has a side chain with rapidly
exchanging protons. In this study, we have synthesized hPRM1 and determined
how its CEST MRI contrast varies as a function of pH, phosphorylation
state, and upon noncovalent interaction with nucleic acids and heparin
(as antagonist). CEST contrast was found to be highly sensitive to
phosphorylation on serine residues, intra- and intermolecular disulfide
bridge formation, and the binding of negatively charged nucleotides
and heparin. In addition, the nucleotide binding constants (<i>K</i><sub>eq</sub>) for the protamines were determined through
plotting the molar concentration of heparin versus CEST contrast and
compared between hPRM1 and salmon protamine. Taken together, these
findings are important for explaining the CEST contrast of existing
arginine-rich probes as well as serving as a guideline for designing
new genetic or synthetic probes