Decreased affinity for efflux transporters increases brain penetrance and molecular targeting of a PI3K/mTOR inhibitor in a mouse model of glioblastoma

Becker, Chani M.; Oberoi, Rajneet K.; McFarren, Stephan J.; Muldoon, Daniel M.; Pafundi, Deanna H.; Pokorny, Jenny L.; Brinkmann, Debra H.; Ohlfest, John R.; Sarkaria, Jann N.; Largaespada, David A.; Elmquist, William F.

doi:10.1093/neuonc/nov081

Cited by 29 publications

(35 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…23–25 NPs were synthesized with encapsulation of IR780, a near-infrared fluorescent dye that allows for non-invasive detection using an IVIS imaging system. We found that mHph2-III-62% NPs had limited ability to penetrate the BBB in tumors but that further conjugation with chlorotoxin (CTX) enhanced the delivery by 1.9 fold (Figure S5).…”

Section: Resultsmentioning

confidence: 99%

Increased Nanoparticle Delivery to Brain Tumors by Autocatalytic Priming for Improved Treatment and Imaging

et al. 2016

View full text Add to dashboard Cite

The blood-brain barrier (BBB) is partially disrupted in brain tumors. Despite the gaps in the BBB, there is an inadequate amount of pharmacological agents delivered into the brain. Thus, the low delivery efficiency renders many of these agents ineffective in treating brain cancer. In this report, we proposed an “autocatalytic” approach for increasing the transport of nanoparticles into the brain. In this strategy, a small number of nanoparticles enter into the brain via transcytosis or through the BBB gaps. After penetrating the BBB, the nanoparticles release BBB modulators that enables more nanoparticles to be transported, creating a positive feedback loop for increased delivery. Specifically, we demonstrated that these autocatalytic brain tumor-targeting poly(amine-co-ester) terpolymer nanoparticles (ABTT NPs) can readily cross the BBB and preferentially accumulate in brain tumors at a concentration of 4.3- and 94.0-fold greater than that in the liver and in brain regions without tumors, respectively. We further demonstrated that ABTT NPs were capable of mediating brain cancer gene therapy and chemotherapy. Our results suggest ABTT NPs can prime the brain to increase the systemic delivery of therapeutics for treating brain malignancies.

show abstract

Section: Resultsmentioning

confidence: 99%

Increased Nanoparticle Delivery to Brain Tumors by Autocatalytic Priming for Improved Treatment and Imaging

et al. 2016

View full text Add to dashboard Cite

show abstract

“…The concentration of many drugs is significantly lower at the infiltrating GBM rim as compared to the necrotic tumor core(28). This impaired drug delivery to infiltrating glioma may be associated with diminished efficacy of these drugs in orthotopic glioma models (32, 41–43). TAL mirrors these experiences by demonstrating a lack of orthotopic efficacy despite activity in heterotopic models.…”

Section: Discussionmentioning

confidence: 99%

Restricted Delivery of Talazoparib Across the Blood–Brain Barrier Limits the Sensitizing Effects of PARP Inhibition on Temozolomide Therapy in Glioblastoma

Kizilbash

Gupta

Chang

et al. 2017

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Poly (ADP-ribose) polymerase PARP inhibitors, including talazoparib (TAL), potentiate temozolomide (TMZ) efficacy in multiple tumor types, however TAL-mediated sensitization has not been evaluated in orthotopic glioblastoma (GBM) models. This study evaluates TAL ± TMZ in clinically relevant GBM models. TAL at 1–3 nmol/L sensitized T98G, U251 and GBM12 cells to TMZ, and enhanced DNA damage signaling and G2/M arrest in vitro. In vivo cyclical therapy with TAL (0.15 mg/kg twice daily) combined with low dose TMZ (5 mg/kg daily) was well tolerated. This TAL/TMZ regimen prolonged tumor stasis more than TMZ alone in heterotopic GBM12 xenografts [median time to endpoint: 76 days vs. 50 days TMZ (p=0.005), 11 days placebo (p <0.001)]. However, TAL/TMZ did not accentuate survival beyond that of TMZ alone in corresponding orthotopic xenografts (median survival 37 vs. 30 days with TMZ (p=0.93), 14 days with placebo, p<0.001). Average brain and plasma TAL concentrations at 2 hours after a single dose (0.15 mg/kg) were 0.49±0.07 ng/g and 25.5±4.1 ng/ml, respectively. The brain/plasma distribution of TAL in Bcrp−/− versus WT mice did not differ, while the brain/plasma ratio in Mdr1a/b−/− mice was higher than WT mice (0.23 vs. 0.02, p<0.001). Consistent with the in vivo brain distribution, overexpression of MDR1 decreased TAL accumulation in MDCKII cells. These results indicate that TAL has significant MDR1 efflux liability that may restrict delivery across the blood-brain barrier, and this may explain the loss of TAL-mediated TMZ sensitization in orthotopic versus heterotopic GBM xenografts.

show abstract

“…These studies are now reaching clinical trials, an exciting landmark in targeted CNS therapeutics. Other groups are investigating inhibition of efflux mechanisms to maintain drug levels in the NVU (95,96). Successful modulation of these endogenous transport systems will prove critical to drug delivery in the NVU.…”

Section: Future Directionsmentioning

confidence: 99%

The Translational Significance of the Neurovascular Unit

McConnell

Kersch

Woltjer

et al. 2017

Journal of Biological Chemistry

247

194

View full text Add to dashboard Cite

Edited by Paul E. FraserThe mammalian brain is supplied with blood by specialized vasculature that is structurally and functionally distinct from that of the periphery. A defining feature of this vasculature is a physical blood-brain barrier (BBB). The BBB separates blood components from the brain microenvironment, regulating the entry and exit of ions, nutrients, macromolecules, and energy metabolites. Over the last two decades, physiological studies of cerebral blood flow dynamics have demonstrated that substantial intercellular communication occurs between cells of the vasculature and the neurons and glia that abut the vasculature. These findings suggest that the BBB does not function independently, but as a module within the greater context of a multicellular neurovascular unit (NVU) that includes neurons, astrocytes, pericytes, and microglia as well as the blood vessels themselves. Here, we describe the roles of these NVU components as well as how they act in concert to modify cerebrovascular function and permeability in health and in select diseases.

show abstract

Decreased affinity for efflux transporters increases brain penetrance and molecular targeting of a PI3K/mTOR inhibitor in a mouse model of glioblastoma

Cited by 29 publications

References 29 publications

Increased Nanoparticle Delivery to Brain Tumors by Autocatalytic Priming for Improved Treatment and Imaging

Increased Nanoparticle Delivery to Brain Tumors by Autocatalytic Priming for Improved Treatment and Imaging

Restricted Delivery of Talazoparib Across the Blood–Brain Barrier Limits the Sensitizing Effects of PARP Inhibition on Temozolomide Therapy in Glioblastoma

The Translational Significance of the Neurovascular Unit

Contact Info

Product

Resources

About